Clinical trial NCT05841758: Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis
Official title: Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis: Multicenter, Prospective, Placebo-controlled, Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Sarcoidosis, Pulmonary
Keywords: Sarcoidosis
Hydroxychloroquine
steroid-sparing agent
Extra pulmonary sarcoidosis
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2023-05-03
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: * 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)

Primary outcomes:
measure: Evaluate the steroid-sparing effect of hydroxychloroquine as an add-on therapy in patients with non severe extra-pulmonary sarcoidosis requiring a systemic treatment.
timeFrame: at Year 1
Secondary outcomes:
measure: Organ-specific response assessed by the extra-pulmonary Physician Organ Severity Tool (ePOST)
timeFrame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
measure: rate of complete, partial, stable or progression of the disease
timeFrame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
measure: Assess the total dose of local steroid treatments
timeFrame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
measure: Assess the efficacy of HCQ in maintaining the relapse-free survival over a prolonged period
timeFrame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
measure: Assess and compare the eventual reduction of steroid-related toxicity (side effects)
timeFrame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
measure: Assess HCQ safety
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess HCQ safety
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess HCQ safety
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess HCQ safety
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess HCQ safety
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess patients' adherence
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess patients' adherence
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess patients' adherence
timeFrame: at Month 3, Month 6 and Month 12
measure: Assess quality of life by the Study Short Form 36 questionnaire (SF-36 questionnaire).
timeFrame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Other outcomes:
Locations:
city: Avignon
country: France
facility: Service de Médecine Interne Infectiologie Aïgue Polyvalente- Hôpital Henri Duffaud
city: Bobigny
country: France
facility: Service de Pneumologie - Hôpital Avicenne
city: Créteil
country: France
facility: Service de medecine interne - Hôpital Henri Mondor
city: Dijon
country: France
facility: Service de Médecine Interne et Immunologie Clinique - CHU Dijon Bourgogne
city: Lille
country: France
facility: Service de medecine interne - Hôpital Claude Huriez
city: Limoges
country: France
facility: Service de medecine interne - Hôpital Duputryen
city: Lyon
country: France
facility: Service de médecine interne - Hôpital de la Croix Rousse
city: Lyon
country: France
facility: Service de médecine interne - Hôpital Edouard Herriot
city: Lyon
country: France
facility: Service de médecine interne - Hôpital Lyon Sud
city: Lyon
country: France
facility: Service de médecine interne - Centre Hospitalier Saint Joseph Saint Luc
city: Montpellier
country: France
facility: Service de medecine interne - Hôpital Saint Eloi
city: Nantes
country: France
facility: Service de medecine interne - Hôpital Hôtel Dieu
city: Paris
country: France
facility: Service de médecine interne - Hôpital Lariboisière
city: Paris
country: France
facility: Service de medecine interne 2- Hôpital de la Pitié-Salpétrière
city: Pessac
country: France
facility: Service de Médecine Interne et maladies infectieuses - Hôpital Haut Lévêque
city: Rennes
country: France
facility: Service de Médecine Interne et Immunologie Clinique - Hôpital Sud
city: Saint-Étienne
country: France
facility: Service de medecine interne - Hôpital Nord
city: Strasbourg
country: France
facility: Service de medecine interne - Hôpital de Hautepierre
city: Toulouse
country: France
facility: Service de médecine interne - Clinique Saint exupéry
Study officials:
References: