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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:
Secondary endpoints:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prednisone 10 mg/day -Hydroxychloroquine 400 mg/day - Azithromycin 250mg*3 | Experimental | The experimental treatment will be the combination of:
|
|
| Standard of care | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azithromycin 250 mg x3/week (3 tablets/week) | Drug | Route of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no |
| 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 |
| 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, |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Annabelle METOIS | Contact | 0140257939 | annabelle/metois@aphp.fr | |
| BORIE Raphaël | Contact | raphael.borie@aphp.fr |
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| Prednisone 10 mg/day | Drug | Route of administration: oral route Duration of treatment: 12 months Market authorization: yes Use in their market authorization indication: no |
|
| Hydroxychloroquine 400 mg/day | Drug | 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 | Drug | 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. |
|
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 |
| ID | Term |
|---|---|
| D017563 | Lung Diseases, Interstitial |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D017963 | Azithromycin |
| D011241 | Prednisone |
| D006886 | Hydroxychloroquine |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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