Evaluation of Efficacy and Safety of Sarilumab in Patients With GCA
- Conditions
- Giant Cell Arteritis
- Interventions
- Registration Number
- NCT03600805
- Lead Sponsor
- Sanofi
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 83
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo+52 Week Taper Sarilumab matching placebo 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. Placebo+52 Week Taper Prednisone matching placebo 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. Placebo+26 Week Taper Sarilumab matching placebo 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. Placebo+26 Week Taper Prednisone matching placebo 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. Sarilumab 150mg q2w+26 Week Taper Sarilumab SAR153191 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. Sarilumab 150mg q2w+26 Week Taper Prednisone matching placebo 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. Sarilumab 200mg q2w+26 Week Taper Sarilumab SAR153191 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. Sarilumab 200mg q2w+26 Week Taper Prednisone 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. Sarilumab 200mg q2w+26 Week Taper Prednisone matching placebo 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. Placebo+52 Week Taper Prednisone 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. Placebo+26 Week Taper Prednisone 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. Sarilumab 150mg q2w+26 Week Taper Prednisone 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants Who Achieved Sustained Disease Remission at Week 52 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.
Percentage of Participants Who Achieved Sustained Disease Remission at Week 24 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Achievement of Disease Remission up to Week 12: Week 52 Analysis Set Up to Week 12 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.
Number of Participants With Achievement of Disease Remission up to Week 12: Intent-to-treat (ITT) Population Up to Week 12 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.
Number of Participants With Absence of Disease Flare From Week 12 Through Week 52: Week 52 Analysis Set From Week 12 through Week 52 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.
Number of Participants With Absence of Disease Flare From Week 12 Through Week 24: ITT Population From Week 12 through Week 24 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.
Number of Participants With Normalization of C-Reactive Protein From Week 12 Through Week 52: Week 52 Analysis Set From Week 12 through Week 52 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.
Number of Participants With Normalization of C-Reactive Protein (CRP) From Week 12 Through Week 24: ITT Population From Week 12 through Week 24 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.
Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52: Week 52 Analysis Set 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 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.
Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 24: ITT Population From Week 12 through Week 24 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.
Total Cumulative Corticosteroid (Including Prednisone) Dose Up to Week 52 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.
Time to First Giant Cell Arteritis Disease Flare Up to Week 52 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.
Composite Glucocorticoid Toxicity Index (C-GTI): Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS) at Week 24: ITT Population At Week 24 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.
Composite Glucocorticoid Toxicity Index: Cumulative Worsening Score and Aggregate Improvement Score at Week 52 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) From first dose (i.e., Day 1) up to 60 days after last dose (i.e., up to Week 60) 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).
Pharmacokinetics (PK): Serum Trough Concentration (Ctrough) of Sarilumab Pre-dose on Week 0 (Baseline), Weeks 2, 4, 12, 16, 24 and 52 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.
Pharmacokinetics: Serum Drug Concentration of Sarilumab Post-dose at Week 24 post-dose at Week 24 Serum concentrations of functional sarilumab were analyzed using validated enzyme linked immunosorbent assay.
Percentage of Participants With Treatment-emergent Antidrug Antibodies (ADA) Response From Day 1 (Baseline) up to last dose date of study drug + 60 days (i.e., up to Week 60) 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).
Pharmacodynamics: Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 52 Baseline, 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.
Pharmacodynamics: Change From Baseline in C-reactive Protein (CRP) Level at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 52 Baseline, 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.
Pharmacodynamics: Change From Baseline in Interleukin-6 (IL-6) at Weeks 2, 12, 24, and 52 Baseline, 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.
Pharmacodynamics: Change From Baseline in Soluble Interleukin-6 Receptor (sIL-6R) Level at Weeks 2, 12, 24, and 52 Baseline, 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.
Trial Locations
- Locations (61)
Investigational Site Number 6200001
🇵🇹Almada, Portugal
Investigational Site Number 2080002
🇩🇰Aarhus C, Denmark
Investigational Site Number 2500006
🇫🇷Pessac, France
Investigational Site Number 1240010
🇨🇦Montreal, Canada
Investigational Site Number 1240001
🇨🇦Rimouski, Canada
Investigational Site Number 0360003
🇦🇺Camberwell, Australia
Investigational Site Number 3760004
🇮🇱Haifa, Israel
Investigational Site Number 5280001
🇳🇱Venlo, Netherlands
Investigational Site Number 3760006
🇮🇱Ashkelon, Israel
Investigational Site Number 8400017
🇺🇸Gainesville, Florida, United States
Investigational Site Number 0360006
🇦🇺Clayton, Australia
Investigational Site Number 8400018
🇺🇸Portland, Oregon, United States
Investigational Site Number 8400019
🇺🇸Philadelphia, Pennsylvania, United States
Investigational Site Number 0320001
🇦🇷Buenos Aires, Argentina
Investigational Site Number 6200004
🇵🇹Ponte De Lima, Portugal
Investigational Site Number 8260006
🇬🇧Aberdeen, United Kingdom
Investigational Site Number 8260004
🇬🇧Gateshead, United Kingdom
Investigational Site Number 5280005
🇳🇱Leeuwarden, Netherlands
Investigational Site Number 7050001
🇸🇮Ljubljana, Slovenia
Investigational Site Number 6430003
🇷🇺Moscow, Russian Federation
Investigational Site Number 0320002
🇦🇷Caba, Argentina
Investigational Site Number 2500007
🇫🇷Mulhouse, France
Investigational Site Number 7240011
🇪🇸La Coruña, Spain
Investigational Site Number 2760003
🇩🇪Kirchheim Unter Teck, Germany
Investigational Site Number 2500005
🇫🇷Brest Cedex, France
Investigational Site Number 2760007
🇩🇪Tübingen, Germany
Investigational Site Number 1240007
🇨🇦Hamilton, Canada
Investigational Site Number 7520001
🇸🇪Uppsala, Sweden
Investigational Site Number 0560001
🇧🇪Leuven, Belgium
Investigational Site Number 3800001
🇮🇹Milano, Italy
Investigational Site Number 3800005
🇮🇹Rozzano, Italy
Investigational Site Number 8260003
🇬🇧Leeds, United Kingdom
Investigational Site Number 6430005
🇷🇺Kemerovo, Russian Federation
Investigational Site Number 1240003
🇨🇦Trois-Rivières, Canada
Investigational Site Number 1240005
🇨🇦Sherbrooke, Canada
Investigational Site Number 2500002
🇫🇷Montivilliers, France
Investigational Site Number 2080003
🇩🇰Svendborg, Denmark
Investigational Site Number 2500003
🇫🇷Montpellier, France
Investigational Site Number 2760002
🇩🇪Dresden, Germany
Investigational Site Number 5280007
🇳🇱Den Haag, Netherlands
Investigational Site Number 5280009
🇳🇱Sittard-Geleen, Netherlands
Investigational Site Number 6200005
🇵🇹Aveiro, Portugal
Investigational Site Number 8260011
🇬🇧Portsmouth, United Kingdom
Investigational Site Number 7560002
🇨🇭St. Gallen, Switzerland
Investigational Site Number 7520003
🇸🇪Örebro, Sweden
Investigational Site Number 7240016
🇪🇸Sabadell, Spain
Investigational Site Number 6430002
🇷🇺Moscow, Russian Federation
Investigational Site Number 7240010
🇪🇸Bilbao, Spain
Investigational Site Number 8400002
🇺🇸Boca Raton, Florida, United States
Investigational Site Number 8400014
🇺🇸Iowa City, Iowa, United States
Investigational Site Number 8400011
🇺🇸Dallas, Texas, United States
Investigational Site Number 0360001
🇦🇺Kogarah, Australia
Investigational Site Number 2760001
🇩🇪Berlin, Germany
Investigational Site Number 2500001
🇫🇷Paris, France
Investigational Site Number 2760004
🇩🇪München, Germany
Investigational Site Number 7240014
🇪🇸Madrid, Spain
Investigational Site Number 8260005
🇬🇧Manchester, United Kingdom
Investigational Site Number 7240015
🇪🇸Santa Cruz De Tenerife, Spain
Investigational Site Number 1910001
🇭🇷Zagreb, Croatia
Investigational Site Number 2330001
🇪🇪Tallinn, Estonia
Investigational Site Number 3480001
🇭🇺Debrecen, Hungary