Pragmatic management of progressive disease in idiopathic pulmonary fibrosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospices Civils De Lyon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

20 Feb 2020 → 9 Jan 2026

Decision date (initial)

2024-04-11

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

French Ministry of Health

External identifiers

EU CT number

2024-511427-34-00

EudraCT number

2019-004326-19

ClinicalTrials.gov

NCT03939520

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the efficacy of combination therapy of pirfenidone and nintedanib as compared to switch monotherapy (pirfenidone or nintedanib) and to no change monotherapy (pirfenidone or nintedanib) based on the slope of the decline in the forced vital capacity (FVC) measured during 24 weeks by hospital spirometry performed at baseline, week 4, week 12 and week 2

Secondary objectives 11

1. To assess the tolerance during 24 weeks of combination therapy versus switch monotherapy and versus no change monotherapy
2. to evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy on time to study drug permanent discontinuation.
3. To evaluate the efficacy of combination therapy as compared to switch monotherapy and to no change monotherapy on time to treatment failure
4. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in death and FVC decline during the 24 weeks follow-up
5. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in hospitalization-free survival during the 24 weeks follow-up
6. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in first non-elective hospitalization from pulmonary cause during the 24 weeks follow-up.
7. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in all-cause mortality during the 24 weeks follow-up.
8. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in the progression of fibrotic features assessed by imaging by computed tomography at 24 weeks compared to baseline.
9. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in supplementary oxygen therapy during the 24 weeks follow-up.
10. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in acute exacerbation of IPF during the 24 weeks follow-up
11. To evaluate the impact of combination therapy as compared to switch monotherapy and to no change monotherapy in the change in IPF questionnaires relative to symptoms and impact on quality of life between baseline and week 24

Conditions and MedDRA coding

idiopathic pulmonary fibrosis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Patient aged ≥ 50 years
2. Diagnosis of Idiopathic Pulmonary Fibrosis according to ATS/ERS/JRS/ALAT criteria (Raghu G et al, AJRCCM 2018). High-resolution computed tomography (HRCT) and histopathology patters are classified according to the table in protocol
3. Patient who fulfill at least 1 of the 4 criteria for IPF progression in the 12 months (+/- six months) before screening, despite antifibrotic treatment in clinical practice (if yes check the option(s)). These criteria are: 0 Relative decline in FVC ≥10% predicted 0 Relative decline in FVC ≥5-<10% predicted and worsened respiratory symptoms 0 Relative decline in FVC ≥5-<10% predicted and increased extent of fibrotic changes on chest imaging 0 Worsened respiratory symptoms and increased extent of fibrotic changes on chest imaging
4. Patient must have been on a stable dose of pirfenidone or nintedanib prescribed as first-line therapy for at least 6 months, with good tolerance of 1602 to 2403 mg per day of pirfenidone or 200 to 300 mg per day of nintedanib
5. Patient who has a FVC ≥ 45% of predicted (according to the GLI standard).
6. Patient who has a forced expiratory volume in 1-second (FEV1)/FVC ratio ≥ 0.70.
7. Patient who has a life expectancy of at least 9 months according to the investigator opinion.
8. Patient who has provided his written informed consent to participate in the study
9. Patient affiliated to a social insurance regimen

Exclusion criteria 17

1. Patients under judicial protection.
2. Female patient who is pregnant or lactating, or is of child bearing potential (defined as a sexually mature woman not surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤ 55 years or 12 months if > 55 years) and who did not agree to use highly effective methods of birth control throughout the study.
3. Patient who is currently on both pirfenidone and nintedanib
4. Patient who has already received pirfenidone and nintedanib either concomitantly or successively.
5. Patient who has a contra-indication to pirfenidone or nintedanib
6. Patient who has a liver function with elevations in ALT and AST >3 × upper limit of normal (ULN)
7. Patient with moderate and severe hepatic impairment classified as Child Pugh B and C
8. Patient who has a severe renal impairment (Creatinine Clearance <30 ml/min) or end stage renal disease requiring dialysis
9. Patient who has emphysema > 15% on HRCT or the extent of emphysema is greater than the extent of fibrosis according to reported results from the most recent HRCT
10. Patient who had acute exacerbation of idiopathic pulmonary fibrosis within the previous 3 months
11. Patient who has a history of cigarette smoking within the previous 3 months
12. Patient who has received experimental therapy for IPF within the previous 4 weeks
13. Patient who is receiving systemic corticosteroids equivalent to prednisone > 10 mg/day or equivalent within the previous 2 weeks
14. Patient who received Immuno-suppressants (e.g. methotrexate, azathioprine, cyclophosphamide, cyclosporine, sirolimus, everolimus or other immunosuppressants) within the previous 4 weeks.
15. Patient who has a history of a malignancy within the previous 2 years, with the exception of basal cell skin neoplasms. In addition, a malignant diagnosis or condition first occurring prior to 2 years must be considered cured, inactive, and not under current treatment
16. Patient who has any concurrent condition other than IPF that, in the Investigator’s opinion, is unstable and/or would impact the likelihood of survival for the study duration or the subject’s ability to complete the study as designed, or may influence any of the safety or efficacy assessments included in the study
17. Patient who has baseline resting oxygen saturation of < 88% on room air or supplemental oxygen.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Slope of the decline in the forced vital capacity (FVC) measured during 24 weeks by hospital spirometry performed on the same spirometer at baseline, week 4, week 12 and week 24.

Secondary endpoints 11

1. Tolerance of antifibrotic therapy expressed as the proportion of patients who continue intent-to-treat therapy at week 24, at a minimal daily dose of two thirds of the full treatment dose (e.g. 200 mg/day of nintedanib and/or 1602 mg/day of pirfenidone), with temporary interruptions of no more than 28 consecutive days.
2. Time to permanent study drug discontinuation, defined as the interval from study treatment randomization to study drug permanent discontinuation or the end of follow-up. Study drug discontinuation will be considered in case of permanent termination of drug treatment allocated by randomization, transient discontinuation for longer than 28 consecutive days, or dose reduction below two thirds of the full treatment dose (i.e. 200 mg per day of nintedanib or 1602 mg per day or pirfenidone).
3. Time to treatment failure, defined as the time from study treatment randomization to the first occurrence during the 24 weeks follow-up of any of the following events: o Death from any cause, o Non-elective hospitalization from pulmonary cause, o Acute exacerbation of idiopathic pulmonary fibrosis , o Decrease from baseline of ≥ 10% in FVC, o Permanent study drug discontinuation or the end of follow-up.
4. Proportion of patients with ≥ 10% FVC relative decline or death at week 24
5. Hospitalization-free survival, defined as the time from randomization to the first occurrence during the 24 weeks follow-up of any of the following events: o Death from any cause, o All-cause unscheduled hospital admission, or the end of follow-up.
6. Time from randomization to the first non-elective hospitalization from pulmonary cause (which is predefined by a set of criteria in protocol) during the 24 weeks follow-up or the end of follow-up.
7. Time from randomization to death from any cause during the 24 weeks of the study or the end of follow-up.
8. Progression of disease evaluated by the change from baseline in volume of fibrotic features at imaging by computed tomography assessed at 24 weeks.
9. Time from randomization to initiation of supplementary oxygen therapy during the 24 weeks of the study or the end of follow-up.
10. Time from randomization to acute exacerbation of idiopathic pulmonary fibrosis (idiopathic or triggered) during the 24 weeks of the study or the end of follow-up.
11. Absolute change in IPF questionnaires relative to symptoms and impact on quality of life between baseline and week 24 assessed by : King’s Brief Interstitial Lung Disease Questionnaire (K-BILD), EQ-5D-5L Questionnaire, Living with Pulmonary Fibrosis (L-PF) Symptoms and Impact questionnaires, and analogy scale and Likert scale for the evaluation of dyspnea, cough and respiratory health.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospices Civils De Lyon

Sponsor organisation

Hospices Civils De Lyon

Address

3 Quai Des Celestins, Bp 2251 Bp 2251

City

Lyon Cedex 02

Postcode

69229

Country

France

Scientific contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr Vincent Cottin

Public contact point

Organisation

Hospices Civils De Lyon

Contact name

Pr Vincent Cottin

Locations

1 EU/EEA country · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications