Study of Anti-Malarials in Incomplete Lupus Erythematosus

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.

Inclusion Criteria:

1. Between 15 and 45 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.