Clinical trial NCT05247554: Randomized Controlled Trial of Hydroxychloroquine Combined With Low-dose Corticosteroid in Pulmonary Sarcoidosis
Official title: Randomized Controlled Trial Testing the Effect of Hydroxychloroquine Combined With Low-dose Corticosteroid Therapy in Pulmonary Sarcoidosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Pulmonary Sarcoidosis
Keywords: Sarcoidosis
Hydroxychloroquine
Pulmonary
Quality of life
Steroids
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-02-21
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The reference treatment for pulmonary sarcoidosis is prolonged systemic corticosteroid therapy, which improves dyspnea, fatigue and respiratory function. However, corticosteroid therapy doesn't improve quality of life, possibly due to its adverse effects. Furthermore, in an international survey study, the first priority in treatment outcome for sarcoidosis patient was quality of life.

Hydroxychloroquine an antimalarial drug, has been shown to be effective in cutaneous and pulmonary forms of sarcoidosis but in studies with imperfect methodology. Our hypothesis is that hydroxychloroquine associated with low-dose corticosteroids improves lung function as much as "conventional" medium-dose corticosteroid therapy but with fewer side effects and a better quality of life in pulmonary sarcoidosis. 

Detailed description: Sarcoidosis is a systemic granulomatosis of unknown etiology with almost systematic pulmonary involvement. The reference treatment for pulmonary sarcoidosis is prolonged systemic corticosteroid therapy, which improves dyspnea, fatigue and respiratory function. However, corticosteroid therapy doesn't improve quality of life, possibly due to its adverse effects, which are dose- and time-dependent, such as weight gain, diabetes, insomnia, hypertension. Furthermore, in an international survey study, the first priority in treatment outcome for sarcoidosis patient was quality of life. Recent optimizations have reduced the attack treatment duration from 3 to 1 month, but with a persistence of adverse effects appearing in the first months.

Hydroxychloroquine is an antimalarial drug, used for systemic lupus erythematosus with a very good benefit/risk ratio and low cost, but also for rheumatoid arthritis. Its anti-inflammatory effects involve inhibition of antigenic presentation, chemotaxis, phagocytosis, lymphocyte proliferation, cytokine production (e.g TNFα), or Toll-like receptors expression. These immunological mechanisms are also involved in the pathogenesis of sarcoidosis. In addition, Hydroxychloroquine decreases the risk of developing diabetes mellitus, dyslipidemia or thrombotic events. Hydroxychloroquine has been shown to be effective in cutaneous and pulmonary forms of sarcoidosis, and in hypercalcemia, but in studies with imperfect methodology. Baltzan et al. showed that a maintenance treatment of hydroxychloroquine versus placebo reduced the risk of relapse and lung function decline in pulmonary sarcoidosis. Our hypothesis is that hydroxychloroquine associated with low-dose corticosteroids improves lung function as much as "conventional" medium-dose corticosteroid therapy but with fewer side effects and a better quality of life in pulmonary sarcoidosis. The main objective is to demonstrate the non-inferiority of the combination of hydroxychloroquine and low-dose corticosteroids versus medium-dose corticosteroid therapy on the improvement of respiratory function at 6 months.

The secondary objectives are to (i) demonstrate the superiority of the combination of hydroxychloroquine and low-dose corticosteroids versus medium-dose corticosteroid therapy at 3, 6 months and 1 year on general quality of life, respiratory quality of life, fatigue, adverse drug event, treatment compliance and (ii) demonstrate the non-inferiority of the combination of hydroxychloroquine and low-dose corticosteroids versus medium-dose corticosteroid therapy at 3, 6 months and 1 year on : respiratory function using complementary tools, respiratory symptoms, and activity of thoracic and extra-thoracic sarcoidosis. 

Eligibility criteria: Inclusion Criteria:

* Age between 18-80 years old
* Pulmonary sarcoidosis meeting the diagnostic criteria form ATS 2020 AJRCCM diagnostic criteria.
* Patient with radiographic stage II (mediastinal-hilar bilateral lymphadenopathy and parenchymal involvement) or III (involvement pulmonary parenchymatous) and FVC\<80% and respiratory symptom(s) among the following: cough, dyspnea, chest pain).
* Effective contraception for women of childbearing ages
* Informed consent signed.
* Affiliation to the social security system

Exclusion Criteria:

* Severe impairment requiring an immediate and urgent result and/or high doses of corticosteroids (neurological, cardiac, ophthalmic (severe uveitis with ocular sequala), laryngeal, nasosinusal, renal, severe hypercalcemia)
* Cardiomyopathy with heart failure
* Presence of other conditions that may influence respiratory function: COPD, Asthma, Obesity (BMI\>30) pulmonary fibrosis disease, pulmonary neoplasia;
* Contraindication to hydroxychloroquinehypersensitivity to active substances or to excipients, retinopathy or severe cataract, or unilateral blindness, QTc prolongation, exposure to known treatments to prolong QT)
* Tamoxifen use
* Renal insufficiency with clearance \<60ml/min
* History of retinopathy or maculopathy
* Contraindication to corticosteroid therapy (hypersensitivity of active substancies, infections and progressive virosis, glaucoma, psychotic state not controlled by treatment, live vaccine, uncontrolled diabetes mellitus and hypertension)
* Intermittent porphyria (risk of acute porphyria crisis)
* Glucose-6-Phosphate Dehydrogenase deficiency
* Seropositivity to HIV, HBV, HCV
* Systemic corticosteroid therapy or immunosuppressive therapy for at least 7 days in the previous year;
* History of treatment with hydroxychloroquine for sarcoidosis;
* Current pregnancy,
* Breastfeeding,
* Patient unable to answer questionnaires despite the presence of a caregiver.
* Patient under trustee
* Patient under legal protection
* Participation in another therapeutic interventional trial within 6 months of inclusion

Primary outcomes:
measure: Difference in percentage of the predicted forced vital capacity (FVC) between inclusion and 6 months
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: ASSISTANCE PUBLIQUE HOPITAUX DE PARIS, Hôpital Avicenne, Service de Pneumologie
name: Florence JENY, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASSISTANCE PUBLIQUE HOPITAUX DE PARIS, Hôpital Avicenne, Service de Pneumologie
name: Dominique VALEYRE, MD
role: STUDY_DIRECTOR
References:
citation: Broos CE, Wapenaar M, Looman CWN, In 't Veen JCCM, van den Toorn LM, Overbeek MJ, Grootenboers MJJH, Heller R, Mostard RL, Poell LHC, Hoogsteden HC, Kool M, Wijsenbeek MS, van den Blink B. Daily home spirometry to detect early steroid treatment effects in newly treated pulmonary sarcoidosis. Eur Respir J. 2018 Jan 18;51(1):1702089. doi: 10.1183/13993003.02089-2017. Print 2018 Jan. No abstract available.
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