Study of Anti-Malarials in Incomplete Lupus Erythematosus

NCT ID: NCT03030118

Last Updated: 2025-09-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 187 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-28
• Study Completion Date: 2024-06-30

Brief Summary

This project is a multicenter, randomized, placebo-controlled, double-blind clinical trial that is designed to test whether treating patients who are at risk for development of lupus with hydroxychloroquine can slow accumulation of disease features. Effects on clinical progression of symptoms, patient-reported outcomes and changes in the immune markers of response will be measured and toxicity of the treatment will be assessed. This trial is a first step in testing a prevention strategy for lupus.

Detailed Description

Systemic lupus erythematosus (SLE) causes major organ damage and shortens lifespan in relatively young persons. Early diagnosis and treatment are essential to improving outcomes for SLE patients. However, evidenced-based approaches to early treatment interventions and the appropriate target population for these interventions are not available. We propose that individuals who have positivity for antinuclear antibodies (ANAs) and who also exhibit some of the other features that are used to classify SLE, are at high risk of progressing to the full systemic form of this disease. These individuals, who have significant levels of ANA with 1 or 2 additional items from the lupus classification criteria, are considered to have incomplete lupus erythematosus (ILE). We propose to treat ILE patients with hydroxychloroquine (HCQ) in the "Study of Anti-Malarials in Incomplete Lupus Erythematosus" or SMILE trial. The primary objective is to determine whether HCQ treatment can prevent acquisition of additional clinical and immunologic features that define SLE.

The major secondary objectives are to determine whether HCQ treatment: (1) lessens lupus disease activity as measured by standard scoring indices; (2) improves patient reported outcomes (3) prevents accumulation of immunologic abnormalities including autoantibodies and cytokines and (4) has an acceptable toxicity profile. The specific aims of this proposal are:

1. To carry out a double-blind, placebo-controlled, multicenter, randomized trial of HCQ vs. placebo in patients with ILE. The study tests the hypothesis that early use of HCQ can modify disease features so that accumulation of abnormalities leading to a classification of SLE can be significantly slowed.

2. To determine effects of HCQ on disease activity and patient-reported outcomes in patients with ILE.

3. To characterize the immunologic profile of HCQ in ILE-treated patients. Autoantibodies, cytokines and chemokines will be measured on multiplex arrays for developing insights into underlying mechanisms.

4. To quantitatively assess the incidence of ophthalmologic toxicity in HCQ-treated ILE patients. All enrolled patients will have standardized ophthalmologic examinations before and after study treatment. Recommendations for use and monitoring in this patient population will be developed.

The SMILE trial will determine whether or not HCQ should be given to ILE patients, will provide insights into the appropriate target population, and will propose candidate biomarkers to guide treatment decisions. While not part of the Precision Medicine Initiative®, SMILE is consistent with its goals. It will be the first step towards testing the feasibility of disease prevention studies in SLE and will accumulate biological samples in a repository that will be available to the lupus research community for further in-depth mechanistic studies.

Conditions

Systemic Lupus Erythematosus

Study Design

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

Study Groups

Hydroxychloroquine

Hydroxychloroquine will be administered as a once daily dose of 200 or 400 mg, based on the patient's weight. Treatment will be for 96 weeks.

Group Type: ACTIVE_COMPARATOR

Hydroxychloroquine

Intervention Type: DRUG

Hydroxychloroquine is classified as an anti-malarial and it is has immunomodulatory functions that make it useful for treatment of autoimmune disorders including systemic lupus erythematosus and rheumatoid arthritis.

Placebo oral capsule

Placebo will be administered as one or two capsules as a single daily dose, based on the patient's weight. Treatment will be for 96 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo Oral Capsule

Intervention Type: DRUG

An oral capsule placebo is made to match the active intervention medication hydroxychloroquine.

Interventions

Hydroxychloroquine

Hydroxychloroquine is classified as an anti-malarial and it is has immunomodulatory functions that make it useful for treatment of autoimmune disorders including systemic lupus erythematosus and rheumatoid arthritis.

Intervention Type: DRUG

Placebo Oral Capsule

An oral capsule placebo is made to match the active intervention medication hydroxychloroquine.

Intervention Type: DRUG

Other Intervention Names

Plaquenil; Placebo

Eligibility Criteria

Inclusion Criteria

1. Between 15 and 49 years of age, inclusive, at Visit 1.

2. Anti-nuclear antibody (ANA) titer of 1:80, or greater, as determined by immunofluorescence assay (IFA).

3. Participants must have at least one (but not three or more) additional clinical or laboratory criterion from the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria.

4. Written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for subject to comply with the requirements of the study.

Exclusion Criteria

1. The subject meets the 2012 SLICC classification criteria for SLE at Visit 1 (i.e., ANA plus 3 other criteria, or ANA plus biopsy-proven lupus nephritis).

2. The subject has been diagnosed with another autoimmune disorder, other than autoimmune thyroid conditions.

3. The subject has fibromyalgia, based on clinical history and exam.

4. The subject has previously been or is currently being treated with oral antimalarial agents including hydroxychloroquine, chloroquine, or quinacrine.

5. The subject is currently or has been treated with immunosuppressive, immune modifying, or cytotoxic medications as listed in Section 7.2.

6. Use of any investigational agent within the preceding 12 months.

7. History of primary immunodeficiency.

8. Active bacterial, viral, fungal, or opportunistic infection.

9. Evidence of infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C.

10. Concomitant malignancy or history of malignancy with the exception of adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.

11. The subject has significant findings on ophthalmological examination that, in the opinion of the examining Ophthalmologist, prevent safe use of hydroxychloroquine.

12. The subject has other contraindications to treatment with hydroxychloroquine including pre-existing ocular disease, hepatic impairment, psoriasis, porphyria, or allergy to the drug or class.

13. Co-morbidities requiring systemic corticosteroid therapy greater than 10 mg of prednisone per day, or equivalent, or a change in corticosteroid dose within the 3 months prior to Visit 1.

14. Starting, stopping, or changing the dose of over the counter or prescription non-steroidal anti-inflammatory drugs (NSAIDs) in the three months prior to Visit 1.

15. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.

16. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.

17. Inability to comply with the study visit schedule and procedures.

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 49 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

NIH

Sponsor Role: collaborator

Milton S. Hershey Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Nancy Olsen

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nancy J Olsen, MD

Role: PRINCIPAL_INVESTIGATOR

Penn State MS Hershey Medical Center

David R Karp, MD PhD

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern Medical Center

Locations

Cedars-Sinai Medical Center

Los Angeles, California, United States

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States

Northwell Health

Great Neck, New York, United States

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, United States

Penn State MS Hershey Medical Center

Hershey, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Countries

United States

References

Karp DR, Chong BF, James JA, Arriens C, Ishimori M, Wallace DJ, Liao D, Olsen NJ. Mock Recruitment for the Study of Antimalarials in an Incomplete Lupus Erythematosus Trial. Arthritis Care Res (Hoboken). 2019 Nov;71(11):1425-1429. doi: 10.1002/acr.23802.

Reference Type: BACKGROUND

PMID: 30369087 (View on PubMed)

Olsen NJ, James JA, Arriens C, Ishimori ML, Wallace DJ, Kamen DL, Chong BF, Liao D, Chinchilli VM, Karp DR. Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE): study protocol for a randomized controlled trial. Trials. 2018 Dec 20;19(1):694. doi: 10.1186/s13063-018-3076-7.

Reference Type: BACKGROUND

PMID: 30572906 (View on PubMed)

Porta SV, Ugarte-Gil MF, Garcia-de la Torre I, Bonfa E, Gomez-Puerta JA, Arnaud L, Cardiel MH, Alarcon GS, Pons-Estel BA, Pons-Estel G. Controversies in Systemic Lupus Erythematosus: Are We Treating Our Patients Adequately? J Clin Rheumatol. 2022 Mar 1;28(2):e651-e658. doi: 10.1097/RHU.0000000000001803.

Reference Type: DERIVED

PMID: 34897194 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

U01AR071077

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00003506

Identifier Type: -

Identifier Source: org_study_id