Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE)

August 29, 2025 updated by: Nancy Olsen, Milton S. Hershey Medical Center
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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
187

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Medical Center
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Anschutz Medical Campus
    • New York
      • Great Neck, New York, United States, 11021
        • Northwell Health
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Oklahoma Medical Research Foundation
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • Penn State MS Hershey Medical Center
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
    • Texas
      • Dallas, Texas, United States, 75390
        • UT Southwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

15 years to 49 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: 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.
Drug: 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.
Other Names:
  • Plaquenil
Placebo Comparator: 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.
Drug: Placebo Oral Capsule
An oral capsule placebo is made to match the active intervention medication hydroxychloroquine.
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
SLICC Score
Time Frame: Measured every 12 weeks for 96 weeks.
The 2012 Systemic Lupus International Collaborating Clinics classification criteria score erythematosus Minimum value = 0 Maximum value = 17 A score of 4 or greater satisfies classification for systemic lupus erythematosus.
Measured every 12 weeks for 96 weeks.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of Subjects With Disease Progression
Time Frame: Measured up to 96 weeks.
The number of subjects who progressed from incomplete lupus to satisfaction of classification criteria for systemic lupus erythematosus using SLICC criteria.
Measured up to 96 weeks.
Number of Subjects Meeting Disease Activity Scores Defined Below
Time Frame: Measured every 12 weeks for 96 weeks.
Disease activity measured by the SLE Disease Activity Index Minimum score = 0 Maximum score = 105 Higher scores indicate greater activity of lupus disease
Measured every 12 weeks for 96 weeks.
Count of Participants With Defined Disease Activity
Time Frame: Measured every 12 weeks for 96 weeks
Disease activity measured by the Cutaneous Lupus Erythematosus Disease Activity Index Minimum score = 0 Maximum score = 70 Higher scores indicate greater cutaneous lupus activity
Measured every 12 weeks for 96 weeks
Patient Reported Outcome Physical Function
Time Frame: Measured every 12 weeks for 96 weeks

The PROMIS 29 Adult Profile: Physical Function T Scores The T-score has a mean of 50 and a standard deviation of 10 within the reference (healthy) population.

Higher score indicates better physical function
Measured every 12 weeks for 96 weeks
Patient Reported Outcomes Fatigue
Time Frame: Measured every 12 weeks for up to 96 weeks

Selected Patient-reported outcomes measurement information system (PROMIS) fatigue items T Scores are reported. The T-score has a mean of 50 and a standard deviation of 10 within the reference (healthy) population.

Higher scores indicate more fatigue
Measured every 12 weeks for up to 96 weeks
Physician Global Asssessment
Time Frame: Measured every 12 weeks for up to 96 weeks
Physician Global Visual Analogue Scale Minimum score = 0 Maximum score = 1.0 Higher scores indicate worse status
Measured every 12 weeks for up to 96 weeks
Fluorescence Intensity (FI) of Autoantibodies in Serum
Time Frame: Measured at baseline and final visit up to 96 weeks.
Fluorescence intensity of Autoantibodies will be measured using a slide array. Minimum score is 0.1 Maximum score >100 A higher score indicates higher level of the autoantibody being measured.
Measured at baseline and final visit up to 96 weeks.
Ophthalmologic Toxicity as Measured by Snellen Visual Acuity
Time Frame: Measured at up to 96 weeks or final visit
Snellen visual acuity measured in right and left eyes Scale 10 to 50 with higher numbers indicating lower visual acuity Number of participants with each level of visual acuity in right eye and left eye are counted in the two groups at the final visit
Measured at up to 96 weeks or final visit
Ophthalmologic Toxicity by Humphrey Visual Field Testing
Time Frame: Measured at final visit up to 96 weeks
Number of participants with abnormal visual field testing at the final visit.
Measured at final visit up to 96 weeks
Ophthalmologic Toxicity as Measured by Spectral Domain Ocular Coherence Tomography.
Time Frame: Measured at up to 96 weeks or final visit
Number of participants with abnormal spectral domain ocular coherence tomography at final visit
Measured at up to 96 weeks or final visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Milton S. Hershey Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Nancy J Olsen, MD, Penn State MS Hershey Medical Center
  • Principal Investigator: David R Karp, MD PhD, UT Southwestern Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 28, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 30, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 30, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 15, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 20, 2017

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 24, 2017

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 16, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 29, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • STUDY00003506
  • U01AR071077 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified data will be shared with other investigators upon reasonable request. This will include all patient-level measurements and instruments, as well as the laboratory results.

IPD Sharing Time Frame

Data will be available after publication of the primary paper, anticipated in last quarter 2025.

IPD Sharing Access Criteria

Reasonable request is defined as having a legitimate and specific purpose for use of the data and ability to accept it in a usable format.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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