Safety and Potential Efficacy of Human Mesenchymal Stem Cells in Non-Cystic Fibrosis Bronchiectasis

Study Overview
=================
Brief Summary
-----------------
To demonstrate the safety of bone marrow-derived allogeneic human Mesenchymal Stem Cells (hMSCs) in patients with bronchiectasis receiving standard of care therapy, and to explore treatment efficacy

Detailed Description
-----------------
A Phase 1 investigation will be performed to test the safety of two doses of bone-marrow derived hMSCs (20,000,000 and 100,000,000) administered via peripheral intravenous infusion. Group 1: 3 subjects will receive a single administration of allogeneic hMSCs: 20 x106 (20 million) cells delivered via peripheral intravenous infusion Group 2: 3 subjects will receive a single administration of allogeneic hMSCs: 1 x108 (100 million) cells delivered via peripheral intravenous infusion Interim safety analysis will be performed four weeks after the 1st subject is enrolled in each cohort. Continued safety and tolerability with review of adverse events (AEs) will be assessed at each visit. Efficacy parameters (pulmonary function tests, lung diffusion capacity, lung volumes, 6-Minute Walk Test (6MWT), and dyspnea/Quality of Life (QOL) questionnaires) will be assessed every 12 weeks until study completion. Clinical laboratory tests to assess safety will be performed at every visit. High Resolution Computed Tomography (HRCT) scan will be performed at the baseline visit (if not done within three months prior to enrollment) and then at week 24.

Official Title
-----------------
A Phase I, Trial to Evaluate the Safety, Tolerability, and Potential Efficacy of Allogeneic Human Mesenchymal Stem Cell (hMSC) Infusion in Patients With Non-Cystic Fibrosis Bronchiectasis

Conditions
-----------------
Bronchiectasis

Intervention / Treatment
-----------------
* Biological: hMSCs


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provide written informed consent, be between 30 and 87 years old at the time of signing the Informed Consent, weight over 45 and under 150 kg, have a clinical diagnosis of non-CF bronchiectasis prior to screening, Have had at least 2 exacerbations in the past year as documented by physician office or hospital visits (Use of antibiotics of at least one time in the last year), Show a baseline FEV1 between 25% and 85% predicted and over or equal to 1 L and a baseline diffusion capacity of lung for carbon monoxide (DLCO) over or equal to 30% (corrected for hemoglobin but not alveolar volume), Have a normal Right Ventricular function, as documented by Doppler echo or right heart catheterization, if a female of childbearing potential, agree to abide by contraception rules defined below. Subjects may receive nondrug therapies including oxygen supplementation not greater than 4 Liters per minute and pulmonary rehabilitation. Subjects may be on chronic macrolide or inhaled antibiotic treatment bronchiectasis Exclusion Criteria: Have HRCT and or surgical lung biopsy results inconsistent with the diagnosis of non-CF bronchiectasis. (Exclusion of emphysema and or diffuse parenchymal disease) be unable to perform any of the assessments required for endpoint analysis (report safety or tolerability concerns, perform Pulmonary Function Tests (PFT) or HRCT, undergo blood draws, read and respond to questionnaire If a female of childbearing potential, have a follicle stimulating hormone (FSH) under 25.8 IU/L be actively treated for an acute infectious exacerbation of bronchiectasis Have an active infection that is not treated Have had active infections occurring within a minimum of 4 weeks of study treatment Be currently on treatment for NTM infections Have had positive sputum cultures for nontuberculous mycobacterial (NTM) within the past 6 months Have a history of drug or alcohol abuse within the past 24 months. Be currently receiving (or have received within four weeks of screening) experimental agents for the treatment of bronchiectasis or have been enrolled in clinical trials within the previous 30 days Be actively listed (or expect future listing) for transplant of any organ. Have clinically important abnormal screening laboratory values. Have a serious comorbid illness that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study. Have any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study. Have known allergies to penicillin or streptomycin. Be an organ transplant recipient. Have a clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease free for 5 years), except curatively-treated basal cell carcinoma of skin, squamous cell carcinoma of skin, or cervical carcinoma. Have a non-pulmonary condition that limits lifespan to less than 1 year. Be serum positive for HIV, hepatitis BsAg (surface agent reactive) or Viremic hepatitis C. Have hypersensitivity to dimethyl sulfoxide (DMSO) Be unable to maintain saturated oxygen (SpO2) of more than 93% on room air at sea level at rest) or an SpO2 of more than 88% on room air over 5,000 feet (1524 meters) above sea level at rest.

Ages Eligible for Study
-----------------
Minimum Age: 30 Years
Maximum Age: 87 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>3 patients will receive a single administration of allogeneic hMSCs: 20 x106 (20 million) cells delivered via peripheral intravenous infusion | Biological: hMSCs<br>* intravenous infusion of bone marrow-derived allogeneic stem cells<br>* Other names: allogeneic mesenchymal stem cell;|
| Experimental: Group 2<br>3 patients will receive a single administration of allogeneic hMSCs: 1 x108 (100 million) cells delivered via peripheral intravenous infusion | Biological: hMSCs<br>* intravenous infusion of bone marrow-derived allogeneic stem cells<br>* Other names: allogeneic mesenchymal stem cell;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participant with treatment emergent serious adverse events | incidence of any treatment-emergent serious adverse events defined as the composite of death, non-fatal pulmonary embolism, stroke, hospitalization for worsening dyspnea and clinically significant laboratory test abnormalities | Week 4 post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Colony Forming Units (CFUs) in semiquantitative culture of sputum | Difference in CFUs in semiquantitative culture of sputum | Participants will be followed from 1 week to an expected average of 24 weeks following infusion. | 
| rate of decline of lung function | difference in absolute decline of forced expiratory volume at one second (FEV1) percent predicted | Participants will be followed from 12 weeks to an expected average of 24 weeks following infusion. | 
| frequency of acute exacerbations | increased cough and sputum production, fever, new or worsened dyspnea in less than 30 days, new or worsened hypoxemia in the absence of other identifiable causes | Participants will be followed from 12 weeks to an expected average of 48 weeks following infusion. | 
| reported dyspnea and quality of life assessment | using quality of life tool questionnaire QOL-B version 2 | Participants will be followed from 4 weeks to an expected average of 48 weeks following infusion. | 
| death from any cause | death from any cause | Participants will be followed for the duration of the trial, which is an expected average of 48 weeks. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
bronchiectasis, mesenchymal stem cell, lung, pulmonary, interstitial lung disease