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

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

Population: Analysis was performed on intent-to-treat (ITT) population that included all participants who were allocated to a randomized treatment group, and were analyzed according to the treatment group allocated by randomization.

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

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

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

Population: Analysis was performed on ITT population.

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

Population: Analysis was performed on ITT population.

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)

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

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)

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

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)

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

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)

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed'= participants evaluable for this outcome measure.

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)

Population: Analysis was performed on safety population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure and 'number analyzed' = participants with available data for each specified category.

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

Population: Analysis was performed on ITT population.

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

Population: Analysis was performed on ITT population.

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)

Population: Analysis was performed on safety population that included participants who had received at least one dose or part of a dose of IMP and were analyzed according to the treatment actually received.

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)

Population: Analysis was performed on ADA population which included participants who had received at least one dose or part of a dose of IMP and were analyzed according to the treatment actually received and had at least one post dose evaluable ADA sample.

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

Population: Analyzed on PK population: participants who had received at least one dose or part of a dose of IMP, were analyzed according to the treatment actually received and had at least 1 post-dose non-missing serum sarilumab concentration value. Here, 'number analyzed' = participants with available data for each specified category.

Serum concentrations of functional sarilumab were analyzed using validated enzyme linked immunosorbent assay.

Time frame: Post-dose at Week 24

Population: Analysis was performed on PK population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure. 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 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

Population: Analysis was performed on ITT population.

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

Population: Analysis was performed on ITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.