Evaluation of Efficacy and Safety of Sarilumab in Patients With GCA

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy of sarilumab in participants with giant cell arteritis (GCA) as assessed by the proportion of participants with sustained remission for sarilumab compared to placebo, in combination with a corticosteroid (CS) tapering course. Secondary Objective: To demonstrate the efficacy of sarilumab in participants with GCA compared to placebo, in combination with CS taper with regards to: Clinical responses (such as responses based on 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 GCA. To measure sarilumab serum concentrations in participants with GCA. To assess the effect of sarilumab on sparing glucocorticoid toxicity as measured by glucocorticoid toxicity index (GTI).

Detailed Description
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Study duration per participant was approximately 82 weeks, including an up to 6-week screening period, 52-week treatment period, and 24-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 Giant Cell Arteritis

Conditions
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Giant Cell Arteritis

Intervention / Treatment
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* Drug: Sarilumab SAR153191
* Drug: Sarilumab matching placebo
* Drug: Prednisone
* Drug: Prednisone matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Diagnosis of GCA according to European League Against Rheumatism/American College of Rheumatology classification criteria. New onset active disease or refractory active disease. At least one of the symptoms of GCA within 6 weeks of baseline. Either erythrocyte sedimentation rate greater than or equal to (>=) 30 millimeter per hour or C-reactive protein >=10 mg per liter within 6 weeks of baseline. Received or were able to receive prednisone 20-60 mg/day for the treatment of active GCA. Exclusion criteria: Organ transplantation recipient (except corneas, unless it is within 3 months prior to baseline visit). Major ischemic event, unrelated to GCA, within 12 weeks of screening. Any prior use of the following therapies, for the treatment of GCA: Janus kinase inhibitor (e.g., tofacitinib) within 4 weeks of baseline. Cell-depletion agents (e.g., anti CD20) without evidence of recovery of B cells to baseline level. Abatacept within 8 weeks of baseline. Anakinra within 1 week of baseline. Tumor necrosis factor inhibitors within 2-8 weeks (etanercept within 2 weeks; infliximab, certolizumab, golimumab, or adalimumab within 8 weeks), or less than at least 5 half-lives had elapsed prior to baseline, whichever was longer. Therapeutic failure, including inadequate response or intolerance, or contraindication, to biological Interleukin 6 (IL-6) IL-6/(R) antagonist (prior experience with IL-6/(R) antagonist that was terminated for reasons unrelated to therapeutic failure at least 3 months before baseline was not exclusionary). Use of any alkylating agents including cyclophosphamide within 6 months of baseline. Use of immunosuppressant, such as hydroxychloroquine, cyclosporine, azathioprine, mycophenolate mofetil or leflunomide within 4 weeks of baseline. (Use of methotrexate (MTX) not exceeding 25 mg per week and had been stable for at least 3 months prior to baseline was not exclusionary). Concurrent use of systemic CS for conditions other than GCA. Use of intervascular CS at a dose equivalent to 100 mg of methylprednisolone or higher within 8 weeks of baseline for GCA therapy. 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 requiring 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 are positive for hepatitis B, hepatitis C and/or HIV. 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 |
| --- | --- |
| Experimental: 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: tablets or capsules Route of administration: oral administration<br>Drug: Prednisone matching placebo<br>* Pharmaceutical form: capsules Route of administration: oral administration<br>|
| Experimental: Placebo+26 Week Taper<br>Participants received sarilumab-matching placebo 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 26 weeks and prednisone-matching placebo from Week 26 up to Week 52. | Drug: Sarilumab matching placebo<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Prednisone<br>* Pharmaceutical form: tablets or capsules Route of administration: oral administration<br>Drug: Prednisone matching placebo<br>* Pharmaceutical form: capsules Route of administration: oral administration<br>|
| Placebo Comparator: Sarilumab 150mg q2w+26 Week Taper<br>Participants received sarilumab 150 milligrams (mg) as SC injection q2w up to 52 weeks along with prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone-matching placebo from Week 26 up to Week 52. | Drug: Sarilumab SAR153191<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Prednisone<br>* Pharmaceutical form: tablets or capsules Route of administration: oral administration<br>Drug: Prednisone matching placebo<br>* Pharmaceutical form: capsules Route of administration: oral administration<br>|
| Placebo Comparator: Sarilumab 200mg q2w+26 Week Taper<br>Participants received sarilumab 200 mg as SC injection q2w up to 52 weeks along with prednisone and/or prednisone-matching placebo according to the protocol-defined schedule. Participants received prednisone tapering oral daily doses during the first 26 weeks and prednisone-matching placebo from Week 26 up to Week 52. | Drug: Sarilumab SAR153191<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Prednisone<br>* Pharmaceutical form: tablets or capsules Route of administration: oral administration<br>Drug: Prednisone matching placebo<br>* Pharmaceutical form: capsules 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 Who Achieved Sustained Disease Remission at Week 52 | Disease remission was defined as resolution of signs and symptoms of giant cell arteries (GCA), and normalization of C-reactive protein (CRP) (<10 mg/L). Sustained remission was defined as meeting all of the following parameters: achievement of disease remission not later than Week 12, absence of disease flare (defined as recurrence of signs and symptoms attributable to active GCA plus an increase in corticosteroid [CS] dose due to GCA or elevation of erythrocyte sedimentation rate [ESR] attributable to active GCA plus an increase in CS dose due to GCA) from Week 12 through Week 52, normalization of CRP (to <10 mg/L, with absence of successive elevations 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 | 
| Percentage of Participants Who Achieved Sustained Disease Remission at Week 24 | Disease remission was defined as resolution of signs and symptoms of GCA, and normalization of CRP <10 mg/L. Sustained remission was defined as meeting all of the following parameters: achievement of disease remission not later than Week 12, absence of disease flare (defined as recurrence of signs and symptoms attributable to active GCA plus an increase in CS dose due to GCA, or elevation of ESR attributable to active GCA plus an increase in CS dose due to GCA) from Week 12 through Week 24, normalization of CRP (to <10 mg/L, with an absence of successive elevations to >=10 mg/L) from Week 12 through Week 24, and successful adherence to the prednisone taper from Week 12 through Week 24. | At Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Achievement of Disease Remission up to Week 12: Week 52 Analysis Set | Disease remission was defined as resolution of signs and symptoms of GCA, 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 corticosteroid (CS) due to active GCA 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. | Up to Week 12 | 
| Number of Participants With Achievement of Disease Remission up to Week 12: Intent-to-treat (ITT) Population | Disease remission was defined as resolution of signs and symptoms of GCA, 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 GCA 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. | Up to Week 12 | 
| Number of Participants With Absence of Disease Flare From Week 12 Through Week 52: Week 52 Analysis Set | Disease flare was defined as either recurrence of signs and symptoms attributable to active GCA plus an increase in CS dose due to GCA, or elevation of ESR attributable to active GCA plus an increase in CS dose due to GCA. Number of participants with absence of disease flare from Week 12 through Week 52 were reported. | From Week 12 through Week 52 | 
| Number of Participants With Absence of Disease Flare From Week 12 Through Week 24: ITT Population | Disease flare was defined as either recurrence of signs and symptoms attributable to active GCA plus an increase in CS dose due to GCA, or elevation of ESR attributable to active GCA plus an increase in CS dose due to GCA. Number of participants with absence of disease flare from Week 12 through Week 24 were reported. | From Week 12 through Week 24 | 
| Number of Participants With Normalization of C-Reactive Protein From Week 12 Through Week 52: Week 52 Analysis Set | Normalization 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 Normalization of C-Reactive Protein (CRP) From Week 12 Through Week 24: ITT Population | Normalization 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 24 | 
| Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52: Week 52 Analysis Set | 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 might include the use of 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 GCA. | From Week 12 through Week 52 | 
| Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 24: ITT Population | Successful adherence to the prednisone taper from Week 12 through Week 24 was defined as participants who did not take rescue therapy from Week 12 through Week 24 and might include the use of 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 AE not related to GCA. | From Week 12 through Week 24 | 
| Total Cumulative Corticosteroid (Including Prednisone) Dose | Cumulative dose of CS used for GCA disease was defined as the dose taken up to the end of treatment, including expected prednisone in tapering regimen per protocol, CS used in rescue therapy and the use of commercial prednisone (an excess of <=100 mg of prednisone during the study treatment period employed to manage AE not related to GCA). 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 | 
| Time to First Giant Cell Arteritis Disease Flare | Time to first GCA flare was defined as the duration (in days) from randomization to first GCA 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 GCA or elevation of ESR attributable to active GCA plus an increase in CS dose due to GCA. 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 24: ITT Population | GTI assessed glucocorticoid (GC) related morbidity and GC-sparing ability of other therapies; composed of 2 components: Composite GTI and Specific List. Composite GTI contained 9 domains and Specific List contained of 23 items (11 domains), used as complementary tool to C-GTI. Composite GTI score was the sum of 9 domain-specific scores at each visit and Cumulative GTI score was the sum of composite GTI scores across each visit. Two cumulative GTI scores: CWS and AIS at Week 24 are reported in this outcome measure (OM). 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. For CWS, composite score ranged from 0 to 439 and for AIS, composite score ranged from -346 to 439. For both CWS and AIS, the minimum score implies the least toxicity and the maximum score implies the most toxicity. | At Week 24 | 
| Composite Glucocorticoid Toxicity Index: Cumulative Worsening Score and Aggregate Improvement Score at Week 52 | GTI assessed glucocorticoid (GC) related morbidity and GC-sparing ability of other therapies; composed of 2 components: Composite GTI and Specific List. Composite GTI contained 9 domains and Specific List contained of 23 items (11 domains), used as complementary tool to C-GTI. Composite GTI score was the sum of 9 domain-specific scores at each visit and Cumulative GTI score was the sum of composite GTI scores across each visit. Two cumulative GTI scores: CWS and AIS at Week 52 are reported in this OM. 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. For CWS, composite score ranged from 0 to 439 and for AIS, composite score ranged from -346 to 439. For both CWS and AIS, the minimum score implies the least toxicity and the maximum score implies the most toxicity. | At Week 52 | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (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 SC IMP +60 days). | From first dose (i.e., Day 1) up to 60 days after last dose (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 arms (Placebo+52 Week Taper and Placebo+26 Week Taper) as pre-specified in the protocol. | Pre-dose on Week 0 (Baseline), Weeks 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 | 
| Percentage 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 SC IMP + 60 days). Titer values were categorized as low (titer <1,000); moderate (1,000<= titer <=10,000) and high (titer >10,000). | From Day 1 (Baseline) up to last dose date of study drug + 60 days (i.e., up to Week 60) | 
| Pharmacodynamics: Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 52 | ESR is a laboratory test to provide non-specific measure of inflammation in the body. The test assessed the rate at which red blood cells fell in a test tube and was measured in millimeters per hour. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Pharmacodynamics: Change From Baseline in C-reactive Protein (CRP) Level at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 52 | CRP is a protein made by the liver. CRP levels increase in blood when inflammation occurs in the body. | Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 52 | 
| Pharmacodynamics: Change From Baseline in Interleukin-6 (IL-6) at Weeks 2, 12, 24, and 52 | Interleukin-6 is a protein produced in the body. Levels of IL-6 often increase when there is inflammation (redness, warmth, swelling, and pain as a result of infection, irritation, or injury), either acute or chronic. | Baseline, Weeks 2, 12, 24, and 52 | 
| Pharmacodynamics: Change From Baseline in Soluble Interleukin-6 Receptor (sIL-6R) Level at Weeks 2, 12, 24, and 52 | Interleukin-6 is a protein produced in the body. Levels of IL-6 often increase when there is inflammation (redness, warmth, swelling, and pain as a result of infection, irritation, or injury), either acute or chronic. sIL-6R is one of the receptors that bind IL-6. | Baseline, Weeks 2, 12, 24, and 52 |