Study of Anti-Malarials in Incomplete Lupus Erythematosus

Study Overview
=================
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: 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. To determine effects of HCQ on disease activity and patient-reported outcomes in patients with ILE. 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. 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.

Official Title
-----------------
Study of Anti-Malarials in Incomplete Lupus Erythematosus

Conditions
-----------------
Systemic Lupus Erythematosus

Intervention / Treatment
-----------------
* Drug: Hydroxychloroquine
* Drug: Placebo Oral Capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Between 15 and 49 years of age, inclusive, at Visit 1. Anti-nuclear antibody (ANA) titer of 1:80, or greater, as determined by immunofluorescence assay (IFA). 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. 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: 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). The subject has been diagnosed with another autoimmune disorder, other than autoimmune thyroid conditions. The subject has fibromyalgia, based on clinical history and exam. The subject has previously been or is currently being treated with oral antimalarial agents including hydroxychloroquine, chloroquine, or quinacrine. The subject is currently or has been treated with immunosuppressive, immune modifying, or cytotoxic medications as listed in Section 7.2. Use of any investigational agent within the preceding 12 months. History of primary immunodeficiency. Active bacterial, viral, fungal, or opportunistic infection. Evidence of infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C. 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. The subject has significant findings on ophthalmological examination that, in the opinion of the examining Ophthalmologist, prevent safe use of hydroxychloroquine. 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. 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. 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. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. 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. Inability to comply with the study visit schedule and procedures.

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 49 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydroxychloroquine<br>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<br>* 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.<br>* Other names: Plaquenil;|
| Placebo Comparator: Placebo oral capsule<br>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<br>* An oral capsule placebo is made to match the active intervention medication hydroxychloroquine.<br>* Other names: Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SLICC Score | The 2012 Systemic Lupus International Collaborating Clinics classification criteria score erythematosus | Measured every 12 weeks for 96 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Progression | The time to progression from incomplete lupus to satisfaction of classification criteria for systemic lupus erythematosus using SLICC criteria. | Measured every 12 weeks for 96 weeks | 
| Disease Activity | Disease activity measured by the SLE Disease Activity Index | Measured every 12 weeks for 96 weeks | 
| Disease Activity | Disease activity measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index | Measured every 12 weeks for 96 weeks | 
| Patient reported outcomes | The PROMIS 29 Adult Profile | Measured every 12 weeks for 96 weeks | 
| Patient reported outcomes | Selected Patient-reported outcomes measurement information system (PROMIS) fatigue items | Measured every 12 weeks for 96 weeks | 
| Patient reported outcomes | Patient Global Visual Analogue Scale | Measured every 12 weeks for 96 weeks | 
| Immunologic mediators | Serum levels of autoantibodies,cytokines and chemokines will be measured. | Measured every 12 weeks for 96 weeks | 
| Ophthalmologic toxicity | Dilated fundoscopic examination | Measured after screening and prior to baseline and within 4 weeks after study completion | 
| Ophthalmologic toxicity | Spectral domain ocular coherence tomography | Measured after screening and prior to baseline and within 4 weeks after study completion | 
| Ophthalmologic toxicity | Humphrey visual field testing | Measured after screening and prior to baseline and within 4 weeks after study completion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hydroxychloroquine