Clinical trial NCT02603146: Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis
Official title: Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Healthy Participants
Rheumatoid Arthritis (RA) Prevention
Keywords: RA prevention
hydroxychloroquine (HCQ)
anti-CCP3
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Autoimmunity Centers of Excellence
First posted: 2015-11-11
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Number of Participants Who Developed Clinically-Apparent Rheumatoid Arthritis (CL - RA) From Treatment Initiation to Month 36 By Treatment Arm
timeFrame: Baseline to Month 36
Secondary outcomes:
measure: Number of Participants Who Developed Clinically-Apparent Rheumatoid Arthritis (CL-RA) From Treatment Initiation to Month 12 By Treatment Arm
timeFrame: Baseline to Month 12
measure: Number of Participants Who Developed Inflammatory Arthritis (IA) From Treatment Initiation to Month 12.
timeFrame: Baseline to Month 12
measure: Time to Development of Clinically-Apparent Rheumatoid Arthritis (CL - RA) By Treatment Arm
timeFrame: Baseline to Month 36
measure: Number of Participants Who Developed Inflammatory Arthritis (IA) From Treatment Initiation to Month 36
timeFrame: Baseline to Month 36
measure: Number of Participant Self-Reported Painful Joints By Treatment Arm
timeFrame: At Week 52 and Month 36/End of Study
measure: Number of Participant Self-Reported Stiff Joints By Treatment Arm
timeFrame: At Week 52 and Month 36/End of Study
measure: Number of Participant Self-Reported Swollen Joints By Treatment Arm
timeFrame: At Week 52 and Month 36/End of Study
measure: Number of Participant Self-Reported Painful Joints in the Hands, Wrists and Feet By Treatment Arm
timeFrame: At Week 52 and Month 36/End of Study
measure: Number of Participant Self-Reported Stiff Joints in the Hands, Wrists and Feet By Treatment Arm
timeFrame: At Week 52 and Month 36/End of Study
measure: Number of Participant Self-Reported Swollen Joints in the Hands, Wrists and Feet By Treatment Arm
timeFrame: At Week 52 and Month 36/End of Study
measure: Level of Anti-Cyclic Citrullinated Peptide-3 (Anti-CCP3) By Treatment Arm
timeFrame: Baseline, Week 52 (End of Treatment), Month 36/End of Study
measure: Level of Immunoglobulin M - Rheumatoid Factor (IgM-RF) By Treatment Arm
timeFrame: Baseline, Week 52 (End of Treatment), Month 36/End of Study
measure: Level of High-Sensitivity C-Reactive Protein (hsCRP) Treatment Arm
timeFrame: Baseline, Week 52 (End of Treatment), Month 36/End of Study
measure: Percent of Participants Experiencing Grade 3 or Higher Adverse Events (AEs)
timeFrame: Non-serious AEs were collected from treatment initiation through month 18. Serious AEs were collected from screening through month 36.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine: Division of Clinical Immunology & Rheumatology
state: Alabama
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center: Division of Rheumatology
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center: Division of Rheumatology
state: California
city: San Francisco
country: United States
facility: University of California San Francisco, San Francisco General Hospital
state: California
city: Aurora
country: United States
facility: University of Colorado School of Medicine: Division of Rheumatology
state: Colorado
city: Atlanta
country: United States
facility: Emory Clinic at 1365 Clifton Road: Emory University School of Medicine
state: Georgia
city: Boston
country: United States
facility: Brigham & Women's Hospital: Department of Medicine, Rheumatology, Immunology
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center: Rheumatology
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System: Department of Internal Medicine, Division of Rheumatology
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Division of Rheumatology
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center: Division of Rheumatology
state: Nebraska
city: Great Neck
country: United States
facility: Northwell Health
state: New York
city: Oklahoma City
country: United States
facility: Oklahoma Medical Research Foundation: Arthritis and Clinical Immunology Research Program
state: Oklahoma
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center, Division of Rheumatic Diseases
state: Texas
Study officials:
affiliation: University of Colorado School of Medicine
name: Kevin Deane, MD, PhD
role: STUDY_CHAIR
affiliation: University of Colorado School of Medicine
name: Michael Holers, MD
role: STUDY_CHAIR
affiliation: University of Colorado School of Medicine
name: Christopher Striebich, MD, PhD
role: STUDY_CHAIR
References: