Efficacy and Safety of Olokizumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study was to evaluate the long-term safety and tolerability of olokizumab (OKZ) 64 mg administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) in subjects with moderately to severely active rheumatoid arthritis (RA) who previously had completed 24 weeks of double-blind treatment in Study CREDO 1, 2 or 3 (core studies). The long-term efficacy, immunogenicity, the physical function and quality of life of subjects received long-term treatment with OKZ were assessed as well.

Detailed Description
-----------------
This OLE study (CL04041024) included an 82-week open-label Treatment Period that followed completion of one of the core studies (Study CREDO 1, 2 or 3). The OLE open-label Treatment Period lasted from Visit 1 (OLE Baseline/Week 24) to Visit 10 (End of Treatment (EoT)/Week 106), followed by a 20-week Safety Follow-Up Period from Week 106 to Week 126. The first visit of the OLE study was the same visit as the Week 24 visit in the core studies. Subjects were randomized to 1 of the 2 OKZ treatment groups in the OLE study based on the treatment received in the core studies. Subjects who had received OKZ (q2w or q4w) in the core study in which they had participated (including subjects who received placebo in Study CREDO 3 and were re-randomized to OKZ at Week 16) received the same OKZ treatment regimen in the OLE study. Subjects who had received placebo (Study CREDO 1 and CREDO 2) or adalimumab (Study CREDO 2) in the core study in which they had participated were randomized in a 1:1 ratio to OKZ 64 mg q2w or OKZ 64 mg q4w regimens in the OLE study. For the first 12 weeks of the OLE, all subjects were required to remain on a stable dose of background methotrexate (MTX) at 15 to 25 mg/week (or≥10 mg/week if there was documented intolerance to higher doses) with a stable route of administration (oral, SC, or intramuscular (IM)). After 12 weeks (Visit 4 [Week 36] of the OLE study), the Investigator might adjust the MTX dosage and route, per local guidelines. Methotrexate might be adjusted only for safety reasons according to Investigator discretion before Visit 4 (Week 36) of the OLE study. Subjects who had been on rescue disease-modifying anti-rheumatic drugs (DMARDs) during the core studies were asked to continue these medications for the first 12 weeks of the OLE study. The Investigator could adjust these background medications if deemed appropriate after Visit 4 (Week 36) of the OLE study. Background rescue therapy might be adjusted only for safety reasons according to Investigator discretion before Visit 4 (Week 36) of the OLE study. Throughout the study, concomitant treatment with folic acid ≥ 5 mg per week or equivalent was required for all subjects. Subjects returned to the study site periodically for safety and response assessments as per the Schedule of Events. The last dose of open-label study treatment in the OLE study was administered at Week 104 for all subjects. After completion of the 82-week open-label Treatment Period, subjects entered the 20-week Safety Follow-Up Period. During the Safety Follow-Up Period, subjects returned for 3 visits at +4, +8, and +22 weeks after the last dose of study treatment. Subjects who discontinued the open-label treatment prematurely required to come for the EoT Visit 2 weeks after the last study treatment administration and then return for the 3 Safety Follow-Up Visits +4, +8, and +22 weeks after the last study treatment administration. Adverse events were assessed throughout the study period and evaluated using the Common Technology Criteria version 4.0 (CTCAE v 4.0). There were ongoing monitoring of safety events, including laboratory findings by the Sponsor or its designee. In addition, safety parameters were assessed throughout the study by an independent Data Safety Monitoring Board (DSMB).

Official Title
-----------------
A Multicenter, Open-Label, Phase III Study of the Efficacy and Safety of Olokizumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Olokizumab 64 mg SC q4w
* Drug: Olokizumab 64 mg SC q2w
* Drug: Concomitant treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects may be enrolled in the study only if they meet all of the following criteria: Subject must be willing and able to sign informed consent Subject must have completed the 24-week double-blind Treatment Period in 1 of the 3 core studies (CL04041022, CL04041023, or CL04041025). Subject must have maintained their stable dose (and route) of MTX 15 to 25 mg/week (or ≥ 10 mg/week if there is documented intolerance to higher doses) during the core study and plan to maintain the same dose and route of administration for ≥ 12 additional weeks Subjects must be willing to take folic acid or equivalent throughout the study. Exclusion Criteria: Subject with any medically important condition in the core study (e.g., clinically significant laboratory values, frequent Adverse events (AEs) or serious adverse events (SAEs), infection SAEs, and/or other concurrent severe and/or uncontrolled medical condition) which would make this subject unsuitable for inclusion in the open-label extension (OLE) study in the Investigator's judgement. Subject has evidence of active tuberculosis (TB) Subject with a positive or repeated indeterminate interferon-gamma release assay (IGRA) result at Week 22 of the core study - Subjects may be enrolled in the OLE study if they fulfill all 3 of the following criteria prior to the first dose of study treatment: Active TB is ruled out by a certified TB specialist or pulmonologist who is familiar with diagnosing and treating TB (as acceptable per local practice); The subject starts prophylaxis for latent TB infection (LTBI) according to country-specific/Centers for Disease Control and Prevention (CDC) guidelines (treatment with isoniazid for 6 months is not an appropriate prophylactic regime for this study and it should not be used); and The subject is willing to complete the entire course of recommended LTBI therapy. Subject has planned surgery during the first 12 weeks of the OLE study Female subjects who are pregnant or who are planning to become pregnant during the study or within 6 months of the last dose of study drug Female subjects of childbearing potential (unless permanent cessation of menstrual periods, determined retrospectively after a woman has experienced 12 months of natural amenorrhea as defined by the amenorrhea with underlying status [e.g., correlative age] or 6 months of natural amenorrhea with documented serum follicle-stimulating hormone levels >40 mIU/mL and estradiol <20 pg/mL) who are not willing to use a highly effective method of contraception during the study and for at least 6 months after the last administration of study treatment OR Male subjects with partners of childbearing potential not willing to use a highly effective method of contraception during the study and for at least 3 months after the last administration of study treatment. Highly effective contraception is defined as: Female sterilization surgery: hysterectomy, surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to the first dose of study treatment in the core study In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by documented follow-up hormone level assessment Total abstinence if it is the preferred and constant lifestyle of the subject. Thus, periodic abstinence such as ovulation, symptothermal, postovulation, calendar methods, and withdrawal are not acceptable methods of contraception. Male sterilization surgery: at least 6 months prior to the first dose of study treatment in the core study (with the appropriate postvasectomy documentation of the absence of sperm in the ejaculate). For female subjects, the vasectomized male should be the only partner. Placement of established intrauterine device (IUD): IUD copper or IUD with progesterone Barrier method (condom and intravaginal spermicide, cervical caps with spermicide, or diaphragm with spermicide) in combination with the following: established oral, injected, or implanted hormone methods of contraception or contraceptive patch. Subject is unwilling or unable to follow the procedures outlined in the protocol. Other medical or psychiatric conditions, or laboratory abnormalities that may increase the potential risk associated with study participation and administration of the study treatment, or that may affect study results interpretation and, as per Investigator's judgement, make the subject ineligible.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm 1: OKZ 64 mg q4w + MTX<br>Olokizumab 64 mg SC q4w + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular). | Drug: Olokizumab 64 mg SC q4w<br>* 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial with target volume of 0.4 mL or in the pre-filled syringe (PFS).PFS is composed of a 1 mL clear Type I glass barrel vial with target volume of 0.4 mL.<br>Drug: Concomitant treatment<br>* Methotrexate 15 to 25 mg/week (or ≥ 10 mg/week if there was documented intolerance to higher doses). (Subject maintained their stable dose and route (oral, SC, or IM) during the core study and for ≥ 12 additional weeks of OLE.) Folic acid ≥ 5 mg per week or equivalent<br>|
| Experimental: Treatment Arm 2: OKZ 64 mg q2w + MTX<br>Olokizumab 64 mg SC q2w + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular). | Drug: Olokizumab 64 mg SC q2w<br>* 160 mg/mL sterile solution for SC injection in a 2 mL clear Type I glass vial with target volume of 0.4 mL or in the pre-filled syringe (PFS). PFS is composed of a 1 mL clear Type I glass barrel vial with target volume of 0.4 mL.<br>Drug: Concomitant treatment<br>* Methotrexate 15 to 25 mg/week (or ≥ 10 mg/week if there was documented intolerance to higher doses). (Subject maintained their stable dose and route (oral, SC, or IM) during the core study and for ≥ 12 additional weeks of OLE.) Folic acid ≥ 5 mg per week or equivalent<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (AEs), by System Organ Class and Preferred Term (Safety Population) | Incidence of Treatment-Emergent Adverse Events Reported for ≥5% of Subjects in Any Treatment Group by System Organ Class or Preferred Term | up to Week 126 | 
| Incidence of Treatment-Emergent Serious Adverse Events (SAEs), by System Organ Class and Preferred Term (Safety Population) | Incidence of Serious Treatment-Emergent Adverse Events by System Organ Class or Preferred Term. Deaths are included. | up to Week 126 | 
| Incidence of Treatment-Emergent Adverse Events of Special Interest (AESI) |  | up to Week 126 | 
| Incidence of Treatment-Emergent AEs Leading to Withdrawal of the Study Treatment |  | up to Week 126 | 
| Incidence Rate of Treatment Emergent AEs Per Patient-years of Exposure | Incidence Rate of all Subjects with at Least One Treatment Emergent AE. Subject Incidence Rate (IR) is summarized per 100 subject years (SY) of follow-up (/100 SY) based on the OLE safety population and presented by study treatments. | up to Week 126 | 
| Incidence Rate of Treatment Emergent SAEs Per Patient-years of Exposure | Incidence Rate of all Subjects with at Least One Treatment Emergent SAE. Subject Incidence Rate (IR) is summarized per 100 subject years (SY) of follow-up (/100 SY) based on the OLE safety population and presented by study treatments. | up to Week 126 | 
| Incidence Rate of Treatment Emergent AESIs (Safety Population) | Incidence Rate of all Subjects with at Least One Treatment Emergent AESI. Subject Incidence Rate (IR) is summarized per 100 subject years (SY) of follow-up (/100 SY) based on the OLE safety population and presented by study treatments. | up to Week 126 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American College of Rheumatology 20% (ACR20) Response Rates Compare Against Core Baseline Through Week 82 | Number and Proportion of subjects achieving an ACR20 response who remain on randomized open-label treatment and in the study, assessed at several timepoints up to Week 82. 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) | up to Week 82 | 
| American College of Rheumatology 50% (ACR50) Response Rates Compare Against Core Baseline Through Week 82 | Number and Proportion of subjects achieving an ACR50 response who remain on randomized open-label treatment and in the study, assessed at several timepoints up to Week 82 American College of Rheumatology 50 % response is a composite defined as a ≥ 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) | up to Week 82 | 
| American College of Rheumatology 70% (ACR70) Response Rates Compare Against Core Baseline Through Week 82 | Number and Proportion of subjects achieving an ACR70 response who remain on randomized open-label treatment and in the study, assessed at several timepoints up to Week 82 American College of Rheumatology 70 % response is a composite defined as a ≥ 70% improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥ 70% 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) | up to Week 82 | 
| Proportion of Subjects With Simplified Disease Activity Index (SDAI) Remission Through Week 82 | The number and proportion of subjects with SDAI score ≤ 3.3 (considered to be in remission). The SDAI was calculated in the statistical database for analysis purposes using the SJC (28 joints), TJC (28 joints), CRP (mg/dL), the Patient Global Assessment of Disease Activity (VAS) (in cm), and the Physician Global Assessment (VAS) (in cm) according to the following formula: SJC + TJC + Patient Global Assessment of Disease Activity (VAS) + Physician Global Assessment (VAS) + CRP (mg/dL) | up to week 82 | 
| Disease Activity Score 28-joint Count (DAS28) Response Rates Through Week 82 | Number and Proportion of subjects with DAS28 low disease activity (based on DAS28 C-reactive protein (CRP) < 3.2), who remain on randomized open-label treatment and in the study, assessed at several timepoints up to Week 82. The DAS28 (CRP) was calculated in the statistical database for analysis purposes using the Swollen joint count (SJC) (28 joints), Tender joint count (TJC) (28 joints), CRP level, and the Patient Global Assessment of Disease Activity Visual Analog Scale (VAS) (100 mm VAS, where 0 is no disease activity and 100 was maximal disease activity) according to the following formula: [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.36 × natural log (CRP+1)] + [0.014 × VAS] + 0.96. | up to Week 82 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 12 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 12 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 20 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 20 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 28 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 28 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 40 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 40 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 52 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 52 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 64 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 64 | 
| Change in Health Assessment Questionnaire-Disability Index (HAQ-DI) From Core Baseline at Week 82 | HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | Core baseline, Week 82 | 
| Proportion of Subjects With Health Assessment Questionnaire - Disability Index (HAQ-DI) Improvement Through Week 82 | The number and proportion of subjects with HAQ-DI improvement ≥ 0.22 Against OLE Baseline. HAQ-DI Range: 0 (the best outcome) - 3 (the worst outcome), with a decrease from baseline indicating improvement. 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 (activity) 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 (i.e., question in each category with the highest score for that category). The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. | up to week 82 | 
| Changes From Core Baseline Over Time in Clinical Disease Activity Index (CDAI) | CDAI Range: 0 (the best outcome) - 76 (the worst outcome), with a decrease from baseline indicating improvement. The CDAI was calculated in the statistical database for analysis purposes using the SJC (28 joints), TJC (28 joints), the Patient Global Assessment of Disease Activity (VAS) (in cm), and the Physician Global Assessment (VAS) (in cm) according to the following formula: CDAI = SJC + TJC + Patient Global Assessment of Disease Activity (VAS) + Physician Global Assessment (VAS) | up to week 82 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rheumatoid Arthritis, moderate, severe, subcutaneous, Olokizumab, open-label