CAESAR: Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05841758

Collaborator

(none)

140

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Extra Pulmonary Sarcoidosis	Drug: Hydroxychloroquine Drug: Placebo	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Sep 1, 2027

Anticipated Study Completion Date :

Sep 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hydroxychloroquine 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 Hydroxychloroquine (200-400 mg /day during a 12 months double blind placebo-controlled period)
Placebo Comparator: Placebo arm 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 Placebo during a 12 months double blind placebo-controlled period

Arm

Intervention/Treatment

Experimental: Hydroxychloroquine

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

Hydroxychloroquine (200-400 mg /day during a 12 months double blind placebo-controlled period)

Placebo Comparator: Placebo arm

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

Placebo during a 12 months double blind placebo-controlled period

Outcome Measures

Primary Outcome Measures

Evaluate the steroid-sparing effect of hydroxychloroquine as an add-on therapy in patients with non severe extra-pulmonary sarcoidosis requiring a systemic treatment. [at Year 1]
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.

Secondary Outcome Measures

Organ-specific response assessed by the extra-pulmonary Physician Organ Severity Tool (ePOST) [at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.]
score comprised between 0 and 6
rate of complete, partial, stable or progression of the disease [at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.]
Global clinical response will be assessed by the physician as complete, partial, stable, or progression
Assess the total dose of local steroid treatments [at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.]
Total dose in Gramme of local steroid treatments
Assess the efficacy of HCQ in maintaining the relapse-free survival over a prolonged period [at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.]
Relapse rate
Assess and compare the eventual reduction of steroid-related toxicity (side effects) [at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.]
Frequencies of steroid-associated side-effects monitored clinically and biologically and Glucocorticoid Toxicity Index (GTI)
Assess HCQ safety [at Month 3, Month 6 and Month 12]
HCQ safety will be assessed through initial and annual electroretinogram
Assess HCQ safety [at Month 3, Month 6 and Month 12]
HCQ safety will be assessed through initial and annual autofluorescence
Assess HCQ safety [at Month 3, Month 6 and Month 12]
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.
Assess HCQ safety [at Month 3, Month 6 and Month 12]
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.
Assess HCQ safety [at Month 3, Month 6 and Month 12]
HCQ safety will be assessed through Optical Coherence Tomography (OCT)
Assess patients' adherence [at Month 3, Month 6 and Month 12]
Patient's adherence will be controlled by patient notebooks
Assess patients' adherence [at Month 3, Month 6 and Month 12]
Patient's adherence will be controlled by pharmacy count of returned tablets
Assess patients' adherence [at Month 3, Month 6 and Month 12]
Patient's adherence will be controlled by serial dosages of blood HCQ levels
Assess quality of life by the Study Short Form 36 questionnaire (SF-36 questionnaire). [at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Service de Médecine Interne Infectiologie Aïgue Polyvalente- Hôpital Henri Duffaud	Avignon	France	84 000
2	Service de Médecine Interne et Immunologie Clinique - CHU Dijon Bourgogne	Dijon	France	21 079
3	Service de medecine interne - Hôpital Claude Huriez	Lille	France	59 000
4	Service de medecine interne - Hôpital Duputryen	Limoges	France	87 042
5	Service de médecine interne - Hôpital de la Croix Rousse	Lyon	France	69004
6	Service de médecine interne - Hôpital Lyon Sud	Lyon	France	69004
7	Service de medecine interne - Hôpital Saint Eloi	Montpellier	France	34 295
8	Service de medecine interne - Hôpital Hôtel Dieu	Nantes	France	44000
9	Service de médecine interne - Hôpital Lariboisière	Paris	France	75010
10	Service de medecine interne 2- Hôpital de la Pitié-Salpétrière	Paris	France	75013
11	Service de Médecine Interne et maladies infectieuses - Hôpital Haut Lévêque	Pessac	France	33 604
12	Service de Médecine Interne et Immunologie Clinique - Hôpital Sud	Rennes	France	35 2000
13	Service de medecine interne - Hôpital Nord	Saint-Étienne	France	42 055
14	Service de medecine interne - Hôpital de Hautepierre	Strasbourg	France	67 200