Human MesenchymAl Stem Cells Infusion in Patients With Cystic Fibrosis

Study Overview
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Brief Summary
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A Safety Run-In will be followed by a Double-Blinded Randomized Phase. All subjects shall meet the inclusion/exclusion criteria, and will be evaluated prior to the scheduled infusion to establish baseline. There will be 3 subjects in the safety run-in phase and 15 subjects in the double-blinded phase.

Detailed Description
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Primary objective is to demonstrate the safety of Mesenchymal Stem Cells (MSCs) intravenously administered to subjects with cystic fibrosis. Secondary Objective is to explore if MSCs can improve the symptoms of cystic fibrosis, including lung function, the rate of pulmonary exacerbation, systemic and local inflammation and symptom-related quality of life. The Safety Run-In will be performed to evaluate the safety of MSC infusion into subjects with cystic fibrosis. 3 subjects will participate and they will receive a single administration of allogeneic MSCs given through intravenous infusion. In the randomized phase the subjects will be randomized at a ratio of 1:1:1 into 3 cohorts to receive infusions. There will be a total of 15 subjects in 3 cohorts. The total duration for each subject after infusion is 12 months, plus up to an additional 2 months for the Screening and Baseline Visits. Approximately 9 visits in total.

Official Title
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A Phase I, Randomized and Placebo-controlled Trial to Evaluate the Safety, Tolerability, and Potential Efficacy of Allogeneic Human MesenchymAl Stem Cells Infusion in Patients With Cystic Fibrosis - HAPI

Conditions
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Cystic Fibrosis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent. Be 20 - 45 years of age at the time of signing the Informed Consent Form. Have a confirmed diagnosis of cystic fibrosis as defined by two or more clinical features of cystic fibrosis (CF), including by the 1997 CF Consensus criteria (NIH Consensus Statement, 1997): One or more accompanying clinical features consistent with Cystic fibrosis, and at least one of the following: Documented sweat chloride test ≥ 60 mEq/L by quantitative pilocarpine iontophoresis or, Abnormal nasal transepithelial potential difference (NPD) test or, Two well-characterized, disease-causing genetic mutations in the CF transmembrane conductance regulator (CFTR) gene on different alleles FEV1 at screening visit between 25% and 80% of predicted values for age, sex, and height taken 4 hours or more after last dose of short-acting bronchodilators (β-agonists and/or anticholinergics). The predicted values will be calculated according to National Health and Nutrition Examination Survey (NHANES). Total bilirubin below 1.9 mg/dL. Non-smoker for the past 60 days (2 months) prior to screening Visit 1 and less than a 5 pack-year lifetime history of smoking Stable regimen of CF medications and chest physiotherapy for the 28 days prior to screening, and no anticipated need for changes during the study period for the immediate future, at least 4 weeks post infusion. Clinically stable for at least 4 weeks with no evidence of new or acute respiratory symptoms, excluding symptoms of allergic (perennial or seasonal) or non-allergic rhinitis. Patients should be on a stable medication regimen as determined by their Cystic fibrosis physician. Allowable medications include: Inhaled medications (bronchodilators, steroids, pulmozyme, hypertonic saline and inhaled antibiotics to suppress chronic infections including tobramycin, amikacin, colistin, aztreonam lysine) Chronic azithromycin use (three times weekly) Vitamin supplementation Pancreatic enzymes CFTR potentiator and/or corrector (ivacaftor and lumacaftor) Exclusion Criteria: All subjects enrolled in this trial must not: Be unable to perform any of the assessments required for endpoint analysis. Use systemic corticosteroids (≥5 mg of prednisone per day). Have been on intravenous or oral antibiotics within the last 4 weeks Have a clinical history of malignancy within 5 years (i.e., subjects with prior malignancy must be disease free for 5 years), except curatively- treated basal cell carcinoma, squamous cell carcinoma, melanoma in situ or cervical carcinoma, if recurrence occurs. Have congestive heart failure (NYHA Class III or IV). Have severe pulmonary hypertension with a right ventricle systolic pressure (RVSP) >50 mmHg as estimated by echocardiography Have chronic kidney disease Stage 4 or 5. Have a non-pulmonary condition that limits lifespan to ≤1 year. Have clinically significant autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), or inflammatory bowel disease). Have HIV, AIDS, or other immunodeficiency. Test positive for hepatitis B HsAg, viremic hepatitis C, HIV1, HIV2, HTLV-I, HTLV-II, syphilis, and West Nile Virus. Have a resting blood oxygen saturation of <93% (measured by pulse oximetry). Have documented current substance and/or alcohol abuse. Be a current user of tobacco products. Have a known hypersensitivity to dimethyl sulfoxide (DMSO). Have had a recent (within prior 3 months) trauma or surgery. Be an organ transplant recipient. Be actively listed (or expected to be listed) for transplant of any organ other than for a lung transplant. Have any clinically important abnormal screening laboratory values, including but not limited to: hemoglobin <12.1 g/dL (females) or <13.6 g/dL (males). white blood cell count < 3000/mm3. platelets < 150,000/mm3. International normalized ratio (INR) ˃ 1.5 not due to a reversible cause (i.e. Coumadin). aspartate transaminase, alanine transaminase, or alkaline phosphatase ˃ 2 times upper limit of normal. Have a sitting or resting systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg at Screening. Have any serious comorbid illness or 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, or that may compromise the validity of the study. Be a female who is pregnant, nursing, or of childbearing potential while not practicing effective contraception (female patients must undergo a blood or urine pregnancy test at screening and prior to infusion). Females who are in childbearing age must agree to practice a highly effective form of contraception throughout the study. Highly effective forms of contraception with a low failure rate include barrier methods, oral contraception or depot contraceptives (unless on Orkambi), an intrauterine device, implantable devices. Be currently participating in an investigational therapeutic or device trial, or have participated in an investigational therapeutic or device trial within the previous 30 days, or participate in any other clinical trial for the duration of the time that the subject actively participates in this trial.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Safety run-in phase will have 3 subjects with 2 treatment groups Randomized phase will have 15 subjects with 3 treatment groups
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Run-In: Treatment 1 Allo-hMSCs<br>Treatment 1: 1 subject will receive a single administration of allogeneic MSCs: 20 x 10^6 MSCs (20 million) cells delivered via peripheral intravenous infusion. | Biological: Allo-hMSCs<br>* 1 peripheral intravenous infusion of allogeneic human mesenchymal stem cells (hMSCs)<br>* Other names: Stem cells;|
| Experimental: Safety Run-In: Treatment 2 Allo-hMSCs<br>2 subjects will receive a single administration of allogeneic MSCs: 100 x 10^6 MSCs (100 million) cells delivered via peripheral intravenous infusion. | Biological: Allo-hMSCs<br>* 1 peripheral intravenous infusion of allogeneic human mesenchymal stem cells (hMSCs)<br>* Other names: Stem cells;|
| Experimental: Randomized: Cohort 1 Allo-hMSCs<br>Cohort 1 (5 subjects): 20 million MSCs A single peripheral intravenous infusion of 20 x 10^6 MSCs (20 million cells) will be administered to each subject. | Biological: Allo-hMSCs<br>* 1 peripheral intravenous infusion of allogeneic human mesenchymal stem cells (hMSCs)<br>* Other names: Stem cells;|
| Experimental: Randomized: Cohort 2 Allo-hMSCs<br>Cohort 2 (5 subjects): 100 million MSCs A single peripheral intravenous infusion of 100 x 10^6 MSCs (100 million cells) will be administered to each subject. | Biological: Allo-hMSCs<br>* 1 peripheral intravenous infusion of allogeneic human mesenchymal stem cells (hMSCs)<br>* Other names: Stem cells;|
| Placebo Comparator: Randomized: Cohort 3 Allo-hMSCs<br>Cohort 3 (5 subjects): Placebo A single peripheral intravenous infusion of placebo (PlasmaLyte A containing 1% HSA) will be administered to each subject. | Biological: Placebo<br>* 1 peripheral intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of any treatment-emergent serious adverse event (TE-SAE) | Incidence of any treatment-emergent serious adverse event (TE-SAE), defined as one or more of the following untoward medical occurrences happening within the first 30 days after infusion. | 30 days after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Symptoms for pulmonary function test | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Resting pulmonary function tests (PFTs) assessed via spirometry: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1 to FVC ratio, and forced expiratory flow between 25 - 75% of VC (FEF25-75) measured in adherence to American Thoracic Society/European Respiratory Society guidelines. | baseline to 12 months | 
| Change in Symptoms 6-minute walk test | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • 6-minute walk test (6MWT). | baseline to 12 months | 
| Change in Symptoms of body mass index | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Changes in body mass index | baseline to 12 months | 
| Change in Rate of pulmonary exacerbations | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: Incidence of investigator-defined pulmonary exacerbation: events meeting the modified Fuchs' criteria (at least 4 of 12 signs and symptoms with or without intravenous or oral antibiotic treatment). Semi-quantitative sputum cultures (change in colony forming units) Procalcitonin serum levels | baseline to 12 months | 
| Change in Local and Systemic Inflammation in inflammatory markers | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Serum Inflammatory markers (CBC with differential, TNFα, C-reactive protein, Interleukin-1, Interleukin-6, D-dimer, Fibrinogen). | baseline to 12 months | 
| Change in Local and Systemic Inflammation for sputum inflammatory markers | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Sputum inflammatory markers | baseline to 12 months | 
| Change in Local and Systemic Inflammation related to quality of life | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Symptom Related Quality of Life | baseline to 12 months | 
| Change in Local and Systemic Inflammation via the short form-36 | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Physical activity via the short form-36 questionnaires. | baseline to 12 months | 
| Change in Local and Systemic Inflammation via the PHQ-9 Questionnaire | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Subject quality of life (QOL) assessments via: - Patient Health Questionnaire-9 (PHQ-9) for depression screening | baseline to 12 months | 
| Change in Local and Systemic Inflammation via the CFQ-R Questionnaire | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Subject quality of life (QOL) assessments via: - Cystic Fibrosis Questionnaire-Revised (CFQ-R) | baseline to 12 months | 
| Change in Local and Systemic Inflammation via the GAD-7 Questionnaire | examining post-infusion changes from baseline between the MSC and Placebo Cohorts in terms of: • Subject quality of life (QOL) assessments via: - Generalized anxiety disorder 7 (GAD-7) | baseline to 12 months |