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A Dose-Range Finding Study for ALX-0061 Combination Therapy in Subjects With Rheumatoid Arthritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02309359
Recruitment Status : Completed
First Posted : December 5, 2014
Results First Posted : August 21, 2019
Last Update Posted : August 21, 2019
Sponsor:
Information provided by (Responsible Party):
Ablynx

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Biological: ALX-0061 Other: Placebo Drug: Methotrexate Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 345 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase IIb Multicenter, Randomized, Double-blind, Placebo-Controlled Dose-Range Finding Study of ALX-0061 Administered Subcutaneously in Combination With Methotrexate, in Subjects With Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy
Study Start Date : January 2015
Actual Primary Completion Date : August 2016
Actual Study Completion Date : August 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo q2w + MTX
Placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
Other: Placebo
Drug: Methotrexate
Stable background dose of commercially available methotrexate (not provided by the Sponsor).

Experimental: ALX-0061 75 mg q4w + MTX
ALX-0061 75 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
Biological: ALX-0061
Other: Placebo
Drug: Methotrexate
Stable background dose of commercially available methotrexate (not provided by the Sponsor).

Experimental: ALX-0061 150 mg q4w + MTX
ALX-0061 150 mg every 4 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
Biological: ALX-0061
Other: Placebo
Drug: Methotrexate
Stable background dose of commercially available methotrexate (not provided by the Sponsor).

Experimental: ALX-0061 150 mg q2w + MTX
ALX-0061 150 mg every 2 weeks + placebo every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24. The last study drug administration was at the Week 22 visit.
Biological: ALX-0061
Other: Placebo
Drug: Methotrexate
Stable background dose of commercially available methotrexate (not provided by the Sponsor).

Experimental: ALX-0061 225 mg q2w + MTX

ALX-0061 225 mg every 2 weeks + MTX (at a stable dose and route) from baseline through Week 24.

The last study drug administration was at the Week 22 visit.

Biological: ALX-0061
Drug: Methotrexate
Stable background dose of commercially available methotrexate (not provided by the Sponsor).




Primary Outcome Measures :
  1. Number and Percentage of Subjects Achieving American College of Rheumatology (ACR) 20 Response at Week 12 [ Time Frame: 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.



Secondary Outcome Measures :
  1. Number and Percentage of Subjects With ACR20 Response at Week 24 [ Time Frame: 24 weeks ]

    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.


  2. Number and Percentage of Subjects With ACR50 Response at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  3. Number and Percentage of Subjects With ACR70 Response at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  4. 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 [ Time Frame: 24 weeks ]

    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.


  5. Number and Percentage of Subjects With LDA Using DAS28 Using Erythrocyte Sedimentation Rate (ESR) at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  6. Number and Percentage of Subjects With LDA Using Simplified Disease Activity Index (SDAI) at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  7. Number and Percentage of Subjects With LDA Using Clinical Disease Activity Index (CDAI) at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  8. Number and Percentage of Subjects With European League Against Rheumatism (EULAR) (CRP) Good Response at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  9. Number and Percentage of Subjects in Remission Using DAS28 (ESR) at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  10. Number and Percentage of Subjects in Remission Using SDAI at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  11. Number and Percentage of Subjects in Remission Using CDAI at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  12. Number and Percentage of Subjects in Remission Using Boolean Defined Remission Criteria at Weeks 12 and 24 [ Time Frame: 24 weeks ]

    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.


  13. Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 12 and 24 [ Time Frame: from baseline till Week 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.


  14. Change From Baseline in Physical Component Score of Short Form Health Survey (SF-36) at Weeks 12 and 24 [ Time Frame: from baseline till Week 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.

  15. Change From Baseline in Mental Component Score of Short Form Health Survey (SF-36) at Weeks 12 and 24 [ Time Frame: from baseline till Week 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.

  16. Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Subscale at Weeks 12 and 24 [ Time Frame: from baseline till Week 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.

  17. Pharmacokinetics: ALX-0061 Concentration in Serum at Weeks 12 and 24 [ Time Frame: at Week 12 and Week 24 visits ]
    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.

  18. Pharmacodynamics: Concentrations of Soluble Interleukin-6 Receptor (sIL-6R) at Weeks 12 and 24 [ Time Frame: from baseline till Week 24 ]
    Values below the limit of quantification are imputed with the lower limit of quantification (LLOQ).

  19. 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) ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of RA for at least 6 months prior to screening, and American College of Rheumatology (ACR) functional class I-III
  • Subjects treated with and tolerating MTX
  • Active RA
  • Others as defined in the protocol

Exclusion Criteria:

  • Have been treated with disease-modifying antirheumatic drugs (DMARDs)/systemic immunosuppressives other than MTX.
  • Have received approved or investigational biological or targeted synthetic DMARD therapies for RA 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, for RA.
  • Have received prior therapy blocking the interleukin-6 (IL-6) pathway, at any time.
  • Others as defined in the protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02309359


Locations
Show Show 94 study locations
Sponsors and Collaborators
Ablynx
Investigators
Layout table for investigator information
Study Director: Ablynx Clinical Department Ablynx
  Study Documents (Full-Text)

Documents provided by Ablynx:
Layout table for additonal information
Responsible Party: Ablynx
ClinicalTrials.gov Identifier: NCT02309359    
Other Study ID Numbers: ALX0061-C201
2014-003033-26 ( EudraCT Number )
First Posted: December 5, 2014    Key Record Dates
Results First Posted: August 21, 2019
Last Update Posted: August 21, 2019
Last Verified: August 2019
Additional relevant MeSH terms:
Layout table for MeSH terms
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors