Clinical Trial Results:
Optimal utilisation of biologic drugs in Behçet’s Disease: a randomised controlled trial of infliximab (IFX) verses alpha interferon (aIFN), with genotyping and metabolomic profiling, towards a stratified medicines approach to treatment.
Summary
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EudraCT number |
2014-005390-36 |
Trial protocol |
GB |
Global end of trial date |
21 Sep 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Oct 2021
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First version publication date |
10 Oct 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
UoL001109
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Additional study identifiers
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ISRCTN number |
ISRCTN49793874 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University of Liverpool
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Sponsor organisation address |
Clinical Directorate 2nd Floor, Block C, Waterhouse Building 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
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Public contact |
Miss Charlotte Rawcliffe, Liverpool Clinical Trials Centre, +44 151 794 8167, c.rawcliffe@liverpool.ac.uk
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Scientific contact |
Miss Charlotte Rawcliffe, Liverpool Clinical Trials Centre, +44 151 794 8167, c.rawcliffe@liverpool.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Sep 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Sep 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Sep 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The aim of this study is to underpin clinically effective prescribing of the biologic drugs infliximab (IFX) and alpha interferon (aIFN) for Behçet’s Disease (BD).
The primary objective of the study is to undertake a randomised controlled trial to compare IFX versus aIFN in patients with BD who are unresponsive to standard oral therapy.
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Protection of trial subjects |
Consent was obtained prior to each patient participating in the trial, after a full explanation had been given of the treatment options, including the conventional and generally accepted methods of treatment. Age and stage-of-development specific Patient Information and Consent Leaflets were also implemented and patient assent obtained where appropriate. The right of patients to refuse their consent to participate in the trial without giving reasons would have been respected.
The study also had a Trial Steering Committee (TSC) and Independent Safety and Data Monitoring Committee (ISDMC). The ISDMC was responsible for safeguarding the interests of trial participants, assessing the safety and efficacy of the interventions during the trial and for monitoring the overall progress and conduct of the clinical trial.
The TSC was responsible for monitoring and supervising the progress of the trial, considering recommendations from the IDSMC and advising the TMG on all aspects of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jul 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 79
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Worldwide total number of subjects |
79
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EEA total number of subjects |
79
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
78
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment took place over 43 months from 8recruiting centres, the first patient was randomised on 21st June 2016 and the last patient was randomised on 18th February 2020. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
161 patients were screened prior to randomisation. 82 patients did not enter the study, 58 of which were due to not meeting the inclusion/exclusion criteria, 4 declined to participate and 10 were due to 'Other' reasons. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Intervention Phase (Overall Period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
Blinding implementation details |
There was partial blinding in this study. Assessing clinicians were blinded to therapy, documenting the disease activity and potential AEs. Patients, nurses and the clinician responsible for prescribing the study drug were not blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Infliximab | |||||||||||||||||||||||||||
Arm description |
Infliximab Intravenous Infusion (Remicade) | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Infliximab
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Investigational medicinal product code |
L04AB02
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Other name |
Infliximab Intravenous Infusion
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Infusion
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Dosage and administration details |
Patients received Remicade at a standard dose of 5mg/kg at weeks 0, 2 and 6 as loading then every 8 weeks for the remaining length of the trial.
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Arm title
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Alpha interferon | |||||||||||||||||||||||||||
Arm description |
Alpha interferon (Roferon-A) pre-filled syringes | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Interferon alfa-2a
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Investigational medicinal product code |
L03AB04
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Other name |
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Pharmaceutical forms |
Solution for infusion in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Patients received Remicade at a standard dose of 5mg/kg at weeks 0, 2 and 6 as loading then every 8 weeks for the remaining length of the trial.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 5 Patients withdrew consent and data are presented on 74 patients included in the final statistical analysis report. |
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Baseline characteristics reporting groups
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Reporting group title |
Infliximab
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Reporting group description |
Infliximab Intravenous Infusion (Remicade) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Alpha interferon
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Reporting group description |
Alpha interferon (Roferon-A) pre-filled syringes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Infliximab
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Reporting group description |
Infliximab Intravenous Infusion (Remicade) | ||
Reporting group title |
Alpha interferon
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Reporting group description |
Alpha interferon (Roferon-A) pre-filled syringes | ||
Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Set on the Intention to treat principle retaining patients in their randomised groups irrespective of any
protocol deviations.
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End point title |
Modified Behçet’s Disease Activity Index (BDAI) after 3 months of treatment | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline to 3 months of treatment
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Statistical analysis title |
mod BDAI - baseline to 3 months | ||||||||||||
Statistical analysis description |
A Bayesian Linear Regression Model
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Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
69
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
Bayesian Linear Regression | ||||||||||||
Parameter type |
alone parameter | ||||||||||||
Point estimate |
0.13
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Confidence interval |
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level |
80% | ||||||||||||
sides |
2-sided
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lower limit |
-0.19 | ||||||||||||
upper limit |
0.46 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.25
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End point title |
Modified Behçet’s Disease Activity Index (BDAI) after 6 months of treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 6 months of treatment.
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Statistical analysis title |
Modified BDAI - baseline to 6 months | ||||||||||||
Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
64
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
Method |
Bayesian Linear Regression | ||||||||||||
Parameter type |
Model parameter | ||||||||||||
Point estimate |
0.05
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Confidence interval |
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level |
80% | ||||||||||||
sides |
2-sided
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lower limit |
-0.3 | ||||||||||||
upper limit |
0.38 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.27
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Notes [1] - Bayesian linear regression Model |
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End point title |
Original BDAI after 3 months of treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 3 months
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Statistical analysis title |
Original BDAI -Baseline to 3 month | ||||||||||||
Comparison groups |
Alpha interferon v Infliximab
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Number of subjects included in analysis |
69
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
Bayesian Linear Regression | ||||||||||||
Parameter type |
Linear regression parameter | ||||||||||||
Point estimate |
0.12
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Confidence interval |
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level |
80% | ||||||||||||
sides |
2-sided
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lower limit |
-0.2 | ||||||||||||
upper limit |
0.44 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.25
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End point title |
Significant improvement in vitreous haze after 3 months | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 months of treatment.
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No statistical analyses for this end point |
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End point title |
Significant improvement in ulcer severity score (USS) after 3 and 6 months of treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 3 months
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Statistical analysis title |
Ulcer severity score | ||||||||||||
Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.76 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Exact test - non aplicable | ||||||||||||
Confidence interval |
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Notes [2] - Test performed is a Fisher exact test based on patients with at least 20% reduction. |
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End point title |
Significant improvement in number of genital ulcers after 3 and 6 months of treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 3 months
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Statistical analysis title |
genital ulcers, baseline to 3 months | ||||||||||||
Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 1 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Exact test - no parameter estimate | ||||||||||||
Confidence interval |
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Notes [3] - Fisher test performed on proportion with at least 20% reduction |
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End point title |
Significant improvement in Likert pain score after 3 and 6 months of treatment | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 3 months
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Statistical analysis title |
Likert paint score - baseline to 3 months | ||||||||||||
Statistical analysis description |
Analysis conducted using a fishers test based on the proportion with at least 20% improvement.
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Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
29
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 1 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Exact test - no parameter specified | ||||||||||||
Confidence interval |
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End point title |
Use of prednisolone (or equivalent glucocorticoid) at 6 months | |||||||||
End point description |
Analyses performed on the
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End point type |
Secondary
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End point timeframe |
Baseline to 6 months
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Statistical analysis title |
Use of prednisolone | |||||||||
Statistical analysis description |
Analysis conducted using a logistical regression model including treatment, timepoints and a treatment by timepoints interaction
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Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
74
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||
P-value |
= 0.891 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.25
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.051 | |||||||||
upper limit |
30.477 | |||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.629
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End point title |
Quality of life scores at 3 and 6 months compared to baseline | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 3 months
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Statistical analysis title |
Quality ofLife (EQ5D) | ||||||||||||
Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
62
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.8318 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Parameter type |
Exact test - no parameter specified | ||||||||||||
Confidence interval |
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End point title |
Physician’s Global Assessment of disease activity at 3 and 6 months | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline to 3 months
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Statistical analysis title |
Clinician perception disease activity | ||||||||||||
Comparison groups |
Infliximab v Alpha interferon
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.421 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Parameter type |
non-parametric test | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Full study period.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
5
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Reporting groups
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Reporting group title |
Infliximab
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
aIFN
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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03 Feb 2015 |
Several changes to the protocol as part of the MHRA approval, to include;
• A change to the wording of the main exclusion criteria (section 1 and section 5.2) and
precautions required (section 7.7.2) to detail the requirements for participants of child
bearing potential to use effective contraception.
• A change to the schedule of assessments (section 8) and changes to the glossary were
made.
• Patient information sheet was amended to reduce the amount of blood sample
required. |
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17 Dec 2015 |
• General - updated trial start date.
• Sections 1 and 5.2 – corrections to the objectives of the trial and confirmation of the
number of trial sites.
• Exclusion criteria updated to include Multiple Sclerosis and HIV patients.
• Section 4.1 – overall design updated to reflect timing of assessments as per standard
care practice.
• Section 4.3 – secondary end points changes to genital ulcer measure with a reduction
of 20% considered to be clinically significant.
• Section 6 – Enrolment/baseline update to screening log information. Update to
randomisation instructions relating to the online enrolment and randomisation
system TARDIS.
• Section 6.1- screening assessments to be completed within 35 days prior to the first
dose of treatment. HIV added.
• Section 6.1- symptom directed assessment removed from baseline assessment and
the inclusion of a chest X-ray. Addition of screening for alterations in mood/suicide
ideation (as known to be a side effect of Roferon treatment).
• Section 7- Study treatment, the standardised use of methotrexate has been removed
from the trial for clarity. Concomitant immunosuppressants will now be administered
at the clinician discretion on a case by case basis.
• Section 8.1 amendments were made to the schedule of assessments.
• Section 8.2 Electronic CRF updated relating to assessment of efficacy.
• Section 8.4.2.2. Further information detailing the collection of urine samples for
metabolomics analyses.
• Section 8.7. Trial closure has been amended as being when the last patient has
completed their final study visit.
• Section 9.2. Updated procedure for generating randomisation code lists.
• Section 13. Update to clarify the method of data capture as utilising electronic CRF’s.
• Quality control procedures at site for primary and secondary endpoints as a
consequence of the use of an eCRF platform at sites.
• The removal of minimisation techniques for randomisation.
• Section 16. Oversight committee members’ inf |
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25 Jan 2016 |
Several changes to the protocol as part of the MHRA approval, to include;
• A change to the wording of the overall design (section 4.1) as per the ISDMC
recommendation. New wording; This is a randomised, two-arm, parallel, open-label
design comparing the efficacies of infliximab vs alpha interferon. The population is
patients with refractory disease eligible for the first biologic drug.
• Primary outcome wording changed to match section 9 of the protocol. New wording;
Primary Outcome: Modified Behçet’s Disease Activity Index (BDAI) after 3 months of
treatment (Week 12 visit), with 20% change in means being defined as the zone of
equivalence of treatment. |
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28 Oct 2016 |
• Change to randomisation directions.
• Section 7.2.2 – “Target dose of azathioprine is 2.5 mg/kg” added as per ISDMC
recommendation.
• Section 7.2.1 – Update to provide sites with more information about the IMP.
• Section 7.3.2 – Wording added as per ISDMC recommendation “Immunosuppressant’s
will be discontinued in Arm B”.
• Section 8.1 – Schedule of assessments – New column added to detail the assessments
required at Week 36 for patients who swap treatment arms at 12 weeks.
• Section 8.2 – Wording changed to include the mandatory visit (Week 36) for patients
who swap treatment at Week 12.
• Section 8.4.3.2 – Change to amount of urine to be collected at each visit.
• Section 9.2 - Additional details were provided in order to make the randomisation
procedure more clearly to the reader.
• Section 9.3.2 - Week 26 replaced with Week 24.
• Section 9.6.1 - Priors were given explicitly as this was missed in the previous version of
the protocol.
• Section 9.6.2 - Corrected sample amount and added “at each trial visit” to make the
collection clearer
• Changes to Remicade SmPC.
• Changes to Roferon SmPC for notification purposes only
• Update to Staff members.
Patient Information Sheet
• IRAS number added – to comply with HRA guidance.
• New wording to make clear that urine sample is required at visit Week 36 if patients
swap treatment at Week 12.
Informed Consent Form
• IRAS number added – to comply with HRA guidance.
• New wording to make clear that urine sample is required at visit Week 36 if patients
swap treatment at Week 12.
GP Letter
• IRAS number added – to comply with HRA guidance |
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16 May 2017 |
Exclusion Criteria added (section 5.2)
• Point 8 Evidence for active Tuberculosis (TB testing using local standard practise)
• New Wording Section 6.1 – If in the opinion of the Principle Investigator, the patient
requires a biologic drug, whether a prior immunosuppressive agent has been given or
not, that the patient will be eligible for a biologic under normal standard of care and
SSBEH_D054/01 Bio Behçet’s Final Statistical Analysis Report 20/09/2021
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therefore may be included in the trial. (Patients previously receiving a prior biologic
agent will, currently, not be eligible for the trial) If, in the opinion of the Principle
Investigator, the disease is so severe that the benefit of starting the biologic before
receiving all screening test results outweighs the risk of not starting it, that patient will
remain eligible for the trial, in line with normal practise.
• New Wording Section 4.1 – This is a randomised, two-arm, parallel design comparing
the efficacies of the infliximab vs alpha interferon. (Previous Wording – This is a
randomised, two-arm, parallel, open label design comparing the efficacies of infliximab
vs alpha interferon
• New Wording Section 6.1 – Section 6.1 Eligibility assessments for entry into the trial will
be performed within 42 days prior to the first dose of treatment.(Previous Wording-
Eligibility assessments for entry into the trial will be performed within 35 days prior to
the first dose of treatment).
• Changes to the wording randomisation procedure – New Wording After a patient has
been screened and their details entered onto MACRO 4 database by the trial site the
randomisation can be performed on the TARDIS website. The clinician must confirm
eligibility by signing a paper eligibility Case Report Form (CRF) which trial site staff will
email or fax to LCTU along with a copy of the Informed Consent Form. This will confirm
eligibility of the patient along with the stratification factors, which will |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
The primary outcome is conducted using a Bayesian approach using priors derived from clinical expertise. As such, the primary outcome is assessed based on a posterior distribution which accounts for both prior information and study data. |