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

Rheumatoid Arthritis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02309359
• Other study ID #: ALX0061-C201
• Secondary ID: 2014-003033-26
• Status: Completed
• Phase: Phase 2
• Start date: January 2015
• Est. completion date: August 2016

Study information

• Verified date: August 2019
• Source: Ablynx
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 345
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 74 Years

Eligibility

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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Biological:
• ALX-0061

Other:
• Placebo

Drug:
• Methotrexate
Stable background dose of commercially available methotrexate (not provided by the Sponsor).

Locations

Country	Name	City	State
Belgium	Investigator Site	Brussels
Belgium	Investigator Site	Brussels
Belgium	Investigator Site	Ghent
Belgium	Investigator Site	Liège
Bulgaria	Investigator Site	Pleven
Bulgaria	Investigator Site	Plovdiv
Bulgaria	Investigator Site 1	Ruse
Bulgaria	Investigator Site 2	Ruse
Bulgaria	Investigator Site	Sofia
Bulgaria	Investigator Site	Sofia
Bulgaria	Investigator Site	Varna
Czechia	Investigator Site	Brno
Czechia	Investigator Site	Olomouc
Czechia	Investigator Site	Prague
Czechia	Investigator Site	Prague
Czechia	Investigator Site	Zlin
Georgia	Investigator Site	Tbilisi
Georgia	Investigator Site	Tbilisi
Georgia	Investigator Site	Tbilisi
Georgia	Investigator Site 1	Tbilisi
Georgia	Investigator Site 2	Tbilisi
Germany	Investigator Site	Bad Nauheim
Germany	Investigator Site	Berlin
Germany	Investigator Site	Berlin
Germany	Investigator Site	Cologne
Germany	Investigator Site	Frankfurt
Germany	Investigator Site	Hamburg
Hungary	Investigator Site	Baja
Hungary	Investigator Site	Balatonfüred
Hungary	Investigator Site	Békéscsaba
Hungary	Investigator Site	Budapest
Hungary	Investigator Site	Gyula
Hungary	Investigator Site	Székesfehérvar
Hungary	Investigator Site	Szikszó
Hungary	Investigator Site	Veszprém
Mexico	Investigator Site	Culiacan
Mexico	Investigator Site	Leon
Mexico	Investigator Site	Merida
Mexico	Investigator Site 1	Mexico City
Mexico	Investigator Site 2	Mexico City
Mexico	Investigator Site	Monclova
Mexico	Investigator Site	Monterey
Mexico	Investigator Site	Monterey
Moldova, Republic of	Investigator Site	Chisinau
North Macedonia	Investigator Site 1	Skopje
North Macedonia	Investigator Site 2	Skopje
Poland	Investigator Site	Bydgoszcz
Poland	Investigator Site	Elblag
Poland	Investigator Site	Elblag
Poland	Investigator Site	Gdynia
Poland	Investigator Site	Grodzisk Mazowiecki
Poland	Investigator Site	Katowice
Poland	Investigator Site	Lublin
Poland	Investigator Site	Poznan
Poland	Investigator Site	Sochaczew
Poland	Investigator Site	Torun
Poland	Investigator Site	Warszawa
Romania	Investigator Site	Braila
Romania	Investigator Site	Bucharest
Romania	Investigator Site	Bucharest
Romania	Investigator Site	Oradea
Romania	Investigator Site	Targu Mures
Romania	Investigator Site	Timisoara
Serbia	Investigator Site 1	Belgrade
Serbia	Investigator Site 2	Belgrade
Serbia	Investigator Site 3	Belgrade
Serbia	Investigator Site	Niska Banja
Serbia	Investigator Site	Novi Sad
Spain	Investigator Site	Madrid
Spain	Investigator Site	Madrid
Spain	Investigator Site	Salamanca
Spain	Investigator Site	Santiago de Compostela
United States	Investigator Site	Albuquerque	New Mexico
United States	Investigator Site	Birmingham	Alabama
United States	Investigator Site	Brooklyn	New York
United States	Investigator Sie	Charleston	South Carolina
United States	Investigator Site	Hemet	California
United States	Investigator Sites	Hialeah	Florida
United States	Investigator Site	Homestead	Florida
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	Memphis	Tennessee
United States	Investigator Site	Mesquite	Texas
United States	Investigator Site	Miami	Florida
United States	Investigator Site	Miami Lakes	Florida
United States	Investigator Site	Monroe	Louisiana
United States	Investigator Site	Myrtle Beach	South Carolina
United States	Investigator Site	New York	New York
United States	Investigator Site	Orlando	Florida
United States	Investigator Site	Overland Park	Kansas
United States	Investigator Site	Stockbridge	Georgia
United States	Investigator Site	Ventura	California
United States	Investigator Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Ablynx

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  Czechia,  Georgia,  Germany,  Hungary,  Mexico,  Moldova, Republic of,  North Macedonia,  Poland,  Romania,  Serbia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Week 12
Secondary	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.	24 weeks
Secondary	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.	24 weeks
Secondary	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.	24 weeks
Secondary	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 × vTJC28) + (0.28 × vSJC28) + (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.	24 weeks
Secondary	Number and Percentage of Subjects With LDA Using DAS28 Using Erythrocyte Sedimentation Rate (ESR) at Weeks 12 and 24	DAS28(ESR) = (0.56 × vTJC28) + (0.28 × vSJC28) + (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.	24 weeks
Secondary	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.	24 weeks
Secondary	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.	24 weeks
Secondary	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.	24 weeks
Secondary	Number and Percentage of Subjects in Remission Using DAS28 (ESR) at Weeks 12 and 24	DAS28(ESR) = (0.56 × vTJC28) + (0.28 × vSJC28) + (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.	24 weeks
Secondary	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.	24 weeks
Secondary	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.	24 weeks
Secondary	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.	24 weeks
Secondary	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.	from baseline till Week 24
Secondary	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.	from baseline till Week 24
Secondary	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.	from baseline till Week 24
Secondary	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.	from baseline till Week 24
Secondary	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.	at Week 12 and Week 24 visits
Secondary	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).	from baseline till Week 24
Secondary	Number of Subjects With Development of a Treatment-emergent Antidrug Antibody Response		from baseline till follow-up (FU) (i.e., 12 weeks after last study drug dosing at Week 22 or after early treatment discontinuation)
Secondary	Number and Percentage of Subjects With Treatment-emergent Adverse Events by Severity		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
Secondary	Number of Treatment-emergent Adverse Events by Severity		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
Secondary	Number and Percentage of Subjects With Treatment-related Treatment-emergent Adverse Events		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
Secondary	Number of Treatment-related Treatment-emergent Adverse Events		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