A Phase IIb Study for ALX-0061 Monotherapy in Subjects With Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is: - To assess the efficacy and safety of dose regimens of ALX-0061 monotherapy administered subcutaneously (s.c.) to subjects with active rheumatoid arthritis (RA). The secondary objectives of this study are: To assess the effects of ALX-0061 on quality of life, the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ALX-0061 and to explore potential dose regimens for ALX-0061 monotherapy, based on safety and efficacy, for further clinical development. To obtain parallel descriptive information concerning the efficacy and safety of tocilizumab (TCZ) s.c. in the same clinical trial RA population.

Official Title
-----------------
A Phase IIb Multicenter, Randomized, Double-blind Study of ALX-0061 Administered Subcutaneously as Monotherapy, in Subjects With Moderate to Severe Rheumatoid Arthritis Who Are Intolerant to Methotrexate or for Whom Continued Methotrexate Treatment is Inappropriate

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

Intervention / Treatment
-----------------
* Biological: ALX-0061
* Biological: Placebo
* Biological: Tocilizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of RA (according to the 2010 EULAR/American College of Rheumatology (ACR) classification criteria) for at least 6 months prior to screening, and ACR functional class I-III. Received previous or current treatment with methotrexate (MTX), and is considered intolerant to MTX, or for whom continued treatment with MTX is inappropriate or has contraindications for MTX use. Subjects must not have received MTX for at least 4 weeks before first administration of the study drug. Have active RA with at least 6 swollen and 6 tender joints(66/68 joint count) at the time of screening and baseline Others as defined in the protocol Exclusion Criteria: Have been treated with DMARDs (Disease Modifying Antirheumatic Drugs)/systemic immunosuppressive drugs during the 4 weeks, or 12 weeks for hydroxychloroquine, chloroquine, or leflunomide (except when an adequate wash-out procedure for leflunomide was completed), prior to first administration of study drug. Have received approved or investigational biological or targeted synthetic DMARD therapies for RA (including tumor necrosis factor alpha-inhibitors, abatacept, rituximab, or Janus kinase [JAK]-inhibitors) less than 6 months prior to screening. Have a history of toxicity, non-tolerance, primary non-response or inadequate response to a biological therapy, or targeted synthetic DMARDs (including JAK inhibitors), for RA. Have received prior therapy blocking the interleukin-6 (IL-6) pathway, at any time. Others as defined in the protocol.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALX-0061 150 mg q4w<br>ALX-0061 150 mg every 4 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit. | Biological: ALX-0061<br> <br> Biological: Placebo<br> <br> |
| Experimental: ALX-0061 150 mg q2w<br>ALX-0061 150 mg every 2 weeks from baseline through Week 12 + placebo every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit. | Biological: ALX-0061<br> <br> Biological: Placebo<br> <br> |
| Experimental: ALX-0061 225 mg q2w<br>ALX-0061 225 mg every 2 weeks from baseline through Week 12. The last injection with study drug was administered at the Week 10 visit. | Biological: ALX-0061<br> <br> |
| Active Comparator: TCZ 162 mg q1w or q2w<br>Open-label TCZ. Injections were to be performed q1w or q2w depending on the approved label per region (last injection was administered at Week 10 or Week 11, depending on the dose regimen). | Biological: Tocilizumab<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With American College of Rheumatology 20 (ACR20) at Week 12 | 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 The primary endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing ACR20 response at Week 12 were treated as non-responders. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With ACR50 and ACR70 Response at Week 12 | ACR50/70 response is defined as: 50/70% improvement in TJC (68 joints) relative to Week 0 AND 50/70% improvement in SJC (66 joints) relative to Week 0 AND 50/70% 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 This endpoint was analyzed using NRI, i.e., subjects with missing response at Week 12 were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects With Low Disease Activity (LDA) Using Disease Activity Score Using 28 Joint Counts (DAS28) Using C-reactive Protein (CRP) at Week 12 | DAS28(CRP) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.36 × ln[CRP+1]) + (0.014 × VASPA) + 0.96 Low disease activity = 2.6 ≤ DAS28 ≤ 3.2 Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects With LDA Using DAS28 Using Erythrocyte Sedimentation Rate (ESR) at Week 12 | DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) +(0.014 × VASPA) Low disease activity = 2.6 ≤ DAS28 ≤ 3.2 Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects With LDA Using Simplified Disease Activity Index (SDAI) at Week 12 | SDAI = TJC28 + SJC28 + VASPA + VASPHA + CRP (mg/dL) Low disease activity: 3.3 < SDAI ≤ 11.0 Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects With LDA Using Clinical Disease Activity Index (CDAI) at Week 12 | CDAI = TJC28 + SJC28 + VASPA + VASPHA Low disease activity: 2.8 < CDAI ≤ 10 Subjects with low disease activity includes subjects who are in remission. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects With European League Against Rheumatism (EULAR) (CRP) Good Response at Week 12 | EULAR good response is defined as an improvement of >1.2 in DAS28 (CRP) relative to baseline. This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects in Remission Using DAS28 (ESR) at Week 12 | DAS28(ESR) = (0.56 × √TJC28) + (0.28 × √SJC28) + (0.70 × ln[ESR]) +(0.014 × VASPA) Remission = DAS28(ESR) < 2.6 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects in Remission Using SDAI at Week 12 | SDAI = TJC28 + SJC28 + VASPA + VASPHA + CRP (mg/dL) Remission: SDAI ≤ 3.3 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects in Remission Using CDAI at Week 12 | CDAI = TJC28 + SJC28 + VASPA + VASPHA Remission: CDAI ≤ 2.8 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Number and Percentage of Subjects in Remission Using Boolean Defined Remission Criteria at Week 12 | Boolean remission: tender joint count (TJC)28 ≤ 1 and swollen joint count (SJC)28 ≤ 1 and VASPA (cm) ≤ 1 and CRP (mg/dL) ≤ 1 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non-responders. | Week 12 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12 | The HAQ-DI is a 20-question instrument which assesses the degree of difficulty the subject had in accomplishing tasks in 8 functional areas over the previous week. The 8 areas are: dressing and grooming, hygiene, arising, reach, eating, grip, walking, common daily activities. Within each area, subjects report the amount of difficulty they have in performing the specific items. There are 4 response options ranging from: 0 = No Difficulty, 1 = With Some Difficulty, 2 = With Much Difficulty, 3 = Unable to Do. The 8 areas are each given a single score equal to the maximum value of their component activities (0, 1, 2, or 3). The sum of the area scores is then divided by the number of areas answered to obtain the final HAQ score (rounded to the nearest value evenly divisible by 0.125). The final HAQ-DI score ranges from 0 to 3. A high score means a high degree of disability (=worse outcome). Missing values were imputed with the last non-missing observation. | From baseline until Week 12 | 
| Change From Baseline in Physical and Mental Component Scores of Short Form Health Survey (SF-36) at Week 12 | The Short Form (36) Health Survey (SF-36) consists of 36 items that can be summarized into 8 domains: physical functioning, role limitations due to physical health problems (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional problems (role-emotional), and mental health. Two summary measures, the physical component summary and the mental component summary, can be derived based on these domain scores. Each score is directly transformed into a 0-100 score on the assumption that each question carries equal weight. Low score indicates greater disability. | From baseline until week 12 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Subscale at Week 12 | The FACIT Measurement System is a collection of health-related quality of life questionnaires that assess multidimensional health status in people with various chronic illnesses. The FACIT Fatigue Scale is a short, 13-item, easy to administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. The level of fatigue is measured on a four point Likert scale (4 = not at all fatigued to 0 = very much fatigued). To score the FACIT-fatigue, all items are summed to create a single fatigue score with a range from 0 to 52. Items are reverse scored when appropriate to provide a scale in which higher scores represent better functioning or less fatigue. | From baseline until Week 12 | 
| Pharmacodynamics: Concentrations of Soluble Interleukin-6 Receptor (sIL-6R) | Values below the limit of quantification are imputed with the lower limit of quantification (LLOQ). | From baseline until Week 12 | 
| Pharmacokinetics: ALX-0061 Concentration in Serum at Week 12 |  | From baseline until Week 12 | 
| Number and Percentage of Subjects With Development of a Treatment-emergent Antidrug Antibody Response |  | From first study drug intake up to and including follow-up (FU), i.e., maximum of 22 weeks (10 weeks of treatment + 12 weeks of FU) | 
| Number and Percentage of Subjects With Treatment-emergent Adverse Event by Severity |  | From baseline until Week 12 | 
| Number of Treatment-emergent Adverse Event by Severity |  | From baseline until Week 12 | 
| Number and Percentage of Subjects With a Treatment-related Treatment-emergent Adverse Event | treatment related = considered at least possibly related to study drug by the Investigator | From baseline until Week 12 | 
| Number of Treatment-related Treatment-emergent Adverse Event | treatment related = considered at least possibly related to study drug by the Investigator | From baseline until Week 12 |