A Study to Evaluate the Potential Role of Mesenchymal Stem Cells in the Treatment of Idiopathic Pulmonary Fibrosis

A Phase I Study to Evaluate the Potential Role of Mesenchymal Stem Cells in the Treatment of Idiopathic Pulmonary Fibrosis

The primary objective of this study is to establish the feasibility and safety of infusions of placental Mesenchymal Stem Cells (MSC) from related or unrelated HLA identical or HLA mismatched donors in the treatment of Idiopathic Pulmonary Fibrosis (IPF).

The secondary objectives are to document changes in lung function, 6 minute walk distance (6MWD), gas exchange and radiological appearance following infusion of MSC over a six month evaluation period.

This is a Phase I, open-label, single centre, non-randomized dose-escalation evaluation of the safety and feasibility of MSC treatment for subjects diagnosed with IPF. The first 4 patients will receive a dose of 1 x 10^6 placenta-derived MSC/kg. An interim safety analysis will be carried out by the Data Safety Management Board (DSMB) when these first 4 patients have all undergone their 3 month study visit. Should no serious adverse events be documented due, or likely due, to the MSC infusion, a subsequent 4 patients will receive an IV infusion of 2 x 10^6 placenta-derived MSC/kg. Therefore a total of up to eight (8) subjects who meet all eligibility criteria and who provide written informed consent will be enrolled in the study.

Inclusion Criteria:

1. Male or female from 40 to 80 years of age (Note: see exclusion 13 regarding women of child-bearing potential).

2. Diagnosis of IPF based on the following criteria in accordance with American Thoracic Society/European Respiratory Society (ATS-ERS) guidelines for diagnosing

   IPF:

   Definite or probable usual interstitial pneumonia confirmed on surgical lung biopsy (SLB)

   or

   In absence of SLB, all of the following "major criteria"

   • High resolution CT scan (HRCT) showing definite findings for IPF (bibasilar reticular abnormalities with minimal ground glass opacities)
   • Absence of other causes of IPF including drug toxicities, environmental exposure and connective tissue disease
   • Abnormal pulmonary function tests including evidence of a restrictive ventilatory impairment and impaired gas exchange
   • Transbronchial biopsy or BAL suggesting no features of an alternative diagnosis and three of four of the following "minor criteria"
   • Age greater than 50 years
   • Insidious onset of otherwise unexplained dyspnea on exertion
   • Duration of illness greater than 3 months
   • Bibasal, inspiratory crackles

   Within 90 days of study enrolment, diagnosis must be confirmed by HRCT chest.

3. Honeycombing greater than 5% in 0 - 3 lung zones (each lung divided into 3 zones - 1) at the level of the carina 2) highest point of right hemi diaphragm and 3) mid way between these two levels) as assessed on HRCT.

4. Forced vital capacity (FVC) greater than 50 of predicted with a ratio of forced expiratory volume in 1 second to FVC (FEV1/FVC) greater than 0.7 (Pulmonary function tests must be completed no more than 90 days before screening).

5. Diffusing capacity for carbon monoxide (DLCO) greater than 25% of predicted capacity.

6. Ability to perform a 6-Minute Walk Test (6MWT) at screening.

7. Competency to understand the information given in the Human Research and Ethics Committee (HREC) approved ICF and must sign the form prior to the initiation of any study procedures.

Exclusion Criteria:

1. Diagnosis of an interstitial lung disease (ILD) or restrictive lung disease other than IPF.

2. Obstructive lung disease as determined by evidence of airflow obstruction on HRCT or physiologic criteria including:

   FEV1/FVC ratio less than 0.7 Residual volume (RV) greater than 120% by plethysmography or significant (verified by radiologist) emphysema on HRCT if plethysmography not available Evidence of reactive airway disease by change in FEV1 of greater than 12% following bronchodilator challenge

3. Evidence of sustained improvement of IPF condition defined as improvement from pre-therapy pulmonary function tests (PFTs) observed with two or more successive post-therapy PFTs over the year prior to randomization.

4. Active or recent (less than 60 days prior to enrolment) significant respiratory tract infection, or a history of frequent (greater than 2 per year for the last 2 years) infective exacerbations of IPF.

5. Hospitalization within 60 days of screening for an acute exacerbation of IPF (AE-IPF).

6. Chronic heart failure (NYHA class III/IV) or known left ventricular ejection fraction less than 25%.

7. Chronic treatment with the following drugs prescribed for IPF (within 4 weeks of randomization):

   oral corticosteroids (greater than 20 mg/day of prednisone or equivalent), immunosuppressive or cytotoxic drugs, antifibrotic drugs, chronic use of N-acetylcysteine

8. Acute or chronic impairment (other than dyspnea) which limits the ability to comply with study requirements and procedures including the 6MWD

9. Chronic treatment with immunosuppressive, cytotoxic, or antifibrotic drugs including pirfenidone, D-penicillamine, colchicine, cyclosporine A, TNF-alpha antagonists, imatinib, interferon-gamma, cyclophosphamide, or azathioprine within 30 days of randomization.

10. Subject requires hemodialysis, peritoneal dialysis or hemofiltration.

11. Systolic blood pressure less than 85 mmHg.

12. History of malignancies within the past 5 years, with the exception of squamous or basal cell carcinoma of the skin or successfully treated in situ carcinoma of the cervix.

13. Female who is of child-bearing potential.

14. Known history of alcohol abuse within 1 year of enrolment.

15. Participation in a clinical study involving another investigational drug or device within 28 days of screening.

16. Co-morbid condition or illness limiting life expectancy to less than 1 year at time of screening.

17. Serious or active medical or psychiatric illness which, in the opinion of the Investigator, would interfere with treatment, assessment or compliance with the protocol.

18. Significant hypoxemia or hypercapnia at rest on room air as defined by a PaO2 less than 55mmHg or PaCO2 greater than 50mmHg.