The purpose of this study is to assess the efficacy and safety of dose regimens of ALX-0061 administered subcutaneously (s.c.) in combination with methotrexate (MTX) to subjects with active rheumatoid arthritis (RA) despite MTX therapy, compared with placebo. To assess the effects of ALX-0061 on quality of life, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ALX-0061, and to define the optimal dose regimen for ALX-0061, based on safety and efficacy, for further clinical development.
Subjects who completed the 24-week assessment period and achieved at least 20% improvement in swollen joint count (SJC) and/or tender joint count (TJC) at Week 24 of study ALX0061-C201 were invited to participate in an open-label extension (OLE) study ALX0061-C203 (NCT02518620), if the study was approved in their country and selection criteria were met.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
345
Stable background dose of commercially available methotrexate (not provided by the Sponsor).
Number and Percentage of Subjects Achieving American College of Rheumatology (ACR) 20 Response 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.
Time frame: Week 12
Number and Percentage of Subjects With ACR20 Response at Week 24
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 This endpoint was analyzed using NRI, i.e., subjects with missing response at Week 24 were treated as non responders.
Time frame: 24 weeks
Number and Percentage of Subjects With ACR50 Response at Weeks 12 and 24
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 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.
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Investigator Site
Birmingham, Alabama, United States
Investigator Site
Hemet, California, United States
Investigator Site
La Palma, California, United States
Investigator Site
Los Angeles, California, United States
Investigator site
Los Angeles, California, United States
Investigator Site
Ventura, California, United States
Investigator Sites
Hialeah, Florida, United States
Investigator Site
Homestead, Florida, United States
Investigator Site
Miami, Florida, United States
Investigator Site
Miami Lakes, Florida, United States
...and 84 more locations
Time frame: 24 weeks
Number and Percentage of Subjects With ACR70 Response at Weeks 12 and 24
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 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.
Time frame: 24 weeks
Number and Percentage of Subjects With Low Disease Activity (LDA) Using Disease Activity Score 28 (DAS28) Using C-reactive Protein (CRP) at Weeks 12 and 24
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 This endpoint was analyzed using NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.
Time frame: 24 weeks
Number and Percentage of Subjects With LDA Using DAS28 Using Erythrocyte Sedimentation Rate (ESR) at Weeks 12 and 24
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.
Time frame: 24 weeks
Number and Percentage of Subjects With LDA Using Simplified Disease Activity Index (SDAI) at Weeks 12 and 24
SDAI = TJC28 + SJC28 + Patient's Global Assessment of Disease Activity (VASPA) + Physician's Global Assessment of Disease Activity (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 NRI, i.e., subjects with missing response at the concerned visit were treated as non responders.
Time frame: 24 weeks
Number and Percentage of Subjects With LDA Using Clinical Disease Activity Index (CDAI) at Weeks 12 and 24
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.
Time frame: 24 weeks
Number and Percentage of Subjects With European League Against Rheumatism (EULAR) (CRP) Good Response at Weeks 12 and 24
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.
Time frame: 24 weeks
Number and Percentage of Subjects in Remission Using DAS28 (ESR) at Weeks 12 and 24
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.
Time frame: 24 weeks
Number and Percentage of Subjects in Remission Using SDAI at Weeks 12 and 24
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.
Time frame: 24 weeks
Number and Percentage of Subjects in Remission Using CDAI at Weeks 12 and 24
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.
Time frame: 24 weeks
Number and Percentage of Subjects in Remission Using Boolean Defined Remission Criteria at Weeks 12 and 24
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 non-responder imputation (NRI), i.e., subjects with missing response at the concerned visit were treated as non responders.
Time frame: 24 weeks
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 12 and 24
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.
Time frame: from baseline till Week 24
Change From Baseline in Physical Component Score of Short Form Health Survey (SF-36) at Weeks 12 and 24
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. The lower the score the more disability. The higher the score the less disability.
Time frame: from baseline till Week 24
Change From Baseline in Mental Component Score of Short Form Health Survey (SF-36) at Weeks 12 and 24
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. The lower the score the more disability. The higher the score the less disability.
Time frame: from baseline till Week 24
Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Subscale at Weeks 12 and 24
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.
Time frame: from baseline till Week 24
Pharmacokinetics: ALX-0061 Concentration in Serum at Weeks 12 and 24
ALX-0061 concentrations were only measured in samples of subjects randomized to any of the ALX-0061 treatment arms. Samples were taken predose at the concerned visits.
Time frame: at Week 12 and Week 24 visits
Pharmacodynamics: Concentrations of Soluble Interleukin-6 Receptor (sIL-6R) at Weeks 12 and 24
Values below the limit of quantification are imputed with the lower limit of quantification (LLOQ).
Time frame: from baseline till Week 24
Number of Subjects With Development of a Treatment-emergent Antidrug Antibody Response
Time frame: from baseline till follow-up (FU) (i.e., 12 weeks after last study drug dosing at Week 22 or after early treatment discontinuation)
Number and Percentage of Subjects With Treatment-emergent Adverse Events by Severity
Time frame: From first study drug intake until the Week 24 or Early Termination visit. Only safety data through Week 24 is reported as 256 of the 293 subjects who completed the 24-week treatment period rolled-over to the C203 Study and did not perform the FU visit
Number of Treatment-emergent Adverse Events by Severity
Time frame: From first study drug intake until the Week 24 or Early Termination visit. Only safety data through Week 24 is reported as 256 of the 293 subjects who completed the 24-week treatment period rolled-over to the C203 Study and did not perform the FU visit
Number and Percentage of Subjects With Treatment-related Treatment-emergent Adverse Events
Time frame: From first study drug intake until the Week 24 or Early Termination visit. Only safety data through Week 24 is reported as 256 of the 293 subjects who completed the 24-week treatment period rolled-over to the C203 Study and did not perform the FU visit
Number of Treatment-related Treatment-emergent Adverse Events
Time frame: From first study drug intake until the Week 24 or Early Termination visit. Only safety data through Week 24 is reported as 256 of the 293 subjects who completed the 24-week treatment period rolled-over to the C203 Study and did not perform the FU visit