Evaluation of the Efficacy and Safety of Sarilumab in Patients With Polymyalgia Rheumatica

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy of KEVZARA (sarilumab) in participants with polymyalgia rheumatica (PMR) as assessed by the proportion of participants with sustained remission for sarilumab with a shorter corticosteroid (CS) tapering regimen as compared to placebo with a longer CS tapering regimen. Secondary Objectives: To demonstrate the efficacy of sarilumab in participants with PMR compared to placebo, in combination with a CS taper with regards to: Clinical responses (such as components of sustained remission, disease remission rates, time to first disease flare) over time. Cumulative CS (including prednisone) exposure. To assess the safety (including immunogenicity) and tolerability of sarilumab in participants with PMR. To measure sarilumab serum concentrations in participants with PMR. To assess the effect of sarilumab in reducing glucocorticoid toxicity as measured by the composite glucocorticoid toxicity index (GTI) questionnaire.

Detailed Description
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Study duration per participant was approximative 62 weeks including up to a 4-week screening period, 52-week treatment period and 6-week follow-up period.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Sarilumab in Patients With Polymyalgia Rheumatica

Conditions
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Polymyalgia Rheumatica

Intervention / Treatment
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* Drug: Sarilumab SAR153191 (REGN88)
* Drug: Sarilumab-matching placebo
* Drug: Prednisone
* Drug: Prednisone-matching placebo
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Diagnosis of PMR according to European League Against Rheumatism/American College of Rheumatology classification criteria. Participants must be on prednisone of at least 7.5 milligrams per day (mg/day) (or equivalent) and not exceeding 20 mg/day at screening and during the screening period. Participant was willing and able to take prednisone of 15 mg/day at randomization. Participants had a history of being treated for at least 8 weeks with prednisone (greater than or equal to [>=]10 mg/day or equivalent). Participants must have had at least one episode of unequivocal PMR flare while attempting to taper prednisone at a dose that was >= 7.5 mg/day (or equivalent) within the past 12 Weeks prior to screening: Unequivocal symptoms of PMR flare included shoulder and/or hip girdle pain associated with inflammatory stiffness. Participants had erythrocyte sedimentation rate >=30 millimeters per hour (mm/hr) and/or C-reactive protein >=10 milligrams per liter (mg/L) associated with PMR disease activity within 12 weeks prior to screening. Exclusion criteria: Diagnosis of giant cell arteritis (e.g., persistent or recurrent localized headache, temporal artery or scalp tenderness, jaw claudication, extremity claudication, blurry or loss of vision, symptoms of stroke). Diagnosis of active fibromyalgia. Concurrent rheumatoid arthritis or other inflammatory arthritis or other connective tissue diseases, such as but not limited to systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis. Concurrent diagnosis of rhabdomyolysis or neuropathic muscular diseases. Inadequately treated hypothyroidism. Organ transplant recipient. Therapeutic failure including inadequate response or intolerance, or contraindication, to biological interleukin-6 antagonist. Any prior (within the defined period below) or concurrent use of immunosuppressive therapies but not limited to any of the following: Janus kinase inhibitor within 4 weeks of Baseline. Alkylating agents including cyclophosphamide within 6 months of Baseline. Cell-depletion agents (e.g., anti CD20) without evidence of recovery of B cells to Baseline level. Tumor necrosis factor inhibitors within 2-8 weeks (etanercept within 2 weeks, infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or after at least 5 half-lives have elapsed, whichever was longer. Abatacept within 8 weeks of Baseline. Anakinra within 1 week of Baseline. Cyclosporine, azathioprine or mycophenolate mofetil or leflunomide within 4 weeks of Baseline. Unstable methotrexate (MTX) dose and/or MTX dose greater than (>) 15 mg/week within 3 months of Baseline Concurrent use of systemic CS for conditions other than PMR. Pregnant or breastfeeding woman. Participants with active or untreated latent tuberculosis. Participants with history of invasive opportunistic infections. Participants with fever associated with infection or chronic, persistent or recurring infections required active treatment. Participants with uncontrolled diabetes mellitus. Participants with non-healed or healing skin ulcers. Participants who received any live, attenuated vaccine within 3 months of Baseline. Participants who were positive for hepatitis B, hepatitis C and/or human immunodeficiency virus. Participants with a history of active or recurrent herpes zoster. Participants with a history of or prior articular or prosthetic joint infection. Prior or current history of malignancy. Participants who have had surgery within 4 weeks of screening or planned surgery during study. Participants with a history of inflammatory bowel disease or severe diverticulitis or previous gastrointestinal perforation. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo+52 Week Taper<br>Participants received sarilumab-matching placebo as subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone/prednisone-matching placebo tapering oral daily doses for 52 weeks. | Drug: Sarilumab-matching placebo<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>Drug: Prednisone<br>* Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration<br>Drug: Prednisone-matching placebo<br>* Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration<br>Drug: Prednisone<br>* Pharmaceutical form:tablets Route of administration: oral administration<br>|
| Experimental: Sarilumab 200mg q2w+14 Week Taper<br>Participants received sarilumab 200 milligrams (mg) as SC injection q2w up to 52 weeks along with the combination of prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 14 weeks and prednisone-matching placebo from Week 14 up to Week 52. | Drug: Sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>Drug: Prednisone<br>* Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration<br>Drug: Prednisone-matching placebo<br>* Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration<br>Drug: Prednisone<br>* Pharmaceutical form:tablets Route of administration: oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Sustained Remission at Week 52 | Sustained remission was defined as meeting all of the following parameters: achievement of disease remission (defined as resolution of signs and symptoms of polymyalgia rheumatica [PMR], and normalization of C-reactive protein [CRP] {less than [<]10 milligrams per liter [mg/L]}) not later than Week 12, absence of disease flare (defined as recurrence of signs and symptoms attributable to active PMR plus an increase in corticosteroid [CS] dose due to PMR or elevation of erythrocyte sedimentation rate [ESR] attributable to active PMR plus an increase in CS dose due to PMR) from Week 12 through Week 52, sustained reduction of CRP (to <10 mg/L, with absence of successive elevations to greater than or equal to [>=]10 mg/L) from Week 12 through Week 52, and successful adherence to prednisone taper from Week 12 through Week 52. | At Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Cumulative Corticosteroid Dose | Cumulative dose of CS used for PMR disease was defined as the dose taken up to the end of treatment, including expected prednisone in tapering regimen per protocol, add-on prednisone, CS used in rescue therapy and the use of commercial prednisone (an excess of <=100 mg of prednisone during the study treatment period). The total cumulative CS dose was based on the total number of days with complete or partial intake, no imputation was done on missed tablets. | Up to Week 52 | 
| Number of Participants Who Achieved Disease Remission up to Week 12 | Disease remission was defined as resolution of signs and symptoms of PMR, and normalization of CRP (< 10 mg/L). The status of normalization of CRP (<10 mg/L) was determined based on the last two non-missing post-baseline CRP values measured up to Week 12. If at least one of the value was <10 mg/L, then it was considered as normalization of CRP. Participants who took rescue CS due to active PMR prior to Week 12 or who permanently withdrew from the study treatment prior to Week 12 were considered as not achieved disease remission by Week 12. During the initial 12 weeks of prednisone taper, treatment for one flare before Week 12 was permitted if it was successfully treated with a low dose (<=5 mg/day) prednisone add-on taper regimen (completed prior to Week 12) and provided that all other sustained remission parameters were met. | Up to Week 12 | 
| Number of Participants With Absence of Disease Flare From Week 12 Through Week 52 | Disease flare was defined as either recurrence of signs and symptoms attributable to active PMR plus an increase in CS dose due to PMR, or elevation of ESR attributable to active PMR plus an increase in CS dose due to PMR. | From Week 12 Through Week 52 | 
| Number of Participants With Sustained Reduction of CRP From Week 12 Through Week 52 | Normalization (sustained reduction) of CRP was defined as CRP levels <10 mg/L. If there were two or more consecutive visits with CRP >=10 mg/L, then it was categorized as no normalization of CRP. | From Week 12 through Week 52 | 
| Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52 | Successful adherence to the prednisone taper from Week 12 through Week 52 was defined as participants who did not take rescue therapy from Week 12 through Week 52 and any excess prednisone (beyond the per protocol CS tapering regimen) with a cumulative dose of <=100 mg (or equivalent), such as those employed to manage adverse event (AE) not related to PMR. | From Week 12 through Week 52 | 
| Time to First Polymyalgia Rheumatica Flare After Clinical Remission up to Week 52 | Time to first PMR flare was defined as the duration (in days) from randomization to first PMR flare after clinical remission (defined as resolution of signs and symptoms and normalization of CRP [<10 mg/L]) and up to 52 weeks. Disease flare was defined as either the recurrence of signs or symptoms attributable to active plus an increase in CS dose due to PMR or elevation of ESR attributable to active PMR plus an increase in CS dose due to PMR. Kaplan-Meier method was used for the analysis. Participants who never achieved remission were censored at randomization day; and those who achieved clinical remission and never flared were censored at the end of treatment assessment date up to Week 52. | Up to Week 52 | 
| Composite Glucocorticoid Toxicity Index (C-GTI): Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS) at Week 52 | GTI assessed glucocorticoid (GC) related morbidity and GC-sparing ability of other therapies; composed of 2 components: C-GTI and Specific List. C-GTI contained 9 domains and Specific List contained of 23 items (11 domains), used as complementary tool to C-GTI. C-GTI score was sum of 9 domain-specific scores at each visit and Cumulative GTI score was sum of C-GTI scores across each visit. Two cumulative GTI scores: CWS and AIS at Week 52 are reported in this outcome measure. CWS assessed cumulative GC toxicity regardless of whether toxicity had lasting effects or was transient. AIS assessed new therapy effectiveness in decreasing any Baseline GC toxicity over time. Negative scores reflect improvement in CS toxicities present from Baseline. For CWS, composite score ranged from 0 to 439 and for AIS, composite score ranged from -346 to 439. For both CWS and AIS, minimum score implies least toxicity and maximum score implies most toxicity. | At Week 52 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. Serious AEs (SAEs) were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were the AEs that developed or worsened or became serious during the TEAE period (defined as the time from the first dose of the investigational medicinal product (IMP) to the last dose of the IMP +60 days). | From first dose (i.e. Day 1) up to 60 days after last dose date of study drug (i.e. up to Week 60) | 
| Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities During TEAE Period | Criteria for potentially clinically significant vital sign abnormalities: Systolic Blood Pressure (SBP): <= 95 mmHg and decrease from baseline (DFB) more than or equal to (>=) 20 mmHg; >= 160 mmHg and increase from baseline (IFB) >= 20 mmHg Diastolic blood pressure (DBP): <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg. Heart Rate (HR): <= 50 beats per min (bpm) and DFB >=20 bpm; >=120 bpm and IFB >= 20 bpm Weight: >=5% DFB; >=5% IFB. TEAE period was defined as the time from the first dose of the IMP to the last dose of the IMP + 60 days. | From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) | 
| Number of Participants With Potentially Clinically Significant Abnormalities - Hematological Parameter | Criteria for potentially clinically significant laboratory abnormalities included: Hemoglobin (Hb): <= 115 grams per liter (g/L) (Male [M]), <= 95 g/L (Female [F]); >= 185 g/L (M), >= 165 g/L (F); DFB >= 20 g/L . Hematocrit: <= 0.37 volume/volume (v/v) (M); <= 0.32 v/v (F); >= 0.55 v/v (M); >= 0.5 v/v (F). Erythrocytes: >=6 Tera/ liter (L). Platelets: < 100 Giga/L, >= 700 Giga/L. Leukocytes: < 3.0 Giga/L (Non-Black [NB]); < 2.0 Giga/L (Black [B]), >= 16.0 Giga/L. Neutrophils: < 1.5 Giga/L (NB); < 1.0 Giga/L (B). Lymphocytes: > 4.0 Giga/L. Monocytes: > 0.7 Giga/L. Basophils: > 0.1 Giga/L. Eosinophils: > 0.5 Giga/L or > upper limit of normal (ULN) (if ULN >= 0.5 Giga/L). | From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) | 
| Number of Participants With Potentially Clinically Significant Abnormalities - Metabolic Parameters | Criteria for potentially clinically significant abnormalities: Glucose: <=3.9 millimoles (mmol)/L and < lower limit of normal (LLN); >=11.1 mmol/L (unfasted [unfas]); >=7 mmol/L (fasted [fas]). HbA1c: >8%. Cholesterol: >=7.74 mmol/L. Triglycerides: >=4.6 mmol/L. C Reactive Protein (CRP): >2 ULN or >10 mg/L (if ULN not provided). | From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) | 
| Number of Participants With Potentially Clinically Significant Abnormalities - Renal Function | Criteria for potentially clinically significant abnormalities: Creatinine: >=150 micromol/L (adults); >=30% change from baseline, >=100% change from baseline. Creatinine clearance: >=60 to <90 milliliters per minute (mL/min); >=30 to <60 mL/min ; >=15 to <30 mL/min; <15 mL/min. Blood urea nitrogen: >=17 mmol/L. Urate: <120 micromol/L; >408 micromol/L. | From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) | 
| Number of Participants With Potentially Clinically Significant Abnormalities - Liver Function | Criteria for potentially clinically significant abnormalities: Albumin: <= 25 g/L. Alanine Aminotransferase (ALT): >3 ULN; >5 ULN; >10 ULN. Aspartate Aminotransferase (AST): >3 ULN; >5 ULN; >10 ULN; >20 ULN. Alkaline Phosphatase: >1.5 ULN. Bilirubin: >1.5 ULN; >2 ULN. ALT and Total Bilirubin: ALT > 3 ULN and Bilirubin > 2 ULN | From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) | 
| Number of Participants With Treatment-emergent Antidrug Antibodies (ADA) Response | ADA response categories: 1) Treatment-boosted ADA positive participant: Participant with a positive ADA assay response at Baseline and with at least a 4-fold increase in titer compared to Baseline during TEAE period. 2) Treatment-emergent ADA positive participant: Participant with non-positive assay (meaning negative or missing) response at Baseline but with a positive assay response during the TEAE period (defined as the time from the first dose of the IMP to the last dose of the IMP +60 days). | From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) | 
| Pharmacokinetics (PK): Serum Trough Concentration (Ctrough) of Sarilumab | Ctrough was pre dose concentration of drug. Data for this outcome measure was not planned to be collected and analyzed for placebo arm (Placebo+52 Week Taper) as pre-specified in the protocol. | Pre-dose on Week 0 (Baseline), Week 2, 4, 12, 16, 24, and 52 | 
| Pharmacokinetics: Serum Drug Concentration of Sarilumab Post-dose at Week 24 | Serum concentrations of functional sarilumab were analyzed using validated enzyme linked immunosorbent assay. | Post-dose at Week 24 |