Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis

Sarcoidosis, Pulmonary Clinical Trial

— CAESAR  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05841758
• Other study ID #: 69HC21_1054
• Secondary ID: 2022-502155-65-0
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: April 1, 2024
• Est. completion date: April 1, 2029

Study information

• Verified date: March 2024
• Source: Hospices Civils de Lyon
• Contact: Thomas El Jammal, Dr
• Phone: 04.26.73.26.29
• Email: thomas.el-jammal[@]chu-lyon.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 140
• Est. completion date: April 1, 2029
• Est. primary completion date: April 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• 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 (ßHCG 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)

Related Conditions & MeSH terms

• Sarcoidosis
• Sarcoidosis, Pulmonary

Intervention

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

Locations

Country	Name	City	State
France	Service de Médecine Interne Infectiologie Aïgue Polyvalente- Hôpital Henri Duffaud	Avignon
France	Service de Pneumologie - Hôpital Avicenne	Bobigny
France	Service de medecine interne - Hôpital Henri Mondor	Créteil
France	Service de Médecine Interne et Immunologie Clinique - CHU Dijon Bourgogne	Dijon
France	Service de medecine interne - Hôpital Claude Huriez	Lille
France	Service de medecine interne - Hôpital Duputryen	Limoges
France	Service de médecine interne - Centre Hospitalier Saint Joseph Saint Luc	Lyon
France	Service de médecine interne - Hôpital de la Croix Rousse	Lyon
France	Service de médecine interne - Hôpital Edouard Herriot	Lyon
France	Service de médecine interne - Hôpital Lyon Sud	Lyon
France	Service de medecine interne - Hôpital Saint Eloi	Montpellier
France	Service de medecine interne - Hôpital Hôtel Dieu	Nantes
France	Service de médecine interne - Hôpital Lariboisière	Paris
France	Service de medecine interne 2- Hôpital de la Pitié-Salpétrière	Paris
France	Service de Médecine Interne et maladies infectieuses - Hôpital Haut Lévêque	Pessac
France	Service de Médecine Interne et Immunologie Clinique - Hôpital Sud	Rennes
France	Service de medecine interne - Hôpital Nord	Saint-Étienne
France	Service de medecine interne - Hôpital de Hautepierre	Strasbourg
France	Service de médecine interne - Clinique Saint exupéry	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Assess and compare the eventual reduction of steroid-related toxicity (side effects)	Frequencies of steroid-associated side-effects monitored clinically and biologically	at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Secondary	Assess HCQ safety	HCQ safety will be assessed through initial and annual electroretinogram	at Month 3, Month 6 and Month 12
Secondary	Assess HCQ safety	HCQ safety will be assessed through initial and annual autofluorescence	at Month 3, Month 6 and Month 12
Secondary	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
Secondary	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
Secondary	Assess HCQ safety	HCQ safety will be assessed through Optical Coherence Tomography (OCT)	at Month 3, Month 6 and Month 12
Secondary	Assess patients' adherence	Patient's adherence will be controlled by patient notebooks	at Month 3, Month 6 and Month 12
Secondary	Assess patients' adherence	Patient's adherence will be controlled by pharmacy count of returned tablets	at Month 3, Month 6 and Month 12
Secondary	Assess patients' adherence	Patient's adherence will be controlled by serial dosages of blood HCQ levels	at Month 3, Month 6 and Month 12
Secondary	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.