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

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ClinicalTrials.gov Identifier: NCT03030118
Recruitment Status : Recruiting
First Posted : January 24, 2017
Last Update Posted : June 18, 2019
Sponsor:
Collaborator:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
Nancy Olsen, Milton S. Hershey Medical Center

Tracking Information
First Submitted Date  ICMJE January 15, 2017
First Posted Date  ICMJE January 24, 2017
Last Update Posted Date June 18, 2019
Actual Study Start Date  ICMJE December 28, 2017
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 20, 2017)
SLICC Score [ Time Frame: Measured every 12 weeks for 96 weeks. ]
The 2012 Systemic Lupus International Collaborating Clinics classification criteria score erythematosus
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03030118 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 20, 2017)
  • Disease Progression [ Time Frame: Measured every 12 weeks for 96 weeks ]
    The time to progression from incomplete lupus to satisfaction of classification criteria for systemic lupus erythematosus using SLICC criteria.
  • Disease Activity [ Time Frame: Measured every 12 weeks for 96 weeks ]
    Disease activity measured by the SLE Disease Activity Index
  • Disease Activity [ Time Frame: Measured every 12 weeks for 96 weeks ]
    Disease activity measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index
  • Patient reported outcomes [ Time Frame: Measured every 12 weeks for 96 weeks ]
    The PROMIS 29 Adult Profile
  • Patient reported outcomes [ Time Frame: Measured every 12 weeks for 96 weeks ]
    Selected Patient-reported outcomes measurement information system (PROMIS) fatigue items
  • Patient reported outcomes [ Time Frame: Measured every 12 weeks for 96 weeks ]
    Patient Global Visual Analogue Scale
  • Immunologic mediators [ Time Frame: Measured every 12 weeks for 96 weeks ]
    Serum levels of autoantibodies,cytokines and chemokines will be measured.
  • Ophthalmologic toxicity [ Time Frame: Measured after screening and prior to baseline and within 4 weeks after study completion ]
    Dilated fundoscopic examination
  • Ophthalmologic toxicity [ Time Frame: Measured after screening and prior to baseline and within 4 weeks after study completion ]
    Spectral domain ocular coherence tomography
  • Ophthalmologic toxicity [ Time Frame: Measured after screening and prior to baseline and within 4 weeks after study completion ]
    Humphrey visual field testing
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Anti-Malarials in Incomplete Lupus Erythematosus
Official Title  ICMJE Study of Anti-Malarials in Incomplete Lupus Erythematosus
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Systemic Lupus Erythematosus
Intervention  ICMJE
  • 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 Name: Plaquenil
  • Drug: Placebo Oral Capsule
    An oral capsule placebo is made to match the active intervention medication hydroxychloroquine.
    Other Name: Placebo
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Hydroxychloroquine
  • 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.
    Intervention: Drug: Placebo Oral Capsule
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 20, 2017)
240
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date September 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years to 45 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nancy J Olsen, MD 7175314921 nolsen@pennstatehealth.psu.edu
Contact: David R Karp, MD PhD 2146489110 david.karp@utsouthwestern.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03030118
Other Study ID Numbers  ICMJE STUDY00003506
U01AR071077 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nancy Olsen, Milton S. Hershey Medical Center
Study Sponsor  ICMJE Milton S. Hershey Medical Center
Collaborators  ICMJE National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators  ICMJE
Principal Investigator: Nancy J Olsen, MD Penn State MS Hershey Medical Center
Principal Investigator: David R Karp, MD PhD UT Southwestern Medical Center
PRS Account Milton S. Hershey Medical Center
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP