Trial of Bone-marrow Derived Mesenchymal Stromal Cells (MSC) for New Onset Chronic Lung Allograft Dysfunction (ASSIST-CLAD)

Phase 2 Randomised Controlled Trial of Bone-marrow Derived Mesenchymal Stromal Cells (MSC) for New Onset Chronic Lung Allograft Dysfunction (CLAD)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Lung Allograft Dysfunction (CLAD)
• Intervention / Treatment: Drug: Bone-marrow derived MSCs; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2010
      • St Vincents Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4032
      • The Prince Charles Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • The Alfred Hospital
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bone-marrow derived MSCs; 4 doses of Allogeneic bone-marrow derived MSCs (2x106 cells/kg) given intravenously twice weekly for 2 weeks	Drug: Bone-marrow derived MSCs; Allogeneic ex vivo expanded, bone marrow-derived mesenchymal stromal cells; Other Names: MSC
Placebo Comparator: Placebo; Placebo product manufactured to look like MSCs	Drug: Placebo; Placebo product visually very similar to mesenchymal stromal cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	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.	From baseline to week 54

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to fall in FEV1 > 10%	Defined as fall in FEV1 > 10% from the baseline (screening visit) FEV1	From the baseline (screening) visit
Freedom from Bronchiolitis Obliterans Syndrome (BOS) grade 3	BOS grade 3 is defined as FEV1 <50% of the best-post-transplant FEV1	Week 54
All cause mortality		Week 54
CLAD-specific mortality	Defined as any death felt by the investigator to be at least partially related to CLAD.	Week 54
Freedom from acute rejection	Acute rejection defined as any biopsy proven episode of acute vascular (A1-A4) or airway (B1R or B2R) rejection.	From baseline to week 54
Freedom from the development of new donor specific anti-HLA antibodies	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	From baseline to week 14
Freedom from CLAD progression	CLAD progression is defined as fall in FEV1 > 10% from the baseline (screening visit) FEV1 at 12 months.	From baseline to week 54
Rate of FEV1 decline	Rate of FEV1 decline is defined as the slope of the regression line for FEV1 between the screening visit and week 54	From baseline to week 54
Rate of FVC decline	Rate of FVC decline is defined as the slope of the regression line for FVC between the screening visit and week 54	From baseline to week 54
Change in 6-minute walk distance (6MWD)	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.	From baseline to week 54
Change in St George's Respiratory Questionnaire (SGRQ) Score	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.	From baseline to week 54
Inpatient bed-days	This is defined as the aggregate of inpatient bed-days between the screening visit and week 54.	From baseline to week 54

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: Isopogen; Cell and Tissue Therapies
• Investigators: Principal Investigator: Daniel Chambers, MBBS MD, University of Queensland & The Prince Charles Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2017
• Primary Completion (Actual): September 13, 2023
• Study Completion (Actual): October 25, 2023

Study Registration Dates

• First Submitted: March 1, 2016
• First Submitted That Met QC Criteria: March 10, 2016
• First Posted (Estimated): March 16, 2016

Study Record Updates

• Last Update Posted (Estimated): December 6, 2023
• Last Update Submitted That Met QC Criteria: December 4, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: ASSIST-CLAD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data will be analysed and shared with collaborators with the plan to publish the results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No