A Pilot Study of the Feasibility of Discontinuation of Adalimumab in Stable Rheumatoid Arthritis Patients in Clinical Remission

AbbVie (prior sponsor, Abbott)33 enrolled

Overview

The purpose of this pilot study is to investigate the possibility of discontinuing adalimumab therapy in patients with rheumatoid arthritis who are in stable remission after treatment with adalimumab in combination with methotrexate.

Treatments with adalimumab and other tumor necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), are usually continued indefinitely. Information concerning the possibility of discontinuing anti-TNF therapy in RA patients who are in remission is limited. This is a pilot study in one country to study the effect of adalimumab discontinuation. The objective is to assess the proportion of patients with established RA in stable remission (Disease Activity Score \[DAS\]28 \<2.6) after treatment with adalimumab in combination with methotrexate, in whom it is possible to discontinue adalimumab and to compare the remission rates among patients on sustained therapy with adalimumab + methotrexate with remission rates among patients who discontinued adalimumab. Rheumatoid arthritis patients in stable remission (DAS28 \< 2.6) treated with adalimumab + methotrexate were randomized in a 1:1 ratio to continue with adalimumab treatment or discontinue adalimumab treatment for the following 52 weeks. Subsequently an observational extension was conducted to observe patients treated at the discretion of the investigator. The observational extension period lasted until Weeks 105 - 156 (average Week 125) and consisted of one follow-up visit. Participants randomized to discontinue adalimumab therapy will be reinstituted to adalimumab if DAS28-score increases by \>1.2 units from baseline and/or is scored ≥2.6 at any visit during the study and will be followed for an additional 12 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Masking

NONE

Enrollment

Conditions

Arthritis, Rheumatoid

Interventions

adalimumabBIOLOGICAL

40 mg every other week via subcutaneous injection

methotrexateDRUG

At least 10 mg/week administered orally or subcutaneously

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥18 years. * Diagnosis of RA as defined by the 1987-revised American College of Rheumatology (ACR)-classification and has positive rheumatoid factor (RF) test or erosion on X-ray of hands or feet. * Currently treated with adalimumab and MTX (at least 10 mg/week; orally or subcutaneously). * In remission as defined by disease activity score (DAS)28 \<2.6 for at least the past 3 months. * Concomitant disease-modifying anti-rheumatic drug (DMARD) or oral corticosteroid therapy has been stable for at least 3 months at study entry. * Female subject is either not of childbearing potential or is practicing a relevant method of birth control. * Subject is judged to be in good general health. * Subjects must be able and willing to provide written informed consent. * Subjects must be able and willing to self-administer subcutaneous (SC) injections or have a qualified person available to administer SC injections. Exclusion Criteria: * Treatment with intra-articular or parenteral administration of corticosteroids in the preceding 4 weeks. * Oral prednisone or prednisone equivalent \> 10 mg/day at baseline. * Joint surgery within the preceding two months. * History of acute inflammatory joint disease other than RA. * Treatment with any investigational drug within 30 days or 5 half lives, whichever is longer prior to study entry. * Poorly controlled medical condition, which would put the subject at risk by participation in the study. * History of clinically significant hematologic, renal or liver disease. * Diagnosis of, or history suggestive of, central nervous system (CNS) demyelinating disease. * History of cancer or lymphoproliferative disease other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or localized carcinoma of the cervix. * History of listeriosis, histoplasmosis, untreated tuberculosis (TB), persistent chronic infections, or recent active infections. * Known immune deficiency or human immunodeficiency virus (HIV). * Female who is pregnant or breast-feeding or considering becoming pregnant or breast feeding during the study.

Locations (8)

Site Reference ID/Investigator# 22062

Linköping, Sweden

Site Reference ID/Investigator# 14022

Lund, Sweden

Site Reference ID/Investigator# 14023

Malmo, Sweden

Site Reference ID/Investigator# 14301

Oskarström, Sweden

Outcomes

Primary Outcomes

Percentage of Participants in Remission at Week 28

Remission is defined as a Disease Activity Score (DAS)28 of less than 2.6. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein (CRP), and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. In this analysis participants in the methotrexate treatment group with a DAS28 score ≥ 2.6 (and thus allocated to rescue therapy with adalimumab) prior to Week 28 were considered not to be in remission at Week 28. Also, participants who did not complete 28 weeks were considered not in remission.

Time frame: Week 28

Percentage of Participants in Remission at Week 28 in the Full Analysis Set 2 (FAS2)

Time frame: Week 28

Secondary Outcomes

Percentage of Participants in Remission at Week 52

Remission is defined as a Disease Activity Score (DAS)28 of less than 2.6. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein (CRP), and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. In this analysis participants in the methotrexate treatment group with a DAS28 score ≥ 2.6 (and thus allocated to rescue therapy with adalimumab) prior to Week 52 were considered not to be in remission at Week 52. Also, participants who did not complete 52 weeks were considered not in remission.

Data from ClinicalTrials.gov

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Site Reference ID/Investigator# 20241

Skövde, Sweden

Site Reference ID/Investigator# 4918

Stockholm, Sweden

Site Reference ID/Investigator# 14021

Stockholm, Sweden

Site Reference ID/Investigator# 14302

Uppsala, Sweden

Percentage of Participants in Remission at Week 52 (FAS2)

Remission is defined as a Disease Activity Score (DAS)28 of less than 2.6. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein (CRP), and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity. Also, participants who did not complete 52 weeks were considered not in remission. In this analysis participants in the methotrexate treatment group with a DAS28 score ≥ 2.6 (and thus allocated to rescue therapy with adalimumab) prior to Week 52 were considered not to be in remission at Week 52.

Time frame: Week 52

Number of Participants With a Flare

Flare is defined as DAS28 ≥2.6 or an increase from Baseline in the DAS28 of greater than 1.2 units. The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein (CRP), and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, and 52

Percentage of Participants With Response to Adalimumab Treatment (Return to Baseline DAS28 + ≤ 10%) After a Flare

For participants with a flare and treated with adalimumab rescue therapy, response was defined as return to Baseline DAS28 + ≤ 10% after reinstitution of adalimumab (rescue therapy). The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein (CRP), and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity.

Time frame: 1 to 4 weeks, 5 to 8 weeks, 9 to 12 weeks, and 13 to 16 weeks after reinstitution of adalimumab rescue therapy

Percentage of Participants With Response to Adalimumab Treatment (DAS28 <2.6 or DAS28 Decrease >1.2 Units) After a Flare

For participants with a flare and treated with adalimumab rescue therapy, response was defined as DAS28 less than 2.6 or DAS28 decrease of greater than 1.2 units after reinstitution of adalimumab (rescue therapy). The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein (CRP), and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10, with higher scores indicating higher disease activity.

Time frame: 1 to 4 weeks, 5 to 8 weeks, 9 to 12 weeks, and 13 to 16 weeks after reinstitution of adalimumab rescue therapy

Health Assessment Questionnaire (HAQ) Total Score by Visit

Physical function was evaluated using the Health Assessment Questionnaire - Disability Index (HAQ-DI), a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. HAQ remission indicating normal physical function is defined by HAQ-DI \< 0.5.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

European Quality of Life-5 Dimensions (EQ-5D) Mobility Score by Visit

The EQ-5D is an international, standardized, generic instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their mobility health state: Level 1: I have no problems in walking about; Level 2: I have some problems in walking about; Level 3: I am confined to bed.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

European Quality of Life-5 Dimensions (EQ-5D) Self-care Score by Visit

The EQ-5D is an international, standardized, generic instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their self-care health state: Level 1: I have no problems with self-care; Level 2: I have some problems washing or dressing myself; Level 3: I am unable to wash or dress myself.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score by Visit

The EQ-5D is an international, standardized, generic instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state with regard to usual activities (work, study, housework, family, or leisure activities): Level 1: I have no problems performing my usual activities; Level 2: I have some problems performing my usual activities; Level 3: I am unable to perform my usual activities.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score by Visit

The EQ-5D is an international, standardized, generic instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their pain/discomfort health state: Level 1: I have no pain or discomfort; Level 2: I have moderate pain or discomfort; Level 3: I have extreme pain or discomfort.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score by Visit

The EQ-5D is an international, standardized, generic instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their anxiety/depression health state: Level 1: I am not anxious or depressed; Level 2: I am moderately anxious or depressed; Level 3: I am extremely anxious or depressed.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) by Visit

The EQ-5D is an international, standardized, generic instrument for describing and evaluating health status. Health status is assessed by patients evaluating their health on a vertical, visual analog scale from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (0) and 'Best imaginable health state' (100).

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale by Visit

The FACIT-Fatigue questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions on a scale from 'not at all' (0) to 'very much' (4). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT-Fatigue subscale score ranges from 0 to 52, where higher scores represent less fatigue.

Time frame: Baseline and Weeks 4, 8, 12, 20, 28, 36, 44, 52, and 104-156 (extension period visit)

Work Instability Score (WIS) for RA: I'm Getting up Earlier Because of Arthritis

Work Instability (defined as the mismatch between the person's abilities and the demands of work) Score is a 23-item questionnaire designed to indicate the participant's level of risk for work disability. In question 1, participants selected either Yes or No if the following statement currently applied to them or not: I'm getting up earlier because of the arthritis.