A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Transplant (LTx) recipients with bronchiolitis obliterans syndrome (BOS) grade 1-2

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2018-001747-31-FR
• Date of registration: 28/12/2018
• Prospective Registration: Yes
• Primary sponsor: ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
• Public title: A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Transplant (LTx) recipients with bronchiolitis obliterans syndrome (BOS) grade 1-2
• Scientific title: A Multi-center, Randomised, Double-blind Trial of Nintedanib in Lung Tranplant (LTx) recipients with bronchiolitis obliterans sydrome (BOS) grade 1-2 - INFINITX BOS
• Date of first enrolment: 09/04/2019
• Target sample size: 80
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001747-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

France

Contacts

• Name: DRCI Hôpital St Louis
• Affiliation: ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)

• Name: DRCI Hôpital St Louis
• Affiliation: ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)

Key inclusion & exclusion criteria

Inclusion criteria:
1) - Written informed consent signed prior to entry into the trial
2) - Patients > ou = à18 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 elligible.
5) - Patients must have diagnosis of BOS defined as a decrement of 20% or more in forced expiratory volume in 1 seconde (FEV1) compared to post-transplant baseline FEV1 individualized for each patient according to ISHLT definition [9]. 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 [9].
6) - Patients must have BOS grade 1 or 2 [9]
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 [3]
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 [16] [34].

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 65
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 15

Exclusion criteria:
- Patients with lung redo transplantation (combined lung transplantation, included heart-lung transplantation are permitted)
- Criteria of restrictive allograft syndrome (RAS) at V0, including the following: (1) Decline of VC > 10% 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) [3].
- 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)
- At V0, patients who already have developed severe BOS grade 3
- 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).
- At visit V1 , 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 [35] [36].
- 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; 2) isolation of an organism from a clinically relevant BAL fluid culture; 3) antibiotic therapy resulting in a full recovery and return to pre-morbid lung function.
- Previous treatment with Nintedanib after the date of lung transplantation (Treatment with Nintedanib before lung transplantation is not an exclusion criteria).
-Within the 2 weeks prior to V1, renal insufficiency with following criteria: Creatinine clearance <30 ml/min estimated by the Cockcroft-Gault equation.
-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
- 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;
- 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 hepa

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Bronchiolitis Obliterating Syndrome (SBO) grade 1 or 2 in patients with pulmonary transplantation.
MedDRA version: 20.0 Level: PT Classification code 10029888 Term: Obliterative bronchiolitis System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Trade Name: OFEV
Pharmaceutical Form: Capsule
INN or Proposed INN: Nintedanib
Other descriptive name: Nintedanib
Concentration unit: mg milligram(s)
Concentration type: equal
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: 1- to assess the efficacy of Nintedanib on exercise tolerance as assessed by the change of 6-minute walking test (6-WT) over 6 months
2- to assess the efficacy of Nintedanib on quality of life (QOL) improvement as assessed by change in the SGRQ (Saint George's Respiratory Questionnaire) over 6 months
3- to assess the efficacy of Nintedanib to hamper FEV1 decrease, as assessed by a repeated FEV1 measurements method over 6 months
4-to assess the efficacy of Nintedanib to hamper progression of BOS, as assessed by change in BOS grade and graft failure (defined as death or retransplantation)
5-to assess the efficacy of Nintedanib on the change of Oxygen saturation (SpO2) over 6 months
6-to assess Nintedanib tolerance in lung-transplant recipients over 6 months, comparing occurrence of adverse events between both arms

Primary end point(s): The absolute difference of FEV1 in mL over 6 months of treatment defined by the rate of decline between inclusion (V1) and month 6 (V4) will be compared between Nintedanib versus placebo groups.

Timepoint(s) of evaluation of this end point: 6 month

Main Objective: To assess Nintedanib efficacy in the reduction of the rate of decline of FEV1 (forced expiratory volume in 1 sec) in BOS post-LTx at a dose of 150 mg twice daily (bid) compared to placebo over 6 months.

Secondary Outcome(s)

Secondary end point(s): (i) Absolute change from baseline in the 6-min walking test (6-WT) at month six (V4).
(ii) Absolute change from baseline in SGRQ total score at month six (V4).
(iii) Absolute change of FEV1 in mL at month 6 by a repeated FEV1 measurements (Month 0 (V1), month 1 (V2), month 3 (V3), month 6 (V4)).
(iv) Proportion of patients with disease progression of BOS disease, as assessed by change in BOS grade and graft failure (defined as death or retransplantation).
(v) Absolute change from baseline in SPO2 (Oxygen saturation, expressed in percent) rest evaluated from baseline at month six (V4).
(vi) Incidence of adverse events of observed with Nintedanib versus placebo over 6 months in LTx recipients
(vii) Explanatory parameters: absolute change of 1) biomarkers of alveolar cells injury: Krebs von den Lungen-6 (KL6), surfactant apoprotein D (SPD), and growth factors as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) since baseline at month 6.

Timepoint(s) of evaluation of this end point: 6 month

Secondary ID(s)

P160907

Source(s) of Monetary Support

DGOS

Ethics review

Status: Approved
Approval date:
Contact: