A Phase 3 interventional study of Sarilumab SAR153191 (REGN88) and Sarilumab-matching placebo in Polymyalgia Rheumatica, sponsored by Sanofi. Terminated at 84 sites in 17 countries. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2022-06-10.
Sponsored by Sanofi · Phase 3, Interventional, and Treatment
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:
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.
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This study's enrollment of 118 is above the median of 60 across 68 interventional studies indexed under Polymyalgia Rheumatica.
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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:
Exclusion criteria:
Any prior (within the defined period below) or concurrent use of immunosuppressive therapies but not limited to any of the following:
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
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 · Drug: Prednisone · Drug: 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.
Drug: Sarilumab SAR153191 (REGN88) · Drug: Prednisone · Drug: Prednisone-matching placebo
Pharmaceutical form:solution for injection Route of administration: subcutaneous
Pharmaceutical form:solution for injection Route of administration: subcutaneous
Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration
Pharmaceutical form:over-encapsulated tablets Route of administration: oral administration
Pharmaceutical form:tablets Route of administration: oral administration
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.
Time frame: At Week 52
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Post-dose at Week 24
The study was conducted at 78 active centers (randomized at least 1 participant) in 17 countries. A total of 196 participants were screened between 09 October 2018 and 19 March 2020, of whom 78 were screen failures. Screen failures were mainly due to not meeting inclusion criteria.
| Milestone | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Started | 58 | 60 |
| Safety population | 58 | 59 |
| Completed | 36 | 42 |
| Not completed | 22 | 18 |
| Withdrew: Adverse event | 4 | 7 |
| Withdrew: Lack of efficacy | 9 | 4 |
| Withdrew: Withdrawal by subject | 4 | 3 |
| Withdrew: Other-unspecified | 5 | 3 |
| Withdrew: Randomized and not treated | 0 | 1 |
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.
| percentage of participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Percentage of Participants Achieving Sustained Remission at Week 52 | 10.3 | 28.3 |
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.
| milligrams | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Total Cumulative Corticosteroid Dose | 2235.8 ± 839.4 | 1039.5 ± 612.2 |
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.
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Number of Participants Who Achieved Disease Remission up to Week 12 | 22 | 28 |
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.
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Number of Participants With Absence of Disease Flare From Week 12 Through Week 52 | 19 | 33 |
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.
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Number of Participants With Sustained Reduction of CRP From Week 12 Through Week 52 | 26 | 40 |
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.
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Number of Participants With Successful Adherence to the Prednisone Taper From Week 12 Through Week 52 | 14 | 30 |
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.
| days | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Time to First Polymyalgia Rheumatica Flare After Clinical Remission up to Week 52 | 99.00 (1.000 to 154.000) | NA (93.000 to NA) |
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.
| units on a scale | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| CWS | 57.22 ± 6.678 | 52.32 ± 6.507 |
| AIS | 2.57 ± 6.275 | -4.02 ± 6.115 |
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).
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Any TEAE | 49 | 56 |
| TESAE | 12 | 8 |
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.
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| SBP <=95 mmHg and DFB >=20 mmHg | 0 | 2 |
| SBP >=160 mmHg and IFB >=20 mmHg | 4 | 5 |
| DBP <=45 mmHg and DFB >=10 mmHg | 1 | 0 |
| DBP >=110 mmHg and IFB >=10 mmHg | 1 | 1 |
| HR <=50 bpm and DFB >= 20 bpm | 1 | 0 |
| HR >=120 bpm and IFB >=20 bpm | 1 | 0 |
| Weight >=5% DFB | 2 | 5 |
| Weight >=5% IFB | 9 | 12 |
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).
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Hb: <= 115 g/L (M), <= 95 g/L (F) | 1 | 1 |
| Hb: >=185 g/L(M), >=165 g/L(F) | 0 | 1 |
| Hb: DFB >=20 g/L | 3 | 2 |
| Hematocrit: <= 0.37 v/v(M); <=0.32 v/v(F) | 1 | 1 |
| Hematocrit: >=0.55 v/v(M); >=0.5 v/v(F) | 0 | 0 |
| Erythrocytes: >=6 Tera/L | 0 | 0 |
| Platelets: < 100 Giga/L | 0 | 2 |
| Platelets: >= 700 Giga/L | 0 | 0 |
| Leukocytes:<3.0Giga/L(NB);<2.0Giga/L(B) | 0 | 11 |
| Leukocytes: >= 16.0 Giga/L. | 1 | 1 |
| Neutrophils: < 1.5 Giga/L (NB); < 1.0 Giga/L (B). | 0 | 18 |
| Lymphocytes: > 4.0 Giga/L | 4 | 2 |
| Monocytes: > 0.7 Giga/L | 12 | 8 |
| Basophils: > 0.1 Giga/L. | 16 | 13 |
| Eosinophils:>0.5 Giga/L; >ULN (if ULN>=0.5Giga/L) | 2 | 2 |
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).
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Glucose: <=3.9 mmol/L and < LLN | 1 | 2 |
| Glucose: >=11.1 mmol/L (unfas); >=7 mmol/L (fas) | 14 | 5 |
| HbA1c: >8% | 4 | 2 |
| Cholesterol: >=7.74 mmol/L | 4 | 8 |
| Triglycerides: >=4.6 mmol/L | 1 | 3 |
| CRP: >2 ULN or >10 mg/L (if ULN not provided) | 37 | 13 |
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.
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Creatinine: >=150 micromol/L (adults) | 2 | 2 |
| Creatinine: >=30% change from baseline | 3 | 14 |
| Creatinine: >=100% change from baseline | 0 | 1 |
| Creatinine clearance: >=60 to <90 mL/min | 30 | 29 |
| Creatinine clearance: >=30 to <60 mL/min | 13 | 17 |
| Creatinine clearance: >=15 to <30 mL/min | 0 | 1 |
| Creatinine clearance: <15 mL/min | 0 | 0 |
| Blood urea nitrogen: >=17 mmol/L | 0 | 0 |
| Urate: <120 micromol/L | 0 | 0 |
| Urate: >408 micromol/L | 16 | 16 |
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
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Albumin: <= 25 g/L | 0 | 0 |
| ALT: >3 ULN | 2 | 0 |
| ALT: >5 ULN | 1 | 0 |
| ALT: >10 ULN | 0 | 0 |
| AST: >3 ULN | 1 | 0 |
| AST: >5 ULN | 1 | 0 |
| AST: >10 ULN | 1 | 0 |
| AST: >20 ULN | 0 | 0 |
| Alkaline Phosphatase: >1.5 ULN | 1 | 0 |
| Bilirubin: >1.5 ULN | 1 | 1 |
| Bilirubin: >2 ULN | 0 | 0 |
| ALT > 3 ULN and Bilirubin > 2 ULN | 0 | 0 |
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).
| Participants | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Treatment-boosted ADA | 0 | 0 |
| Treatment-emergent ADA | 1 | 2 |
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.
| nanograms per milliliter (ng/mL) | Sarilumab 200mg q2w+14 Week Taper |
|---|---|
| Baseline | 0.00 ± 0.00 |
| Week 2 | 5209.02 ± 4357.37 |
| Week 4 | 9259.25 ± 7668.95 |
| Week 12 | 17494.20 ± 11146.33 |
| Week 16 | 23082.86 ± 15878.92 |
| Week 24 | 27289.75 ± 17927.73 |
| Week 52 | 27604.95 ± 24880.13 |
Serum concentrations of functional sarilumab were analyzed using validated enzyme linked immunosorbent assay.
| ng/mL | Sarilumab 200mg q2w+14 Week Taper |
|---|---|
| Pharmacokinetics: Serum Drug Concentration of Sarilumab Post-dose at Week 24 | 35757.69 ± 15353.96 |
Collected over From first dose (i.e., Day 1) of IMP to last dose date of IMP + 60 days (i.e., up to Week 60).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo+52 Week Taper | 0/58 (0%) | 12/58 (20.7%) | 42/58 (72.4%) |
| Sarilumab 200mg q2w+14 Week Taper | 0/59 (0%) | 8/59 (13.6%) | 42/59 (71.2%) |
| Event | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| Covid-19Infections and infestations | 2/58 | 0/59 |
| NeutropeniaBlood and lymphatic system disorders | 0/58 | 2/59 |
| Covid-19 PneumoniaInfections and infestations | 1/58 | 0/59 |
| Alanine Aminotransferase IncreasedInvestigations | 1/58 | 0/59 |
| Intervertebral Disc ProtrusionMusculoskeletal and connective tissue disorders | 1/58 | 0/59 |
| Lumbar Spinal StenosisMusculoskeletal and connective tissue disorders | 1/58 | 0/59 |
| Polymyalgia RheumaticaMusculoskeletal and connective tissue disorders | 1/58 | 1/59 |
| Basal Cell CarcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/58 | 0/59 |
| Erdheim-Chester DiseaseNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/58 | 0/59 |
| SyncopeNervous system disorders | 1/58 | 0/59 |
| Event | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper |
|---|---|---|
| InsomniaPsychiatric disorders | 9/58 | 6/59 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 3/58 | 9/59 |
| NeutropeniaBlood and lymphatic system disorders | 0/58 | 7/59 |
| DiarrhoeaGastrointestinal disorders | 1/58 | 7/59 |
| NasopharyngitisInfections and infestations | 6/58 | 2/59 |
| FallInjury, poisoning and procedural complications | 6/58 | 3/59 |
| DepressionPsychiatric disorders | 6/58 | 5/59 |
| OsteoarthritisMusculoskeletal and connective tissue disorders | 5/58 | 6/59 |
| HypertensionVascular disorders | 2/58 | 6/59 |
| Oedema PeripheralGeneral disorders | 5/58 | 3/59 |
Analysis was performed on randomized population.
| Age, Continuous(Years) | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper | Total Title |
|---|---|---|---|
| Mean | 69.1 ± 8.5 | 68.8 ± 7.8 | 68.9 ± 8.1 |
| Sex: Female, Male(Participants) | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper | Total Title |
|---|---|---|---|
| Female | 37 | 45 | 82 |
| Male | 21 | 15 | 36 |
| Race (NIH/OMB)(Participants) | Placebo+52 Week Taper | Sarilumab 200mg q2w+14 Week Taper | Total Title |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 2 | 1 | 3 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 48 | 50 | 98 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 8 | 9 | 17 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org
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