Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 (REGN88) in Patients With Ankylosing Spondylitis (ALIGN)

A Randomized Double Blind-placebo Controlled Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 in Participants With Ankylosing Spondylitis (AS)

Primary objective:

- to evaluate the efficacy of Sarilumab in participants with Ankylosing Spondylitis (AS) using the assessment in AS working group criteria (ASAS) 20% response criteria (ASAS20)

Secondary objectives:

• to demonstrate that Sarilumab was effective on:

  • assessment of higher level of response [ASAS 40% response criteria (ASAS40)]
  • partial remission
  • disease activity
  • range of motion
  • Magnetic Resonance Imaging (MRI) of the spine
• to assess the safety and tolerability of Sarilumab in participants with AS as well as the pharmacokinetic profile of Sarilumab in participants with AS

Study Overview

• Status: Completed
• Conditions: Ankylosing Spondylitis
• Intervention / Treatment: Drug: Placebo; Drug: Sarilumab

Detailed Description

The duration of participation in this study for each participant was approximately 22 weeks; including up to 4 weeks screening period, 12-weeks double-blind treatment period and 6-weeks safety follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 301
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • East Malvern, Australia, 3145
    • Investigational Site Number 036001
  • Hobart, Australia, 7001
    • Investigational Site Number 036003
  • Shenton Park, Australia, 6008
    • Investigational Site Number 036004
  • Woolloongabba, Australia, 4102
    • Investigational Site Number 036002
• Austria
  • Graz, Austria, 8036
    • Investigational Site Number 040001
  • Wien, Austria, 1100
    • Investigational Site Number 040002
• Belgium
  • Brussels, Belgium, 1020
    • Investigational Site Number 056003
  • Genk, Belgium, 3600
    • Investigational Site Number 056005
  • Gent, Belgium, 9000
    • Investigational Site Number 056001
  • Leuven, Belgium, 3000
    • Investigational Site Number 056002
  • Liège, Belgium, 4000
    • Investigational Site Number 056004
• Canada
  • London, Canada, N6A 4V2
    • Investigational Site Number 124007
  • Montreal, Canada, H2L 1S6
    • Investigational Site Number 124004
  • Newmarket, Canada, L3Y 3R7
    • Investigational Site Number 124008
  • Pointe-Claire, Canada, H9R 3Z2
    • Investigational Site Number 124003
  • Quebec, Canada, G1V 4R4
    • Investigational Site Number 124001
  • Saskatoon, Canada, S7K 0H6
    • Investigational Site Number 124006
  • Toronto, Canada, M5T 2S8
    • Investigational Site Number 124005
  • Trois-Rivières, Canada, G8Z 1Y2
    • Investigational Site Number 124009
  • Vancouver, Canada, V5Z 1L7
    • Investigational Site Number 124002
  • Vancouver, Canada, V5Z 3Y1
    • Investigational Site Number 124010
• Czechia
  • Brno, Czechia, 63800
    • Investigational Site Number 203003
  • Hlucin, Czechia, 74801
    • Investigational Site Number 203005
  • Hradec Kralove, Czechia, 50005
    • Investigational Site Number 203002
  • Praha 2, Czechia, 12850
    • Investigational Site Number 203001
  • Uherske Hradiste, Czechia, 68601
    • Investigational Site Number 203004
• France
  • Besancon, France, 25030
    • Investigational Site Number 250001
  • Bordeaux, France, 33076
    • Investigational Site Number 250005
  • Creteil Cedex, France, 94010
    • Investigational Site Number 250002
  • Paris, France, 75014
    • Investigational Site Number 250003
• Germany
  • Berlin, Germany, 12200
    • Investigational Site Number 276002
  • Erlangen, Germany, 91054
    • Investigational Site Number 276004
  • Frankfurt Am Main, Germany, 60590
    • Investigational Site Number 276003
  • Hamburg, Germany, 22081
    • Investigational Site Number 276005
  • Herne, Germany, 44652
    • Investigational Site Number 276001
• Hungary
  • Budapest, Hungary, 1023
    • Investigational Site Number 348001
  • Debrecen, Hungary, 4032
    • Investigational Site Number 348003
  • Sátoraljaújhely, Hungary, 3980
    • Investigational Site Number 348005
  • Veszprém, Hungary, 8200
    • Investigational Site Number 348004
• Lithuania
  • Kaunas, Lithuania, LT-50009
    • Investigational Site Number 440001
  • Vilnius, Lithuania, LT-08661
    • Investigational Site Number 440002
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Investigational Site Number 528001
  • Nijmegen, Netherlands, 6525 GA
    • Investigational Site Number 528002
• Poland
  • Bialystok, Poland, 15-354
    • Investigational Site Number 616002
  • Krakow, Poland, 30-510
    • Investigational Site Number 616001
  • Lublin, Poland, 20-607
    • Investigational Site Number 616004
  • Torun, Poland, 87-100
    • Investigational Site Number 616005
  • Warszawa, Poland, 02-637
    • Investigational Site Number 616003
• Spain
  • Barcelona, Spain, 08907
    • Investigational Site Number 724005
  • La Coruña, Spain, 15006
    • Investigational Site Number 724004
  • Madrid, Spain, 28007
    • Investigational Site Number 724002
  • Sevilla, Spain, 41008
    • Investigational Site Number 724001
• Turkey
  • Ankara, Turkey, 06100
    • Investigational Site Number 792002
  • Izmir, Turkey, 35340
    • Investigational Site Number 792001
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Investigational Site Number 840006
  • California
    • Anaheim, California, United States, 92801
      • Investigational Site Number 840033
    • Los Angeles, California, United States, 90048
      • Investigational Site Number 840027
    • San Diego, California, United States, 92108
      • Investigational Site Number 840007
    • San Francisco, California, United States, 94143
      • Investigational Site Number 840013
    • Upland, California, United States, 91786
      • Investigational Site Number 840017
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Investigational Site Number 840009
    • Naples, Florida, United States, 34102
      • Investigational Site Number 840001
    • Orlando, Florida, United States, 32806
      • Investigational Site Number 840032
  • Idaho
    • Boise, Idaho, United States, 83702
      • Investigational Site Number 840015
  • Illinois
    • Rock Island, Illinois, United States, 61201
      • Investigational Site Number 840021
  • Kansas
    • Kansas City, Kansas, United States, 66160-7321
      • Investigational Site Number 840018
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • Investigational Site Number 840003
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Investigational Site Number 840029
  • Michigan
    • Lansing, Michigan, United States, 48823
      • Investigational Site Number 840008
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Investigational Site Number 840002
  • New Jersey
    • Freehold, New Jersey, United States, 07728
      • Investigational Site Number 840028
  • New York
    • Albany, New York, United States, 12206
      • Investigational Site Number 840016
    • Syracuse, New York, United States, 13210
      • Investigational Site Number 840036
  • Ohio
    • Toledo, Ohio, United States, 43606
      • Investigational Site Number 840010
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73109
      • Investigational Site Number 840005
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • Investigational Site Number 840023
    • Duncansville, Pennsylvania, United States, 16635
      • Investigational Site Number 840014
  • Texas
    • Dallas, Texas, United States, 75231
      • Investigational Site Number 840004
    • Houston, Texas, United States, 77034
      • Investigational Site Number 840030
  • Virginia
    • Chesapeake, Virginia, United States, 23320
      • Investigational Site Number 840034

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Diagnosis of AS according to the New York modified criteria
• Participants must had an adequate trial of at least 2 different Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) taken for at least 2 weeks in each case and, on a stable dose for ≥2 weeks or be intolerant to NSAIDs

• Participants must had active AS for ≥3 months before screening and active disease must be present at screening and at baseline; Active AS being defined by:

  • Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥4 (Numerical Rating Scale 0-10)
  • Total back pain score ≥4 (Numerical Rating Scale 0-10)

Participants treated with corticosteroid must be on a stable dose for ≥2 weeks prior to baseline

Participants treated with the Disease Modifying Anti-Rheumatic Drugs (DMARDs) hydroxychloroquine, sulfasalazine and methotrexate (MTX) must be on stable dose ≥12 weeks prior to baseline

Exclusion criteria:

• <18 years old or ≥75 years old
• Complete fusion of the spine
• Past history of non response to any anti-Tumor Necrosis Factors (TNFs) treatment or non response to any other biological treatment for AS
• Any past or current treatment with anti-TNF's or any biological agent within 3 months prior to screening
• Treatment with DMARDs except for hydroxychloroquine, sulfasalazine and MTX
• MTX >25 mg/week
• hydroxychloroquine >400 mg/day
• Sulfasalazine >3 g/day
• Treatment with oral prednisone or equivalent corticosteroids >10 mg/day within 6 weeks prior to screening
• Use of intramuscular or intra-articular corticosteroids within the last 4 weeks before screening
• Previous treatment with cyclosporine, azathioprine

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Placebo (for sarilumab) weekly (qw) for 12 weeks.	Drug: Placebo; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous
EXPERIMENTAL: Sarilumab 100 mg q2w; Sarilumab 100 mg Subcutaneous (SC) injection alternating with placebo every other week (q2w) for 12 weeks.	Drug: Placebo; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Drug: Sarilumab; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: SAR153191; REGN88
EXPERIMENTAL: Sarilumab 150 mg q2w; Sarilumab 150 mg SC injection alternating with placebo q2w for 12 weeks.	Drug: Placebo; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Drug: Sarilumab; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: SAR153191; REGN88
EXPERIMENTAL: Sarilumab 100 mg qw; Sarilumab 100 mg SC injection qw for 12 weeks.	Drug: Sarilumab; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: SAR153191; REGN88
EXPERIMENTAL: Sarilumab 200 mg q2w; Sarilumab 200 mg SC injection alternating with placebo q2w for 12 weeks.	Drug: Placebo; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Drug: Sarilumab; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: SAR153191; REGN88
EXPERIMENTAL: Sarilumab 150 mg qw; Sarilumab 150 mg SC injection qw for 12 weeks.	Drug: Sarilumab; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: SAR153191; REGN88

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved 20% Response According to the Assessment in Ankylosing Spondylitis (AS) Working Group Criteria for Response (ASAS20) at Week 12	Clinical response to treatment for ASAS20 was assessed according to ASAS20 criteria. Treatment response for ASAS20 was defined as an improvement by a decrease of ≥20% and ≥1unit on a 0 (no pain) - 10 (most severe pain) numerical rating scale (NRS) in at least 3 of the 4 ASAS improvement criteria (ASAS-IC) domains: assessment of physical function (measured by Bath Ankylosing Spondylitis Functional Index [BASFI]), back pain (0-10 NRS), participant global assessment (0-10 NRS) and inflammation (measured as the mean of the last 2 Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] questions) and no worsening (increase in score) of ≥20% and ≥1 unit on a 0-10 NRS in the remaining 4th domain.	Baseline to Week 12 (Last Observation Carried Forward [LOCF])

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved 40% Response According to the Assessment in AS Working Group Criteria for Response (ASAS40) at Week 12	Clinical response to treatment for ASAS40 was assessed according to ASAS40 criteria. Treatment response for ASAS40 was defined as an improvement by a decrease of ≥40% and ≥2 units on a 0 (no pain)-10 (most severe pain) NRS in at least 3 of the 4 ASAS-IC domains (participant global assessment, back pain, physical function and inflammation) and no worsening (increase in score) at all in the remaining 4th domain.	Baseline to Week 12 (LOCF)
Percentage of Participants Who Achieved Partial Remission According to the Assessment in AS Working Group Criteria for Response (ASAS) at Week 12	Participants were classified as having achieved ASAS partial remission if they had a value ≤ 2 units on a 0 -10 NRS in each of the 4 domains: (participant global assessment, back pain, physical function and inflammation) of the ASAS-IC.	Baseline to Week 12 (LOCF)
Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12	ASDAS consists of five components: (Total back pain assessed by BASDAI question 2 on a 0 [no pain] - 10 [most severe pain] NRS, participant global of disease activity on a 0 [none] - 10 [severe] NRS, peripheral pain/swelling assessed by BASDAI question 3 on a 0 [none] - 10 [most severe pain] NRS, duration of morning stiffness assessed by BASDAI question 6 on a NRS from 0 [0 hour] - 10 [2 or more hours] and hs-CRP in mg/L). ASDAS score was calculated as follows: 0.121 x total back pain + 0.110 x participant global of disease activity + 0.073 x peripheral pain/swelling + 0.058 x duration of morning stiffness + 0.579 x ln(CRP + 1). The scores were categorized as: inactive disease (< 1.3), moderate (1.3 - < 2.1), high (2.1 - 3.5) and very high disease activity (> 3.5).	Baseline, Week 12 (LOCF)
Change From Baseline in BASDAI Score at Week 12	BASDAI comprises of a 0 (no pain) -10 (very severe pain) NRS, used to answer 6 questions (Q) related to symptoms of AS (fatigue/tiredness, neck, back or hip pain, pain / swelling in joints, discomfort in tender areas, morning stiffness duration and morning stiffness severity). The BASDAI total score was calculated by computing the mean of Q5 and Q6 and adding it to the sum of Q1 to Q4. This score was then divided by 5. BASDAI total score=Q1+Q2+Q3+Q4+[Q5+Q6/2]/5. The total BASDAI score ranges from 0=none to 10=severe, where lower score indicated less disease activity.	Baseline, Week 12 (LOCF)
Change From Baseline in Range of Motion Assessed by the Bath AS Metrology Index (BASMI) at Week 12	The range of motion was measured by the BASMI (11-point scale) including chest expansion in cm. It composed of 5 clinical measurements associated with a score: tragus to wall distance, modified schober's test, lateral spinal flexion, intermalleolar distance and cervical rotation. BASMI score was calculated by dividing the total of the score by 5, and the score ranges from 0-10. Higher BASMI score indicates more severe limitation of movement.	Baseline, Week 12 (LOCF)
Change From Baseline in Magnetic Resonance Imaging (MRI) Score of the Spine Assessed by the Berlin Modification of the AS Spine MRI-active (ASspiMRI-a) Score at Week 12	ASspiMRI-a scoring system was used on all MRIs to score the level of the disease. MRIs were obtained using 1.0 or 1.5 Tesla scanners and phased array coils. Sagittal images of the upper (C2 to T10) and lower (T8 to S1) spine were used using both T1 weighted spin echo and fat saturated Short Tau Inversion Recovery (STIR) sequences. Each vertebral body unit was given an activity score based on the amount of bone marrow edema or erosion. Both T1 and STIR sequences were analyzed for change. Total spine ASspiMRI-a score in the Berlin modification range from 0 to 69 with higher scores indicating higher disease activity. A negative value in total spine ASspiMRI-a score change from baseline indicates an improvement from baseline. The higher the negative value the higher the reduction of inflammation.	Baseline, Week 12
Percentage of Participants Who Achieved ASAS 5/6 Improvement Criteria at Week 12	ASAS 5/6 responder had an improvement of 20% in 5 of 6 domains (physical function, back pain, participant global assessment, inflammation, spinal mobility and acute phase reactants) of ASAS-IC without deterioration in the 6th domain. Spinal mobility was assessed by the mean of the 5 BASMI scores on the 11-point scale (score ranges from 0-10) and the hs-CRP for the acute phase reactant.	Baseline to Week 12 (LOCF)
Change From Baseline in Chest Expansion at Week 12	The difference between maximal inspiration and expiration to the nearest 0.1 cm was recorded. The best of 2 tries were recorded.	Baseline, Week 12 (LOCF)
Change From Baseline in Swollen Joint Index at Week 12	44 swollen joints were examined including sternal, clavicular, elbow, shoulder, wrist, knee, metacarpophalangian, interphalangian, metatarpophalangian and metatarsophalangeal joints.	Baseline, Week 12 (LOCF)
Change From Baseline in Hs-CRP at Week 12	Participant's blood samples were collected at screening, baseline before dosing and at every visit to evaluate the level of hs-CRP. The hs-CRP is a protein marker in the blood associated with inflammation with higher values indicating a greater degree of inflammation.	Baseline, Week 12 (LOCF)
Change From Baseline in ASAS Individual Components at Week 12	ASAS consists of 4 individual components: Participant global assessment to assess the disease activity over the last week on a 0 (no pain) - 10 (severe pain) NRS; back pain which consist of the mean of the nocturnal back pain and the total back pain at every visit on a 0 (no pain) - 10 (most severe pain) NRS; inflammation measured as the mean of the last 2 BASDAI questions (intensity and duration of morning stiffness) and physical function measured as mean of 10 scores of BASFI at every visit on 0 (easy) -10 (impossible) NRS. Lower score corresponds to a better functioning.	Baseline, Week 12 (LOCF)

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Sieper J, Braun J, Kay J, Badalamenti S, Radin AR, Jiao L, Fiore S, Momtahen T, Yancopoulos GD, Stahl N, Inman RD. Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. 2015 Jun;74(6):1051-7. doi: 10.1136/annrheumdis-2013-204963. Epub 2014 Feb 18.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (ACTUAL): June 1, 2011
• Study Completion (ACTUAL): June 1, 2011

Study Registration Dates

• First Submitted: February 2, 2010
• First Submitted That Met QC Criteria: February 2, 2010
• First Posted (ESTIMATE): February 3, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 8, 2017
• Last Update Submitted That Met QC Criteria: July 7, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Joint Diseases; Musculoskeletal Diseases; Arthritis; Spinal Diseases; Bone Diseases; Spondylarthropathies; Bone Diseases, Infectious; Ankylosis; Spondylitis; Spondylarthritis; Spondylitis, Ankylosing
• Other Study ID Numbers: DRI11073; 2009-016068-35 (EUDRACT_NUMBER)