Effects of Stopping Hydroxychloroquine in Elderly Lupus Disease

Study Overview
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Brief Summary
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Hydroxychloroquine (HCQ) is a systemic lupus erythematosus (SLE) medication that has been very effective in reducing lupus disease activity and keeping patients stable with reduced symptoms. Despite a track record of safety with regard to infection compared to traditional immunosuppressive agents, the risk of HCQ retinal toxicity escalates with continued use. Evaluation using sensitive standard of care approaches suggests nearly a third of patients accrue retinal damage. Data are needed to accurately weigh the balance between accumulating ocular exposure of HCQ versus the risk of disease flare in a population that may have more inactive disease than younger patients. The purpose of this trial is to address the safety of withdrawal of HCQ in SLE patients =60 years old. The central hypothesis is that HCQ can be safely discontinued in stable/quiescent patients assessed by validated disease activity and flare instruments in the context of serologic, cytokine and transcriptomic profiling. Patients will be randomized to either the placebo or active arm and followed every 2 months for one year to assess disease activity and flares.

Official Title
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A Phase III, Randomized, Double-Blind Placebo-Controlled, Non-Inferiority, Multi-Center Study of the Effects of Stopping Hydroxychloroquine in Elderly Lupus Disease

Conditions
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Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Age ≥ 60 years at time of enrollment Normal OCT and VF assessment within 6 months of screening visit Ability to take oral medication Have established SLE (≥ 4 ACR criteria or SLICC criteria or ≥ 10 points by EULAR criteria, SLE diagnosed at least seven years ago) Stable disease at screening visit by attaining DORIS remission (meeting all criterion listed below) and not on any immunosuppressants. Criterion 1: Clinical SLEDAI= 0 Criterion 2: SELENA-SLEDAI PGA ≤ 0.5 (on a scale from 0-3, where 0 is no disease activity and 3 is maximum disease activity) Criterion 3: Current prednisolone (or equivalent corticosteroid) dose ≤ 5 mg daily No moderate or severe flares one year prior to screening Taking ≥ 200 HCQ daily for ≥ 7 years Exclusion Criteria: Any patient that does not attain stable disease status by DORIS Ophthalmologic evidence of retinopathy (these patients would be advised to discontinue HCQ and therefore unethical to randomize for this study) Clinical SLEDAI > 0 Taking > 5 mg/day prednisone Taking any immunosuppressive drugs or biological agents (including: methotrexate, azathioprine, mycophenolate mofetil, mycophenolic acid, leflunomide, cyclosporine, cyclophosphamide, tacrolimus, rituximab, and belimumab) Any reason the treating rheumatologist is concerned about ongoing activity not captured by SLEDAI HCQ level < 100 ng/ml as this would support noncompliance and less reliance on HCQ to control activity Patient unwilling or unable to comply with study procedures for any reason Any indications of potentially diminished capacity, such as a diagnosis of dementia or cognitive impairment (including, but not limited to stroke-related cognitive impairment)

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine (HCQ)<br>Patients will receive a 90-day supply of HCQ at their screening visit, at 2 months, 4 months, 6 months, 8 months, and 10 months. All patients will return their current supply along with a completed dosing diary at each visit and receive a new supply in exchange. The HCQ dose administered will match each patient's dosage of HCQ at enrollment. | Drug: Hydroxychloroquine<br>* Hydroxychloroquine 200mg capsules. Administered orally.<br>|
| Placebo Comparator: HCQ-Matching Placebo<br>Patients will receive a 90-day supply of HCQ-matching placebo at their screening visit, at 2 months, 4 months, 6 months, 8 months, and 10 months. All patients will return their current supply along with a completed dosing diary at each visit and receive a new supply in exchange. The HCQ-matching placebo dose administered will match each patient's dosage of HCQ at enrollment. | Drug: Placebo<br>* Hydroxychloroquine-matching placebo capsule. Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants who Develop Moderate or Severe Flare based on the Revised SELENA SLEDAI Flare Index (rSFI) | Number of participants who experience moderate or severe flares as defined by the rSFI. | Up to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants who Develop Moderate Flare based on rSFI | Number of participants who experience moderate flares as defined by the rSFI. | Up to Month 12 | 
| Physician Global Assessment (PGA) Score at Month 12 | The Physician Global Assessment (PGA) of treatment response measures the overall response to treatment as assessed by the physician. The score ranges from +4 to (-4), where 4 = Markedly Improved, 0 = No change, and (-4) = markedly worse. | Month 12 | 
| Number of Participants who Begin Prednisone Treatment |  | Up to Month 12 | 
| Number of Participants who Increase Prednisone Use |  | Up to Month 12 | 
| Number of Participants who Experience Thromboembolic Event | Thromboembolic event includes, but is not limited to, venous thrombosis. | Up to Month 12 | 
| Number of Participants who Experience Cardiovascular Event |  | Up to Month 12 | 
| Number of Participants with New-Onset Diabetes |  | Up to Month 12 | 
| Number of Participants with New Retinal Toxicity |  | Up to Month 12 | 
| Change in 36-Item Short Form Survey Instrument (SF-36) Score | The SF-36 is 36-item self-rated measure of quality of life. A scoring algorithm is used to convert the raw scores into a range from zero (the respondent has the worst possible health) to 100 where the respondent is in the best possible health. | Baseline, Month 12 | 
| Change in 29-Question Patient-Reported Outcomes Measurement Information System (PROMIS-29) Score | PROMIS-29 consists of 29 questions rated on a scale from 1-5. The raw score is converted to a final T-score metric with a mean T-score of 50 and a standard deviation of 10. The final score ranges from 0 (worst possible outcome) to 100 (best possible outcome). The questionnaire assesses seven domains - depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities. | Baseline, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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systemic lupus erythematosus, elderly lupus disease, sle, Hydroxychloroquine, lupus, plaquenil