Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating Efficacy and Safety of SAR339658 in Patients with Active Moderate to Severe Ulcerative Colitis (UC)
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Summary
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EudraCT number |
2012-002013-19 |
Trial protocol |
BE AT IT DE PL |
Global end of trial date |
25 Apr 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Jan 2017
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First version publication date |
05 Jan 2017
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Other versions |
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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 |
ACT12688
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01659138 | ||
WHO universal trial number (UTN) |
U1111-1124-1076 | ||
Other trial identifiers |
Study Name: FUSCIA | ||
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Sponsors
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Sponsor organisation name |
Sanofi aventis recherche & développement
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Sponsor organisation address |
1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
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Public contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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Scientific contact |
Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
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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 |
05 May 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Apr 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To assess the induction of clinical response at Week 8 with intravenous (I.V.) SAR339658 20 mg/kg administered as 4 infusions once every 2 weeks (q2w) in subjects with active moderate to severe ulcerative colitis (UC).
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Protection of trial subjects |
Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency.
Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Aug 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
24 Months | ||
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 |
Poland: 1
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
United States: 23
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Worldwide total number of subjects |
28
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EEA total number of subjects |
4
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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) |
27
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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 |
The study was conducted at 41 sites in 7 countries. A total of 90 subjects were screened between August 2012 and March 2014. The decision to discontinue the study was notified to investigators in March 2014 due to slow enrollment. Indeed 28 subjects were randomized by that date. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
The 62 screen failures were mainly due to failure to meet the inclusion/exclusion criteria. Enrolled subjects were initially randomized according to a 1:1 ratio. Then, from April 2013, the randomization schedule was changed to 2:1 ratio (SAR339658: Placebo) and the sample size was adjusted according to protocol amendment. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Double-Blind Treatment Period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Assessor | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||
Arm description |
Placebo matched to SAR339658 infusion at Week 0, 2, 4, and 6. | |||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Placebo for SAR339658 infusion over 60 minutes (for subjects weighing <120 kg) or 120 minutes (for subjects weighing >120 kg).
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Arm title
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SAR339658 | |||||||||||||||||||||||||||
Arm description |
SAR339658 20 mg/kg infusion at Week 0, 2, 4, and 6. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Vatelizumab
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Investigational medicinal product code |
SAR339658
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
SAR339658 20 mg/kg infusion over 60 minutes (for subjects weighing <120 kg) or 120 minutes (for subjects weighing >120 kg).
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo matched to SAR339658 infusion at Week 0, 2, 4, and 6. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SAR339658
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Reporting group description |
SAR339658 20 mg/kg infusion at Week 0, 2, 4, and 6. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo matched to SAR339658 infusion at Week 0, 2, 4, and 6. | ||
Reporting group title |
SAR339658
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Reporting group description |
SAR339658 20 mg/kg infusion at Week 0, 2, 4, and 6. | ||
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End point title |
Number of Subjects with Clinical Response (Per Mayo Score) at Week 8 [1] | |||||||||
End point description |
The Mayo Score is a discrete ordinal scale to assess ulcerative colitis activity. It is a composite of 4 sub-scores for stool frequency, rectal bleeding, endoscopy, and Physician's Global Assessment (PGAS), each of which ranges from 0 (normal) to 3 (severe disease). Total score ranges from 0 (normal or inactive disease) to 12 (severe disease). Clinical response per Mayo score (also known as the Disease Activity Index- DAI) was defined as a decrease in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the sub score for rectal bleeding of at least 1 point or an absolute sub score for rectal bleeding of 0 or 1 and with the endoscopic sub-score read by a central reader. Analysis was performed on intent-to-treat (ITT) population that included all randomized subjects.
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End point type |
Primary
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End point timeframe |
Baseline to Week 8
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to the early termination of the study, and because of the small number of randomized subjects (18 instead of 93), statistical comparison was not performed. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Subjects with Clinical Remission (Per Mayo Score) at Week 8 | |||||||||
End point description |
Clinical remission per Mayo score was defined as a total Mayo score of 2 points or lower, with no individual sub score exceeding 1 point. Analysis was performed on ITT population.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of Subjects with Mucosal Healing (per Mayo Endoscopic Sub-score) at Week 8 | |||||||||
End point description |
Mucosal healing was defined as an absolute endoscopic sub-score of 0 or 1, obtained from colonoscopy (read by a central reader). Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, and mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, and erosions), 3 = Severe disease (spontaneous bleeding, ulceration). Analysis was performed on ITT population.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 8
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change from Baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score at Week 4 and Week 8 | ||||||||||||||||||
End point description |
The IBDQ is a self-administered 32-item questionnaire that evaluates the disease specific quality of life across 4 dimensional scores: Bowel, Systemic, Social and Emotional. The total IBDQ score is the sum of the responses to the individual questions and can range from 32 to 224; a higher scores indicating a better quality of life. Analysis was performed on ITT population. Here, 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4 and Week 8
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change from Baseline in Quality of Life Measured by 36-Item Short-Form Health Survey (SF-36) Scores at Week 4 and Week 8 | ||||||||||||||||||||||||
End point description |
SF-36 is a self-rated 36-item questionnaire measuring health-related quality of life across eight domains: physical function, role limitations due to physical problems, pain, and general health perception (physical component), vitality, social function, role limitations due to emotional problems, and mental health (mental component). Eight sub-scale scores are obtained by computerizing items scores, and can range from 0 (maximum disability) to 100 (no disability). Component scores are mean average of sub-scale scores. Analysis was performed on ITT population. Here, 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4 and Week 8
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Change from Baseline in Partial Mayo Score at Week 4 and Week 6 | ||||||||||||||||||
End point description |
The partial Mayo score is calculated as a sum of three sub-scores: stool frequency sub-score, rectal bleeding sub-score and Physician's Global Assessment sub-score. It is in a range from 0-9 points; higher partial Mayo scores indicate more severe disease. Analysis was performed on ITT population. Here, 'n' signifies number of subjects with available data for specified category.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 4 and Week 6
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Long Term Safety Follow-up: Number of Subjects who experienced Opportunistic or Progressive Multifocal Leukoencephalopathy (PML) | |||||||||
End point description |
Subjects were contacted by phone at 3, 6, 12, 18 and 24 months post-treatment. During the phone contact, subject was asked specific questions regarding any new signs or symptoms indicative of infection. Any positive findings on questioning was expeditiously referred to a physician for additional evaluation. If any abnormal signs and symptoms are observed or identified, the subject was subsequently referred to an infectious disease specialist or a neurologist for a complete assessment. Analysis included all subjects who received at least one dose of study drug and consented in participating in the post-treatment long term safety follow-up, excluding those who enrolled in the long-term open-label extension study LTS12593 (EudraCT no. 2013-001012-30). For the lasts, the long term safety follow-up results are provided with the LTS12593 results.
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End point type |
Other pre-specified
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End point timeframe |
Up to 24 months after the last dose of investigational medicinal product (IMP)
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All Adverse Events (AE) were collected from signature of the informed consent form up to the last visit (Week 14 [Week 30 for German subjects]) or enrollment in the LTS12593 (2013-001012-30) study regardless of seriousness or relationship to study drug.
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Adverse event reporting additional description |
Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during the ‘on treatment period’ (from the first dose of study drug up to the last visit in the study or enrollment in the LTS12593 study).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects exposed to Placebo (mean exposure of 41 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
SAR339658
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Reporting group description |
Subjects exposed to SAR339658 (mean exposure of 48 days). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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20 Mar 2012 |
It included following changes:
- The inclusion criteria was modified to focus the study target population to those who failed treatment with immunosuppressant and or biological medications.
- Modified information on the risk of PML observed with other immunomodulatory medications in the protocol and in the whole slide imaging (WSI).
- Clarified the signs and symptoms of PML.
- A post study follow-up was included in the form of a phone call at 3 months and 6 months from the end of treatment to question the subjects regarding the presence of any neurological signs or symptoms or symptoms of other potential adverse events and refer the subject to specialist if needed.
- Added monitoring for a potential increase in bleeding (eg. petechiae, mucosal bleeding).
- Further instructions on the infusion of study medications and potential allergic reactions were provided.
- Erythrocyte sedimentation rate (ESR) testing was removed.
- Some of the laboratory testings were clarified.
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16 Jul 2012 |
It included following changes:
- Baseline testing for John Cunningham Virus (JCV) antibody at screening and at Week 14 was included.
- Added that the results of the baseline JCV antibody test would be provided to the subject and that the subject would be given the option to withdraw from the study before they received any treatment.
- Added that upon subsequent JCV antibody testing at Week 14, the subject would also be informed of their antibody status as soon as results were available.
- Added that subjects would be informed that the risk of developing PML might be higher for those who were antibody positive, based on data from another drug in the class (natalizumab) and that subjects who were JCV antibody negative were still at risk for the development of PML.
- After the 3 and 6 months post treatment follow-up additional follow up at 12, 18 and 24 months post treatment follow-up was added to better clarify features to enhance the completeness of follow-up.
- The inclusion criteria was modified to include a definition of both inadequate response to immunosuppressants and intolerance to immunosuppressants; and to include a definition of both inadequate response to Tumor necrosis factor (TNF)-alpha antagonists and intolerance to TNF-alpha antagonists.
- Additional PK testing post treatment was added.
- The screening period was extended from 2 weeks to 3 weeks.
- An additional blood test at Week 14 for CD4/CD8 ratio and CD19, CD34 was added.
- Geographic region (North America, Western Europe and Eastern Europe) was added as a randomization stratification factor in addition to prior anti-TNF alpha therapy.
- Geographic region was added as a stratification factor in the supportive Cochran-Mantel-Haenszel test.
- Specific cytokines measurement at Week 0 and Fluorescence-activated cell sorting (FACS) assay measurement at Week 8 were removed. |
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25 Jan 2013 |
It included following changes:
- Clarified that only subjects who were JCV antibody negative at baseline would be retested at Week 14.
- Clarified that the QuantiFERON TB Gold test could be repeated in case the result was indeterminate or believed to be false positive test.
- Clarified that subjects could have flexible sigmoidoscopy at screening if a colonoscopy was done within the last 12 months and also clarified that subjects could have a flexible sigmoidoscopy at Week 8 (end of treatment).
- The randomization ratio was changed from 1:1 to 2:1 to increase the probability of receiving the active treatment. As a result, the sample size was increased by 9 subjects.
- A section was added to explain that subjects could be rescreened once at the discretion of investigator.
- The screening period was increased by 1 week.
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12 Apr 2013 |
- Added the possibility for subjects who had completed the study treatment period in the ACT trial to transition to a long-term open-label extension safety study LTS12593.
- Removed CD4/CD8<1 as an exclusion criterion but continued to evaluate and monitor.
- Clarified and simplified the safety reporting and ensured the key important events would be reported and analyzed in an expedited manner.
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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 sample size was much smaller than the planned because the study was terminated early due to slow enrollment. | |||
