How to use the protocol template

How to use the protocol template
The template is provided as is i.e. although the template was written to the best of
our knowledge CTU Bern assumes no liability when using this template and does
not guarantee for accuracy of information. Any suggestions or corrections are
welcome and should be sent to [email protected]
The template was cross-checked with the SPIRIT guideline (http://www.spiritstatement.org/) and contains all SPIRIT items.
What follows is an exact match of the original MS Word template but with
additional content, explanations, and examples. Only headings are provided in the
MS Word template. Most content provided in this guiding document is mandatory
for all trial protocols. Such content is provided with a comment or highlighted
yellow (to be copied as is; sometimes place-holders need to be replaced). Other
text is provided for illustrative purposes. Explanations are highlighted in grey.
It should be stressed that formatting should not be changed in the MS Word
template unless you know MS Word well e.g. you know how to handle list styles or
you know the difference between character and paragraph styles.
You should not delete any of the headings. If you do not need a section with
specific heading put in "not applicable" as text.
Use the styles starting with "ProtocolTemplate_ …" provided within the template to
format headings, text, lists, and tables.
Clinical study protocol
Version #.## (dd.mm.yyyy)
Study title
Short title (NCT###)
Kommentar [TS1]: The title should
identify:
 Study design
 Aim
 Population
 Intervention(s)
Example: "A multi-center, investigatorblinded, randomized, 12-month,
parallel-group, non-inferiority study to
compare the efficacy of 1.6 to 2.4 g
Asacol® (once daily) versus divided
dose (twice daily) in the maintenance of
remission of ulcerative colitis"
Kommentar [TS2]: Trial acronym or
other short name
Sponsor
Prof. Dr. Martina Trialist
Department of Clinical Trials
Inselspital, Bern University Hospital
CH-3010 Bern
Switzerland
Kommentar [TS3]: Provide
clinicaltrials.gov number or alternative
registry number. Ensure that the
registry is a WHO approved registry.
This is often only be available after
approval and should be added then.
Study title
Content
1
Protocol summary ...................................................................................................... 6
2
Zusammenfassung ...................................................................................................... 8
3
Protocol signature page ............................................................................................. 9
4
Abbreviations ........................................................................................................... 10
5
Background ............................................................................................................... 11
5.1
Standard treatment ............................................................................................ 11
5.2
Rationale of the study ....................................................................................... 14
5.3
Other relevant on-going studies ........................................................................ 15
6
Objectives of the study ............................................................................................. 16
7
Investigational plan .................................................................................................. 17
8
9
7.1
General study design......................................................................................... 17
7.2
Categorization of the study according to HFV-1/2........................................... 17
7.2.1 Rationale for categorization .................................................................... 17
7.3
Organization of the study.................................................................................. 17
7.3.1 Study Steering Committee ...................................................................... 17
7.3.2 Study coordination .................................................................................. 18
7.3.3 Data Monitoring Board ........................................................................... 18
7.3.4 Procedures for early stopping of the study .............................................. 19
7.4
Time schedule ................................................................................................... 19
Study population and patient registration ............................................................. 21
8.1
Recruitment....................................................................................................... 21
8.2
Pre-study assessments (screening/baseline) ..................................................... 21
8.3
Inclusion criteria ............................................................................................... 21
8.4
Exclusion criteria .............................................................................................. 22
8.5
Patient registration ............................................................................................ 23
8.6
Sample size and feasibility ............................................................................... 23
Study treatment ........................................................................................................ 27
9.1
Administration of study treatment .................................................................... 27
9.2
Dose modifications ........................................................................................... 28
9.3
Early withdrawal from study treatment ............................................................ 28
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Study title
9.3.1 Procedures ............................................................................................... 28
9.4
10
Concomitant interventions ................................................................................ 28
Information on study interventions ........................................................................ 30
10.1 Compliance ....................................................................................................... 30
10.2 Intervention I (Investigational Medicinal Product) .......................................... 30
10.2.1 Summary of findings from non-clinical studies ................................. 30
10.2.2 Summary of findings from clinical studies ........................................ 30
10.2.3 Summary of known and potential risks .............................................. 30
10.2.4 Storage and handling .......................................................................... 30
10.3 Intervention II .................................................................................................. 30
10.4 Summary of findings from non-clinical studies ............................................... 30
10.4.1 Summary of findings from clinical studies ........................................ 30
10.4.2 Summary of known and potential risks .............................................. 31
10.4.3 Storage and handling .......................................................................... 31
10.4.4 Product supply and retrieval of unused products ............................... 31
10.5 Blinding procedures .......................................................................................... 31
10.6 Labelling ........................................................................................................... 31
10.7 Unblinding ........................................................................................................ 32
11
Study assessments .................................................................................................... 34
11.1 Baseline assessments ........................................................................................ 34
11.1.1 Case history and clinical examination ................................................ 34
11.1.2 Laboratory diagnostics ....................................................................... 34
11.1.3 Imaging diagnostics ............................................................................ 34
11.2 Assessments during treatment .......................................................................... 34
11.2.1 Clinical examination ........................................................................... 34
11.2.2 Laboratory diagnostics ....................................................................... 34
11.2.3 Imaging diagnostics ............................................................................ 34
11.3 Assessments at the end of treatment or early withdrawal from treatment ........ 34
11.3.1 Clinical examination ........................................................................... 34
11.3.2 Laboratory diagnostics ....................................................................... 35
11.3.3 Imaging diagnostics ............................................................................ 35
11.4 Assessments during follow-up (after end of treatment) ................................... 35
11.4.1 Clinical examination ........................................................................... 35
11.4.2 Laboratory diagnostics ....................................................................... 35
11.4.3 Imaging diagnostics ............................................................................ 35
11.5 Assessments at the end of study (final visit) .................................................... 35
11.5.1 Clinical examination ........................................................................... 35
11.5.2 Laboratory diagnostics ....................................................................... 35
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Study title
11.5.3
12
Imaging diagnostics ............................................................................ 36
Study outcomes ......................................................................................................... 37
12.1 Definition of primary outcomes........................................................................ 37
12.2 Definition of secondary outcomes .................................................................... 37
12.3 Definition of other outcomes of interest ........................................................... 37
13
Adverse events .......................................................................................................... 38
13.1 Surveillance of adverse events.......................................................................... 38
13.2 Exceptions for rapid notification of serious adverse events ............................. 38
13.3 Adverse events that require rapid notification (besides SAEs/SUSARs) ......... 38
14
Statistics .................................................................................................................... 41
14.1 Randomization .................................................................................................. 41
14.2 Datasets to be analyzed ..................................................................................... 41
14.2.1 Full analysis dataset ............................................................................ 41
14.2.2 Per-Protocol analysis dataset .............................................................. 41
14.3 Statistical analysis ............................................................................................. 42
14.3.1 Primary analysis ................................................................................. 42
14.3.2 Key secondary analyses ...................................................................... 42
14.3.3 Interim analyses and stopping rule of the study ................................. 42
15
Ethical and regulatory aspects ................................................................................ 43
15.1 Ethics committee approval ............................................................................... 43
15.2 Regulatory authority approval .......................................................................... 43
15.3 Study registration .............................................................................................. 43
15.4 Informed consent .............................................................................................. 43
15.4.1 Amendments ....................................................................................... 44
15.5 Participant privacy and confidentiality ............................................................. 44
16
Administrative aspects ............................................................................................. 45
16.1 Protocol amendments........................................................................................ 45
16.2 Insurance ........................................................................................................... 45
16.3 Funding and other support for the trial ............................................................. 45
17
Data handling and record keeping ......................................................................... 47
17.1 Investigator site file .......................................................................................... 47
17.2 Case Report Forms ........................................................................................... 47
17.3 Record keeping ................................................................................................. 48
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Study title
17.4 Data management ............................................................................................. 48
17.4.1 Hardware and software ....................................................................... 48
17.4.2 Data security, access and back-up ...................................................... 48
17.4.3 Analysis and archiving ....................................................................... 49
18
Quality assurance and control ................................................................................ 50
18.1 Electronic and central data validation............................................................... 50
18.2 On-site monitoring ............................................................................................ 50
18.3 Inspections ........................................................................................................ 50
18.4 Closure of study centers.................................................................................... 50
19
Dissemination policy ................................................................................................ 51
19.1 Public access to the full protocol, dataset, and statistical code ........................ 51
19.2 Publication policy and final report ................................................................... 51
20
Post-trial care ........................................................................................................... 52
20.1 Individual information of participants after end of trial ................................... 52
20.2 Access to effective trial interventions............................................................... 52
21
Accompanying scientific projects ........................................................................... 53
22
References ................................................................................................................. 54
23
Appendices ................................................................................................................ 55
23.1 Study flow diagram........................................................................................... 56
23.2 Study assessments overview ............................................................................. 57
23.3 Insurance certificate .......................................................................................... 58
23.4 Study contacts ................................................................................................... 59
23.4.1 Sponsor ............................................................................................... 59
23.4.2 Principal Investigator.......................................................................... 59
23.4.3 Trial coordination/management.......................................................... 59
23.4.4 Monitoring .......................................................................................... 59
23.4.5 Drug supply ........................................................................................ 59
23.4.6 Data management ............................................................................... 59
23.4.7 Statistics .............................................................................................. 60
23.5 Declaration of interests ..................................................................................... 61
Short study title, Version #.## (dd.mm.yyyy)
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Study title
1
Protocol summary
Sponsor
Prof. Dr. Martina Trialist
Department of Clinical Trials
Inselspital, Bern University Hospital
CH-3010 Bern
Switzerland
Principal Investigator
Prof. Dr. Peter Trialist
Department of Clinical Trials
Inselspital, Bern University Hospital
CH-3010 Bern
Switzerland
Study title
Study title
Investigators
Investigators will be documented in the trial master file
Study sites
Sites will be documented in the trial master file
Time schedule
First patient in:
dd.mm.yyyy
Last patient in:
dd.mm.yyyy
Last patient out:
dd.mm.yyyy
Interim analyses:
dd.mm.yyyy
Database closure:
dd.mm.yyyy
Statistical analysis:
dd.mm.yyyy
Study report:
dd.mm.yyyy
Objectives
Primary objectives

To assess whether intervention X improves survival
in patients with disease D as compared to
intervention Y
Secondary objectives

Design
Number of patients
To assess the adverse effects of intervention X as
compared to intervention Y in patients with disease
D
This trial is an international, multicenter, open-label, twoarm, parallel-group, randomized-controlled trial.
The proposed trial is a superiority trial. We assume a mean
baseline score on the NCCN distress thermometer of around
3.5 with a standard deviation of 2.5 and a difference between
groups of 1 point as clinically relevant. Based on a repeated
measures ANCOVA (correcting for baseline values), a
Short study title, Version #.## (dd.mm.yyyy)
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Kommentar [TS4]: Ensure that the
summary exactly matches to the main
protocol (including front page) and the
German translation.
It is recommended that the summary is
written after the main protocol is
finalized.
Study title
power of 90% and a two-sided alpha of 0.05 we calculated a
required sample size of 55 patients per group. To account for
drop-outs and losses to follow-up we set the final sample size
to 75 per group or 150 patients overall.
Main eligibility criteria
Do not list all but only the most important ones
Interventions
Intervention I (name, dose, route of administration,
frequency, duration)
Intervention II (name, dose, route of administration,
frequency, duration)
Intervention III (name, dose, route of administration,
frequency, duration)
Follow-up/assessments
Outcomes will be assessed every other month over the first
six months using postal questionnaires. In case of nonresponse outcomes will be assessed via telephone interviews.
Outcomes
Primary outcomes

Overall survival defined as time from randomization
to death or last follow-up available
Secondary outcomes
Statistical analysis

Incidence of any adverse events
Survival time will be compared between groups using
Kaplan-Meier curves and a Cox proportional hazards model.
Adverse events will be described using descriptive statistics.
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Study title
2
Kommentar [TS5]: Ensure that the
Zusammenfassung exactly matches to
the main protocol (including front page)
and the English summary.
It is suggested that the German
translation is done as the final step
(after the English summary was
written).
Zusammenfassung
Sponsor:
Principal Investigator
Studientitel
PrüferInnen
Eine Liste aller PrüferInnen wird im Trial Master File
ausgewiesen.
Studienzentren
Eine Liste aller Studienzentren wird im Trial Master File
ausgewiesen
Zeitplan
Einschluss erster Patient:
dd.mm.yyyy
Einschluss letzter Patient:
dd.mm.yyyy
Studienende letzter Patient:
dd.mm.yyyy
Interimanalysen:
dd.mm.yyyy
Abschluss Datenbank:
dd.mm.yyyy
Statistische Analyse:
dd.mm.yyyy
Studienreport:
dd.mm.yyyy
Studienziele
Primäre Studienziele

Sekundäre Studienziele

Design
Anzahl Studienteilnehmer
Haupteinschlusskriterien
Interventionen
Nachbeobachtung/
Untersuchungen
Endpunkte
Primäre Endpunkte

Sekundäre Endpunkte

Statistische Analyse
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Study title
3
Protocol signature page
Study title (same as on title page!)
Reviewed and approved by the following:
Sponsor
Name (same as on title page!)
...................................................
Inselspital Bern
Date, Signature
Study site:
Name
...................................................
Site name
Date, Signature
Kommentar [TS6]: Maybe deleted if
there are separate contracts for each
site where adherence to the protocol is
mentioned
Please note that study responsibilities are documented in the Trial Master and Investigator
Site File.
Contribution (chapter)
Background, Objectives, Investigational plan,
Study population, Study treatment, Study
assessments, Study outcomes
Background, Study population, Study
treatment, Study assessments, Study
outcomes
Objectives, Study outcomes, Statistics
Name
Martina Trialist
Information on study interventions
Matthias Pharmacist
Quality assurance and control
Brigitte Quality
Peter Trialist
Claudia Maths
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Signature
Kommentar [TS7]: Provide
contributorship for the most relevant
parts of the protocol
Add appropriate rows as needed
Study title
4
Abbreviations
AE ................................ Adverse event
CRF.............................. Case report form
EDC ............................. Electronic Data Capture
GCP ............................. Good Clinical Practice
ICH .............................. International Conference on Harmonization
IEC ............................... Independent ethics committee
ITT ............................... Intention to treat
SAE .............................. Serious adverse event
SOP .............................. Standard operating procedure
SSL .............................. Secure Sockets Layer
SUSAR ........................ Suspected unexpected serious adverse reaction
Complete as applicable
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Study title
5
Background
Describe disease of interest
EXAMPLE: INIS trial
Background
Neonatal sepsis is a major cause of mortality and morbidity and has been implicated in the
causation of perinatal brain damage and cerebral palsy, both in term and preterm infants1 2.
Although antibiotics are the mainstay of therapy, increasing numbers of bacteria are resistant to
them3 4. Effective adjunctive strategies are therefore needed.
Incidence, potential impact on mortality and problems in diagnosis
In a prospective study in seven Australian neonatal intensive care units (NICUs), Isaacs and
colleagues reported an annual incidence of sepsis of 6.6 per 1000 live births, of which 75% were
late onset (more than 48 hours after birth). Overall hospital mortality for sepsis was 10%5. In a
cohort of 54 UK neonatal units in 1998 (www.child-health.dundee.ac.uk/research/ukneonatalstaffing/)6, 204 (5%) of 3,963 consecutive admissions to neonatal units had a positive blood
culture. Of these, 16 (8%) died. Of 3,759 (95%) babies with negative blood cultures, 95 babies
died (2.5%). For very low birthweight (VLBW) infants with positive blood cultures, mortality was
14% (see table 1, p 10). In a recent North American cohort, mortality in VLBW infants with
septicaemia was 21%7. However, these figures may underestimate the true incidence of
neonatal sepsis. Blood cultures may often be negative if less than 1 ml of blood is sampled8.
Furthermore, while sepsis was the primary cause of death in most infants under 1000g at
autopsy, it was clinically undiagnosed in 61% of cases 9. Sepsis-specific mortality rates should
therefore be interpreted with caution, as the diagnosis may often be inaccurate. More reliable
evidence would be provided by randomised comparisons of the effects of specific interventions
on mortality from all causes.
Potential impact of sepsis on the perinatal brain
Recent evidence suggests that sepsis is also important in the pathogenesis of neurodevelopmental impairment of perinatal origin. In a case-control study of 424 births, Grether and
Nelson found that infants exposed in utero to maternal infection at term were 9 times more likely
to have cerebral palsy than controls1. In another case-control study of 96 term infants, levels of
cytokines in neonatal blood spots were consistently higher in children diagnosed with cerebral
palsy at 3 years of age than in controls, suggesting that an inflammatory response may be
important in the aetiology of cerebral impairment10. In preterm infants, sepsis is also associated
with subsequent adverse neuro-developmental outcome2. Dammann and Leviton have
suggested that infection remote from.
5.1
Standard treatment
Describe how you searched for systematic reviews or primary studies
Describe results of any systematic reviews or the systematic literature search
Short study title, Version #.## (dd.mm.yyyy)
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Study title
EXAMPLE: MAGPIE trial
Systematic review of anticonvulsants for women with pre-eclampsia
A recent systematic review of randomised trials demonstrates that, currently, there is insufficient
evidence to either support or refute the use of prophylactic anticonvulsants13. Twelve trials have
evaluated anticonvulsants for women with pre-eclampsia. Two small studies were excluded from
the review because either no clinical outcomes were reported, or they were not reported
separately for pre-eclampsia and eclampsia14,15. Two trials have compared magnesium sulphate
with no anticonvulsant16,17 (228 women, South Africa; 64 women, Taiwan) and two have
compared magnesium sulphate with placebo18,19 (822 women, South Africa; 135 women, USA).
One quasi-randomised study (59 women, Tanzania)20 compared oral diazepam with no
anticonvulsant. The remaining trials compared magnesium sulphate with diazepam21,22 (38
women, Mexico; 28 women, Malaysia) or with phenytoin12,23,24 (2138 women, USA; 115 women,
USA; 54 women, USA).
Results
Overall, the methodological quality of these trials was average to poor. In most, concealment of
the allocation at trial entry was inadequate, and two studies excluded from their analyses >10%
of women randomised18,23. In the comparison of magnesium sulphate with no
anticonvulsant/placebo, three women allocated magnesium sulphate had a fit, compared to 13
amongst those allocated no anticonvulsant/placebo (Relative Risk 0.33; 95% CI 0.11-1.02).
There was also a non-significant trend towards a small increase in the risk of Caesarean section
for women allocated magnesium sulphate (RR 1.04; CI 0.92-1.17). There is little information
about possible effects on other important outcomes. In the comparison of magnesium sulphate
with phenytoin, women allocated magnesium were less likely to develop eclampsia (RR 0.09; CI
0.01-0.72), but more likely to have a Caesarean section (RR 1.21; CI 1.05-1.41). There were no
statistically significant differences in stillbirths (RR 0.62; CI 0.27-1.41) or neonatal deaths (RR
0.84; CI 0.41-1.74) amongst the babies allocated magnesium sulphate rather than phenytoin in
utero. There is little information about other relevant outcomes. No woman in the comparison of
magnesium sulphate with diazepam developed eclampsia. No trials have reported follow-up of
the children beyond the perinatal period, an economic evaluation, or an assessment of the costs
to the health services.
Discussion
To date, 1200 women with pre-eclampsia have been entered into trials comparing an
anticonvulsant with none. The results of these trials, when taken together, are promising in terms
of a reduction in the risk of eclampsia associated with the use of anticonvulsants. These data
should be interpreted with caution, however, as the number of events was small and the largest
study18 had a large proportion of post randomisation exclusions. Also, apart from the suggestion
of a small increase in the risk of Caesarean section associated with the use of magnesium
sulphate, there is little information about possible effects on other important outcomes, including
toxicity and side effects. Nearly 2400 women have been randomised into trials comparing
different anticonvulsants, most of whom were in one study comparing magnesium sulphate with
phenytoin12. Women allocated magnesium sulphate were less likely to fit than those allocated
phenytoin but this study provides no insight into whether giving magnesium sulphate is
preferable to withholding it. Also, the number of events was small (0 versus 10) and, apart from
an increase in the risk of Caesarean section, there are few data on other measures of maternal
morbidity. Finally, 1% of the women allocated phenytoin developed eclampsia. This is an
unusually high incidence for the reported severity of disease (only 18% had ³2+ proteinuria and
4% had been given an antihypertensive) and may, at least in part, be due to chance.
In conclusion this review, combined with evidence that magnesium sulphate is the drug of choice
for women with eclampsia25, supports magnesium sulphate as the best choice of anticonvulsant
to evaluate for women with pre-eclampsia. There is a suggestion that magnesium sulphate may
be associated with an increase in the risk of Caesarean section, which may be a tocolytic
effect26. If true, this tocolytic action might have other consequences such as an increase in length
of labour, postpartum haemorrhage and retained placenta.
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Study title
EXAMPLE: MAGPIE trial
Current use of prophylactic anticonvulsants
Internationally there is considerable variation in the use of anticonvulsants for women with preeclampsia. Amongst those who do use them, there is no consensus on either choice of agent or
which women are most likely to benefit. In the USA, for example, 99% of obstetricians use
magnesium sulphate which is given to an estimated 5% of pregnant women before delivery12. In
contrast, 23% of UK obstetricians never use any prophylactic anticonvulsants27. In the past, only
2% used magnesium sulphate, others preferring diazepam, phenytoin or chlormethiazole6,28,29.
There has recently been a substantial shift towards using magnesium sulphate in the UK, with
40% of obstetricians now reporting that they use it27.
Mode of action for magnesium sulphate
Exactly how magnesium sulphate might control eclamptic convulsions is unclear. Magnesium
may have a localised cerebral effect. For example, it may cause vasodilatation with subsequent
reduction of cerebral ischaemia15, and/or block some of the neuronal damage associated with
ischaemia30,31.
A possible mechanism for vasodilatation is relaxation of smooth muscle, and it has been
suggested that magnesium may have a generalised effect on all smooth muscle, including the
peripheral vasculature and uterus. Alternatively, any effects of magnesium sulphate in control of
eclamptic convulsions may be, wholly or partially, through its role as a blocker of N-methyl-Daspartate (NMDA) receptors in the brain. These NMDA receptors are activated in response to
asphyxia, leading to calcium influx into the neurones which causes cell injury. It is suggested that
magnesium may block these receptors, so reducing calcium influx and protecting the neurones
from damage.
Possible benefits of magnesium sulphate
Magnesium sulphate may reduce the risk of eclampsia. This effect may be reflected in a lower
risk of other complications of eclampsia, such as renal failure, cerebrovascular accident and liver
failure, as well as improved blood pressure control. If real, these potential benefits may lead to
less time spent in hospital and less use of intensive care facilities. Suggestions about the
possible mode of action for magnesium sulphate have also led to hypotheses about potential
benefits for children who are exposed while in utero. For example, if magnesium sulphate
administration does delay progression of pre-eclampsia this may be reflected in a reduction in
preterm delivery. The mechanism for such a reduction could be either later onset of spontaneous
labour or less obstetric intervention. In addition, it has been suggested that magnesium sulphate
administration may improve the outcome for asphyxiated babies 32. For preterm babies, exposure
to magnesium sulphate may also be associated with a lower risk of cerebral haemorrhage33,
which in turn could be reflected in a reduction in the risk of cerebral palsy for these low
birthweight infants34,35,36. All these hypotheses are based on observational data and, although
they are being tested in randomised trials, these data await confirmation37,38.
Possible hazards of magnesium sulphate
Potential hazards of magnesium sulphate include, for the woman, respiratory depression,
respiratory arrest and hypotension39. Cardiac arrest is a theoretical risk, but in practice is likely to
be rare as a complication of magnesium sulphate. If magnesium does relax smooth muscle it
may also have a tocolytic effect26 leading to an increase in a length of labour, postpartum
haemorrhage, retained placenta and blood transfusion. In addition, potential side effects include
nausea, vomiting, thirst, flushing of the skin, hypotension, arrythmias, drowsiness, confusion, and
muscle weakness. We therefore need reassurance that magnesium sulphate, when used for
women with pre-eclampsia, is well tolerated. Also magnesium sulphate may have an effect on
mood post partum and so it is important to check whether it has any influence on the incidence of
postpartum depression. For the baby, possible hazards related to hypermagnesaemia are similar
to the mother and include respiratory depression, hypotonia and hypotension32,40. Recently it has
been suggested that in utero exposure to magnesium sulphate for prevention of preterm delivery
may increase the risk of mortality for the baby41, when compared to other tocolytic agents.
However there are several other possible explanations for these data, as the number of events
was very small and there were imbalances between the treatment groups37,38. Also, the dose of
magnesium sulphate was very high (median 49.5g). Whatever the effects of magnesium sulphate
on the outcome for low birthweight children, reassurance will still be required about possible
effects for bigger babies, as the pathophysiology of cerebral palsy in these two groups is very
different36.
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Study title
5.2
Rationale of the study
Summarize the need for the study. The rationale should include the perceived benefits of
any intervention which is to be evaluated. It should outline how the intervention under
investigation might work, especially if there is little or no previous experience. Also
provide justification for placebo-control if applicable.
EXAMPLE: MAGPIE trial
Why is a trial needed now?
In 1995, magnesium sulphate was shown to be the anticonvulsant of choice for women with
eclampsia (see table). These results had a major impact on both practice and policy throughout
the world. Magnesium sulphate for the treatment of eclampsia is now included in the essential
drugs list of the World Health Organisation and is recommended in the practice guideline
produced by the Royal College of Obstetricians and Gynaecologists, London.
Table: Data from the Collaborative Eclampsia Trial on maternal deaths and recurrence of
convulsions
*RR = relative risk; CI = confidence interval; * outcome not known for 1 woman
Having switched to magnesium sulphate for women with eclampsia, many clinicians are also
reviewing their policies for anticonvulsant prophylaxis. As discussed above further evidence is
required to help them decide whether its use would be beneficial and, if so, for
whom. Nevertheless many clinicians have begun using magnesium sulphate for women with
preeclampsia, and others are considering starting to use it. There is currently a window of
opportunity for properly evaluating this use of magnesium sulphate. Results of the Magpie Trial
will provide a reliable basis for decision-making about the care of women with preeclampsia.
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Study title
EXAMPLE: PVAG-14 pilot trial
III. RATIONALE OF THE STUDY
Although huge progress has been achieved in the treatment of patients with Hodgkin's lymphoma
in the last decades, the prognosis of patients with intermediate-stage disease is still
unsatisfactory. Unlike the progress in patients with early- and advanced-stage disease, the
standard regimen ABVD for these patients has remained unchanged for many years. Therefore,
clinical trials are warranted to further improve the treatment of these patients incorporating new
and possibly more effective agents.
A new regimen derived from the ABVD-regimen was developed for this study (PVAG-14). No
prospective trial has been published about the proposed chemotherapy regimen so far but
preliminary data from an ongoing phase I/II trial showed promising results with favorable safety
profile in a three-weekly schedule (I.2.2, p. 21). Given the experience of earlier trials with
gemcitabine-combinations (I.2.2, p. 21) the proposed approach seems promising and feasible.
Radiation will be administered after chemotherapy at a dose of 30 Gy of IF-RT since no definitive
results are available from the HD11 yet justifying a lower radiation dose.
No phase I dose-finding trial has been conducted to determine the optimal dose of gemcitabine
administered concomitantly with doxorubicin, vinblastine, and prednisone in a bi-weekly regimen.
According to pharmacokinetic studies a weekly dose of at least 350 mg/m² is required for optimal
tumor control. Given the extensive data of clinical trials with gemcitabine (either administered as
single-agent or in combinations) a dose of 1000 mg/m² (corresponding to a dose intensity of 500
mg/m²/week) seems to be most promising. However, the dose of doxorubicin in the ABVDregimen has not been challenged since its introduction in the 1970's. Recent trials in nonHodgkin lymphoma indicate that higher dose-intensities may be more effective than standard
dosing regimens for the treatment of lymphoma. Doxorubicin doses of 50 mg/m² seem to be too
high to be given in combination with other myelosuppressive agents like gemcitabine and
vinblastine. Given the dose-intensities administered in trials of gemcitabine and doxorubicin
combinations the most promising doses seem to be 25 mg/m² and 35 mg/m². Since complete
response rate with ABVD is more than 90% in this population, a phase I dose-escalation study
was deemed unfeasible by the trial steering committee. Therefore, a randomized phase II trial is
the appropriate design to evaluate the activity and optimal dose level of this new regimen.
FDG-PET performed early during treatment (e.g., after two cycles of chemotherapy) may be a
promising approach for response-adapted treatment strategies. However, no data are available
from prospective studies of patients with HD treated with a uniform regimen regarding its
predictive value – a prerequisite to develop such strategies. Therefore, assessment of the
predictive power of early FDG-PET will be another objective of the trial. Since assessment and
quantification of predictive value is limited if the results of early FDG-PET evaluations guide
subsequent treatment of patients no consequences regarding treatment will be drawn in this trial.
5.3
Other relevant on-going studies
Briefly describe other relevant studies currently enrolling patients identified at
clinicaltrials.gov or other study registers and the difference to the proposed trial.
EXAMPLE
Other relevant studies
The International Clinical Trials Registry Platform (ICTRP) was last searched on May 4th, 2009
using the following search terms: 'osteoarthritis' (in Condition) AND 'glucosamine' (in
Intervention) AND 'recruiting' (in Recruitment status). The search identified no ongoing placebo
controlled trials.
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6
Objectives of the study
Describe the aims of the trial. This does not necessarily require exact descriptions of the
outcomes (i.e. definitions) but the concept of the outcome measures (e.g. activity,
effectiveness, safety). When stating the aims of a trial, consider using the PICO
(Population, Intervention, Control, Outcome) approach. Note that exact definition of
outcomes should be described in 12. Think about classifying the trial according to ICH
Harmonized Tripartite Guideline E8 as human pharmacology, therapeutic exploratory,
therapeutic confirmatory, or therapeutic use trial.
EXAMPLE: SYTRUST trial
Overall Goal
To determine the feasibility, accuracy, cost-effectiveness and impact on pregnancy outcome of
on-site syphilis testing and related health promotion strategies in the community antenatal clinics
of a rural South African health district.
Specific Objectives
1. Through a pre-intervention phase, to document the current strategies for screening and
treating maternal syphilis and other STDs in the antenatal clinics, and to determine their
effectiveness.
2. To gain an understanding of women’s health seeking behaviours during pregnancy through
an assessment of 1) awareness and understanding of syphilis and other STDs and their impact
on pregnancy, and 2) reasons why women often book late for antenatal care, or do not book at
all.
3. To implement in six intervention clinics, on-site syphilis testing and health promotion
strategies aimed at 1) increasing awareness of the impact of STDs, particularly syphilis, on
pregnancy, 2) reducing the gestational age that women book for antenatal care, 3) increasing the
number of women that book for antenatal care, 4) increasing the proportion of infected women
who complete a course of treatment for syphilis.
4. To develop effective partner notification strategies within the context of antenatal care.
5. To evaluate the feasibility, accuracy, and cost-effectiveness of this strategy.
6. To implement the strategy in control clinics if the findings are positive.
7. To disseminate this data and thereby inform reproductive health policy and practice, and
hence improve reproductive health status.
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7
Investigational plan
7.1
General study design
Use "labels" (no details) to provide an overall picture of the study
EXAMPLE: ASCEND trial
Design
ASCEND is a mail-based, multi-centre, randomised controlled trial which aims to demonstrate
whether aspirin and/or omega-3 fatty acids reduce the risk of cardiovascular events in individuals
with diabetes who do not already have diagnosed occlusive arterial disease, and whether such
benefits outweigh any potential risks.
In order to do this reliably, at least 10,000 patients with diabetes and no clinical evidence of
occlusive arterial disease will be randomly allocated to receive 100mg aspirin daily or matching
placebo tablets and 1g omega-3 fatty acid or matching placebo capsules for about 5 years. A
study of this size should have excellent power to detect a 20% proportional reduction in the
cardiovascular event rate among such patients. In order to be cost-effective, this study is being
undertaken predominantly by mail, with back-up from a 24-hour Freefone Service.
A flowchart of the study is provided in the appendix (p. 55).
7.2
Categorization of the study according to HFV-1/2
This study is considered to fall under category A/B/C according to HFV-1/2.
7.2.1
Rationale for categorization
Provide evidence and justification for categorization. Provide sound evidence in case of
downgrading
7.3
Organization of the study
Describe the general organization of the study i.e. number of centers, types of
centers/settings, coordination, data management, etc.
EXAMPLE
Organization of the study
This multicenter trial is centrally coordinated by CTU Bern and conducted in 56 tertiary care
centers in Switzerland, France, Germany, and Italy.
7.3.1
Study Steering Committee
A steering committee/board is usually responsible for the scientific oversight of a study
e.g. was responsible for the initiation of the study, wrote (main parts of) the protocol,
decides about amendments. Describe general organization, members, responsibilities, etc.
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EXAMPLE: RECORD trial
The Steering Committee
The trial is supervised by an MRC Steering Committee. This is made up of three independent
members selected by the MRC, together with those originally granted funds to mount the trial.
Observers from the MRC and host university (University of Aberdeen) may also attend. Other
members of the Project Management Group may attend as observers at the invitation of the
Chair of the Steering Committee.
7.3.2
Study coordination
Describe the study coordination including all tasks centrally coordinated
EXAMPLE: RECORD trial
The Trial Office
The Trial Office is in the Health Services Research Unit at Aberdeen and gives day to day
support to the clinical centres. It is responsible for collection of data (in collaboration with the
local study nurses), data processing and analysis. It is also responsible for randomisation,
despatch of trial materials to participants, and unblinding, as clinically necessary.
EXAMPLE: CRASH trial
Co-ordinating Centre responsibilities
•
Provide study materials and a 24-hour randomisation (and unblinding) service (Figure 5)
•
Give collaborators regular information about the progress of the study
•
Help ensure complete data collection at discharge and at six months
•
Respond to any questions (e.g. from collaborators) about the trial
7.3.3
Data Monitoring Board
A Data (and Safety) Monitoring Board/Committee is a group of independent experts who
monitor aspects of a study while it is running. Most often safety data is monitored but other
aspects such as efficacy data, recruitment, overall quality of the study performance, centerspecific performance might also be monitored by the DSMB. Note that the DSMB acts
independently from the sponsor or any other study organization (such as the steering
committee) and provides recommendations but no decisions. The final responsibility for
the study remains always with the sponsor. Describe organization, participants,
responsibilities and procedures. Data and safety monitoring is closely related to interim
analyses and requires a detailed statistical analysis approach.
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EXAMPLE: RECORD trial
The Data Monitoring Committee
A data monitoring committee will be established. This will be independent of the trial organisers.
During the period of recruitment to the trial, interim analyses will be supplied, in strict confidence,
to the data monitoring committee, together with any other analyses that the committee may
request. This may include analyses of data from other comparable trials. In the light of these
interim analyses, the data monitoring committee will advise the Steering Committee if, in its view,
one or more of the randomised comparisons in the trial has provided both (a) proof beyond
reasonable doubt1 that for all or some types of patients one particular type of intervention is
clearly indicated in terms of a net reduction in fracture risk without any increased risk of death (or
clearly contraindicated because of a net increase in fracture risk or mortality), and (b) evidence
that might reasonably be expected to influence materially the care of people who sustain a
fracture by clinicians who know the results of this and comparable trials. The Steering Committee
can then decide whether or not to modify intake to the trial. Unless this happens, however, the
steering committee, project management group, clinical collaborators, and trial office staff
(except those who supply the confidential analyses) will remain ignorant of the interim results.
The frequency of interim analyses will depend on the judgement of the chairman of the
committee, in consultation with the Steering Committee. Initially, the principal concern will be
possible adverse effects. Data on new fractures will accumulate slowly so the committee is
unlikely to be able to consider these reliably until some way into the trial.
Appropriate criteria for proof beyond reasonable doubt cannot be specified precisely. A difference of at least three
standard deviations in the interim analysis of a major endpoint may be needed to justify halting, or modifying, such a
study prematurely. If this criteria were to be adopted, it would have the practical advantage that the exact number of
interim analyses would be of little importance, and so no fixed schedule is proposed (Peto R et al. Br J Cancer 1976;
34: 584-612).
1
7.3.4
Procedures for early stopping of the study
Describe procedures when formal stopping rules are met if not described above. (see also
chapter 14.3.3 Interim analyses and stopping rule of the study)
7.4
Time schedule
First patient in: ............. dd.mm.yyyy
Last patient in: ............. dd.mm.yyyy
Last patient out: ........... dd.mm.yyyy
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Interim analyses: .......... dd.mm.yyyy
Database closure: ......... dd.mm.yyyy
Statistical analysis: ...... dd.mm.yyyy
Study report: ................ dd.mm.yyyy
EXAMPLE: PVAG-14 pilot trial
Time schedule
First patient in:
01.04.2006
Inclusion last patient (Randomization):
30.11.2007
Interim analysis:
31.05.2007
Analysis of primary endpoints:
31.08.2008
Last patient out (end of 5-year follow up):
31.05.2013
Final statistical analysis:
30.11.2013 (final analysis)
Study report:
31.12.2013
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8
Study population and patient registration
Patients with main diagnoses will be included in this study.
Patients must meet all of the inclusion criteria and none of the exclusion criteria to be
enrolled in the study. No study-specific procedures (i.e., assessments/treatments not
required in clinical practice) may be performed until an eligible patient has signed an
approved informed consent to participate in the study.
8.1
Recruitment
Describe the process of recruitment (for example advertisements with place(s) of
publication, consecutive patients with no selective recuitment) and enrolment.
8.2
Pre-study assessments (screening/baseline)
See section 11.1, p. 34 for a description of required pre-study assessments. Note that
assessments done before study inclusion are only allowed if part of routine clinical
practice. These assessments are done to establish eligibility of patients. Study-specific
procedures must only be done after study inclusion i.e. after the informed consent form
was signed. Pre-study assessments should be performed within 28 days prior to
registration.
8.3
Inclusion criteria
1.
List criteria that describe the overall nature of the population of interest
2.
Signed informed consent with understanding of the study procedures and the
investigational nature of the study
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EXAMPLE: RECORD trial
2.1 Who will be considered for trial entry?
The trial will involve people aged 70 or over who have had a previous fracture:
I.
Those who have sustained a fracture (except cervical spine, skull or face) in a fall from no
more than a standing height within the previous two years (while eligible patients may have
sustained more than one fracture, those who have high energy transfer injury will not be
eligible)
II.
Those with a clinical vertebral fracture (defined as a definite clinical event with radiological
evidence* of an incident vertebral fracture)
Potential participants will be identified by study nurses based in each clinical centre from
amongst patients attending hospital as outpatients or inpatients. A log will be kept of patients
meeting these criteria, describing the reasons if they are not subsequently recruited to the trial.
(Depending on the numbers of people attending hospital who are recruited, additional patients
may also be identified from medical records as having sustained an eligible fracture in the
preceding two years.)
EXAMPLE: PVAG-14 pilot trial
Inclusion criteria
-
Age: 18-60 years
-
Histologically confirmed diagnosis of Hodgkin's lymphoma
-
Clinical Stage IA, IB, IIA with at least one of the riskfactors a-d given below
-
Clinical Stage IIB with one or both riskfactors c-d given below
Riskfactors:
a) Large mediastinal mass (≥ 1/3 of the greatest thorax diameter as measured by chest x-ray)
b) Extranodal involvement
c) High erythrocyte sedimentation rate (≥ 50 mm/h in patients without B-symptoms, ≥ 30 mm
inpatients with B-symptoms)
d) Three or more involved lymph node areas
-
No prior therapy for Hodgkin's lymphoma (exception: pre-phase treatment with corticosteroids
and vinca-alkaloids for a maximum of seven days may not preclude trial participation if
clinically indicated and all staging examinations have been performed; all forms of prior
radiotherapy preclude trial participation)
-
Life expectancy > 3 months according to investigator judgement.
-
Signed informed consent with understanding of the study procedures and the investigational
nature of the study.
-
Patient agrees that personal data and tissue samples are provided to the GHSG
8.4
Exclusion criteria
1.
List criteria that exclude patients from the study although inclusion criteria are
met e.g. specific laboratory values
2.
Pregnant or nursing women
3.
Known intolerance to any protocol intervention
4.
Participation in another clinical trial
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5.
8.5
Patient's lack of accountability, inability to appreciate the nature, meaning and
consequences of the study and to formulate his/her own wishes correspondingly
Patient registration
All patients who meet the eligibility criteria for study entry can be enrolled into the study.
Eligible patients will be registered and randomized in the study centrally via the Internet:
URL: enter the URL of the study database
For randomization, the following is required:



All inclusion criteria satisfied
No exclusion criterion satisfied
Patient briefing and signed informed consent form
EXAMPLE: CRASH trial
Randomisation
Patients eligible for inclusion should be randomised, and the study treatment started, as soon as
possible. Randomisation is done by telephoning a 24-hour toll-free service
###
and takes only about two minutes. The questions that will be asked by the telephone operator
prior to allocation of the treatment packs are shown in Appendix 2. The study computer will then
randomly assign a treatment pack number that will identify one of the CRASH treatment packs
stored in the emergency department. Once a patient has been randomised, we will definitely wish
to learn the outcome in hospital, even if the trial treatment gets interrupted or is not actually
given.
8.6
Sample size and feasibility
Provide the number of participants to be enrolled (including a projection per study site).
Describe sample size calculation and feasibility of recruitment. A justification of sample
size requires details on: 1) Outcome(s) on which sample size calculation is based; 2) Null
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hypothesis; 3) level of type I error; 4) level of type II error; 5) minimal clinically relevant
difference; 6) allocation ratio; 7) underlying statistical test/methods; 8) software used for
sample size calculation; 9) corrections for drop-outs/withdrawals; 10) Assumptions of any
parameter used
EXAMPLE: Magpie trial
Sample size estimates
Sample size estimates For women with severe pre-eclampsia the risk of convulsions is around
1%. To demonstrate a halving in this risk would require 14,000 women (alpha 0.05, beta 0.1).
The aim is therefore to recruit 14,000 women. The trial may include women with a lower seizure
risk and, if this was 0.75%, the power to demonstrate a halving would then be 80%. Most women
(90%) are likely to be randomised before delivery and, if total mortality for the babies was 12%,
this would give a power of 90% to detect a 15% proportional reduction to 10.2% (alpha 0.05). If
total mortality for the babies was reduced from 10% to 8.5% (15% reduction), the power would
be 80% (alpha 0.05).
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EXAMPLE: INIS trial
Sample size
Table 4 shows positive blood culture rates (including probable contaminants) in 3,963
consecutive infants of all birthweights admitted to a randomly selected, nationally representative
cohort of 54 UK neonatal units between 1st March 1998 and 4th September 1998 in a study of
organisation and outcomes of neonatal care funded by the NHS Executive6.
Table 4
Number with
positive cultures
Mortality
(all causes)
Number with
negative cultures
Mortality
(all causes)
204 / 3,963 (5%)
16 / 204 (8%)
3,759 / 3,963 (95%)
95 / 3,759 (2.5%)
Among VLBW infants with positive blood cultures, mortality was 14%. In a recent North American
cohort, mortality in VLBW infants with septicaemia was 21%7. Assuming combined rates of
mortality and major morbidity of 10-20% for all infants and 20-30% for VLBW infants, Table 5
outlines estimated sample sizes.
Table 5
Mortality or
major
morbidity
in control
group
Mortality or
major
morbidity
in IVIG group
Relative
risk
reduction
30%
26%
30%
Total sample size required to
detect difference with 95%
confidence
80% power
90% power
13%
4,052
5,392
25%
17%
2,580
3,428
30%
20%
33%
626
824
25%
21%
16%
3,572
4,748
25%
20%
20%
2,266
3,006
25%
15%
40%
540
708
20%
16%
20%
2,994
3,972
20%
15%
25%
1,890
2,502
20%
12.5%
37.5%
810
1,066
15%
12%
20%
4,204
5,582
15%
10%
33%
1,450
1,914
12%
9%
25%
3,408
4,516
10%
7.5%
25%
4,166
5,524
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EXAMPLE: INIS trial
Feasibility
About 5,000 infants will be needed to demonstrate moderate reductions in mortality or survival
with major developmental delay with adequate power. Over a three year recruitment period,
assuming that 7-10% of all admissions are diagnosed with clinical sepsis and considered eligible
for recruitment, 150 NICUs with an average of 300 admissions per year will be required to
achieve the recruitment target, assuming a 40-50% rate of recruitment of eligible infants.
Neonatal units will initially be recruited in the UK, Australia and New Zealand. A census of all 186
UK neonatal intensive care units (NICUs) and 60 special care baby units in 199662 (which is a
100% response rate) found that the median number of admissions per year per NICU was 317. If
a broadly representative sample of about half all UK NICUs and SCBUs participate, then over
50% of the projected recruitment rate for the trial will be possible within the UK, leaving the
additional 50% to be recruited from the rest of the world. This study reflects the philosophy that
the only practicable way to achieve comparisons which are sufficiently large to minimise the risk
of being seriously misled by the play of chance is to design trials that are extremely simple and
flexible63. Experience in the OSIRIS64 and MRC ORACLE study48 49 suggest that a large, simple
trial of this scale of a potentially important intervention supplied free of charge to participating
centres is feasible. Furthermore, systematic reviews of RCTs of IVIG therapy in neonatal sepsis
suggest a substantial reduction in mortality. This contrasts with the systematic reviews of RCTs
of antibiotics in threatened preterm birth which led to the ORACLE study, as these showed no
evidence of a difference in neonatal mortality. This preliminary evidence that IVIG may reduce
mortality may further enhance the appeal of the study.
The estimate of the incidence of the outcome (the event rate) for the trial is imprecise, particularly
as the threshold at which clinicians will enter patients cannot be estimated. If clinicians enter
babies where the likelihood of serious sepsis is lower then the event rate will also be lower. If
clinicians restrict entry to only those babies who are very sick, then the event rate will be high.
Either of these two scenarios is reasonable because it will define a population to which the trial
result can be generalised. However, it does mean that until the trial has recruited sufficient
numbers of babies it will not be possible to determine the optimum trial sample size with any
certainty. As a consequence the trial sample size currently represents the minimum size
desirable. Assuming the trial recruits for three years, the maximum number of babies which can
be recruited during this time will be recruited and it is possible that this number may exceed
5,000. During recruitment to the trial the accumulating data will be seen by an independent Data
Monitoring and Ethics Committee at least once per year (see above) and they will advise the
Trial Steering Committee whether the trial has answered the clinical question being addressed. If
not, the trial will continue to recruit until 5,000 babies have been recruited, or until funding is
exhausted.
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9
Study treatment
Patients are expected to begin treatment at the day of randomization. Study treatment must
be administered in a hospital setting. Outpatient treatment is allowed but depends on the
investigator's judgment.
9.1
Administration of study treatment
Describe administration of study treatment. Include details about: type of intervention,
dosage, route of administration, frequency, duration. If intervention is a drug (including
placebo) or device provide details about manufacturer, labelling etc. in chapter 10.
EXAMPLE: CRASH trial
Study treatment (Table 2)
Each CRASH treatment pack contains:
•
•
•
•
•
11 x 2g vials of methylprednisolone (MP) or placebo
1 x 20mL sterile water for injection (for use with the loading dose)
1 x 100mL bag of 0.9% NaCl (for use with the loading dose)
CRASH stickers (for attaching to infusion bags and patient notes)
Patient information leaflet and Early Outcome Forms
Loading
2g MP (or matching placebo) over 1 hour in 100mL infusion:
1. Add 20mL water for injection to one 2g vial and mix well
2. Add contents of vial to the 100mL bag of 0.9% NaCl provided
3. Infuse over one hour
Daily Maintenance
1.
2.
3.
4.
5.
6.
0.4 g/hour for about 24 hours in 20 mL/hour infusion (MP or matching placebo):
Remove 100 mL from a 500 mL bag of 0.9% NaCl (to make room for the steroid)
Add 20 mL water for injection to each of five 2 g vials and mix well
Add all five (about 100 mL) to the 500 mL bag of 0.9% NaCl
Infuse at 20 mL/hour for about 24 hours
Repeat for maintenance day 2
N.B. As children under 16 are excluded, a simple fixed-dose treatment can be used. The dosing
regimen is that used in the NASCIS-2 and NASCIS-3 trials of MP in acute spinal cord injury.
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EXAMPLE: Bortezomib in HD trial
Study drug administration
Patients receive 1.3 mg of bortezomib per square meter of body-surface area (SA) twice weekly
for two weeks (day 1, 4, 8, 11) followed by one week without treatment (one cycle). The
maximum number of cycles per patient is eight (24 weeks).
Bortezomib is given as a short intravenous bolus injection (3-5 seconds).
9.2
Dose modifications
Describe dose modification: how, under which circumstances etc.
9.3
Early withdrawal from study treatment
Describe circumstances under which treatment should/must be stopped prematurely and
subsequent procedures.
EXAMPLE: Bortezomib in HD trial
Early withdrawal from study treatment
Protocol therapy will be discontinued at any time if any of the following situations occurs:
• The development of toxicity which, in the investigator’s judgment, precludes further therapy,
• Progressive disease,
• Intercurrent illness precluding further therapy, in the investigator’s opinion,
• Pregnancy,
• Patient refusal to continue,
• Patient lost to follow-up or non-compliance.
9.3.1
Procedures
Investigators will make every reasonable effort to keep each patient on the study until all
planned treatments and assessments have been performed. When a patient ends the
treatment phase of the study prematurely, the date and reason for early treatment
discontinuation will be noted in the source document and the appropriate portion of the
CRF add additional notification if required e.g. direct information to sponsor with
timeframe. Investigators will make any reasonable effort to collect and report end-oftreatment evaluations (11.3) and all follow-up evaluations (11.4). The end-of-treatment
evaluation should be performed before any other therapeutic intervention.
For procedures for patients withdrawing consent at a later stage see also 11.5.
9.4
Concomitant interventions
Describe concomitant interventions received by all patients in the study. If there is no
regulation/restriction on concomitant interventions state this explicitly.
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EXAMPLE: Bortezomib in HD trial
Concomitant medication
In addition to bortezomib, patients will take dexamethasone 20 mg p.o. on every treatment day
(day 1, 4, 8, 11).
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10 Information on study interventions
10.1 Compliance
Describe how compliance will be ensured AND assessed e.g. pill counting.
EXAMPLE: HWI trial
Compliance
Patients will have to record their compliance in the diary. In addition patients are asked to send
back all study medications (including Monuril® 3g), which were not used, as well as empty
packages, together with the diary to the CTU Bern after the interview on day 10.
10.2 Intervention I (Investigational Medicinal Product)
10.2.1
Summary of findings from non-clinical studies
One may refer to the Investigator’s Brochure (IB), Investigational Medicinal Product
Dossier (IMPD), Summary of Product Characteristics (SPC) or a similar document (if
applicable), by mentioning the relevant pages in that document. Be sure that the
information is up to date and references to peer reviewed papers in (biomedical/scientific)
journals should be given where appropriate.
10.2.2
Summary of findings from clinical studies
See 10.2.1
10.2.3
Summary of known and potential risks
See 10.2.1
10.2.4
Storage and handling
Describe any storage and handling guidelines if appropriate, including keeping a
temperature log.
10.3 Intervention II
10.4 Summary of findings from non-clinical studies
One may refer to the Investigator’s Brochure (IB), Investigational Medicinal Product
Dossier (IMPD), Summary of Product Characteristics (SPC) or a similar document (if
applicable), by mentioning the relevant pages in that document. Be sure that the
information is up to date and references to peer reviewed papers in (biomedical/scientific)
journals should be given where appropriate.
10.4.1
Summary of findings from clinical studies
See 10.4
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Kommentar [TS8]: Repeat chapter
for multi-arm trials as appropriate
Study title
10.4.2
Summary of known and potential risks
See 10.4
10.4.3
Storage and handling
Describe any storage and handling guidelines if appropriate
10.4.4
Product supply and retrieval of unused products
Describe procedures for study product supply and retrieval of unused products (mention
drug accountability log)
10.5 Blinding procedures
Describe how blinding is ensured i.e production and packaging.
10.6 Labelling
Provide a graph of the label for all trial interventions. According to Annex 13 of the EU
Guidance "Manufacture of investigational medicinal products" the label should include:
a)
Name of the sponsor;
b)
Pharmaceutical dosage form, route of administration, quantity of dosage units
(and name/identifier of the product and strength/potency in case of open trial);
c)
The batch and/or code number to identify the contents and packaging operation;
d)
The trial subject identification number, where applicable;
e)
Directions for use;
f)
Imprint "For clinical trial use only";
g)
The name of the investigator (if not included as a code in the trial reference code);
h)
A trial reference code allowing identification of the trial site and investigator;
i)
The storage conditions;
j)
The period of use (use-by date, expiry date or re-test date as applicable), in
month/year);
k)
"Keep out of reach of children" except when the product is for use only in
hospital;
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The outer packaging may include symbols or pictograms to clarify certain information,
mentioned above and the request “return empty packaging and unused products”.
Additional information for example any warnings and handling instructions, where
applicable may be displayed according to the order. A copy of each type of label should be
kept in the batch record.
On the immediate packaging when the outer packaging carries the particulars mentioned
above (a-k), the particulars a-f shall be given.
The label needs to be in the home language of the canton of each study site unless the
intervention is applied by the investigator directly (no information to study participants
required) in which case an English label is sufficient.
If regular market products are used an additional label with the following information is
sufficient:
a)
Name of the sponsor;
d)
The trial subject identification number, where applicable;
f)
Imprint "For clinical trial use only";
h)
A trial reference code allowing identification of the trial site and investigator;
EXAMPLE: Lichen trial
10.7 Unblinding
Describe unblinding procedures if applicable. Refer to a SOP if appropriate.
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EXAMPLE: HWI trial
9.6 Unblinding
In general, breaking the statistical blind should be considered only when knowledge of the
treatment assignment is deemed essential for the study patient's care by the participant's
physician or a regulatory body. Unblinding should be restricted to emergency situations and is
expected to be extremely rare in this trial. It may be required in the following circumstances:
- Occurrence of a serious adverse event where the event appears possibly related to one of the
interventions and the event is not listed in one of the package inserts i.e. the serious adverse
event is considered to be a potential suspected unexpected serious adverse drug reaction
(SUSAR) and would require expedited reporting.
- Occurrence of a severe allergic reaction and knowledge of the treatment assignment is deemed
essential for the participant's care.
- Use of the investigational medicinal product by someone not participating in the clinical trial e.g.
if a child in the household of a participant accidentially takes a study medication.
- Knowledge of the treatment assignment is deemed essential for the participant's care for any
reason.
Code breaks/emergency envelopes will be held in the pharmacy. The on-call pharmacist at the
Institute for Hospital Pharmacy of the Inselspital Bern will be available to perform the code break
at any time (contact by the central number of the Inselspital Bern, 031 632 21 11).
Only healthcare professionals involved in the care of the relevant study patient can require
unblinding. The healthcare professional should immediately contact the Institute for Hospital
Pharmacy and request code breaking by giving specific reasons. The responsible pharmacist will
provide the information as required. On receipt of the relevant information, the treating healthcare
professional should attend to the participant's medical emergency. Where possible, it is important
that all other members of the study team e.g. other investigators, statisticians etc. remain blinded.
The responsible pharmacist of the Institute for Hospital Pharmacy will inform the principal
investigator of any request for unblinding and the reasons for the request. The investigator
responsible for the care of the study patient will record the unblinding and reasons in the medical
chart and in the eCRF. The responsible pharmacist will also record any unblinding and the
reasons in the code list.
Any unblinding will be documented in the study report.
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11 Study assessments
11.1 Baseline assessments
Baseline assessments should be performed within 14 days of randomization but before any
treatment.
11.1.1


11.1.2

11.1.3


Case history and clinical examination
List what elements of the history and clinical examination are required
Describe specific clinical examinations in detail
Laboratory diagnostics
List all laboratory diagnostics
Imaging diagnostics
List all imaging diagnostics
Chest X-raya
11.2 Assessments during treatment
The following assessments have to be performed every month during treatment.
11.2.1


11.2.2

11.2.3

Clinical examination
List what elements of the clinical examination are required
Describe specific clinical examinations in detail
Laboratory diagnostics
List all laboratory diagnostics
Imaging diagnostics
List all imaging diagnostics
11.3 Assessments at the end of treatment or early
withdrawal from treatment
The following assessments have to be performed at the end of treatment or if a patient is
withdrawn prematurely from treatment.
11.3.1


a
Clinical examination
List what elements of the clinical examination are required
Describe specific clinical examinations in detail
This assessment is trial-specific
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Kommentar [TS9]: All study-specific
procedures i.e. not done routinelyin
clinical practice should be marked
clearly e.g. with a star and explained in
a footnote
Study title
11.3.2

11.3.3

Laboratory diagnostics
List all laboratory diagnostics
Imaging diagnostics
List all imaging diagnostics
11.4 Assessments during follow-up (after end of
treatment)
If assessments vary depending on the type of follow-up visit structure this chapter
accordingly.
The following assessments have to be performed schedule e.g. every 6 months after the
end of treatment.
11.4.1


11.4.2

11.4.3

Clinical examination
List what elements of the clinical examination are required
Describe specific clinical examinations in detail
Laboratory diagnostics
List all laboratory diagnostics
Imaging diagnostics
List all imaging diagnostics
11.5 Assessments at the end of study (final visit)
The following assessments have to be performed at the final visit ($$$ years/months after
end of treatment).
If a patient withdraws consent after the end of treatment investigators will make every
reasonable effort to keep each patient on the study until all assessments have been
performed. When a patient still wants to end the study prematurely, the date and reason for
early discontinuation will be noted in the source document and the appropriate portion of
the CRF. Investigators will make any reasonable effort to collect and report all end-ofstudy evaluations in these patients. Patients should be informed that data collected until the
withdrawal will be kept in the study database and used for analysis.
11.5.1


11.5.2

Clinical examination
List what elements of the clinical examination are required
Describe specific clinical examinations in detail
Laboratory diagnostics
List all laboratory diagnostics
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11.5.3

Imaging diagnostics
List all imaging diagnostics
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12 Study outcomes
Describe exact definitions for each outcome: what (method) is assessed by whom
(independent adjudication?), at which timepoint under which conditions (blinded?). The
following components need to be described explicitly (for each outcome if different): 1)
domain (e.g. pain, quality of life etc.); 2) specific measure/instrument (e.g. "Hamilton
Anxiety Rating Scale", "blood pressure measured in sitting position on both upper arms
after resting for 5 minutes using a sphygmomanometer", etc.); 3) metric i.e. the analytic
approach (e.g. risk ratio, difference in absolute values, repeated-measures using all followup values, etc.); 4) cut-off for continuous/quantitative measures if used; 5) time frame i.e.
the follow-up visit from which the outcome will derived (e.g. 2 years after randomization);
6) outcome assessor (e.g. patient, blinded and independent adjudication committee).
12.1 Definition of primary outcomes
Description as detailed above for all primary outcomes (usually one but not more than
three as a rough guidance). The primary outcome(s) should be the most relevant one(s)
regarding the objective of the trial i.e. for phase III trials the most clinically relevant
efficacy outcomes, for phase II trials activity outcomes or safety outcomes to determine
dosing, for phase I trials pharmacokinetic/-dynamic or tolerability outcomes, and for phase
0/proof-of-concept trials pharmacodynamics or activity outcomes.
EXAMPLE
11.1.1. Hematological toxicity
Toxicity will be assessed according to NCI Common Terminology Criteria version 3.0 (CTCAE)
published June 10, 2003 (see Study Manual).
The primary toxicity outcome is defined as the percentage of patients with at least one episode of
a hematological toxicity grade III/IV between treatment start until 28 days after the last study drug
administration as assessed by each investigator based on regular laboratory studies as defined
in chapter 10. For the purpose of this study an episode of a hematological toxicity grade III/IV is
defined as one or more laboratory studies with:
•
Neutrophils < 1000/μL or
•
Leukocytes < 2000/μL or
•
Platelets < 50,000/μL or
•
Hemoglobin < 8.0 g/dl
An episode ends if all hematological parameter(s) return to at least toxicity grade II.
12.2 Definition of secondary outcomes
Ditto (approximately four other (clinically) relevant outcomes addressing the objective)
12.3 Definition of other outcomes of interest
Ditto. Any other outcomes of interest e.g. to disentangle how interventions might work
(different survival outcomes, components of composite event outcomes, subscales.
Exploratory outcomes, or outcomes with unclear validity.
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13 Adverse events
Pre-existing diseases present prior to administration of study intervention, will be
documented as concomitant diseases as part of participant history in the CRF. Any disease
newly occurring or increasing in severity during the course of the trial will be documented
as an AE.
The most up to date version of the CTU Bern SOP "Safety reporting in clinical studies
with drugs (CS_CI_SOP-01)" (current version: 01, 1.1.2013) will be used to manage
adverse event related issues in this trial. The SOP contains





Definitions of terms
Instructions on assessing adverse events
Instructions for handling, documenting, and reporting adverse events
Guidance on responsibilities
Guidance on annual safety reports
Kommentar [TS10]: If the SOP is not
used for the trial provide all required
details. The SOP might be a starting
point.
13.1 Surveillance of adverse events
Provide details about study specific surveillance of adverse events: passive ("Watch and
wait" approach with spontaneous reports by participants), unspecific active, specific active.
Take into consideration already known and clinically relevant harms.
Patients will regularly be assessed for development of adverse events during study visits.
The safety office/sponsor will be timely informed about all serious adverse events as
defined in the SOP mentioned above. The following potential adverse events will be
actively monitored during this study:


List all laboratory assessments
List all other tests/questionnaires that apply
13.2 Exceptions for rapid notification of serious adverse
events
The instructions for rapid notification of SAEs as outlined in the SOP mentioned above do
not apply for the following events:


Adverse reactions listed in the package insert or investigator's brochure
List any other adverse events
13.3 Adverse events that require rapid notification
(besides SAEs/SUSARs)
For the purpose of this study the following adverse events will be handled like a SUSAR
(regarding reporting requirements) as described in the SOP mentioned above:

List all adverse events that require rapid notification (which are not necessarily a
SAE/SUSAR)
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Kommentar [TS11]: Ensure that this
section agrees with study assessments
in section 10
Study title
The flow chart on the next page shows graphically the process of expedited safety
reporting.
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Study title
Expedited Safety Reporting
No EC
reporting
LOCAL Investigator
Serious
Adverse Event
No
No
Safety Signal
Continued
Vigilance
No
Causality
Assessment
Fatal?
Life
threatening?
No
Yes
Related?
Safety
Signal?
Yes
Possibly Probably Definitely
Yes
Report to LOCAL EC within
7 days if fatal or life threatening
1
Report within
Report to LOCAL EC
® within max 7 days
24 h
Report within 24 h to
- Sponsor
- LOCAL EC
New Risks and / or new Aspects
of known adverse reactions
Serious Adverse Event
15 days all other Events
to Sponsor
Unlikely
Not related
No SUSAR
Related?
Report within 24 h to
- Swissmedic
- All Investigators
No
Possibly Probably Definitely
No
Investigators report to their
LOCAL EC (24 h)
Sponsor
Sponsor / Investigator
No
Yes
Unexpected?
Yes
SUSAR
1
Independent Ethics Committee
Serious?
If different from
Investigator see App 1
Multicentre Studies
Report to LEAD EC
® within max 7 days
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Report to:
1.Swissmedic
2. LEAD EC
3. All participating study sites
® within 7
days if fatal or life threatening
days for all other Events
® within 15
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Study title
14 Statistics
14.1 Randomization
Describe the exact randomization method. The following elements need to be included:








The unit of randomization; usually patients but sometimes body parts or clusters
(hospital wards, physicians) are randomized
What is randomized i.e. the interventions
Allocation ratio
Mechanism of how random numbers are generated
Blocking: whether simple randomization or randomization in blocks is planned.
For block randomization, block size(s) and the mechanism of variation need to be
specified
Stratification: whether or not randomization is stratified. For stratified
randomization, all stratification variables need to be specified
Who is responsible for generating and implementing the randomization list
A statement that randomization list(s) is concealed from any study personnel
involved in patient recruitment
EXAMPLE: Randomization SOP CTU Bern
Randomization
After patient registration in the web-based data entry system and confirmation of all inclusion and
exclusion criteria patients are randomized using the same system thus ensuring concealment of
allocation (central web-based randomization). Patients are randomized in a 1:1 ratio to one of the
two intervention groups: Intervention 1, intervention 2. The allocation sequence is generated by
an independent statistician at CTU Bern not involved in the final analysis of the trial. It is based
on computer generated random numbers in randomly varying blocks of 4, 6, and 8 using the
statistical software package Stata (StataCorp LP, College Station, TX, USA). Randomization is
stratified by the following factors: study center, age (<60years vs. >/= 60 years). Correct
implementation of the randomization list in the web-based system is quality controlled by the
responsible statistician. The randomization list is kept electronically at CTU Bern in a password
protected file. Study personnel involved in patient recruitment will have no access to the list. The
statistician responsible for the final analysis will also have no access to the list until the primary
analysis of the trial is finished.
14.2 Datasets to be analyzed
14.2.1
Full analysis dataset
The main analysis will be based on all randomized patients regardless of whether they
actually received the allocated intervention or not or any other protocol deviations. Patients
will be analyzed in the group they were randomized regardless of any cross-overs
(intention-to-treat principle).
14.2.2
Per-Protocol analysis dataset
Secondary analyses will allow for a per-protocol analysis where only patients will be
included who actually received the allocated product for at least (give minimum amount of
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Kommentar [TS12]: Provide a
definition of the intention-to-treat
analysis set for this trial.
Study title
intervention received e.g. two weeks) and other details that need to be fulfilled (e.g. the
number of follow-up visits attended).
14.3 Statistical analysis
All analyses will be done using provide details on statistical package(s) that will be used.
All confidence intervals will relate to the 95% level and the two-sided significance level
will be set at 0.05. No adjustment for multiple testing will be done.
A detailed statistical analysis plan will be developed before the final analysis describing
the exact procedures including assessments of model fit and consequences.
14.3.1
Primary analysis
Describe how the primary outcomes will be analysed e.g. statistical model. Describe how
missing data will handled.
14.3.2
Key secondary analyses
Describe how the secondary analyses will be done e.g. statistical model.
14.3.3
Interim analyses and stopping rule of the study
No interim analysis is foreseen in this study.
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Study title
15 Ethical and regulatory aspects
This trial is conducted in accordance with the Declaration of Helsinki {World Medical
Association, 2008 #2}, the International Conference on Harmonization Good Clinical
Practice Guidelines (ICH-GCP) {International Conference on Harmonisation, 1996 #1}
and all applicable national and cantonal laws.
The participating investigators/institutions permit study-related monitoring, audits,
independent ethics committee (IEC) review, and regulatory inspections and provide direct
access to source documents/data.
15.1 Ethics committee approval
The responsible investigator at each site ensures that an appropriately constituted
independent ethics committee (IEC) is responsible for the initial and continuing review and
approval of the clinical study. Before initiation of the study, the investigator forwards
copies of the protocol, consent form and any other required document to the IEC for its
review and approval.
The investigator ensures that all changes in the research activity and all unanticipated
problems involving risks to human subjects are reported promptly to the IEC, and that no
changes are made to the protocol without prior sponsor and IEC approval, except where
necessary to eliminate apparent immediate hazards to study participants.
15.2 Regulatory authority approval
The sponsor ensures that the clinical study is approved by all relevant regulatory
authorities according to local laws.
15.3 Study registration
The sponsor ensures that the study is registered in a WHO approved clinical study register,
preferably at clinicaltrials.gov, before participant recruitment in the study starts.
15.4 Informed consent
The investigator assumes the responsibility of obtaining written informed consent for each
participant before any study-specific procedures are performed and before any study
intervention is administered.
Persons meeting the criteria set forth in the protocol are offered the opportunity to
participate in the study. To avoid introduction of bias, the investigator must exercise no
selectivity with regard to offering eligible persons the opportunity to participate in the
study. Eligible persons or parents/legal guardians of candidate persons receive a
comprehensive explanation of the proposed treatment, including the nature of the therapy,
alternative therapies available, any known previously experienced adverse reactions, the
investigational status of the study interventions, and other factors that are part of obtaining
a proper informed consent. Persons are given the opportunity to ask questions concerning
the study, and adequate time to consider their decision whether to or not to participate.
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Study title
Informed consent is documented by the use of a written consent form that includes all the
elements required by regulations and as approved by the relevant ethics committee. The
form is to be signed and dated by the participant or participant's legally authorized
representative and by the person who administers the consent process. A copy of the
signed form is given to the person who signed it, the original signed consent form is filed
in the investigator site file An additional copy may be filed in the participant's medical
chart. The following information must be recorded in the source documents:

Date and time of the informed consent interview including any agreements if
applicable e.g. participant will come back next day with a decision

Confirmation that participant received the written participant information

Any witnesses if applicable

Any other information that seems important
Persons can make a free decision on participation in the study at any time. If study
participation is refused, the choice of treatment is at the discretion of the study participant.
15.4.1
Amendments
If an amendment to the protocol changes the study schedule in scope or activity, or
changes the potential risk to the participant, the informed consent document must be
revised or amended with clear reference to the original document, submitted to the IEC for
review and approved by the IEC before use. The revised or amended informed consent
document must be used to obtain re-consent from any participants currently enrolled in the
study if the participant is affected by the amendment, and must be used to document
consent from any new participant enrolled after the approval date of the amendment.
15.5 Participant privacy and confidentiality
The investigator affirms and upholds the principle of the participant's right to privacy.
Investigators shall comply with applicable privacy laws.
The written informed consent form will explain that the study data will be stored in a
computer database, maintaining confidentiality in accordance with local data legislation.
Subjects in this database will be identified by participant identifier or pseudonym. The
participant information will also explain that for data verification purposes, authorized
representatives of the sponsor, a regulatory authority, or an ethics committee may require
direct access to parts of the medical records relevant to the study, including participants’
medical history.
Especially, anonymity of the participants will be guaranteed when presenting the data at
scientific meetings or publishing them in scientific journals.
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Study title
16 Administrative aspects
16.1 Protocol amendments
In order to maintain comparable conditions in all study sites and to obtain an
unobjectionable data analysis changes of the protocol are not intended. If nonetheless
changes become necessary they are reported as amendment.
Any change or addition to this protocol requires a written protocol amendment that must be
approved by the study sponsor before implementation. Amendments affecting the safety of
participants, the scope of the investigation or the scientific quality of the study, require
additional full approval by the IEC of all sites, and by regulatory authorities. Examples of
amendments requiring such approval are:

Increase in intervention dosage or duration of exposure of participants

Changes in the study design

Increase in the number of invasive procedures to which participants are exposed

Addition or deletion of a test procedure for safety monitoring
The requirements for approval should in no way prevent any immediate action from being
taken by the investigator or the study sponsor in the interests of preserving the safety of all
participants included in the study. If an immediate change to the protocol is felt to be
necessary by the investigator and is implemented by him/her for safety reasons the study
sponsor should be notified immediately and the IEC at the centre should be informed
within ten working days.
Amendments affecting only administrative aspects of the study do not require formal
protocol amendments or IEC approval but the IEC of each site must be kept informed of
such administrative changes. Examples of administrative changes not requiring formal
protocol amendments and IEC approval that can be treated as administrative amendments
include but are not limited to:


Changes in the staff used to monitor the study
Changes in addresses
16.2 Insurance
Insurance will be provided by the Sponsor. A copy of the certificate is filed in each
investigator site file and the trial master file.
16.3 Funding and other support for the trial
Provide sources and types of financial, material, and other support for the trial
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Study title
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Study title
17 Data handling and record keeping
17.1 Investigator site file
At each site an Investigator Site File will be maintained including at least the following
documents/information:


























Signed protocol and amendments
Sample case report forms (CRF)
Current informed consent form and all revisions
Current patient information and all revisions
Any other written information
Financial aspects of the study
Insurance statement
All signed agreements/contracts
Dated, documented approval of ethics committee and regulatory authorities
Signed CVs of all investigators and any study personnel (update regularly)
Instructions for handling of investigational product and study related materials
Monitoring reports

Study initiation report

Follow-up letters of on-site visits

Study close out report
Relevant communication

Letters

Meeting notes

Notes of telephone calls
Signed informed consent forms
Signed, dated and completed case report forms if applicable
SAE reporting
Notification by sponsor of safety information
Interim and annual reports to ethics committee and regulatory authorities
Subject screening log
Subject identification code list
Subject enrolment log
Investigational product accountability
Authorisation/signature sheet
Record of retained body fluids/tissue samples
Documentation of investigational product destruction
Clinical study report
17.2 Case Report Forms
All protocol required procedures along with information necessary to report the
observations and tests described in this protocol are recorded in the case report forms
(CRFs). CRFs must be completed and signed in a timely and accurate manner by study site
personnel (usually within ten working days after completion of a visit). Dedicated study
personnel at CTU Bern monitors the data entry progress per center to ensure timely data
collection.
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Study title
All data entered on the CRFs must be documented in a source document. The case report
form is not a source document. If data is directly entered in the CRF without any source
document this needs to be explicitly mentioned in the CRF. All the information on which
the entries in the CRF are based must be available in the patient files e. g. results of
laboratory investigations. The investigator must review all CRFs for accuracy and
consistency with the protocol, and sign the CRFs upon completion.
The investigator or a designee is responsible for the presence of the data in the patient file
and the correct entry of the data into the CRF.
After prior agreement, a check of the consistency of data between the patient files, raw
data and CRF as well as with other documents related to the study may be conducted by
the responsible authorities and/or by monitors (inspection/audit/monitoring).
17.3 Record keeping
A copy of the final completed CRFs is retained by the investigator, who must ensure that it
is stored with other study documents, such as the signed informed consent forms, protocol,
the investigator’s brochure and any protocol amendments, in a secure place for 10 (15 for
trials with implants) years.
17.4 Data management
17.4.1
Hardware and software
The CRFs in this trial are implemented electronically using a dedicated electronic data
capturing (EDC) system (WebSpirit®/RedCAP). The EDC system is activated for the trial
only after successfully passing a formal test procedure.
All data entered in the CRFs are stored on a Linux/Windows server in a dedicated
PostgreSQL database.
Responsibility for implementing and hosting the EDC system and the database lies with
CTU Bern.
17.4.2
Data security, access and back-up
The server hosting the EDC system and the database is kept in a locked server-room. Only
the system administrators have direct access to the server and back-up tapes. A role
concept with personal passwords (site investigator, statistician, monitor, administrator etc.)
regulates permission for each user to use the system and database as he/she requires.
All data entered into the CRFs are transferred to the database using Secure Sockets Layer
(SSL) encryption. Each data point has attributes attached to it identifying the user who
entered it with the exact time and date. Retrospective alterations of data in the database are
recorded in an audit table. Time, table, data field, original value and altered value, and the
person are recorded (audit trail).
A multi-level back-up system is implemented. Back-ups of the whole system including the
database are run internally several times per day and on external tapes once a day. The
back-up tapes are stored in a secure place in a different building.
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17.4.3
Analysis and archiving
At interim (if applicable) and final analyses, data files will be extracted from the database
into statistical packages to be analyzed. The status of the database at this time is recorded
in special archive tables.
The study database with all archive tables will be securely stored by CTU Bern for at least
15 years. The sponsor also keeps the Trial Master File and interim and final reports both in
electronic and in hard copy form for at least 10 (15 in case of implants) years.
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18 Quality assurance and control
A multilevel data validation/monitoring plan is conceived in order to guarantee the
correctness and consistency of the data in the CRFs and database.
18.1 Electronic and central data validation
Data can be entered into the database only after a check of completeness and plausibility.
Furthermore, selected data points are cross-checked for plausibility with previously entered
data for that participant.
In addition, data will be extracted from the database regularly to perform central data
validation checks using statistical software packages. Any detected inconsistencies and
relevant missing data will be queried at the respective center.
18.2 On-site monitoring
In order to guarantee a high quality of the study and data retrieval, participating centers
may be visited on site by independent monitors. Data protection rights are respected. All
findings and comments are documented in a monitoring report and communicated to the
investigator and to the sponsor. The investigator in the participating centers supports the
monitor in his/her activities.
Before study start (first participant in) a monitoring plan detailing all on-site monitoring
related procedures is developed.
On-site monitoring will be conducted by CTU Bern.
18.3 Inspections
A regulatory authority or independent ethics committee may wish to conduct an inspection
(during the study or even after its completion). If an inspection is requested, the
investigator must inform the sponsor immediately that this request has been made. The
investigators in the participating sites will support the inspectors in their activities.
18.4 Closure of study centers
The study sponsor may exclude participating sites/investigators from further participation
in the study because of fraud or non-compliance with the study protocol, ICH-GCP
guidelines, or applicable laws.
Study sites or investigators may stop recruiting patients to this study when the investigator
deems inclusion of patients into this study to be no longer ethical for medical or
organizational reasons. In this case, the investigator should give detailed reasons to the
study sponsor.
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19 Dissemination policy
19.1 Public access to the full protocol, dataset, and
statistical code
Describe whether and how access to the protocol, dataset, and statistical code is enabled.
19.2 Publication policy and final report
The final report will present the results of the study, including appropriate tables and
figures in the spirit of an unbiased objectivity. The sponsor will provide the IEC with a
summary of the study’s findings, and if applicable the regulatory authorities with any
reports required. The report, or parts of it, may be submitted in the form of a summary, a
synopsis, published article or in some other similar way.
The sponsor assures that all results of this study are published in a peer-reviewed journal in
line with the Declaration of Helsinki {World Medical Association, 2008 #2}. All results
relate to all outcomes as defined in this protocol regardless of the direction or statistical
significance. It will be assured that the manuscript follows the principle of the CONSORT
guidelines or any other applicable reporting guideline (www.equator.org). Co-authorship
on any of the publications will be based on contribution to the study and manuscript
according to the criteria of the International Committee of Medical Journal Editors
{International Committee of Medical Journal Editors, 2009 #3}.
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20 Post-trial care
20.1 Individual information of participants after end of
trial
Describe whether any procedures are in place to inform participants about the results of the
trial.
Describe whether and how participants are allowed to be informed about the intervention
received during the trial in case of a blinded trial.
20.2 Access to effective trial interventions
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21 Accompanying scientific projects
Provide details on accompanying scientific project such as nested studies,
biomarker/genetic studies etc. This might require additional sub-headings identifying the
population, describing the outcomes, assessments, analyses, etc.
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22 References
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23 Appendices
Study flow diagram ............................................................................................................. 56
Study assessments overview ................................................................................................ 57
Insurance certificate............................................................................................................. 58
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23.1 Study flow diagram
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23.2 Study assessments overview
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23.3 Insurance certificate
Provide a scan of the insurance certificate
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23.4 Study contacts
23.4.1
Sponsor
Name: ...................................
Address: ................................
Tel: ........................................
E-mail: ..................................
23.4.2
Principal Investigator
Name: ...................................
Address: ................................
Tel: ........................................
E-mail: ..................................
23.4.3
Trial coordination/management
Name: ...................................
Address: ................................
Tel: ........................................
E-mail: ..................................
23.4.4
Monitoring
Responsible for study site:....
Name: ...................................
Address: ................................
Tel: ........................................
Kommentar [TS13]: Add if more than
one monitor is responsible
E-mail: ..................................
23.4.5
Drug supply
Name: ...................................
Address: ................................
Tel: ........................................
E-mail: ..................................
23.4.6
Data management
Name: ...................................
Address: ................................
Tel: ........................................
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E-mail: ..................................
23.4.7
Statistics
Name: ...................................
Address: ................................
Tel: ........................................
E-mail: ..................................
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Kommentar [TS14]: Provide financial
and other competing interests of
sponsor and (principal) investigators for
the overall trial and each study site
23.5 Declaration of interests
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