Clinical Trial Results:
A Randomized, Double-Masked and Placebo-Controlled Study to Evaluate the Efficacy and Safety of Sarilumab Administered Subcutaneously Every 2 Weeks in Patients with Non-Infectious, Intermediate, Posterior or Pan-Uveitis (NIU)
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Summary
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EudraCT number |
2012-004845-34 |
Trial protocol |
CZ DE IT ES |
Global end of trial date |
19 Apr 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
04 May 2017
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First version publication date |
04 May 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 |
ACT13480
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01900431 | ||
WHO universal trial number (UTN) |
U1111-1130-6500 | ||
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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 |
20 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 |
19 Apr 2016
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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 |
To evaluate the efficacy of 200 mg sarilumab every 2 weeks (q2w) at Week 16 in subjects with NIU.
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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 |
Following background therapy was given to subjects during the study: Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Oct 2013
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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 |
Spain: 7
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Country: Number of subjects enrolled |
Czech Republic: 16
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Italy: 5
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Country: Number of subjects enrolled |
Turkey: 16
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Country: Number of subjects enrolled |
United States: 11
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Worldwide total number of subjects |
58
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EEA total number of subjects |
31
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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) |
54
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From 65 to 84 years |
4
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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 18 centers in 6 countries. A total of 82 subjects were screened between 30 October 2013 and 17 March 2015 of whom 58 subjects were randomized and 24 were screen failures. Screen failures were mainly due to exclusion criteria met. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were randomized in 2:1 ratio (Sarilumab : Placebo) and treated for 16 weeks during principal treatment period (Part A), 30 responders treated up to Week 50 with same dose during extension treatment period (Part B) while 10 non-responders and 11 subjects (not completed Part A) treated with open label treatment up to Week 50 (Part C). | |||||||||||||||||||||
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Period 1
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Period 1 title |
Principal Treatment Period (Part A)
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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, Carer | |||||||||||||||||||||
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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 (Part A) | |||||||||||||||||||||
Arm description |
Placebo (for Sarilumab) subcutaneous (SC) injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo (for Sarilumab)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo (for Sarilumab) as SC injection in the abdomen, thigh or upper arm.
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Arm title
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Sarilumab 200 mg q2w (Part A) | |||||||||||||||||||||
Arm description |
Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Sarilumab
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Investigational medicinal product code |
SAR153191, REGN88
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Sarilumab as SC injection in the abdomen, thigh or upper arm.
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Period 2
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Period 2 title |
Extended Treatment Period (Part B)
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer | |||||||||||||||||||||
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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 (Part B) | |||||||||||||||||||||
Arm description |
During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with placebo SC injection q2w as per principal treatment period (Part A) up to Week 50. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo (for Sarilumab)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo (for Sarilumab) as SC injection in the abdomen, thigh or upper arm.
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Arm title
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Sarilumab 200 mg q2w (Part B) | |||||||||||||||||||||
Arm description |
During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with Sarilumab 200 mg SC injection q2w as per principal treatment period (Part A) up to Week 50. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Sarilumab
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Investigational medicinal product code |
SAR153191, REGN88
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Sarilumab as SC injection in the abdomen, thigh or upper arm.
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| Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Out of 41 subjects who completed Part A, 30 responders (8 Placebo, 22 Sarilumab) entered Part B. |
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Period 3
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Period 3 title |
Open-Label Treatment Period (Part C)
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||
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Arms
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Arm title
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Sarilumab 200 mg q2w : Open-Label Treatment (Part C) | |||||||||||||||||||||
Arm description |
During Open-Label Treatment Period (Part C), Non-responders (defined as no decrease in VH ≥2 steps and corticosteroids dose missing at Week 16) and non-completers (not-completed) Part A were treated with Sarilumab 200 mg SC injection q2w for 34 weeks as open-label treatment in open-label treatment period (Part C) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Sarilumab
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Investigational medicinal product code |
SAR153191, REGN88
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Sarilumab as SC injection in the abdomen, thigh or upper arm.
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| Notes [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Total 21 subjects entered Part C. 10 non-responders as started (5 placebo, 5 Sarilumab) and 11 non-completers (Also non-responders) from Part A as joined (6 placebo, 5 Sarilumab). |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo (Part A)
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Reporting group description |
Placebo (for Sarilumab) subcutaneous (SC) injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sarilumab 200 mg q2w (Part A)
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Reporting group description |
Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo (Part A)
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Reporting group description |
Placebo (for Sarilumab) subcutaneous (SC) injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||
Reporting group title |
Sarilumab 200 mg q2w (Part A)
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Reporting group description |
Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||
Reporting group title |
Placebo (Part B)
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Reporting group description |
During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with placebo SC injection q2w as per principal treatment period (Part A) up to Week 50. | ||
Reporting group title |
Sarilumab 200 mg q2w (Part B)
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Reporting group description |
During extension treatment period (Part B), responders defined as subjects with decrease in vitreous haze (VH) ≥2; or corticosteroids dose <10 mg/day at Week 16 continued with Sarilumab 200 mg SC injection q2w as per principal treatment period (Part A) up to Week 50. | ||
Reporting group title |
Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
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Reporting group description |
During Open-Label Treatment Period (Part C), Non-responders (defined as no decrease in VH ≥2 steps and corticosteroids dose missing at Week 16) and non-completers (not-completed) Part A were treated with Sarilumab 200 mg SC injection q2w for 34 weeks as open-label treatment in open-label treatment period (Part C) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||
Subject analysis set title |
Sarilumab 200 mg q2w (Part A + Part B)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B).
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End point title |
Percentage of Subjects With at Least 2-step Reduction in Vitreous Haze (VH) or Prednisone Dose <10 mg/Day at Week 16 | ||||||||||||
End point description |
At least 2-step reduction in VH per central review from baseline was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 [low opacity] to 8 [more opacity]) images (in increasing order of opacity) are equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Subjects with prednisone dose <10 mg/day (or equivalent oral corticosteroid) were also evaluated. Modified intent-to-treat population (mITT) included all randomized subjects who received at least 1 injection analyzed according to the group to which the subject was allocated by the randomization schedule. Modified multiple imputation approach was used on VH missing adjudicated scores.
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End point type |
Primary
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End point timeframe |
Week 16
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Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using combined estimate for odds ratio obtained by combining the log-transformation of odds ratio from Cochran Mantel-Haenszel (CMH) analyses of the different imputed datasets, using Rubin's formulae, and then by back-transforming the combined estimate. The CMH analyses were adjusted for randomization stratification factor VH level (VH >= 4 versus VH<4).
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Comparison groups |
Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
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Number of subjects included in analysis |
58
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.2354 [1] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
2.1
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.8 | ||||||||||||
upper limit |
5.6 | ||||||||||||
| Notes [1] - Threshold for significance at 0.05 level. |
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End point title |
Change From Baseline in VH Scale at Week 16 | ||||||||||||
End point description |
Change from baseline in VH scale was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 [low opacity] to 8 [more opacity]) images (in increasing order of opacity) were equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Least squares (LS) mean was calculated using mixed model for repeated measurements (MMRM) model with treatment groups, visits and visit-by- treatment groups interaction as fixed categorical effects as well as fixed continuous covariate of baseline adjudicated VH. Analysis was performed on mITT population. Number of subjects analyzed = subjects with VH assessment at baseline and post-baseline visits.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using mixed effect model with repeated measures (MMRM) with treatment groups, visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline adjudicated VH.
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Comparison groups |
Sarilumab 200 mg q2w (Part A) v Placebo (Part A)
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Number of subjects included in analysis |
41
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.0127 [2] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Least Square (LS) Mean Difference | ||||||||||||
Point estimate |
-0.7
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
-1.223 | ||||||||||||
upper limit |
-0.262 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.29
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| Notes [2] - Threshold for significance at 0.05 level. |
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End point title |
Percentage of Subjects With Anterior Chamber (AC) Cell Score = 0 or At Least 2-step Reduction in Score at Week 16 | ||||||||||||
End point description |
Subjects with AC cell score = 0 or with ≥2 step reduction from baseline at Week 16 were evaluated. Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: grade 0 = no cells; grade +0.5 = 1 - 5 cells; grade +1 = 6 - 25 cells; grade +2= 26 - 50 cells; grade +3 = too many to count. Analysis was performed on mITT population. Number of subjects analyzed = subjects with non-missing AC cell score at Week 16.
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End point type |
Secondary
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End point timeframe |
Week 16
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Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using common odds ratio which came from CMH analysis adjusted for randomization stratification factor VH level (VH>=4 versus VH<4).
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Comparison groups |
Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
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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 | ||||||||||||
P-value |
= 1 [3] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
0.95
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.11 | ||||||||||||
upper limit |
6.093 | ||||||||||||
| Notes [3] - Threshold for significance at 0.05 level. |
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End point title |
Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Week 16 | ||||||||||||
End point description |
BCVA score is based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters, and then at 1 meter. The range of ETDRS is 0 to 100 letters. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline BCVA. Analysis was performed on mITT population. Number of subjects analyzed = subjects with BCVA score assessment at baseline and post-baseline visits.
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End point type |
Secondary
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End point timeframe |
Baseline to Week 16
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Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline BCVA.
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Comparison groups |
Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
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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 | ||||||||||||
P-value |
= 0.0153 [4] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
5.8
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
1.99 | ||||||||||||
upper limit |
9.67 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.26
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| Notes [4] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in Central Retinal Thickness (CRT) At Week 16 | ||||||||||||
End point description |
CRT was measured by spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT. Analysis was performed on mITT population. Number of subjects analyzed = subjects with CRT assessment at baseline and post-baseline visits.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT (Automatic measurement from SD-OCT).
|
||||||||||||
Comparison groups |
Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
|
||||||||||||
Number of subjects included in analysis |
43
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0683 [5] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-26.5
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-50.41 | ||||||||||||
upper limit |
-2.68 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
14.2
|
||||||||||||
| Notes [5] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
Percent Change From Baseline in CRT at Week 16 | ||||||||||||
End point description |
CRT was measured by SD-OCT, a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT. Analysis was performed on mITT population. Number of subjects analyzed = subjects with CRT assessment at baseline and post-baseline visits.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using MMRM model with treatment groups, randomization strata of VH level (<4, >=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT (Automatic measurement from SD-OCT).
|
||||||||||||
Comparison groups |
Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
|
||||||||||||
Number of subjects included in analysis |
43
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.0825 [6] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||
Point estimate |
-6.4
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-12.374 | ||||||||||||
upper limit |
-0.35 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
3.55
|
||||||||||||
| Notes [6] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With CRT Thickness <300 Microns at Week 16 | ||||||||||||
End point description |
This endpoint was replaced by the percent change from baseline in CRT at Week 16 as this is more clinically relevant. Zero subject was analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 16
|
||||||||||||
|
|||||||||||||
| Notes [7] - Zero subject analyzed as this endpoint was replaced with another more clinically relevant endpoint. [8] - Zero subject analyzed as this endpoint was replaced with another more clinically relevant endpoint. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects Without Retinal Vessel Leakage on Fluorescein Angiography (FA) at Week 16 | ||||||||||||
End point description |
Analysis of this endpoint was not performed as no retinal vessel leakage data was collected at Week 16. Zero subjects were analyzed.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 16
|
||||||||||||
|
|||||||||||||
| Notes [9] - No retinal vessel leakage data was collected at Week 16. [10] - No retinal vessel leakage data was collected at Week 16. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Prednisone Dose of ≤ 5 mg/Day (or Equivalent Oral Corticosteroid) at Week 16 | ||||||||||||
End point description |
Subjects with prednisone dose ≤5mg/day (or equivalent oral corticosteroid) at Week 16 were evaluated. Analysis was performed on mITT population. Number of subjects analyzed = subjects with non-missing data for prednisone (or equivalent oral corticosteroid) dose at Week 16.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Week 16
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Sarilumab 200 mg q2w (Part A) vs Placebo (Part A) | ||||||||||||
Statistical analysis description |
Analysis was performed using common odds ratio which came from CMH analysis adjusted for randomization stratification factor VH level (VH>=4 versus VH<4).
|
||||||||||||
Comparison groups |
Placebo (Part A) v Sarilumab 200 mg q2w (Part A)
|
||||||||||||
Number of subjects included in analysis |
44
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 1 [11] | ||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
1.07
|
||||||||||||
Confidence interval |
|||||||||||||
level |
90% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.306 | ||||||||||||
upper limit |
3.845 | ||||||||||||
| Notes [11] - Threshold for significance at 0.05 level. |
|||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Pharmacokinetics (PK) Assessment: Serum Functional Sarilumab Concentration | ||||||||||||||||||||||||||||
End point description |
Serum functional (unbound) sarilumab concentrations were determined using enzyme-linked immunosorbent assay (ELISA) method with a lower limit of quantification (LLOQ) of 294 ng/mL. Concentrations below LLOQ were set to zero for samples at pre-dose. Post-treatment concentrations below LLOQ were replaced by LLOQ/2. The samples were considered non-eligible for analysis if previous dosing time was <11 days or >17 days before sampling time for every other week regimens. PK population: all subjects who received at least one dose or part of a dose of investigational medicinal product (IMP) with at least one post-dose, non-missing serum concentration value & were analyzed according to treatment actually received. Data of this endpoint was planned to be analyzed for Sarilumab 200 mg q2w arm in Part A & B only. Here, 'n' signifies number of subjects with available data for specified category. 99999 represents that only one subject was analyzed at EOS, standard deviation could not be calculated.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Pre-dose on Day 1 (Baseline), Week 2, 4, 8, 12, 16, 24, 36, 52, and end of study (EOS) (Week 56)
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| 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 (AEs) were collected from signature of the informed consent form up to the final visit (6 weeks after the last treatment administration [Week 56]) regardless of seriousness or relationship to investigational product.
|
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Adverse event reporting additional description |
Reported AEs are treatment-emergent adverse events that is AEs that developed/worsened during the 'on treatment period' (time from the first injection of IMP to the last injection of IMP + 6 weeks).
|
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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 |
19.0
|
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Reporting groups
|
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Reporting group title |
Placebo (Part A + Part B)
|
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Reporting group description |
Placebo (for Sarilumab) SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sarilumab 200mg q2w (Part A + Part B)
|
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Reporting group description |
Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sarilumab 200 mg q2w : Open-Label Treatment (Part C)
|
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Reporting group description |
Non-responders and non-completers observed in Part A were proposed to be treated with Sarilumab 200 mg SC injection q2w for 34 weeks as open-label treatment in open-label treatment period (Part C) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and <80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
02 Oct 2013 |
Following were the changes: • Facilitate the enrollment of subjects, with fewer constraints, on the dose of corticosteroids as background therapy before randomization. • Added a clear definition of worsening and to consider sensitivity analysis. • Revised and added treatment failure and non-responder definitions. • Address the comments from some Ethic Committees regarding the continuation of non-responder
subjects in the optional open-label treatment part of the study (part C, open-label administration of sarilumab) without breaking the randomization code. • Considered more appropriate rules for corticosteroid tapering depending on the activity status of the disease at study entry (active disease and recently active disease) in order to prevent inducing disease flare ups that may be a consequence of tapering the corticosteroid dose too fast. • Revised the safety follow-up of subjects receiving sarilumab in the optional open-label part C with the addition of safety visits at Week 6, Week 10, and Week 14 and to include additional blood samples to measure antinuclear antibodies and anti-ds-DNA antibody in order to assess the effect of sarilumab to induce autoimmune disorders, more specifically systemic lupus erythematosus. • Added specific ocular AEs on the list of AEs of Special Interest list.
|
||
09 Sep 2014 |
Following were the changes: • Added other conventional standard of care immunomodulatory therapies to methotrexate and corticosteroids as therapies allowed at study entry and during the study treatment period. • Facilitated and hastened the enrollment of subjects by removing the restriction of the number of subjects in the VH <4 and VH ≥4 categories. • Facilitated enrollment by allowing subjects presenting with more severe ‘active disease’ that was not adequately controlled by the existing standard of care. • Revisions were implemented in order to ensure consistency with the ongoing rheumatoid arthritis clinical trials with Sarilumab including infliximab and etanercept washout periods, management of alanine aminotransferase elevation, updates to laboratories values exclusion criterion, changes to blood pressure measurements, and chest X-ray only mandatory at screening or within the 90 days preceding screening. • The role of the Reading Center in the selection of the subjects was clarified. • The selection of the study eye was clarified. • Steroids tapering could begin as early as Visit 4 (ie, after 2 treatment injections). • Exclusion criterion, E11 (glaucoma treatment) and E35 (magnetic resonance imaging in intermediate uveitis subjects) were rewritten to be clearer. • The flow chart was updated in order to clarify some items. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
