Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis

NCT ID: NCT02603146

Last Updated: 2025-06-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 144 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-04-27
• Study Completion Date: 2022-11-01

Brief Summary

The purpose of this study is to determine if hydroxychloroquine (HCQ) is safe and effective for the prevention of future onset of rheumatoid arthritis (RA) in individuals who have elevations of an autoantibody, anti-cyclic citrullinated peptide (anti-CCP3).

The following recruitment strategies will be employed towards identifying healthy subjects with elevated anti-cyclic citrullinated peptide (anti-CCP3) levels:

-Pre-screening:

• first degree relatives of patients with rheumatoid arthritis (RA);
• subjects at health-fairs; and
• identification of subjects with elevated anti-CCP3 levels in the absence of inflammatory arthritis in rheumatology clinics.

Detailed Description

Rheumatoid arthritis (RA) affects an estimated 1% of the population. RA is a disease where the immune system attacks the joints, leading to joint inflammation and damage that is felt by someone with RA as joint pain, stiffness and swelling.

Recent studies have shown that there are markers in the blood called 'autoantibodies' that precede the onset of joint symptoms of RA. Antibodies are commonly made in the blood to fight infections. Sometimes, these antibodies attack one's own body. These are called autoantibodies.

Certain autoantibodies are specific for certain diseases. The autoantibody known as anti-CCP3 is specific for RA and can predict the development of RA in the future, especially if the level of anti-CCP3 is high. The investigators of this study believe that individuals with elevations of anti-CCP3 ≥2 times the normal value have approximately a 50% chance of developing RA within 3 years.

Hydroxychloroquine (HCQ) is already used successfully and safely in the treatment of malaria, lupus and RA. The objective of this study is to determine whether treatment with HCQ in individuals with elevations of anti-CCP3 without joint inflammation may help prevent the future onset of RA. This will involve a 12-month course of HCQ in the prevention of the development of clinically apparent RA at 36 months in individuals at high-risk for future RA due to high titer elevations of anti-CCP3. This study will recruit for individuals without a history or clinical findings of inflammatory arthritis. Eligible subjects will be randomized in a 1:1 ratio to HCQ versus HCQ placebo.

Conditions

Healthy Participants; Rheumatoid Arthritis (RA) Prevention

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Hydroxychloroquine Group

Subjects randomized to hydroxychloroquine (HCQ). Subjects will receive 200-400 mg of HCQ (1-2 pills), based upon ideal body weight (IBW), taken daily for 12 months.

Group Type: EXPERIMENTAL

Hydroxychloroquine

Intervention Type: DRUG

As described. Dosing will be based upon Screening IBW.

Placebo Group

Subjects randomized to placebo HCQ. Subjects will receive 200 - 400 mg of HCQ placebo (1-2 pills), based upon IBW, taken daily for 12 months.

Group Type: PLACEBO_COMPARATOR

HCQ Placebo

Intervention Type: DRUG

As described. Dosing will be based upon Screening IBW.

Interventions

Hydroxychloroquine

As described. Dosing will be based upon Screening IBW.

Intervention Type: DRUG

HCQ Placebo

As described. Dosing will be based upon Screening IBW.

Intervention Type: DRUG

Other Intervention Names

HCQ; Plaquenil; Placebo

Eligibility Criteria

Inclusion Criteria

Subjects who meet all of the following criteria are eligible for enrollment into the study:

• Able and willing to give written informed consent and comply with requirements of the study;
• Age ≥18 years-old at the Screening Visit; and
• Elevation of autoantibody anti-cyclic citrullinated peptide-3 (anti-CCP3) defined by result of anti-CCP3 ≥40 units, at Screening.

Exclusion Criteria

Subjects who meet any of the following criteria are ineligible to participate in the study:

-A medical history of inflammatory arthritis (IA) of any type and/or rheumatic disease and immunologic disease(s) that may be associated with IA . These diseases include but are not limited to:

• rheumatoid arthritis (RA);
• systemic lupus erythematosus (SLE);
• seronegative spondyloarthropathies;
• inflammatory bowel disease;
• Sjögren's syndrome;
• polymyalgia rheumatic; or
• vasculitis.

Note: Crystalline arthropathies are not exclusionary.

• A medical history of:

• congestive heart failure or functional status of New York Heart Association (NYHA) Class III or higher at the Screening Visit;
• cardiomyopathy or significant cardiac conduction disorders;
• chronic liver disease;
• psoriasis (due to potential for increased risk for flare of skin disease);
• porphyria;
• and/or serologic evidence during Screening Visit of chronic infections including, but not limited to, human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV);

---Exception: hepatitis C antibody positive subjects are eligible with documentation of:

• receipt of HCV treatment AND
• a negative hepatitis C viral load test post-treatment.
• malignancy within the last 5 years, except for treated basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer Grade I; or
• alcohol or substance abuse within 1 year of treatment randomization.
• Prior or current systemic treatment with disease modifying anti-rheumatic agents, immunomodulatory agents, or glucocorticoids for IA, other rheumatic diseases, or other immunologic diseases;
• Tetracycline class antibiotic use for autoimmune conditions, taken within 12 months prior to Screening;
• Systemic corticosteroid use for non-IA conditions taken 28 days prior to Screening;
• More than 3 local corticosteroid injections, including but not limited to intra-articular, epidural, and intrabursal injections, during the 3 months prior to randomization;
• A history of a chronic condition that, in the opinion of the investigator, is highly likely to require therapy with systemic corticosteroids (oral or intravenous) within the study period, including but not limited to severe asthma and severe crystalline arthropathy;
• Women who are pregnant, breastfeeding or desire to become pregnant and/or breast feed within the duration of the 12-month treatment phase of the study;
• Women of childbearing potential who are not using or who do not agree to use adequate birth control measures (for example, total abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, surgical sterilization, Depo-Provera, or hormonal implants) during the treatment phase of the study;
• An ideal or actual body weight ≤ 24.4 kg (e.g., ≤53 lbs) at Screening Visit;
• Any of the following laboratory abnormalities at the Screening Visit:

• Serum Creatinine Clearance < 50ml/min (as calculated by the Cockcroft-Gault formula: Creatinine clearance (CrCl)= (140-age) X (Weight in kg) X (0.85 if female) / (72 X Creatinine));
• Alanine Aminotransferase (ALT) > 2 times the upper limit of normal (ULN);
• Aspartate Aminotransferase (AST) > 2x the upper limit of normal (ULN);
• Total white blood count (WBC) < 3.0 x 10^9/L;
• Platelet count ≤ 150 x10^9/L;
• Hemoglobin < 11.5g/dL;
• Absolute Neutrophil Count (ANC) < 2.0 x 10^9/L;
• Evidence of significant retinal disease upon eye examination during the screening period that in the opinion of the examiner would make identification of potential future retinal toxicity from HCQ difficult to evaluate:

-- Retinal exam results may be applied to evaluations of subject eligibility for up to 6 months after the initial retinal exam.

• When, in the opinion of the study physician, the subject is not a good study candidate.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Autoimmunity Centers of Excellence

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kevin Deane, MD, PhD

Role: STUDY_CHAIR

University of Colorado School of Medicine

Michael Holers, MD

Role: STUDY_CHAIR

University of Colorado School of Medicine

Christopher Striebich, MD, PhD

Role: STUDY_CHAIR

University of Colorado School of Medicine

Locations

University of Alabama at Birmingham School of Medicine: Division of Clinical Immunology & Rheumatology

Birmingham, Alabama, United States

Cedars Sinai Medical Center: Division of Rheumatology

Los Angeles, California, United States

UCLA Medical Center: Division of Rheumatology

Los Angeles, California, United States

University of California San Francisco, San Francisco General Hospital

San Francisco, California, United States

University of Colorado School of Medicine: Division of Rheumatology

Aurora, Colorado, United States

Emory Clinic at 1365 Clifton Road: Emory University School of Medicine

Atlanta, Georgia, United States

Brigham & Women's Hospital: Department of Medicine, Rheumatology, Immunology

Boston, Massachusetts, United States

University of Massachusetts Memorial Medical Center: Rheumatology

Worcester, Massachusetts, United States

University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology

Ann Arbor, Michigan, United States

Mayo Clinic, Division of Rheumatology

Rochester, Minnesota, United States

University of Nebraska Medical Center: Division of Rheumatology

Omaha, Nebraska, United States

Northwell Health

Great Neck, New York, United States

Oklahoma Medical Research Foundation: Arthritis and Clinical Immunology Research Program

Oklahoma City, Oklahoma, United States

University of Texas Southwestern Medical Center, Division of Rheumatic Diseases

Dallas, Texas, United States

Countries

United States

References

Deane KD, Striebich CC, Feser ML, O'Dell JR, James JA, Sparks JA, Davis JM, Graf J, McMahon MA, Solow EB, Forbess L, Tiliakos A, Schiopu E, Danila MI, Horowitz DL, Kay J, Strickland CD, Guthridge JM, Arriens C, Grossman JM, Demoruelle MK, Bemis EA, Frazer-Abel A, Fleischer CL, Fox DA, Mikuls TR, Greenleaf M, York K, Walker S, Keyes-Elstein L, Byron M, Fedler J, Goldmuntz EA, Holers VM. A phase 2 trial of hydroxychloroquine in individuals at risk for rheumatoid arthritis. Arthritis Rheumatol. 2025 Aug 29. doi: 10.1002/art.43366. Online ahead of print.

Reference Type: DERIVED

PMID: 40884017 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT)

Other Identifiers

NIAID CRMS ID#: 20681

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT ARA08

Identifier Type: -

Identifier Source: org_study_id