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

Primary Purpose

Extra Pulmonary Sarcoidosis

Status
Not yet recruiting
Phase
Phase 4
Locations
France
Study Type
Interventional
Intervention
Hydroxychloroquine
Placebo
Sponsored by
Hospices Civils de Lyon
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Extra Pulmonary Sarcoidosis focused on measuring Sarcoidosis, Hydroxychloroquine, steroid-sparing agent

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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)

Sites / Locations

  • Service de Médecine Interne Infectiologie Aïgue Polyvalente- Hôpital Henri Duffaud
  • Service de Médecine Interne et Immunologie Clinique - CHU Dijon Bourgogne
  • Service de medecine interne - Hôpital Claude Huriez
  • Service de medecine interne - Hôpital Duputryen
  • Service de médecine interne - Hôpital de la Croix Rousse
  • Service de médecine interne - Hôpital Lyon Sud
  • Service de medecine interne - Hôpital Saint Eloi
  • Service de medecine interne - Hôpital Hôtel Dieu
  • Service de médecine interne - Hôpital Lariboisière
  • Service de medecine interne 2- Hôpital de la Pitié-Salpétrière
  • Service de Médecine Interne et maladies infectieuses - Hôpital Haut Lévêque
  • Service de Médecine Interne et Immunologie Clinique - Hôpital Sud
  • Service de medecine interne - Hôpital Nord
  • Service de medecine interne - Hôpital de Hautepierre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Hydroxychloroquine

Placebo arm

Arm Description

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)

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)

Outcomes

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.
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)
score comprised between 0 and 6
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
Assess the total dose of local steroid treatments
Total dose in Gramme of local steroid treatments
Assess the efficacy of HCQ in maintaining the relapse-free survival over a prolonged period
Relapse rate
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)
Assess HCQ safety
HCQ safety will be assessed through initial and annual electroretinogram
Assess HCQ safety
HCQ safety will be assessed through initial and annual autofluorescence
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.
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.
Assess HCQ safety
HCQ safety will be assessed through Optical Coherence Tomography (OCT)
Assess patients' adherence
Patient's adherence will be controlled by patient notebooks
Assess patients' adherence
Patient's adherence will be controlled by pharmacy count of returned tablets
Assess patients' adherence
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).
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.

Full Information

First Posted
March 17, 2023
Last Updated
April 24, 2023
Sponsor
Hospices Civils de Lyon
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1. Study Identification

Unique Protocol Identification Number
NCT05841758
Brief Title
Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis
Acronym
CAESAR
Official Title
Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis: Multicenter, Prospective, Placebo-controlled, Randomized Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 1, 2023 (Anticipated)
Primary Completion Date
September 1, 2027 (Anticipated)
Study Completion Date
September 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Extra Pulmonary Sarcoidosis
Keywords
Sarcoidosis, Hydroxychloroquine, steroid-sparing agent

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Hydroxychloroquine
Arm Type
Experimental
Arm Description
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)
Arm Title
Placebo arm
Arm Type
Placebo Comparator
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Hydroxychloroquine
Intervention Description
Hydroxychloroquine (200-400 mg /day during a 12 months double blind placebo-controlled period)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo during a 12 months double blind placebo-controlled period
Primary Outcome Measure Information:
Title
Evaluate the steroid-sparing effect of hydroxychloroquine as an add-on therapy in patients with non severe extra-pulmonary sarcoidosis requiring a systemic treatment.
Description
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.
Time Frame
at Year 1
Secondary Outcome Measure Information:
Title
Organ-specific response assessed by the extra-pulmonary Physician Organ Severity Tool (ePOST)
Description
score comprised between 0 and 6
Time Frame
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Title
rate of complete, partial, stable or progression of the disease
Description
Global clinical response will be assessed by the physician as complete, partial, stable, or progression
Time Frame
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Title
Assess the total dose of local steroid treatments
Description
Total dose in Gramme of local steroid treatments
Time Frame
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Title
Assess the efficacy of HCQ in maintaining the relapse-free survival over a prolonged period
Description
Relapse rate
Time Frame
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Title
Assess and compare the eventual reduction of steroid-related toxicity (side effects)
Description
Frequencies of steroid-associated side-effects monitored clinically and biologically and Glucocorticoid Toxicity Index (GTI)
Time Frame
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.
Title
Assess HCQ safety
Description
HCQ safety will be assessed through initial and annual electroretinogram
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess HCQ safety
Description
HCQ safety will be assessed through initial and annual autofluorescence
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess HCQ safety
Description
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.
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess HCQ safety
Description
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.
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess HCQ safety
Description
HCQ safety will be assessed through Optical Coherence Tomography (OCT)
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess patients' adherence
Description
Patient's adherence will be controlled by patient notebooks
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess patients' adherence
Description
Patient's adherence will be controlled by pharmacy count of returned tablets
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess patients' adherence
Description
Patient's adherence will be controlled by serial dosages of blood HCQ levels
Time Frame
at Month 3, Month 6 and Month 12
Title
Assess quality of life by the Study Short Form 36 questionnaire (SF-36 questionnaire).
Description
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.
Time Frame
at Month 0, Month 1, Month 3, Month 6, Month 12, Month 18 and Month 24.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yvan Jamilloux, Dr
Phone
04.26.73.26.36
Email
Yvan.jamilloux@chu-lyon.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Nora Martel
Phone
04 26 73 28 62
Email
nora.martel@chu-lyon.fr
Facility Information:
Facility Name
Service de Médecine Interne Infectiologie Aïgue Polyvalente- Hôpital Henri Duffaud
City
Avignon
ZIP/Postal Code
84 000
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Philip Bielfed, Dr
Phone
04 32 75 30 01
Email
BIELEFELD.Philip@ch-avignon.fr
First Name & Middle Initial & Last Name & Degree
Philip Bielfed, Dr
Facility Name
Service de Médecine Interne et Immunologie Clinique - CHU Dijon Bourgogne
City
Dijon
ZIP/Postal Code
21 079
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bernard Bonnotte, Dr
Phone
03 80 29 34 32
Email
bernard.bonnotte@chu-dijon.fr
First Name & Middle Initial & Last Name & Degree
Bernard Bonnotte, Dr
Facility Name
Service de medecine interne - Hôpital Claude Huriez
City
Lille
ZIP/Postal Code
59 000
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emmanuel LEDOULT, Dr
Phone
03 20 44 50 48
Email
emmanuel.ledoult2@chu-lille.fr
First Name & Middle Initial & Last Name & Degree
Emmanuel LEDOULT
Facility Name
Service de medecine interne - Hôpital Duputryen
City
Limoges
ZIP/Postal Code
87 042
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kim Ly, Dr
Phone
05 55 05 69 90
Email
kim.ly@chu-limoges.fr
First Name & Middle Initial & Last Name & Degree
Kim Ly, Dr
Facility Name
Service de médecine interne - Hôpital de la Croix Rousse
City
Lyon
ZIP/Postal Code
69004
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yvan Jamilloux, Dr
Phone
04.26.73.26.36
Email
Yvan.jamilloux@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Yvan Jamilloux, MD
Facility Name
Service de médecine interne - Hôpital Lyon Sud
City
Lyon
ZIP/Postal Code
69004
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Reynaud Quitterie, Dr
Phone
04 78 86 13 54
Email
Reynaud.quitterie@chu-lyon.fr
First Name & Middle Initial & Last Name & Degree
Reynaud Quitterie, Pr
Facility Name
Service de medecine interne - Hôpital Saint Eloi
City
Montpellier
ZIP/Postal Code
34 295
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sophie Rivière, Dr
Phone
04 67 33 05 94
Email
s-riviere@chu-montpellier.fr
First Name & Middle Initial & Last Name & Degree
Sophie Rivière, Dr
Facility Name
Service de medecine interne - Hôpital Hôtel Dieu
City
Nantes
ZIP/Postal Code
44000
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Antoine Néel, Dr
Phone
02 40 08 33 55
Email
mohamed.hamidou@chu-nantes.fr
First Name & Middle Initial & Last Name & Degree
Antoine Néel, Dr
Facility Name
Service de médecine interne - Hôpital Lariboisière
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Damien Sène, Dr
Phone
01 49 95 63 21
Email
damien.sene@aphp.fr
First Name & Middle Initial & Last Name & Degree
Damien Sène, Dr
Facility Name
Service de medecine interne 2- Hôpital de la Pitié-Salpétrière
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fleur Cohen, Dr
Phone
01 42 17 81 66
Email
Fleur.cohen@aphp.fr
First Name & Middle Initial & Last Name & Degree
Fleur Cohen, Dr
Facility Name
Service de Médecine Interne et maladies infectieuses - Hôpital Haut Lévêque
City
Pessac
ZIP/Postal Code
33 604
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jean-François Viallard
Phone
05 57 65 64 83
Email
jean-francois.viallard@chu-bordeaux.fr
First Name & Middle Initial & Last Name & Degree
Jean-François Viallard, MD
Facility Name
Service de Médecine Interne et Immunologie Clinique - Hôpital Sud
City
Rennes
ZIP/Postal Code
35 2000
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolas Belhomme, Dr
Phone
02 99 26 71 28
Email
nicolas.belhomme@chu-rennes.fr
First Name & Middle Initial & Last Name & Degree
Nicolas Belhomme, dr
Facility Name
Service de medecine interne - Hôpital Nord
City
Saint-Étienne
ZIP/Postal Code
42 055
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Killian Martin, Dr
Phone
04 77 82 83 42
Email
pascal.cathebras@chu-st-etienne.fr
First Name & Middle Initial & Last Name & Degree
Killian Martin, Dr
Facility Name
Service de medecine interne - Hôpital de Hautepierre
City
Strasbourg
ZIP/Postal Code
67 200
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maxime Dubois, Dr
Phone
03 69 55 05 18
Email
Maxime.dubois@chu-strasbourg.fr
First Name & Middle Initial & Last Name & Degree
Maxime Dubois, Dr

12. IPD Sharing Statement

Learn more about this trial

Hydroxychloroquine as a Steroid-sparing Agent in Extrapulmonary Sarcoidosis

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