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

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.

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.

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.

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.

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 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.

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.

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).

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.

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).

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).

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.

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

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).

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.

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