Nintedanib in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome Grade 0p-1-2

• Register: ClinicalTrials.gov
• Last refreshed on: 17 October 2022
• Main ID: NCT03283007
• Date of registration: 06/09/2017
• Prospective Registration: Yes
• Primary sponsor: Assistance Publique - Hôpitaux de Paris
• Public title: Nintedanib in Lung Transplant Recipients With Bronchiolitis Obliterans Syndrome Grade 0p-1-2 INFINITx-BOS
• Scientific title: A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Transplant (LTx) Recipients With Bronchiolitis Obliterans Syndrome (BOS) Grade 0p-1-2
• Date of first enrolment: October 30, 2019
• Target sample size: 80
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/show/NCT03283007
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

France

Contacts

• Name: Olivier Brugière, MD, PhD

• Name: Olivier Brugière, MD, PhD

• Name: Olivier Brugière, MD, PhD
• Affiliation: Assistance Publique - Hôpitaux de Paris

Key inclusion & exclusion criteria

Inclusion Criteria:

1. Written informed consent signed prior to entry into the trial

2. Patients =18 years of age when signing his/her informed consent

3. Patients at least at 6 months post-LTx

4. Single- or double-LTx or combined cardio-pulmonary LTx are eligible

5. Patients must have diagnosis of BOS defined as a decrement of 10% or more in forced
expiratory volume in 1 seconde (FEV1) compared to post-transplant baseline FEV1
individualized for each patient according to ISHLT definition. The documented post-LTx
baseline value of FEV1 is defined as the mean of the 2 highest values measured at
least 3 weeks apart according to ISHLT criteria, and post-LTx VC measurements

6. Patients must have BOS grade 0p, 1 or 2

7. Patients must have documented progressive BOS as demonstrated by the following
criteria: at least 3 FEV1 and VC measurements in the last 12 months prior V1, each at
least 3 weeks apart, with a total decline of at least 200ml in FEV1 in these last 12
months AND FEV1/VC<0.7

8. Azithromycin therapy for at least 4 weeks prior to V1, with an Azithromycin dose of
minimum 250 mg/day at least 3 times per week as this is considered standard therapy
for bronchiolitis obliterans syndrome

Exclusion Criteria:

Related to LTx

1. Criteria of restrictive allograft syndrome (RAS) at V0, including the following: (1)
Decline of VC < 20% of best post-LTx value (FVCBest is defined as the average of the
two FVCs associated with the two PFTs used in FEV1 baseline calculation for CLAD
diagnosis) AND FEV1/VC > 0.7 AND (2) Thorax HRCT at entry demonstrate new significant
findings which are compatible with RAS like interstitial fibrosis, consolidation,
appearances suggesting Restrictive Allograft Syndrome (RAS)

2. FEV1 and/or FV and/or TLC decline related to other nonCLAD causes (eg Diaphragm
dysfunction, pneumothorax or pleural effusion, evolutive bronchial stricture within
the previous 3 months)

3. At V0, patients who already have developed severe BOS grade 3

4. Patients with severe comorbidity complicating CLAD which might determine the prognosis
and functional level of the patient (e.g. evolutive invasive aspergillosis or
mycobacterial infection within the last 3 months, active malignant disease within the
last 12 months)

5. At visit V1 (end of screening period), diagnosis of documented acute cellular (AR)
perivascular rejection higher than grade A1 within the 4 prior weeks OR diagnosis of
acute antibody-mediated rejection within the 4 prior weeks, based on presence of all 4
following criteria: 1) acute lung allograft dysfunction, 2) detection of
donor-specific antibodies, 3) histological findings compatible with AMR on
transbronchial lung biopsy TBBx, and 4) detection of C4d > 50% on TBBx

6. At visit V1 (end of screening period), diagnosis of documented acute pulmonary
infection within the 2 prior weeks, on the basis of the following: 1) clinical,
radiological and physiological deterioration; AND 2) isolation of an organism from a
clinically relevant BAL fluid culture; AND 3) antibiotic therapy resulting in a full
recovery and return to pre-morbid lung function

7. Previous treatment with Nintedanib after the date of lung transplantation (Treatment
with Nintedanib before lung transplantation is not an exclusion criteria)

8. Ongoing treatment with photopheresis at V1 or planned treatment with photopheresis
within the study period.

Laboratory parameter thresholds

9. Within the 2 weeks prior to V1, renal insufficiency with following criteria:
Creatinine clearance <30 ml/min estimated by the Cockcroft-Gault equation

10. Within the 2 weeks prior to V1, any of the following liver test criteria above the
specified limit: Total bilirubin > 1.5 above the upper limit of the normal range
(ULN), except in patients with predominantly unconjugated hyperbilirubinemia (e.g.,
Gilbert's syndrome). Aspartate or alanine aminotransferase (AST or ALT) >3 × ULN
(refer to the protocole, for the management of liver enzyme elevation).

General exclusion criteria

11. Pregnancy or lactation (women of childbearing capacity are required to have a negative
serum pregnancy test before treatment and must agree to maintain highly effective
contraception by practicing abstinence or by using at least two methods of birth
control from the date of consent to three months after the end of the patient study
participation)

12. Other investigational therapy received within 1 month or 6 half-lives (whichever was
greater) prior to screening visit (V0)

13. Alcohol or drug abuse which in the opinion of the treating physician would interfere
with treatment

14. Patients not able to understand and follow study procedures including completion of
self-administered questionnaires without help.

Other diseases

15. Cardiac disease: (1) History of myocardial infarction within 6 months of visit 1 or
unstable angina within 6 months of visit 1; (2) Presence of aortic stenosis (AS) per
investigator judgement at visit 1; (3) Severe chronic heart failure: defined by left
ventricular ejection fraction (EF) < 25% per investigator judgement at visit 1

16. Known allergy or hypersensitivity to Nintedanib or intolerance to nintedanib, peanut
or soya, or any other components of the study medication

17. Bleeding Risk: Known genetic predisposition to bleeding; Patients who require
fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists,
direct thrombin inhibitors, heparin, hirudin, etc.) or high dose antiplatelet therapy
(acetyl salicylic acid >325 mg/day, or clopidogrel >75 mg/day) [NB: Prophylactic low
dose heparin or heparin flush as needed for maintenance of an indwelling intravenous
device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of
antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at
75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited];
History of haemorrhagic central nervous system (CNS) event within 12 months prior to
visit 1; History of haemoptysis or haematuria within 3 months prior to visit 1, active
gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months
prior to visit 1; International normalised ratio (INR) > 2 at visit 1; Prothrombin
time (PT) and activated partial thromboplastin time (aPTT) > 150% of institutional ULN
at visit 1

18. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Lung-transplant Recipients

Intervention(s)

Drug: Placebo

Drug: Nintedanib

Primary Outcome(s)

Nintedanib efficacy in the reduction of the rate of decline of FEV1 (forced expiratory volume in 1 sec) in BOS post-LTx grade 0p-1-2 at a dose of 150 mg twice daily (bid) compared to placebo over 6 months [Time Frame: 6 months]

Secondary Outcome(s)

Explanatory parameters of fibrotic pathways [Time Frame: 6 months]

Nintedanib efficacy to hamper FEV1 decrease in LTx recipients [Time Frame: 6 months]

Nintedanib efficacy on the change of Oxygen saturation in LTx recipients [Time Frame: 6 months]

Nintedanib efficacy on exercise tolerance in LTx recipients [Time Frame: 6 months]

Nintedanib efficacy on quality of life improvement in LTx recipients [Time Frame: 6 months]

Nintedanib tolerance in LTx recipients [Time Frame: 6 months]

Nintedanib efficacy to hamper progression of BOS in LTx recipients [Time Frame: 6 months]

Secondary ID(s)

AOR16076 - P160907

Source(s) of Monetary Support

Please refer to primary and secondary sponsors