Evaluation of the Efficacy and Safety of Sarilumab in Patients With Polymyalgia Rheumatica
- Conditions
- Polymyalgia Rheumatica
- Interventions
- Drug: Sarilumab-matching placeboDrug: Prednisone-matching placebo
- Registration Number
- NCT03600818
- Lead Sponsor
- Sanofi
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 118
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Sarilumab 200mg q2w+14 Week Taper Sarilumab SAR153191 (REGN88) 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. 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. Sarilumab 200mg q2w+14 Week Taper Prednisone-matching placebo 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. 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. Sarilumab 200mg q2w+14 Week Taper Prednisone 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. 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants Achieving Sustained Remission at Week 52 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.
- Secondary Outcome Measures
Name Time Method Time to First Polymyalgia Rheumatica Flare After Clinical Remission up to Week 52 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.
Total Cumulative Corticosteroid Dose Up to Week 52 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.
Number of Participants Who Achieved Disease Remission up to Week 12 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.
Number of Participants With Potentially Clinically Significant Abnormalities - Metabolic Parameters From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) 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).Number of Participants With Treatment-emergent Antidrug Antibodies (ADA) Response From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (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 IMP +60 days).
Number of Participants With Absence of Disease Flare From Week 12 Through Week 52 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.
Number of Participants With Sustained Reduction of CRP From Week 12 Through Week 52 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.
Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52 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.
Composite Glucocorticoid Toxicity Index (C-GTI): Cumulative Worsening Score (CWS) and Aggregate Improvement Score (AIS) at Week 52 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.
Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities During TEAE Period From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) 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.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 date of study drug (i.e. up to Week 60) 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).
Number of Participants With Potentially Clinically Significant Abnormalities - Hematological Parameter From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) 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).Number of Participants With Potentially Clinically Significant Abnormalities - Renal Function From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) 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.Number of Participants With Potentially Clinically Significant Abnormalities - Liver Function From first dose (i.e., Day 1) up to 60 days after last dose date of study drug (i.e., up to Week 60) 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 ULNPharmacokinetics: 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.
Pharmacokinetics (PK): Serum Trough Concentration (Ctrough) of Sarilumab Pre-dose on Week 0 (Baseline), Week 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 arm (Placebo+52 Week Taper) as pre-specified in the protocol.
Trial Locations
- Locations (84)
Investigational Site Number 8400009
🇺🇸Stamford, Connecticut, United States
Investigational Site Number 0320001
🇦🇷Buenos Aires, Argentina
Investigational Site Number 6430001
🇷🇺Moscow, Russian Federation
Investigational Site Number 8400006
🇺🇸Boston, Massachusetts, United States
Investigational Site Number 8400014
🇺🇸Iowa City, Iowa, United States
Investigational Site Number 0360004
🇦🇺Woodville South, Australia
Investigational Site Number 0360002
🇦🇺Maroochydore, Australia
Investigational Site Number 1240007
🇨🇦Hamilton, Canada
Investigational Site Number 2760004
🇩🇪München, Germany
Investigational Site Number 5280002
🇳🇱Almelo, Netherlands
Investigational Site Number 5280007
🇳🇱Den Haag, Netherlands
Investigational Site Number 0560003
🇧🇪Gent, Belgium
Investigational Site Number 8400003
🇺🇸Upland, California, United States
Investigational Site Number 8400002
🇺🇸Boca Raton, Florida, United States
Investigational Site Number 8400011
🇺🇸Dallas, Texas, United States
Investigational Site Number 8400005
🇺🇸Denver, Colorado, United States
Investigational Site Number 8400022
🇺🇸New York, New York, United States
Investigational Site Number 8400025
🇺🇸Lufkin, Texas, United States
Investigational Site Number 8400015
🇺🇸Spokane, Washington, United States
Investigational Site Number 0320002
🇦🇷Caba, Argentina
Investigational Site Number 0320005
🇦🇷Buenos Aires, Argentina
Investigational Site Number 0320003
🇦🇷San Miguel de Tucuman, Argentina
Investigational Site Number 0360003
🇦🇺Camberwell, Australia
Investigational Site Number 0560001
🇧🇪Leuven, Belgium
Investigational Site Number 0360001
🇦🇺Kogarah, Australia
Investigational Site Number 1240005
🇨🇦Sherbrooke, Canada
Investigational Site Number 1240010
🇨🇦Montreal, Canada
Investigational Site Number 1240001
🇨🇦Rimouski, Canada
Investigational Site Number 2500015
🇫🇷Le Kremlin Bicetre, France
Investigational Site Number 2330001
🇪🇪Tallinn, Estonia
Investigational Site Number 2500005
🇫🇷Brest Cedex, France
Investigational Site Number 2500011
🇫🇷Caen Cedex 9, France
Investigational Site Number 1240003
🇨🇦Trois-Rivières, Canada
Investigational Site Number 2500003
🇫🇷Montpellier, France
Investigational Site Number 2500004
🇫🇷Paris, France
Investigational Site Number 2500010
🇫🇷Lille Cedex, France
Investigational Site Number 2500014
🇫🇷Toulouse Cedex 09, France
Investigational Site Number 2500002
🇫🇷Montivilliers, France
Investigational Site Number 2500016
🇫🇷Pierre Benite Cedex, France
Investigational Site Number 2760008
🇩🇪Bad Abbach, Germany
Investigational Site Number 2760002
🇩🇪Dresden, Germany
Investigational Site Number 2760001
🇩🇪Berlin, Germany
Investigational Site Number 2760009
🇩🇪Berlin, Germany
Investigational Site Number 2760003
🇩🇪Kirchheim Unter Teck, Germany
Investigational Site Number 2760007
🇩🇪Tübingen, Germany
Investigational Site Number 3760001
🇮🇱Haifa, Israel
Investigational Site Number 3480001
🇭🇺Debrecen, Hungary
Investigational Site Number 3760004
🇮🇱Haifa, Israel
Investigational Site Number 3760003
🇮🇱Kfar Saba, Israel
Investigational Site Number 3800001
🇮🇹Milano, Italy
Investigational Site Number 3760002
🇮🇱Petah-Tikva, Israel
Investigational Site Number 3760005
🇮🇱Tel Hashomer, Israel
Investigational Site Number 3800003
🇮🇹Milano, Italy
Investigational Site Number 3800004
🇮🇹Pisa, Italy
Investigational Site Number 3800002
🇮🇹Reggio Emilia, Italy
Investigational Site Number 3800005
🇮🇹Rozzano, Italy
Investigational Site Number 3920002
🇯🇵Fuchu-Shi, Japan
Investigational Site Number 3800008
🇮🇹Verona, Italy
Investigational Site Number 3920003
🇯🇵Kamakura-Shi, Japan
Investigational Site Number 5280003
🇳🇱Alkmaar, Netherlands
Investigational Site Number 3920005
🇯🇵Kawachinagano-Shi, Japan
Investigational Site Number 5280005
🇳🇱Leeuwarden, Netherlands
Investigational Site Number 6430002
🇷🇺Moscow, Russian Federation
Investigational Site Number 5280008
🇳🇱Rotterdam, Netherlands
Investigational Site Number 3920001
🇯🇵Takasaki-Shi, Japan
Investigational Site Number 5280004
🇳🇱Nijmegen, Netherlands
Investigational Site Number 6430003
🇷🇺Moscow, Russian Federation
Investigational Site Number 7240004
🇪🇸A Coruña / Santiago De Compostela, Spain
Investigational Site Number 6430004
🇷🇺Moscow, Russian Federation
Investigational Site Number 6430008
🇷🇺Saint-Petersburg, Russian Federation
Investigational Site Number 7240005
🇪🇸Badalona, Spain
Investigational Site Number 7240001
🇪🇸Getafe, Spain
Investigational Site Number 7240008
🇪🇸Granada, Spain
Investigational Site Number 7240007
🇪🇸Valencia, Spain
Investigational Site Number 7240002
🇪🇸Madrid, Spain
Investigational Site Number 7240006
🇪🇸Santander, Spain
Investigational Site Number 7560001
🇨🇭Bern, Switzerland
Investigational Site Number 7560002
🇨🇭St. Gallen, Switzerland
Investigational Site Number 8260004
🇬🇧Gateshead, United Kingdom
Investigational Site Number 8260009
🇬🇧Manchester, United Kingdom
Investigational Site Number 8260003
🇬🇧Leeds, United Kingdom
Investigational Site Number 8260002
🇬🇧Plymouth, United Kingdom
Investigational Site Number 8260001
🇬🇧Southend, United Kingdom
Investigational Site Number 8260007
🇬🇧Newport, United Kingdom