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Olokizumab 64mg subcutaneous q4w + placebo + Methotrexate

Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)

Olokizumab 64mg subcutaneous q2w + Methotrexate

64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)

Placebo q2w subcutaneous + Methotrexate

Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)

Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w; equal numbers of subjects were planned to be assigned to each OKZ treatment group.

160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial

Olokizumab

sodium chloride 0.9% solution provided as either a 10 mL vial or ampoule, depending on market availability. Each placebo will be packed into a cardboard carton to contain 1 vial or ampoule

Placebo

Mikhail Samsonov

The purpose of this study was to determine how effective and safe the study drug Olokizumab was in patients with Rheumatoid Arthritis (RA) who had been already receiving, but not fully responding to treatment with an existing medication called a tumour necrosis factor alpha inhibitor

The primary objective of this study was to evaluate the efficacy of olokizumab (OKZ) 64 mg administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) relative to placebo in subjects with moderately to severely active rheumatoid arthritis (RA) inadequately controlled by TNF-α inhibitor (TNFi) therapy.

The goal of this Phase III study was to assess the efficacy, safety and tolerability of OKZ in subjects with moderately to severely active RA who had responded inadequately to TNFi therapy. The primary endpoint of the trial was assessed at Week 12. Olokizumab was expected to reduce the disease activity and improve physical function. The study was expected to provide safety information in a large group of subjects over at least a 24 week period.

This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter study. This study included a 4-week Screening Period, a double-blind Treatment Period from Week 0 to Week 24, and a Safety FollowUp Period from Week 24 to Week 44.

A total of 350 subjects were planned to be randomized.Subjects were assessed for eligibility to enter the study during a 4-week Screening Period. Eligible subjects were randomized at Visit 2 in a 2:2:1 ratio in one of 3 treatment groups (planned 140, 140, and 70 subjects per group, respectively) :

1. Olokizumab 64 mg q4w: SC injection of OKZ 64 mg q4w (alternating with SC injection of placebo OKZ q4w to maintain blinding) + MTX for 24 weeks,
2. Olokizumab 64 mg q2w: SC injection of OKZ 64 mg q2w + MTX for 24 weeks or
3. Placebo: SC injection of placebo q2w + MTX for 16 weeks.

Subjects who received placebo were re-randomized at Week 16 to receive 64 mg OKZ q4w + Methotrexate or 64 mg OKZ q2w +Methotrexate for 8 weeks.

Throughout the double-blind Treatment Period, all subjects were required to remain on a stable dose of background MTX with a stable route of administration. Concomitant treatment with folic acid was required for all subjects. The last dose of OKZ was administered at Week 20 for subjects receiving OKZ 64 mg q4w and at Week 22 for subjects receiving OKZ 64 mg q2w.

Following Visit 2 (randomization; Week 0), subjects returned to the study site at least every 2 weeks through Week 24 for response and safety assessments.

At Week 14, subjects who did not improve by at least 20% in both swollen and tender joint counts were classified as nonresponders and were administered sulfasalazine and/or hydroxychloroquine as rescue medication in addition to the assigned treatment.

After completion of the 24-week double-blind Treatment Period, subjects either rolled over into the long-term open-label extension (OLE) study or entered the Safety Follow-Up Period. During the Safety Follow-Up Period, subjects returned for visits +4, +8, and +22 weeks after the last dose of study treatment.

Subjects who discontinued randomized treatment prematurely were required to come for the End of Treatment (EoT) Visit 2 weeks after the last study treatment administration and then continue with the scheduled study visits.

Adverse events (AEs) were assessed throughout the study (starting when the subject signed the informed consent form) and evaluated using the Common Terminology Criteria for Adverse Events Version 4.0. There was ongoing monitoring of safety events, including laboratory findings, by the Sponsor or the Sponsor's designee. In addition, safety was assessed throughout the study by an independent Data Safety Monitoring Board and potential major adverse cardiac events were evaluated by an independent Cardiovascular Adjudication Committee.

The study was conducted at 123 sites across 11 countries globally (in US,EU, Russian Federation, Asia, Latin America)

Evaluation of the Efficacy and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo, in Subjects With Rheumatoid Arthritis (RA) Who Were Taking an Existing Medication Called a Tumour Necrosis Factor Alpha Inhibitor But Had Active Disease

A Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Phase III Study of the Efficacy and Safety of Olokizumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Tumor Necrosis Factor Alpha (TNF-α) Inhibitor Therapy

The difference between OKZ and placebo in the percentage of subjects achieving an ACR20 response and remaining on randomized treatment and in the study at Week 12. A responder is defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 12.

American College of Rheumatology 20 % response is a composite defined as a ≥ 20% improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥20% improvement from baseline in at least 3 of the 5 remaining core set measures:

* Patient Global Assessment of Disease Activity (VAS)
* Patient Assessment of Pain (VAS)
* HAQ-DI
* Physician Global Assessment (VAS)
* Level of acute phase reactant (CRP)

Defined as Disease Activity Score 28-joint count (DAS28) C-reactive protein (CRP) \<3.2, and remaining on randomized treatment and in the study at Week 12

Change of physical ability from baseline (the last available assessment prior to the first dose of the study treatment) to week 12, as measured by HAQ-DI. The HAQ-DI assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions.The domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities, and each domain consists of 2 or 3 items. For each question, the level of difficulty is scored from 0 to 3 where 0 = without any difficulty (the best outcome), 1 = with some difficulty, 2 = much difficulty, and 3 = unable to do (the worst outcome). Each category is given a score by taking the maximum score of each question. A decrease from baseline indicates improvement for HAQ-DI.The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. The HAQ-DI total score ranges from 0 (the best outcome) to 3 (the worst outcome).

Difference between OKZ and placebo in the percentage of subjects achieving an ACR50 response and remaining on randomized treatment and in the study at Week 12.

American College of Rheumatology 50% Response is a composite defined as ≥50%, improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥50%, improvement from baseline in at least 3 of the 5 remaining core set measures:

* Patient Global Assessment of Disease Activity (VAS)
* Patient Assessment of Pain (VAS)
* HAQ-DI
* Physician Global Assessment (VAS)
* Level of acute phase reactant (CRP)

Difference between OKZ and placebo in the percentage of subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) and remaining on randomized treatment and in the study at Week 12

Quintiles, Inc.

OCT Clinical Trials

Mene Research

R-Pharm International, LLC

All AEs and SAEs reported below are related to the Safety Population (safety population included all subjects who receive at least 1 dose of study treatment).

Data for TEAEs were reported below. A Treatment Emergent Adverse Event (TEAE) is defined as an AE that first occurred or worsened in severity after the first dose of the study treatment.

refers to subjects initially randomized to receive OKZ q4w and relates to AEs reported for this group during the total 24-week study treatment period

Arm 1: OKZ 64 mg q4w

refers to subjects initially randomized to receive OKZ q2w and relates to AEs reported for this group during the total 24-week study treatment period

Arm 2: OKZ 64 mg q2w

refers to subjects initially randomized to receive placebo and relates only to AEs reported for this group during the 16-week treatment period up to re-randomization

Arm 3: Placebo q2w

refers to subjects re-randomized to receive OKZ q4w and relates only to AEs reported for this group during the treatment period after re-randomization from Week 16 to Week 24

Arm 4: Placebo-OKZ 64 mg q4w

refers to subjects re-randomized to receive OKZ q2w and relates only to AEs reported for this group during the treatment period after re-randomization from Week 16 to Week 24

Arm 5: Placebo-OKZ 64 mg q2w

refers to a combination of the AEs reported for the OKZ 64 mg q4w group and the Placebo-OKZ 64 mg q4w group

Arm 6: Any OKZ 64 mg q4w

refers to a combination of the AEs reported for the OKZ 64 mg q2w group and the Placebo-OKZ 64 mg q2w group

Arm 7: Any OKZ 64 mg q2w

refers to AEs reported for all subjects at all visits

Total

Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate

Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)

Arm 1: Olokizumab q4w

Arm 2: Olokizumab q2w

refers to subjects who initially received placebo q2w, but then were re-randomized at week 16 to receive OKZ 64 mg q4w

(Arm 6 (Any Olokizumab q4w) combines the subjects from Arm 1 and Arm 4 (AEs were collected starting from the first OKZ dose after rerandomization). This group is included in the safety data presentation.)

refers to subjects who initially received placebo q2w, but then were re-randomized at week 16 to receive OKZ 64 mg q2w

(Arm 7 (Any Olokizumab q2w) combines the subjects from Arm 2 and Arm 5 (AEs were collected starting from the first OKZ dose after rerandomization). This group is included in the safety data presentation.)

refers to subjects who were initially randomized to placebo, but who were not re-randomized to OKZ 64 mg q2w or OKZ 64 mg q4w

Arm 8: Placebo Only

Age, Categorical

Age, Continuous

Sex: Female, Male

Asian

Black of African American

White

Other/Mixed

Race/Ethnicity, Customized

Colombia

Argentina

South Korea

Hungary

United States

Czechia

Brazil

Poland

Mexico

Germany

Russia

Region of Enrollment

Body Mass Index (BMI),Continuous

Arm 3 (Placebo) combines all subjects from Arms 4, 5 and 8. Starting at Week 16, subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w. (Efficacy data are presented for Arm 1, Arm 2, and Arm 3.)

Maria Lemak, Scientific Advisor

The ACR20 response rate at Week 12 for the placebo group is estimated to be 20% in this study population. The OKZ ACR20 response rate for 64 mg q4w treatment group at Week 12 are expected to be at least 45%, resulting in an expected difference in ACR20 response rates of 25 percentage points between the respective OKZ treatment group and placebo. Sample size yield 100% disjunctive power for testing the primary hypothesis

The ACR20 response rate at Week 12 for the placebo group is estimated to be 20% in this study population .The OKZ ACR20 response rate for 64 mg q2w treatment group at Week 12 is expected to be at least 50%, resulting in an expected difference in ACR20 response rates of 30 percentage points between the respective OKZ treatment group and placebo. Sample size yield 100% disjunctive power for testing the primary hypothesis

Arm 1: Olokizumab 64 mg q4w

Arm 2: Olokizumab 64 mg q2w

Placebo q2w subcutaneous + Methotrexate

Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)

Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w;

Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 8 reported previously

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis population.

Percentage of Subjects Achieving American College of Rheumatology 20% (ACR20) Response

The DAS28 low disease activity (based on DAS28 \[CRP\] \<3.2) response rate at Week 12 was estimated to be 5% in the placebo group and 18% and 21% in 64 mg q4w and q2w OKZ groups, respectively, resulting in an expected difference of 13 and 16 percentage points between respective OKZ groups and placebo.

Percentage of Subjects Achieving Low Disease Activity

Intent-to-treat (ITT) population: The ITT population includes all randomized subjects. Subjects were analyzed according to the treatment group to which they were randomized. The ITT population is the primary analysis population. Subjects with a missing baseline are not included. Data after treatment discontinuation are Included, Data after discontinuing study are multiply Imputed based on the return to baseline assumption.

Improvement of Physical Ability From Baseline to Week 12, as Measured by the Health Assessment Questionnaire Disability Index (HAQ-DI)

Placebo q2w subcutaneous + Methotrexate

Placebo q2w subcutaneous + Methotrexate

Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)

Starting at Week 16, all subjects in the placebo group were randomized in a blinded fashion to receive either OKZ 64 mg q2w or OKZ 64 mg q4w;

Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 8 reported previously

Percentage of Subjects Achieving American College of Rheumatology 50% (ACR50) Response

Percentage of Subjects With Clinical Disease Activity Index (CDAI) ≤ 2.8 (Remission)

Olokizumab 64mg subcutaneous q4w +placebo + Methotrexate

Olokizumab 64 mg subcutaneous q4w + placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)

There was no re-randomization at week 16 for this arm

Olokizumab 64mg subcutaneous q2w + Methotrexate

64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)

There was no re-randomization at week 16 for this arm

refers to subjects who initially received placebo q2w (Arm 3: Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate), but then were re-randomized at week 16 to receive OKZ 64 mg q4w. Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 8).

(Arm 6 (Any Olokizumab q4w) combines the subjects from Arm 1 and Arm 4 (AEs were collected starting from the first OKZ dose after rerandomization). This group is included in the safety data presentation).

refers to subjects who initially received placebo q2w (Arm 3:Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate), but then were re-randomized at week 16 to receive OKZ 64 mg q2w. Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 8).

(Arm 7 (Any Olokizumab q2w) combines the subjects from Arm 2 and Arm 5 (AEs were collected starting from the first OKZ dose after rerandomization). This group is included in the safety data presentation).

refers to subjects who were initially randomized to placebo q2w (Arm3: Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate), but who were not re-randomized to OKZ 64 mg q2w or OKZ 64 mg q4w. Arm 3 (placebo q2w) consisted of subjects from arms 4, 5 and 8).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Evaluation of the Efficacy and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo, in Subjects With Rheumatoid Arthritis (RA) Who Were Taking an Existing Medication Called a Tumour Necrosis Factor Alpha Inhibitor But Had Active Disease	NCT02760433	Rheumatoid Arth...	Olokizumab Placebo	18 Years -	R-Pharm
Evaluation of the Efficacy and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo, in Subjects With Rheumatoid Arthritis (RA) Who Were Taking an Existing Medication Called a Tumour Necrosis Factor Alpha Inhibitor But Had Active Disease	NCT02760433	Rheumatoid Arth...	Olokizumab Placebo	18 Years -	R-Pharm

Spots Global Cancer Trial Database for moderate rheumatoid arthritis