Idiopathic Pulmonary Fibrosis
Conditions
Keywords
Mesenchymal stem cells, Idiopathic pulmonary fibrosis
Brief summary
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.
Detailed description
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.
Interventions
OTHERPlacental MSC
MSC will be derived from mothers donating their term placenta for clinical trial research purposes at Mater Mothers Hospital, Brisbane. The donation, isolation and expansion of placental-derived MSC for research purposes has been approved by the Mater Health Services (MHS) Human Research Ethics Committee (Reference No. 1292A). These volunteer donor mothers are unrelated to and will be HLA-unmatched with the IPF recipients.
Sponsors
Mater Medical Research Institute
The Prince Charles Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Demonstrated Acute Adverse Events Following Infusion | 4 hours post-infusion | Acute adverse events following infusion was defined as the development of anaphalaxis and/or a 25% increase or decrease from baseline of hemodynamic measurements. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Lung Function as Assessed by FVC Compared to Baseline | 6 months post MSC infusion | Forced Vital Capacity (FVC) was measured and reported as a percentage of predicted and comapred from 6 months post-infusion to baseline |
| Percentage Change in 6 Minute Walk Distance Compared to Baseline | Baseline and 6 months post MSC infusion | At 6 months 6 Minute Walk Distance was mesured and compared as a percentage to baseline |
| Percentage Change in Lung Function as Assessed by DLCO Compared to Baseline | 6 months post MSC infusion | DLCO was measured as a percentage of predicted, and the percentage change between 6 months post-infusion and baseline is reported. |
Countries
Australia
Participant flow
Recruitment details
All Participants known to doctors through standard of care appointments in clinic.
Pre-assignment details
All patients meet all inclusion criteria and none of the exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| 1*10^6 MSC / kg Placental MSC
Placental MSC: MSC will be derived from mothers donating their term placenta for clinical trial research purposes at Mater Mothers Hospital, Brisbane. The donation, isolation and expansion of placental-derived MSC for research purposes has been approved by the Mater Health Services (MHS) Human Research Ethics Committee (Reference No. 1292A). These volunteer donor mothers are unrelated to and will be HLA-unmatched with the IPF recipients. | 4 |
| 2*10^6 MSC / kg Placental MSC
Placental MSC: MSC will be derived from mothers donating their term placenta for clinical trial research purposes at Mater Mothers Hospital, Brisbane. The donation, isolation and expansion of placental-derived MSC for research purposes has been approved by the Mater Health Services (MHS) Human Research Ethics Committee (Reference No. 1292A). These volunteer donor mothers are unrelated to and will be HLA-unmatched with the IPF recipients. | 4 |
| Total | 8 |
Baseline characteristics
| Characteristic | 2*10^6 MSC / kg | 1*10^6 MSC / kg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants |
| Age, Continuous | 66.2 years | 64.1 years | 64.1 years |
| Region of Enrollment Australia | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 1 / 4 | 0 / 4 |
Outcome results
Primary
Number of Participants Who Demonstrated Acute Adverse Events Following Infusion
Acute adverse events following infusion was defined as the development of anaphalaxis and/or a 25% increase or decrease from baseline of hemodynamic measurements.
Time frame: 4 hours post-infusion
Population: Data from 8 participants was analyzed. (4 from each group)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1*10^6 MSC / kg | Number of Participants Who Demonstrated Acute Adverse Events Following Infusion | 0 participants |
| 2*10^6 MSC / kg | Number of Participants Who Demonstrated Acute Adverse Events Following Infusion | 0 participants |
Secondary
Percentage Change in 6 Minute Walk Distance Compared to Baseline
At 6 months 6 Minute Walk Distance was mesured and compared as a percentage to baseline
Time frame: Baseline and 6 months post MSC infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1*10^6 MSC / kg | Percentage Change in 6 Minute Walk Distance Compared to Baseline | 104 percentage of baseline |
| 2*10^6 MSC / kg | Percentage Change in 6 Minute Walk Distance Compared to Baseline | 104 percentage of baseline |
Secondary
Percentage Change in Lung Function as Assessed by DLCO Compared to Baseline
DLCO was measured as a percentage of predicted, and the percentage change between 6 months post-infusion and baseline is reported.
Time frame: 6 months post MSC infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1*10^6 MSC / kg | Percentage Change in Lung Function as Assessed by DLCO Compared to Baseline | 117 percentage of baseline |
| 2*10^6 MSC / kg | Percentage Change in Lung Function as Assessed by DLCO Compared to Baseline | 86 percentage of baseline |
Secondary
Percentage Change in Lung Function as Assessed by FVC Compared to Baseline
Forced Vital Capacity (FVC) was measured and reported as a percentage of predicted and comapred from 6 months post-infusion to baseline
Time frame: 6 months post MSC infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1*10^6 MSC / kg | Percentage Change in Lung Function as Assessed by FVC Compared to Baseline | 99 percentage of baseline |
| 2*10^6 MSC / kg | Percentage Change in Lung Function as Assessed by FVC Compared to Baseline | 94 percentage of baseline |