Chronic Lung Allograft Dysfunction (CLAD)
Conditions
Brief summary
This study is designed for lung transplant patients who have developed chronic lung allograft dysfunction (CLAD). Consented patients will receive 4 intravenous doses of allogeneic, bone-marrow-derived MSCs (2\*10\^6 cells/kg/dose) or matching placebo over a period of 2 weeks with a 12 month follow up.
Detailed description
This is a phase 2, multi-center, randomized study (n=82, 1:1 MSC:placebo) where consented patients will receive 4 intravenous doses of IMP over a period of 2 weeks. Patients must provide written informed consent and meet the all Inclusion Criteria and none of the Exclusion Criteria to be eligible. Screening procedures include obtaining medical history, current medications, questionnaires, vital signs, Chest Xray, 6 Minute walk test and blood tests. Historical chest CT and full lung function from 12 weeks prior to screening may be used. Bronchoscopy with biopsy must have been performed no more than 6 months prior to screening. A bronchoscopy with bronchoalveolar lavage (BAL) is required, however will not need to be repeated if performed within 14 days prior to the baseline visit. Patients will then receive 4 infusions of MSC/placebo over a period of 2 weeks, with follow up at Week 3,6,10,14,28,41 and week 54.
Interventions
DRUGBone-marrow derived MSCs
Allogeneic ex vivo expanded, bone marrow-derived mesenchymal stromal cells
DRUGPlacebo
Placebo product visually very similar to mesenchymal stromal cells
Sponsors
Isopogen
Cell and Tissue Therapies
The University of Queensland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Bilateral lung transplant recipients aged ≥ 18 years and at least 6 months post-transplant. Patients with other organs transplanted (eg heart, liver, kidney) or those who have undergone lobar transplantation, or re-transplantation, are potentially eligible. 2. New-onset CLAD (defined as a persistent (3weeks apart) fall in FEV1 of at least 20% from the mean of the two best post-transplant values taken at least 3 weeks apart) in the 12 months prior to the screening visit. Other causes of a fall in FEV1 (acute cellular or humoral rejection, active infection, anastomotic stenosis etc.) must be excluded as per international guidelines. 3. Stable immunosuppression regimen, as assessed by the investigator, in the 8 weeks prior to the screening visit. 4. Available for all specified assessments at the study site through the completion of the study, including the protocol bronchoscopies. 5. Provision of written informed consent.
Exclusion criteria
1. Any condition that in the opinion of the Investigator may interfere with the safety of the patient, his / her completion of required follow-up visits or evaluation of the study objectives 2. Untreated cellular or humoral rejection 3. Clinically meaningful and untreated viral, bacterial or fungal infection 4. Use of azithromycin or another macrolide antibiotic, if commenced within 8 weeks of the screening visit 5. Intravenous pulsed methylprednisolone, within 4 weeks of the screening visit 6. Use of extracorporeal photopheresis, within 4 weeks of the screening visit 7. Use of total lymphoid irradiation, within 4 weeks of the screening visit 8. Poor functional status not expected to survive 6 months 9. Allergy to beef products 10. Women who are pregnant, breast-feeding or unwilling to use adequate contraception 11. Patients who are currently participating in another interventional clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival | From baseline to week 54 | Progression-free survival is a composite end-point of freedom from CLAD progression or death from any-cause. CLAD progression is defined as fall in FEV1 \> 10% from the baseline (screening visit) FEV1 to the 12 month (week 54) visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Freedom from Bronchiolitis Obliterans Syndrome (BOS) grade 3 | Week 54 | BOS grade 3 is defined as FEV1 \<50% of the best-post-transplant FEV1 |
| All cause mortality | Week 54 | — |
| CLAD-specific mortality | Week 54 | Defined as any death felt by the investigator to be at least partially related to CLAD. |
| Freedom from acute rejection | From baseline to week 54 | Acute rejection defined as any biopsy proven episode of acute vascular (A1-A4) or airway (B1R or B2R) rejection. |
| Freedom from the development of new donor specific anti-HLA antibodies | From baseline to week 14 | An anti-HLA antibody (any mean fluorescent intensity level) with specificity for a donor HLA type at 3 months which was not present prior to IMP treatment |
| Time to fall in FEV1 > 10% | From the baseline (screening) visit | Defined as fall in FEV1 \> 10% from the baseline (screening visit) FEV1 |
| Rate of FEV1 decline | From baseline to week 54 | Rate of FEV1 decline is defined as the slope of the regression line for FEV1 between the screening visit and week 54 |
| Rate of FVC decline | From baseline to week 54 | Rate of FVC decline is defined as the slope of the regression line for FVC between the screening visit and week 54 |
| Change in 6-minute walk distance (6MWD) | From baseline to week 54 | Change in 6MWD is defined as the difference between the 6MWD at screening and the week 54 visit. Patients who have died by week 54 will receive a 6MWD of 0. |
| Change in St George's Respiratory Questionnaire (SGRQ) Score | From baseline to week 54 | Change in SGRQ is defined as the difference between the total SGRQ at screening and the week 54 visit. Patients who have died by week 54 will receive a SGRQ of 0. |
| Inpatient bed-days | From baseline to week 54 | This is defined as the aggregate of inpatient bed-days between the screening visit and week 54. |
| Freedom from CLAD progression | From baseline to week 54 | CLAD progression is defined as fall in FEV1 \> 10% from the baseline (screening visit) FEV1 at 12 months. |
Countries
Australia
Outcome results
None listed