Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis (CAESAR)

March 5, 2024 updated by: Hospices Civils de Lyon

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

140

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Avignon, France, 84 000
        • Service de Médecine Interne Infectiologie Aïgue Polyvalente- Hôpital Henri Duffaud
        • Contact:
        • Principal Investigator:
          • Philip Bielfed, Dr
      • Bobigny, France, 93000
        • Service de Pneumologie - Hôpital Avicenne
        • Contact:
        • Principal Investigator:
          • Hilario Nunes, Dr
      • Créteil, France, 94000
        • Service de medecine interne - Hôpital Henri Mondor
        • Contact:
        • Principal Investigator:
          • Matthieu Mahévas, Dr
      • Dijon, France, 21 079
        • Service de Médecine Interne et Immunologie Clinique - CHU Dijon Bourgogne
        • Contact:
        • Principal Investigator:
          • Bernard Bonnotte, Dr
      • Lille, France, 59 000
        • Service de medecine interne - Hôpital Claude Huriez
        • Contact:
        • Principal Investigator:
          • Emmanuel LEDOULT
      • Limoges, France, 87 042
        • Service de medecine interne - Hôpital Duputryen
        • Contact:
        • Principal Investigator:
          • Kim Ly, Dr
      • Lyon, France, 69004
        • Service de médecine interne - Hôpital de la Croix Rousse
        • Contact:
        • Principal Investigator:
          • Thomas EL JAMMAL, MD
      • Lyon, France, 69004
        • Service de médecine interne - Hôpital Lyon Sud
        • Contact:
        • Principal Investigator:
          • Reynaud Quitterie, Pr
      • Lyon, France, 69004
        • Service de médecine interne - Hôpital Edouard Herriot
        • Contact:
        • Principal Investigator:
          • Thomas Barba, Dr
      • Lyon, France, 69007
        • Service de médecine interne - Centre Hospitalier Saint Joseph Saint Luc
        • Contact:
        • Principal Investigator:
          • Laurent Perard, Dr
      • Montpellier, France, 34 295
        • Service de medecine interne - Hôpital Saint Eloi
        • Contact:
        • Principal Investigator:
          • Sophie Rivière, Dr
      • Nantes, France, 44000
        • Service de medecine interne - Hôpital Hôtel Dieu
        • Contact:
        • Principal Investigator:
          • Antoine Néel, Dr
      • Paris, France, 75010
        • Service de médecine interne - Hôpital Lariboisière
        • Contact:
        • Principal Investigator:
          • Damien Sène, Dr
      • Paris, France, 75013
        • Service de medecine interne 2- Hôpital de la Pitié-Salpétrière
        • Contact:
        • Principal Investigator:
          • Fleur Cohen, Dr
      • Pessac, France, 33 604
        • Service de Médecine Interne et maladies infectieuses - Hôpital Haut Lévêque
        • Principal Investigator:
          • Jean-François Viallard, MD
        • Contact:
      • Rennes, France, 35 2000
        • Service de Médecine Interne et Immunologie Clinique - Hôpital Sud
        • Contact:
        • Principal Investigator:
          • Nicolas Belhomme, dr
      • Saint-Étienne, France, 42 055
        • Service de medecine interne - Hôpital Nord
        • Contact:
        • Principal Investigator:
          • Killian Martin, Dr
      • Strasbourg, France, 67 200
        • Service de medecine interne - Hôpital de Hautepierre
        • Contact:
        • Principal Investigator:
          • Maxime Dubois, Dr
      • Toulouse, France, 31077
        • Service de médecine interne - Clinique Saint exupéry
        • Contact:
        • Principal Investigator:
          • Martin Michaud, Dr

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

  • 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

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.
Time Frame: 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.
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)
Time Frame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
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
Time Frame: 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
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Assess the total dose of local steroid treatments
Time Frame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
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
Time Frame: at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Relapse rate
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Assess HCQ safety
Time Frame: at Month 3, Month 6 and Month 12
HCQ safety will be assessed through initial and annual electroretinogram
at Month 3, Month 6 and Month 12
Assess HCQ safety
Time Frame: at Month 3, Month 6 and Month 12
HCQ safety will be assessed through initial and annual autofluorescence
at Month 3, Month 6 and Month 12
Assess HCQ safety
Time Frame: 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.
at Month 3, Month 6 and Month 12
Assess HCQ safety
Time Frame: 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.
at Month 3, Month 6 and Month 12
Assess HCQ safety
Time Frame: at Month 3, Month 6 and Month 12
HCQ safety will be assessed through Optical Coherence Tomography (OCT)
at Month 3, Month 6 and Month 12
Assess patients' adherence
Time Frame: at Month 3, Month 6 and Month 12
Patient's adherence will be controlled by patient notebooks
at Month 3, Month 6 and Month 12
Assess patients' adherence
Time Frame: at Month 3, Month 6 and Month 12
Patient's adherence will be controlled by pharmacy count of returned tablets
at Month 3, Month 6 and Month 12
Assess patients' adherence
Time Frame: at Month 3, Month 6 and Month 12
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).
Time Frame: 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.
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)
Time Frame: 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
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospices Civils de Lyon

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2024

Primary Completion (Estimated)

April 1, 2028

Study Completion (Estimated)

April 1, 2029

Study Registration Dates

First Submitted

March 17, 2023

First Submitted That Met QC Criteria

April 24, 2023

First Posted (Actual)

May 3, 2023

Study Record Updates

Last Update Posted (Actual)

March 6, 2024

Last Update Submitted That Met QC Criteria

March 5, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 69HC21_1054
  • 2022-502155-65-00 (Other Identifier: EUCT number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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