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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Interstitial Lung Disease
• Intervention / Treatment: Drug: Azithromycin 250 mg x3/week (3 tablets/week); Drug: Prednisone 10 mg/day; Drug: Hydroxychloroquine 400 mg/day; Drug: Active Comparator: Standard of care

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Annabelle METOIS; Phone Number: 0140257939; Email: annabelle/metois@aphp.fr
• Study Contact Backup: Name: BORIE Raphaël; Email: raphael.borie@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years and <80 years
2. 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
3. ILD whatever the pattern corresponding to a volume > 10% of the total lung on a CT scan of less than 2 years

Exclusion Criteria:

1. Contraindication to azithromycin and hydroxychloroquine and prednisone
2. Pregnancy and breastfeeding
3. Enrolment to another interventional study (clinical trial on medicinal product, medical device and interventional research involving human participants not concerning health product)
4. Subject deprived of liberty or subject under legal protection measure
5. No affiliation to any health insurance system
6. Refusal to participate to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prednisone 10 mg/day -Hydroxychloroquine 400 mg/day - Azithromycin 250mg*3; The experimental treatment will be the combination of: Prednisone 10 mg/day (1 tablet/day); Hydroxychloroquine 400 mg/day (2 tablets/day); 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: 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
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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 one year after randomization)	12 months
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	12 months
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,	12 months
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)	6 months
tolerance of the triple therapy	Clinical and biological tolerance (occurrence of an adverse effect during treatment), ECG (including QTc prolongation) at 3 months after randomization (only HCQ or AZI patients) and ophthalmological (at one year after randomization)	3 months
correlation between the respiratory, radiological and clinical functional response,	Thoracic CT scan (progression criteria [99]) and PFT (Pulmonary function tests) at 6 months after randomization	6 months
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 9 months after randomization,	9 months
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 6 months after randomization,	6 months
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 3 months after randomization,	3 months
Overall survival	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	12 months
Transplant-free survival	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	12 months
Exacerbation free-survival	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	12 months
Hospitalization-free survival	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	12 months
tolerance of the triple therapy	Clinical and biological tolerance (occurrence of an adverse effect during treatment),	9 months
tolerance of the triple therapy	ECG (including QTc prolongation) at 12 months after randomization (only HCQ or AZI patients)	12 months
tolerance of the triple therapy	Ophthalmological (at one year after randomization)	12 months
tolerance of the triple therapy	ECG (including QTc prolongation) at , 9 months after randomization (only HCQ or AZI patients)	9 months
tolerance of the triple therapy	ECG (including QTc prolongation) at 6 months after randomization (only HCQ or AZI patients)	6 months
tolerance of the triple therapy	ECG (including QTc prolongation) at 3 months after randomization (only HCQ or AZI patients)	3 months
Overall survival	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 9 months after randomization	9 months
Overall survival	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 6 months after randomization	6 months
Overall survival	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 3 months after randomization	3 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: February 11, 2026
• First Submitted That Met QC Criteria: February 27, 2026
• First Posted (Actual): March 2, 2026

Study Record Updates

• Last Update Posted (Actual): March 2, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Interstitial; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Macrolides; Lactones; Pregnadienediols; Quinolines; Aminoquinolines; Erythromycin; Polyketides; Chloroquine; Prednisone; Hydroxychloroquine; Azithromycin
• Other Study ID Numbers: APHP251230

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No