Immunomodulatory Treatment of Interstitial Lung Disease Associated With Surfactant Related Gene Variants

Summary

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.

Conditions

• Interstitial Lung Disease

Interventions

DRUG

Azithromycin 250 mg x3/week (3 tablets/week)

Route of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no

DRUG

Prednisone 10 mg/day

Route of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no

DRUG

Hydroxychloroquine 400 mg/day

Route of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no

DRUG

Active Comparator: Standard of care

Standard 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-10-01

Primary Completion

2027-10-01

Completion

2027-10-01