Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis

Study Overview
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Brief Summary
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Sarcoidosis is a systemic granulomatous disease of unknown aetiology, mainly affecting the lungs and lymphatics. It affects people worldwide (incidence, 4.7-64/100000; prevalence, 1-36/100000/year). Although it is most often a benign acute or subacute condition, sarcoidosis may progress to a disabling chronic disease in 25% of the cases, with severe complications in about 5%, such as lung fibrosis, cardiac or neurosarcoidosis, defacing lupus pernio or blindness due to uveitis. When indicated, corticosteroids (CS) are the mainstay of treatment. Due to the kinetics of granuloma resolution, the usual and quite 'dogmatic' duration of treatment is said to be one year, following four classical steps. The long-term use of CS is hindered by cumulative toxicity and efforts have to be made to taper them, as quickly as possible, to the lowest effective dose. A recent report mentioned 39% of the CS-treated patients requiring a steroid-sparing agent. Chloroquine (CQ) and hydroxychloroquine (HCQ) are anti-malarial drugs that have been used since the 1960's as steroidsparing agents on the basis of a landmark study by Siltzbach reporting their efficacy in 43 patients with skin and intrathoracic sarcoidosis. Subsequently, two small randomized controlled trials have shown significant and prolonged improvement on pulmonary symptoms. Only small case series/reports have shown CQ/HCQ efficacy on extra-pulmonary sarcoidosis with response rates ranging from 67 to 100%. Nevertheless, CQ/HCQ are daily used for skin, bone, and joint sarcoidosis, as well as hypercalcemia. Nowadays, HCQ is preferred over CQ because of a lower incidence of gastrointestinal and ocular adverse reactions, which can be minimized by close attention to the dosage and regular retinal examination. Its profile of safety is well-known since it has long been employed to treat systemic lupus erythematous or rheumatoid arthritis. Its action is thought to rely on its ability to accumulate in lysosomes of phagocytic cells, to affect antigen presentation and reduce pro-inflammatory cytokines. The investigator hypothesize that HCQ may be an efficacious add-on therapy for extra-pulmonary sarcoidosis leading to a significant steroid-sparing effect.

Official Title
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Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis: Multicenter, Prospective, Placebo-controlled, Randomized Trial

Conditions
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Extra Pulmonary Sarcoidosis

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : at least 18 years of age pathologically proven sarcoidosis as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS)/World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) criteria non severe ocular sarcoidosis requiring systemic treatment non severe skin sarcoidosis requiring systemic treatment non severe osseous sarcoidosis requiring systemic treatment non severe sarcoidosis with joint involvement requiring systemic treatment non severe sarcoidosis-related hypercalcemia requiring systemic treatment non severe peripheral nervous system sarcoidosis requiring systemic treatment non severe sarcoidosis-related non-severe Ear, Nose and Throat (ENT) involvement requiring systemic treatment signed informed consent affiliated to National French social security system Exclusion Criteria : severe sarcoidosis involvement requiring another immunosuppressant or anti-TNF antibody or methylprednisolone i.v. pulses previous (<3 months before screening) or concurrent treatment with immunosuppressants previous treatment with antimalarial drugs (HCQ/CQ) treatment with citalopram, escitalopram, hydroxyzin, domperidone and piperaquine known hypersensitivity or intolerance to HCQ/CQ or 4-aminoquinoline derivatives and prednisone history of drug induced maculopathy heart rhythm disorders on EKG (QT prolongation) severe ophthalmological impairment or ophthalmological impairment that does not allow ophthalmic monitoring; previous history of maculopathy or retinopathy end-stage lung, liver, cardiac, or renal disease sarcoidosis with central nervous system involvement cardiac sarcoidosis clinical evidence of active infection (including infection with herpes virus and varicella-zoster virus) or severe/unstabilized comorbidity (e.g. moderate to severe heart failure) or unstabilized psychosis chronic viral (HIV or HBV) infection untreated latent/active tuberculosis pregnancy or lactation (βHCG will be test by blood analysis at inclusion) concurrent vaccination with live vaccines during therapy inability to understand information about the protocol and to sign informed consent or not suitable candidate to comply with the requirements of this study patient participating in other interventional research persons under court protection women must not be pregnant, breastfeeding, or considering pregnancy during the study or within 30 days of the last study drug administration. (Contraception is considered effective when it consists of one of the following: use of a male condom during all sexual activity and/or efficient oral hormonal contraception (better considered combined contraception) and/or an intrauterine device (IUD) and/or hormone-releasing intrauterine system (IUS) and/or history of bilateral tubal ligation and/or history of vasectomy, provided the male partner is the trial participant's only sexual partner and/or sexual abstinence)

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine<br>prednisone (scheduled protocol) + hydroxychloroquine (200-400 mg /day during a 12 months double blind placebo-controlled period, then according to the treating the physician for an additional open period of 12 months) | Drug: Hydroxychloroquine<br>* Hydroxychloroquine (200-400 mg /day during a 12 months double blind placebo-controlled period)<br>|
| Placebo Comparator: Placebo arm<br>prednisone (scheduled protocol) + placebo (1-2 tablets/day during a 12 months double blind placebocontrolled period, then the treatment is left to the physician's discretion until M24) | Drug: Placebo<br>* Placebo during a 12 months double blind placebo-controlled period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the steroid-sparing effect of hydroxychloroquine as an add-on therapy in patients with non severe extra-pulmonary sarcoidosis requiring a systemic treatment. | The primary endpoint is the percentage of patients in remission and off prednisone at month 9, without relapse until month 12. The primary endpoint will thus be assessed at M12. Remission is defined by either complete or partial response. Complete response is defined as the absence of clinical or paraclinical sign of disease activity. Partial response is defined as the persistence of clinical or paraclinical sign of disease activity, which do not require substantial treatment modification (high dose CS, immunosuppressant or anti-Tumor Necrosis Factor (TNF) drugs). Relapse is defined as the persistence, or recurrence of existing manifestations and/or the occurrence of new sarcoidosis manifestations requiring substantial treatment modification. | at Year 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Organ-specific response assessed by the extra-pulmonary Physician Organ Severity Tool (ePOST) | score comprised between 0 and 6 | at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24. | 
| rate of complete, partial, stable or progression of the disease | Global clinical response will be assessed by the physician as complete, partial, stable, or progression | at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24. | 
| Assess the total dose of local steroid treatments | Total dose in Gramme of local steroid treatments | at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24. | 
| Assess the efficacy of HCQ in maintaining the relapse-free survival over a prolonged period | Relapse rate | at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24. | 
| Assess and compare the eventual reduction of steroid-related toxicity (side effects) | Frequencies of steroid-associated side-effects monitored clinically and biologically and Glucocorticoid Toxicity Index (GTI) | at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24. | 
| Assess HCQ safety | HCQ safety will be assessed through initial and annual electroretinogram | at Month 3, Month 6 and Month 12 | 
| Assess HCQ safety | HCQ safety will be assessed through initial and annual autofluorescence | at Month 3, Month 6 and Month 12 | 
| Assess HCQ safety | HCQ safety will be assessed through initial and annual electroretinogram or autofluorescence or Optical Coherence Tomography (OCT), yearly eye evaluation and monitoring of eventual Adverse Event (AE)s. An AE will be considered as serious if it leads to HCQ cessation, hospitalization, or death. | at Month 3, Month 6 and Month 12 | 
| Assess HCQ safety | HCQ safety will be assessed through yearly eye evaluation with monitoring of eventual Adverse Event (AE)s. An AE will be considered as serious if it leads to HCQ cessation, hospitalization, or death. | at Month 3, Month 6 and Month 12 | 
| Assess HCQ safety | HCQ safety will be assessed through Optical Coherence Tomography (OCT) | at Month 3, Month 6 and Month 12 | 
| Assess patients' adherence | Patient's adherence will be controlled by patient notebooks | at Month 3, Month 6 and Month 12 | 
| Assess patients' adherence | Patient's adherence will be controlled by pharmacy count of returned tablets | at Month 3, Month 6 and Month 12 | 
| Assess patients' adherence | Patient's adherence will be controlled by serial dosages of blood HCQ levels | at Month 3, Month 6 and Month 12 | 
| Assess quality of life by the Study Short Form 36 questionnaire (SF-36 questionnaire). | 11 questions are asked, the minimum score is 36 and the maximum score is 149. Statistical analysis of the SF-36 questionnaire will be performed by a statician, analysis is more complex than only higher score means better health. | at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcoidosis, Hydroxychloroquine, steroid-sparing agent