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

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ClinicalTrials.gov Identifier: NCT01061723
Recruitment Status : Completed
First Posted : February 3, 2010
Results First Posted : August 8, 2017
Last Update Posted : August 8, 2017
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE February 2, 2010
First Posted Date  ICMJE February 3, 2010
Results First Submitted Date  ICMJE May 24, 2017
Results First Posted Date  ICMJE August 8, 2017
Last Update Posted Date August 8, 2017
Study Start Date  ICMJE February 2010
Actual Primary Completion Date June 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 7, 2017)
Percentage of Participants Who Achieved 20% Response According to the Assessment in Ankylosing Spondylitis (AS) Working Group Criteria for Response (ASAS20) at Week 12 [ Time Frame: Baseline to Week 12 (Last Observation Carried Forward [LOCF]) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 2, 2010)
Percentage of patients who achieve the assessment in AS International Working Group Criteria for improvement (ASAS20) [ Time Frame: 12 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2017)
  • Percentage of Participants Who Achieved 40% Response According to the Assessment in AS Working Group Criteria for Response (ASAS40) at Week 12 [ Time Frame: Baseline to Week 12 (LOCF) ]
    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.
  • Percentage of Participants Who Achieved Partial Remission According to the Assessment in AS Working Group Criteria for Response (ASAS) at Week 12 [ Time Frame: Baseline to Week 12 (LOCF) ]
    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.
  • Change From Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    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).
  • Change From Baseline in BASDAI Score at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    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.
  • Change From Baseline in Range of Motion Assessed by the Bath AS Metrology Index (BASMI) at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    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.
  • 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 [ Time Frame: Baseline, 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.
  • Percentage of Participants Who Achieved ASAS 5/6 Improvement Criteria at Week 12 [ Time Frame: Baseline to Week 12 (LOCF) ]
    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.
  • Change From Baseline in Chest Expansion at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    The difference between maximal inspiration and expiration to the nearest 0.1 cm was recorded. The best of 2 tries were recorded.
  • Change From Baseline in Swollen Joint Index at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    44 swollen joints were examined including sternal, clavicular, elbow, shoulder, wrist, knee, metacarpophalangian, interphalangian, metatarpophalangian and metatarsophalangeal joints.
  • Change From Baseline in Hs-CRP at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    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.
  • Change From Baseline in ASAS Individual Components at Week 12 [ Time Frame: Baseline, Week 12 (LOCF) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2010)
  • Percentage of patients who achieve ASAS40 [ Time Frame: 12 weeks ]
  • Percentage of patients who achieve ASAS partial remission [ Time Frame: 12 weeks ]
  • Change from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS) [ Time Frame: 12 weeks ]
  • Change from baseline in disease activity (BASDAI) score [ Time Frame: 12 weeks ]
  • Change from baseline in range of motion assessed by the Bath Ankylosing Spondylitis Metrology Index (BASMI) (10-point scale) [ Time Frame: 12 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 (REGN88) in Patients With Ankylosing Spondylitis
Official Title  ICMJE A Randomized Double Blind-placebo Controlled Dose Ranging Study to Evaluate the Efficacy and Safety of SAR153191 in Participants With Ankylosing Spondylitis (AS)
Brief Summary

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
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Ankylosing Spondylitis
Intervention  ICMJE
  • Drug: Sarilumab

    Pharmaceutical form: Solution for injection

    Route of administration: Subcutaneous

    Other Names:
    • SAR153191
    • REGN88
  • Drug: Placebo

    Pharmaceutical form: Solution for injection

    Route of administration: Subcutaneous

Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Placebo (for sarilumab) weekly (qw) for 12 weeks.
    Intervention: Drug: Placebo
  • Experimental: Sarilumab 100 mg q2w
    Sarilumab 100 mg Subcutaneous (SC) injection alternating with placebo every other week (q2w) for 12 weeks.
    Interventions:
    • Drug: Sarilumab
    • Drug: Placebo
  • Experimental: Sarilumab 150 mg q2w
    Sarilumab 150 mg SC injection alternating with placebo q2w for 12 weeks.
    Interventions:
    • Drug: Sarilumab
    • Drug: Placebo
  • Experimental: Sarilumab 100 mg qw
    Sarilumab 100 mg SC injection qw for 12 weeks.
    Intervention: Drug: Sarilumab
  • Experimental: Sarilumab 200 mg q2w
    Sarilumab 200 mg SC injection alternating with placebo q2w for 12 weeks.
    Interventions:
    • Drug: Sarilumab
    • Drug: Placebo
  • Experimental: Sarilumab 150 mg qw
    Sarilumab 150 mg SC injection qw for 12 weeks.
    Intervention: Drug: Sarilumab
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 2, 2012)
301
Original Estimated Enrollment  ICMJE
 (submitted: February 2, 2010)
300
Actual Study Completion Date  ICMJE June 2011
Actual Primary Completion Date June 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Czechia,   France,   Germany,   Hungary,   Lithuania,   Netherlands,   Poland,   Spain,   Turkey,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01061723
Other Study ID Numbers  ICMJE DRI11073
2009-016068-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP