Scientific justification : Variants in surfactant-related genes (SRG) explain approximately 6% of familial pulmonary fibrosis (FPF).
The pathophysiology is unknown and seems to involve endoplasmic reticulum stress in type 2 alveolar epithelial cells.
Variable improvement in the prognosis of childhood and adult interstitial lung disease (ILD) associated with a variant of a SRG, initially reported to be lethal within months of diagnosis, has been observed since the consensual use of prednisone, azithromycin and hydroxychloroquine targeting endoplasmic reticulum stress, without demonstration of the efficacy of any of these treatments alone or in combination.
The investigators hypothesize that a treatment combining prednisone, azithromycin and hydroxychloroquine is safe and could improve the prognosis of adult patients with ILD associated with SRG variant.
Main objective and primary endpoint : Main objective:
Evaluate the efficacy of triple immunomodulatory therapy (prednisone, azithromycin and hydroxychloroquine) for 12 months in patients with ILD associated with a variant of a surfactant-related gene.
Primary endpoint:
Difference in forced vital capacity decline between the 2 groups at one year.
Secondary objectives and endpoints : Secondary objectives:
1. tolerance of the triple therapy, 2. correlation between the respiratory, radiological and clinical functional response, 3. quality of life of the patients, 4. overall survival, transplant-free survival, exacerbation free-survival, hospitalization-free survival
Secondary endpoints:
1. Clinical and biological tolerance (occurrence of an adverse effect during treatment), ECG (at 3, 6, 9, 12 months after randomization) (only HCQ or AZI patients) and ophthalmological (at one year after randomization) 2. Thoracic CT scan and PFT at 6 months and one year after randomization 3. Quality of life questionnaire (EORTC QLQ-C30, v3.0) at 3 months, 6 months, 9 months and one year after randomization, 4. Collection of vital status, lung transplantation, hospitalization for pulmonary and non-pulmonary causes and episodes of exacerbation at each visit until the end of follow-up 12 months after randomization.
Design of the study : Multicenter, randomized, controlled, two-arm, parallel, open-label superiority study comparing triple immunomodulatory therapy (prednisone, azithromycin, and hydroxychloroquine) to standard of care
Category : Category 2
Population of study participants: Patients aged over 18 years with ILD and SRG variant
Number of participants included : 30
Design of the study : Multicenter, randomized, controlled, two-arm, parallel, open-label superiority study comparing triple immunomodulatory therapy (prednisone, azithromycin, and hydroxychloroquine) to standard of care.
Age ≥ 18 years and <80 years
Carrier of a variant classified as pathogenic or probably pathogenic or considered as eligible by the genetic multidisciplinary discussion in SFTPA1, SFTPA2, SFTPC, NKX2-1, SFTPB or two variants classified as pathogenic or probably pathogenic or considered as eligible by the genetic multidisciplinary discussion in ABCA3 or SFTPB
ILD whatever the pattern corresponding to a volume > 10% of the total lung on a CT scan of less than 2 years
Contraindication to azithromycin and hydroxychloroquine and prednisone (details in section 6.2)
Pregnancy and breastfeeding
Female of childbearing potential* not willing to use reliable contraception from inclusion and during 22 months
Desire to have a child within 22 months
Parallel
Azithromycin 250 mg x3/week (3 tablets/week)
DrugRoute of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no
Prednisone 10 mg/day
DrugRoute of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no
Hydroxychloroquine 400 mg/day
DrugRoute of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no
Active Comparator: Standard of care
DrugStandard of care: any symptomatic treatment to interstitial lung disease. No other experimental or off-label treatment (such as ivacaftor) will be allowed during the study.
Difference in forced vital capacity decline between the 2 groups at one year.
Evaluate the efficacy of triple immunomodulatory therapy (prednisone, azithromycin and hydroxychloroquine) for 12 months in patients with ILD associated with a variant of a surfactant-related gene.
tolerance of the triple therapy
Clinical and biological tolerance (occurrence of an adverse effect during treatment), ECG (including QTc prolongation) (at 3, 6, 9, 12 months after randomization) (only HCQ or AZI patients) and ophthalmological (at 6 months and 12 months after randomization)
correlation between the respiratory, radiological and clinical functional response,
Thoracic CT scan (progression criteria \[99\]) and PFT (Pulmonary function tests) at one year after randomization
Quality of life of the patients
Quality of life questionnaire (SF-36, scale from 0 to 100, where 0 represents the poorest health and 100 represents the best possible health) (EORTC QLQ-C30, v3.0 : a validated patient-reported questionnaire for assessing quality of life in cancer patients.) at one year after randomization,
tolerance of the triple therapy
Clinical and biological tolerance (occurrence of an adverse effect during treatment), ECG (including QTc prolongation) at 6, months after randomization (only HCQ or AZI patients) and ophthalmological (at one year after randomization)
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