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Nintedanib in Patients With Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation (NINBOST2018)

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ClinicalTrials.gov Identifier: NCT03805477
Recruitment Status : Recruiting
First Posted : January 15, 2019
Last Update Posted : March 27, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Basel, Switzerland

Brief Summary:
This study investigates the safety and tolerability of Nintedanib in patients with bronchiolitis obliterans syndrome (BOS) following allogeneic hematopoietic cell transplantation. All study patients with BOS will be treated with the study drug Nintedanib (300 mg/day) as an add-on therapy to their basic immunosuppressive treatment over a 12-months treatment period.

Condition or disease Intervention/treatment Phase
Bronchiolitis Obliterans Syndrome (BOS) Bronchiolitis Obliterans (BO) Drug: Nintedanib Phase 2

Detailed Description:
Allogeneic hematopoietic stem cell transplantation (HCT) is an established treatment option for several malignant and non-malignant disorders. An important limitation of long-term survival after HCT is chronic graft-versus-host disease (cGvHD). The manifestation of cGvHD in the lungs, bronchiolitis obliterans (BO - if proven by lung biopsy) or bronchiolitis obliterans syndrome (BOS - clinical diagnosis), has a reported incidence between 5 and 20%. Despite different treatment approaches, prognosis of BO remains poor, with an overall 3-year mortality of up to 65%. Nintedanib is an orally available indolinone derivate that competitively binds to the vascular endothelial growth factor (VEGF) receptors, fibroblast growth factor (FGF) receptors, and platelet derived growth factor (PDGF) receptors. The anti-fibrotic activities of Nintedanib may impact the progressive course of fibrotic lung diseases like BO. This study investigates the safety and tolerability of Nintedanib in patients with bronchiolitis obliterans syndrome following allogeneic hematopoietic cell transplantation.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nintedanib in Patients With Bronchiolitis Obliterans Syndrome Following Hematopoietic Stem Cell Transplantation (HSCT)- a Multicentre Phase II Trial
Actual Study Start Date : March 20, 2019
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021


Arm Intervention/treatment
Experimental: Nintedanib
Nintedanib 150 mg Kps bid (oral)
Drug: Nintedanib
Nintedanib 150 mg Kps bid (oral); in order to manage adverse events, the dose of Nintedanib may be reduced from 150 mg twice daily to 100 mg twice daily




Primary Outcome Measures :
  1. adverse event rate leading to interruption/ discontinuation of study treatment [ Time Frame: from screening to month 12 after screening ]
    adverse events of the following severity according to Common terminology criteria for adverse events(CTCAE): Diarrhoea ≥ grade 3; Nausea ≥ grade 3; Vomiting ≥ grade 3; Abdominal pain ≥ grade 3; Elevation of liver enzymes (AST, ALT) ≥ grade 2; Elevation of total bilirubin ≥ 2


Secondary Outcome Measures :
  1. change of the percent of predicted forced expiratory volume in 1 second (FEV1) [ Time Frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months ]
    absolute change of the percent of predicted FEV1 by ≥10% from FEV1 before enrolment (eg, 50% to 40% predicted FEV1), confirmed by 2 pulmonary function tests (PFT) performed at least two weeks apart and after exclusion of infections and extra pulmonary causes

  2. change in forced vital capacity (FVC) [ Time Frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months ]
    volume of air that can forcibly be blown out after full inspiration, (measured in Liters)

  3. change in total lung capacity (TLC) [ Time Frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months ]
    the volume in the lungs at maximal Inflation (measured in liters)

  4. Change in diffusion capacity of the lung for carbon monoxide (DLCO) [ Time Frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months ]
    extent to which oxygen passes from the air sacs of the lungs into the blood (measured in "ml/min/kPa)

  5. Change in exhaled nitric oxide (eNO) [ Time Frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months ]
    Change in exhaled nitric oxide (eNO) (measured in parts per Billion)

  6. Nitrogen (N2)-washout [ Time Frame: Pulmonary function tests will be performed at screening, after 1, 2, 3, 6, 9, 12 and after 13 months ]
    The following describes a single-breath nitrogen test: A subject takes a breath of 100% oxygen and exhales through a one-way valve measuring nitrogen content and volume. A plot of the nitrogen concentration (as a % of total gas) vs. expired volume is obtained by increasing the nitrogen concentration from zero to the percentage of nitrogen in the alveoli. The nitrogen concentration is initially zero because the subject is exhaling the dead space oxygen they just breathed in (does not participate in alveolar exchange), and climbs as alveolar air mixes with the dead space air. The dead space can be determined from this curve by drawing a vertical line down the curve such that the areas below the curve (left of the line) and above the curve (right of the line) are equal

  7. changes in in 6 minutes walking distance (6-MWD) [ Time Frame: 6-MWD will be performed at screening, after 6, after 12 months ]
    standardized 6-minute walk test will be performed breathing room air and performed according to the guidelines of the American Thoracic Society. Significant drop of transcutaneous measured arterial oxygen Saturation (SaO2) is defined as a ΔSaO2 ≥ 4% or SaO2 < 90%. A significant change in walking distance will be Δ distance = 40 metre.

  8. cumulative steroid doses [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    steroid doses per month (in mg)

  9. occurrence of GvHD in other organs [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    occurrence of GvHD in other organs

  10. disease-free survival of underlying hematologic disease [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    disease-free survival of underlying hematologic disease

  11. changes in St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    The SGRQ is designed to measure health impairment in patients with asthma and chronic obstructive pulmonary disease (COPD); 3 component scores are calculated: symptoms; activity; impacts. Each questionnaire response has a unique empirically derived 'weight'. The lowest possible weight is zero and the highest is 100.

  12. changes in NIH GvHD grading score [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    NIH symptom-based lung score (score 0: no symptoms, score 1: shortness of breath with stairs, score 2: shortness of breath on flat ground, score 3: shortness of breath at rest or requiring oxygen)

  13. changes in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    specific HSCT-patients validated self-report questionnaire using a 5 point Likert scale and covering 4 specific domains that include physical, social and family, emotional and functional well-being. Scoring produces a range from 0-148, the higher the score, the better the Quality of Life (QOL).

  14. overall survival [ Time Frame: assessed at screening, after 1, 2, 3, 6, 9, 12, and after 13 months ]
    overall survival



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Time interval from transplant </= 5 years at the time of inclusion
  • BOS as defined per the National Institute of Health (NIH) criteria:

    1. FEV1/vital capacity < 0.7 or the fifth percentile of predicted.
    2. FEV1 < 75% of predicted with ≥ 10% decline over less than 2 years.
    3. Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, computed tomographic (CT) scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, and broncho-alveolar lavage).
    4. One of the 2 supporting features of BOS: 1. Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT, or 2. Evidence of air trapping by PFTs: residual volume > 120% of predicted or residual volume/total lung capacity elevated outside the 90% confidence interval and prior or current diagnosis of cGvHD per NIH criteria or histologically proven BO
  • Diagnosis of BOS within 6 months before enrollment or prior diagnosis of BOS with an absolute decline of the percentage of predicted forced expiratory volume in 1 second (FEV1) by >/= 10% within the past 12 months before inclusion

Exclusion Criteria

  • Known intolerance to Nintedanib or any of its component
  • Pregnancy or nursing
  • Serum ALT > 5 x upper limit of normal (ULN) unless explained entirely by liver GvHD or total bilirubin > 3x ULN unless explained entirely by liver GvHD
  • Any acute pulmonary infection with viruses, bacteria or fungi within four weeks before study inclusion
  • Chronic oxygen therapy; non-invasive ventilation
  • Inability to give informed consent or to perform repeated pulmonary function tests (PFT)
  • Life expectancy < 1 year at the time of enrolment as suggested by the treating physician
  • Hematologic malignancy in hematologic relapse
  • Symptomatic angina pectoris
  • Therapeutic anticoagulation (primary or secondary prophylactic platelet anti-aggregation allowed)
  • Recent abdominal surgery or untreated gastric ulcer

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03805477


Contacts
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Contact: Katrin Hostettler Haack, PD Dr. med +41 61 328 69 16 Katrin.Hostettler@usb.ch

Locations
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Austria
University Hospital Graz Not yet recruiting
Graz, Austria, 8096
University Hospital Wien Not yet recruiting
Wien, Austria, 1090
Germany
Charité University Hospital Not yet recruiting
Berlin, Germany, 13353
University Hospital Freiburg im Breisgau Not yet recruiting
Freiburg, Germany, 79106
University Hospital Hamburg Not yet recruiting
Hamburg, Germany, 20246
University Hospital Regensburg Not yet recruiting
Regensburg, Germany, 93053
Switzerland
Clinic of Hematology, University Hospital Basel Recruiting
Basel, Switzerland, 4031
Contact: Joerg Halter, PD Dr. med    +41 61 328 65 74    joerg.halter@usb.ch   
Clinic of Respiratory Medicine, University Hospital Basel Recruiting
Basel, Switzerland, 4031
Contact: Katrin Hostettler Haack, PD Dr. med    +41 61 328 69 16    katrin.hostettler@usb.ch   
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Investigators
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Principal Investigator: Katrin Hostettler Haack, PD Dr. med Clinic of Respiratory Medicine, University Hospital Basel

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Responsible Party: University Hospital, Basel, Switzerland
ClinicalTrials.gov Identifier: NCT03805477     History of Changes
Other Study ID Numbers: 2018-00837; me17Hostettler
First Posted: January 15, 2019    Key Record Dates
Last Update Posted: March 27, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Basel, Switzerland:
allogeneic hematopoietic cell transplantation.
chronic graft-versus-host disease (cGvHD)
Nintedanib
fibrotic lung disease

Additional relevant MeSH terms:
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Disease
Pathologic Processes
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Syndrome
Bronchiolitis
Bronchiolitis Obliterans
Bronchitis
Respiratory Tract Infections
Nintedanib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action