Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis

Phase 2

Terminated

Conditions: Healthy Participants
Rheumatoid Arthritis (RA) Prevention

Interventions: Drug: HCQ Placebo
Drug: Hydroxychloroquine

Registration Number: NCT02603146

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 144

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Group	HCQ Placebo	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.
Hydroxychloroquine Group	Hydroxychloroquine	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Developed Clinically-Apparent Rheumatoid Arthritis (CL - RA) From Treatment Initiation to Month 36 By Treatment Arm	Baseline to Month 36	Clinically-Apparent RA is defined by the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria as either: 1.) a score of ≥ 6 defining "definite RA" or 2.) a joint examination consistent with Inflammatory Arthritis (IA) with ≥ 1 erosion confirmed by x-ray imaging of the hands, wrists, and feet.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Developed Inflammatory Arthritis (IA) From Treatment Initiation to Month 12.	Baseline to Month 12	IA is defined as the development of at least one swollen joint consistent with rheumatoid arthritis-like (RA-like) synovitis. The joint exams conducted by a physician at each clinic visit were used to identify the presence of swollen joints due to IA.
Number of Participants Who Developed Clinically-Apparent Rheumatoid Arthritis (CL-RA) From Treatment Initiation to Month 12 By Treatment Arm	Baseline to Month 12	Clinically-Apparent RA is defined by the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria as either: 1.) a score of ≥ 6 defining "definite RA" or 2.) a joint examination consistent with IA with ≥ 1 erosion confirmed by x-ray imaging of the hands, wrists, and feet.
Time to Development of Clinically-Apparent Rheumatoid Arthritis (CL - RA) By Treatment Arm	Baseline to Month 36	Mean Time from treatment initiation until development of CL-RA. CL- RA is defined by the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification Criteria as either: 1.) a score of ≥ 6 defining "definite RA" or 2.) a joint examination consistent with IA with ≥ 1 erosion confirmed by x-ray imaging of the hands, wrists, and feet.
Number of Participants Who Developed Inflammatory Arthritis (IA) From Treatment Initiation to Month 36	Baseline to Month 36	IA is defined as the development of at least one swollen joint consistent with rheumatoid arthritis-like (RA-like) synovitis. The joint exams conducted by a physician at each clinic visit were used to identify the presence of swollen joints due to IA.
Number of Participant Self-Reported Painful Joints By Treatment Arm	At Week 52 and Month 36/End of Study	The Participant Self-Reported Joint Symptoms assessment was used by participants to indicate which joints were painful on the day of the visit or in the past week. The Participant Self-Reported Joint Symptoms assessment contained a diagram of the body joints which participants used to mark their painful joints.
Number of Participant Self-Reported Stiff Joints By Treatment Arm	At Week 52 and Month 36/End of Study	The Participant Self-Reported Joint Symptoms assessment was used by participants to indicate which joints were stiff on the day of the visit or in the past week. The Participant Self-Reported Joint Symptoms assessment contained a diagram of the body joints which participants used to mark their stiff joints.
Number of Participant Self-Reported Swollen Joints By Treatment Arm	At Week 52 and Month 36/End of Study	The Participant Self-Reported Joint Symptoms assessment was used by participants to indicate which joints were swollen on the day of the visit or in the past week. The Participant Self-Reported Joint Symptoms assessment contained a diagram of the body joints which participants used to mark their swollen joints.
Number of Participant Self-Reported Painful Joints in the Hands, Wrists and Feet By Treatment Arm	At Week 52 and Month 36/End of Study	The Participant Self-Reported Joint Symptoms assessment was used by participants to indicate which joints were painful on the day of the visit or in the past week. The Participant Self-Reported Joint Symptoms assessment contained a diagram of the body joints which participants used to mark their painful joints.
Number of Participant Self-Reported Stiff Joints in the Hands, Wrists and Feet By Treatment Arm	At Week 52 and Month 36/End of Study	The Participant Self-Reported Joint Symptoms assessment was used by participants to indicate which joints were stiff on the day of the visit or in the past week. The Participant Self-Reported Joint Symptoms assessment contained a diagram of the body joints which participants used to mark their stiff joints.
Number of Participant Self-Reported Swollen Joints in the Hands, Wrists and Feet By Treatment Arm	At Week 52 and Month 36/End of Study	The Participant Self-Reported Joint Symptoms assessment was used by participants to indicate which joints were swollen on the day of the visit or in the past week. The Participant Self-Reported Joint Symptoms assessment contained a diagram of the body joints which participants used to mark their swollen joints.
Level of Anti-Cyclic Citrullinated Peptide-3 (Anti-CCP3) By Treatment Arm	Baseline, Week 52 (End of Treatment), Month 36/End of Study	Anti-CCP3 is a laboratory test for the presence of antibodies to citrullinated protein antigens (ACPAs) in serum. ACPA positivity assists with the classification/diagnosis of Rheumatoid Arthritis (RA) of a patient with Inflammatory Arthritis (IA). In addition, determining autoantibody positivity helps with the prediction of RA disease severity. Anti-CCP3 positivity at any level, and in particular anti-CCP3 levels of ≥2 times the normal cut-off level (or ≥ 40 units) are highly predictive of future RA development.
Level of High-Sensitivity C-Reactive Protein (hsCRP) Treatment Arm	Baseline, Week 52 (End of Treatment), Month 36/End of Study	HsCRP is used to detect systemic inflammation in the body, assists with the classification/diagnosis of Rheumatoid Arthritis (RA), and elevations of hsCRP in patients with RA have been associated with poor disease outcomes.
Percent of Participants Experiencing Grade 3 or Higher Adverse Events (AEs)	Non-serious AEs were collected from treatment initiation through month 18. Serious AEs were collected from screening through month 36.	Adverse Events (AEs) grading will be defined by the National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. The number of AEs will be identified by monitoring participant-reported AEs, vital signs, medical history, physical exams and blood safety tests.
Level of Immunoglobulin M - Rheumatoid Factor (IgM-RF) By Treatment Arm	Baseline, Week 52 (End of Treatment), Month 36/End of Study	IgM-RF is a laboratory test for the presence of antibodies to RF in serum. IgM-RF positivity assists with the classification/diagnosis of Rheumatoid Arthritis (RA) of a patient with Inflammatory Arthritis (IA). In addition, determining autoantibody positivity helps with the prediction of RA disease severity. Higher levels of antibodies (e.g. \>2-3 times the normal cut-off values) have greater specificity for RA disease.

Trial Locations

Locations (14): University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology
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Ann Arbor, Michigan, United States
University of Nebraska Medical Center: Division of Rheumatology
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Omaha, Nebraska, United States
Cedars Sinai Medical Center: Division of Rheumatology
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Los Angeles, California, United States
Emory Clinic at 1365 Clifton Road: Emory University School of Medicine
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Atlanta, Georgia, United States
Northwell Health
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Great Neck, New York, United States
University of Texas Southwestern Medical Center, Division of Rheumatic Diseases
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Dallas, Texas, United States
Brigham & Women's Hospital: Department of Medicine, Rheumatology, Immunology
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Boston, Massachusetts, United States
University of Alabama at Birmingham School of Medicine: Division of Clinical Immunology & Rheumatology
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Birmingham, Alabama, United States
University of Colorado School of Medicine: Division of Rheumatology
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Aurora, Colorado, United States
University of California San Francisco, San Francisco General Hospital
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San Francisco, California, United States
University of Massachusetts Memorial Medical Center: Rheumatology
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Worcester, Massachusetts, United States
Mayo Clinic, Division of Rheumatology
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Rochester, Minnesota, United States
Oklahoma Medical Research Foundation: Arthritis and Clinical Immunology Research Program
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Oklahoma City, Oklahoma, United States
UCLA Medical Center: Division of Rheumatology
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Los Angeles, California, United States