An Open-Label Extension Study Assessing the Long-Term Efficacy and Safety of ALX-0061 in Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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This was a multicenter, open-label extension (OLE) Phase II study designed to evaluate the long-term efficacy and safety of ALX-0061 (i.e., vobarilizumab) administered subcutaneously (s.c.) in subjects with active rheumatoid arthritis (RA) who had completed the treatment and assessment period of one of the preceding Phase IIb studies with ALX-0061 (ALX0061-C201 and ALX0061-C202; placebo and ALX-0061 treatment arms only), and who achieved at least 20% improvement in swollen joint count (SJC) and/or tender joint count (TJC) (66/68 counts) compared to Baseline at the final visit of the preceding study (i.e., Week 24 for Study ALX0061-C201 and Week 12 for Study ALX0061-C202).

Detailed Description
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Eligible subjects received one of the following treatments during the preceding Phase IIb studies ALX0061-C201 and ALX0061-C202: Study ALX0061-C201: Placebo (+ methotrexate [MTX]), or ALX-0061 75 mg every 4 weeks (q4w) (+ MTX), or ALX-0061 150 mg q4w (+ MTX), or ALX-0061 150 mg every 2 weeks (q2w) (+ MTX), or ALX-0061 225 mg q2w (+ MTX), for 24 weeks Study ALX0061-C202: ALX-0061 150 mg q4w, or ALX-0061 150 mg q2w, or ALX-0061 225 mg q2w, for 12 weeks At the Week 24 (ALX0061-C201) or Week 12 (ALX0061-C202) visit of the previous study, informed consent was obtained from all subjects who were deemed potentially eligible for the OLE study, according to the inclusion and exclusion criteria. This was marked as the Week 0 visit of the C203 study. Of note, the Baseline time point in the analyses of this study was defined the Baseline value of the parent study. In this OLE study, eligible subjects received ALX-0061 150 mg s.c. injections, beginning at Week 0 and every 2 weeks thereafter, up to and including Week 102. Eligible subjects from the preceding study ALX0061-C201 also continued their MTX treatment. Maintenance of the response (i.e., at least 20% improvement in both SJC and TJC compared to Baseline of the preceding study) was reassessed at the study visits at Weeks 12, 24, 36, 48, 60, 72, 84, and 96. Subjects who failed to maintain response and met the Efficacy Discontinuation Criteria were discontinued from this study.

Official Title
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A Phase II Multicenter, Open-Label Extension Study Assessing the Long-Term Efficacy and Safety of Subcutaneous ALX-0061 in Subjects With Moderate to Severe Rheumatoid Arthritis Who Have Completed One of the Preceding Phase IIb Studies With ALX-0061

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: ALX-0061


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have been eligible for one of the preceding Phase IIb studies with ALX-0061 (study ALX0061-C201 or ALX0061-C202), have been randomized to placebo or one of the ALX-0061 arms (subjects randomized to tocilizumab [TCZ] in study ALX0061-C202 were not eligible), and completed the entire treatment and assessment period of the preceding studies (i.e., 24 weeks for study ALX0061-C201 and 12 weeks for study ALX0061-C202). Must have reached at least 20% improvement in SJC and/or TJC (66/68 counts) compared to Week 0 at Week 24 for subjects participating in the preceding Phase IIb ALX0061 C201 study, or at Week 12 for subjects participating in the preceding Phase IIb ALX0061-C202 study Female subjects of childbearing potential (excluding postmenopausal women, sterilized, ovariectomized, and hysterectomized women) must agree to use 2 generally accepted adequate contraceptive methods of which 1 is a barrier method (e.g., hormonal contraception stabilized for at least 1 month [oral, patch, depot, injectable, vaginal ring] in combination with condom by partner) or should agree upon continuous abstinence from heterosexual contact from screening/baseline until at least 6 months after last dosing. Male subjects must use condoms for the duration of the study and for at least 6 months after last administration of study drug. Ability to comprehend and willingness to sign the informed consent form (ICF). An understanding of and ability and willingness to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: Received TCZ during the previous Study ALX0061-C202. Received any prohibited treatment during the previous Phase IIb studies (ALX0061-C201 or ALX0061-C202. Diagnosis of or suspicion of a serious infection (requiring parental antibiotics and/or hospitalization) or tuberculosis during the preceding study. Diagnosis of malignancy or demyelinating disease during the preceding study. Any active or recurrent viral infection that made the subject unsuitable for the study based on the Investigator's clinical assessment, including recurrent/disseminated herpes zoster. Diagnosis of congestive heart failure class III or IV (as defined by the New York Heart Association), unstable angina pectoris, myocardial infarction, and/or cerebrovascular accident during the preceding study. Abnormality in laboratory test results observed at the Week 22 visit for subjects participating in the preceding Phase IIb ALX0061-C201 study, or observed at the Week 10 visit for subjects participating in the preceding Phase IIb ALX0061-C202 study: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 2 times the upper limit of normal (ULN). Hemoglobin levels ≤ 85 g/L (8.5 g/dL). Platelet count ≤ 75 x 109/L (75,000 cells/mm³). Absolute neutrophil count < 1.5 x 109/L. Serum creatinine levels ≥ 1.5 mg/dL (133 μmol/L). Any other clinically significant abnormal laboratory result as evaluated by the Investigator. If no laboratory test results of the Week 22 Visit (for subjects participating in the preceding ALX0061-C201 study) or the Week 10 Visit (for subjects participating in the preceding ALX0061-C202 study) were available, then laboratory values of tests performed between Week 22 and 24 (for study ALX0061-C201) or Week 10 and 12 (for study ALX0061-C202) were taken into account for the exclusion criteria a to e listed above.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALX-0061 150 mg q2w (+ MTX)<br> | Biological: ALX-0061<br>* Subjects received ALX-0061 150 mg s.c. injections, beginning at Week 0 and q2w thereafter, up to and including Week 102. Subjects from the preceding study ALX0061-C201 also continued their MTX treatment.<br>* Other names: Vobarilizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With American College of Rheumatology (ACR) 20 Response. | ACR 20 response is defined as: 20% improvement in tender joint count (TJC; 68 joints) relative to Week 0 AND 20% improvement in swollen joint count (SJC; 66 joints) relative to Week 0 AND 20% improvement in 3 of the following 5 areas relative to Week 0: Subject's Assessment of Pain (100 mm - visual analogue scale [VAS]) Subject's Global Assessment of Disease Activity (VASPA) Physician's Global Assessment of Disease Activity (VASPHA) Subject's assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) C-reactive protein (CRP) level ACR20 responses were measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104 and Weeks 0, 12, 48, and 104 reported. | At Weeks 0, 12, 48, and 104 | 
| Number and Percentage of Subjects With ACR50 Response. | ACR50 response is defined as: 50% improvement in TJC (68 joints) relative to Week 0 AND 50% improvement in SJC (66 joints) relative to Week 0 AND 50% improvement in 3 of the following 5 areas relative to Week 0: Subject's Assessment of Pain (100 mm - VAS) Subject's Global Assessment of Disease Activity (VASPA) Physician's Global Assessment of Disease Activity (VASPHA) Subject's assessment of physical function as measured by HAQ-DI CRP level ACR50 responses were measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104 and Weeks 0, 12, 48, and 104 reported. | At Weeks 0, 12, 48, and 104 | 
| Number and Percentage of Subjects With ACR70 Response. | ACR70 response is defined as: 70% improvement in TJC (68 joints) relative to Week 0 AND 70% improvement in SJC (66 joints) relative to Week 0 AND 70% improvement in 3 of the following 5 areas relative to Week 0: Subject's Assessment of Pain (100 mm - VAS) Subject's Global Assessment of Disease Activity (VASPA) Physician's Global Assessment of Disease Activity (VASPHA) Subject's assessment of physical function as measured by HAQ-DI CRP level ACR70 responses were measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104 and Weeks 0, 12, 48, and 104 reported. | At Weeks 0, 12, 48, and 104 | 
| ACR-N Index of Improvement | The ACR-N Index of Improvement is defined as the minimum of the following 3 criteria: The percent improvement from Week 0 in TJCs The percent improvement from Week 0 in SJCs The median percent improvement from Week 0 for the following 5 assessments: Subject's assessment of pain (VAS) Subject's global assessment of disease activity (VASPHA) Physician's global assessment of disease activity (VASPHA) Subject's assessment of physical function as measured by the HAQ-DI CRP level ACR-N Index of Improvement was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104 and Weeks 0, 12, 48, and 104 reported. | At Weeks 0, 12, 48, and 104 | 
| Number and Percentage of Subjects in Remission or With Low, Moderate or High Disease Activity Based on Disease Activity Score Using 28 Joint Counts (DAS28) Using Estimated Sedimentation Rate (ESR) | DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) +(0.014 × VASPA) Remission = DAS28(ESR) < 2.6 Low disease activity = 2.6 ≤ DAS28 ≤ 3.2 Moderate disease activity = 3.2 < DAS28 ≤ 5.1 High disease activity = DAS28 > 5.1 Disease activity based on DAS28(ESR) was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104 and Weeks 0, 12, 48, and 104 reported. | At Weeks 0, 12, 48, and 104 | 
| Number and Percentage of Subjects With DAS28 Using C-reactive Protein (CRP) < 2.6, Low, Moderate or High Disease Activity Based on DAS28(CRP) | DAS28(CRP) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.36 × ln[CRP+1]) + (0.014 × VASPA) + 0.96 DAS28(CRP) < 2.6 Low disease activity = 2.6 ≤ DAS28 ≤ 3.2 Moderate disease activity = 3.2 < DAS28 ≤ 5.1 High disease activity = DAS28 > 5.1 Disease activity based on DAS28(CRP) was measured at Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, and 104 and Weeks 0, 12, 48, and 104 reported. | At Weeks 0, 12, 48, and 104 |