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

NCT03283007 | Completed Phase 3 DMC

• 1 other identifier: P160907
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

Lung transplantation (TxP) is now a validated treatment of end-stage pulmonary diseases, but long-term graft and patient survival are still hampered by the development of chronic allograft dysfunction (CLAD) affecting \> 50% of patients. The investigators propose to conduct a phase III clinical randomized trial that will assess the efficacy of Nintedanib to hamper the lung decline in LTx recipients with BOS. This is the first trial testing this molecule in lung Tx recipients. If case of demonstrated effectiveness of Nintedanib, the benefit for lung transplant patients carrying a BO is high in terms of stabilization of lung function and enhancement of survival.

Conditions

Lung-transplant Recipients

Keywords

Nintedanib, lung transplantation, bronchiolitis obliterans syndrome

Outcome Measures

Primary Outcomes (1)

• 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

  The absolute difference of FEV1 in mL over 6 months of treatment defined by the rate of decline between inclusion (Visit 1) and month 6 (Visit 4) will be compared between Nintedanib versus Placebo groups

  6 months

Secondary Outcomes (7)

• Nintedanib efficacy on exercise tolerance in LTx recipients

  6 months

• Nintedanib efficacy on quality of life improvement in LTx recipients

  6 months

• Nintedanib efficacy to hamper FEV1 decrease in LTx recipients

  6 months

• Nintedanib efficacy to hamper progression of BOS in LTx recipients

  6 months

• Nintedanib efficacy on the change of Oxygen saturation in LTx recipients

  6 months

Study Arms (2)

Nintedanib

EXPERIMENTAL

Eligible LTx recipients with BOS receive Nintedanib treatment at a dose of 150 mg twice daily (bid) for 6 months

Drug: Nintedanib

Placebo

PLACEBO COMPARATOR

Eligible LTx recipients with BOS receive Nintedanib 150 mg BID matching placebo treatment for 6 months

Drug: Placebo

Interventions

Nintedanib DRUG

Eligible LTx recipients with BOS receive Nintedanib treatment at a dose of 150 mg twice daily (bid) for 6 months

Nintedanib

Placebo DRUG

Eligible LTx recipients with BOS receive Nintedanib 150 mg BID matching placebo treatment for 6 months

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent signed prior to entry into the trial
• Patients ≥18 years of age when signing his/her informed consent
• Patients at least at 6 months post-LTx
• Single- or double-LTx or combined cardio-pulmonary LTx are eligible
• 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
• Patients must have BOS grade 0p, 1 or 2
• 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
• 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

You may not qualify if:

• Related to LTx
• 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)
• 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 (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
• 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
• Ongoing treatment with photopheresis at V1 or planned treatment with photopheresis within the study period.
• Laboratory parameter thresholds
• 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 (refer to the protocole, for the management of liver enzyme elevation).
• 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)
• Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (V0)
• Alcohol or drug abuse which in the opinion of the treating physician would interfere with treatment
• Patients not able to understand and follow study procedures including completion of self-administered questionnaires without help.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Foch Hospital

Suresnes, 92150, France

Location

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

nintedanib

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Study Officials

• Olivier Brugière, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 6, 2017
• First Posted: September 14, 2017
• Study Start: October 30, 2019
• Primary Completion: March 30, 2025
• Study Completion: March 30, 2025
• Last Updated: September 8, 2025

Record last verified: 2025-05

Locations

FR (1)