The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12616000338460
Ethics application status
Approved
Date submitted
7/03/2016
Date registered
16/03/2016
Date last updated
7/01/2020
Date data sharing statement initially provided
15/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase 2 Randomised controlled trial of bone-marrow derived mesenchymal stromal cells (MSC) for new onset chronic lung allograft dysfunction (CLAD)
Scientific title
Phase 2 Randomised controlled trial of bone-marrow derived mesenchymal stromal cells (MSC) for new onset chronic lung allograft dysfunction (CLAD)
Secondary ID [1] 288683 0
nil known
Universal Trial Number (UTN)
Trial acronym
ASSIST CLAD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lung transplant patients with Chronic Lung Allograph Dysfunction (CLAD) 297891 0
Condition category
Condition code
Respiratory 298057 298057 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible lung transplant patients diagnosed with new onset of CLAD will receive 4 infusions of allogenic bone - marrow derived Mesenchymal stromal cells (MSC) or 4 infusions of placebo within 2 weeks (at the clinical discretion of the treating physician) with a 12 month follow up period. The MSC/placebo dose is 2 x 10 6 cells/kg administered intravenously twice a week for 2 weeks.
Allogenic ex vivo expanded, bone marrow derived MSC are produced by Cell and Tissue Therapies in Western Australia from a adult human healthy donor. MSCs are tested for possible infectious agents such as viruses or bacteria at several time points within the manufacturing of the MSC product.
Intervention code [1] 294106 0
Treatment: Other
Comparator / control treatment
This is a randomised placebo controlled trial 1;1
The Placebo infusion mix is 75% Plasmalyte, 10% saline, 10% Albumex, 5% dimethyl sulfoxide (DMSO).
Control group
Placebo

Outcomes
Primary outcome [1] 297580 0
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.
Timepoint [1] 297580 0
12 months
Secondary outcome [1] 321456 0
Assessment of spirometry to assess time to fall in FEV1 greater then 10%
Timepoint [1] 321456 0
Spirometry assessed at screening, Week 3,6,10,14,28,41 and Week 52
Secondary outcome [2] 321457 0
Freedom from Bronchiolitis Obliterans Syndrome (BOS) grade 3
Assessed by review of spirometry
Timepoint [2] 321457 0
12 months
Secondary outcome [3] 321565 0
All cause mortality
Timepoint [3] 321565 0
12 Months
Secondary outcome [4] 321566 0
CLAD-specific mortality.
This is assessed by review of medical records .
Defined as any death felt by the investigator to be at least partially related to CLAD.
Timepoint [4] 321566 0
12 Months
Secondary outcome [5] 321567 0
Freedom from acute rejection.
Acute rejection defined as any biopsy proven episode of acute vascular (A1-A4) or airway (B1R or B2R) rejection.
Timepoint [5] 321567 0
12 Months
Secondary outcome [6] 321568 0
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.
This is meaured by a anti- HLA specific blood test which is performed at screening, week 14 and week 54.
Timepoint [6] 321568 0
This outcome is assessed at screening, week 14 and week 54.
Secondary outcome [7] 321569 0
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.
This is assessed by reviewing the patients spirometry .
Timepoint [7] 321569 0
FEV1 decline is assessed/reviewed at Week 3, 6,10,14,28,41 and for the final outcome measure at Week 54.
Secondary outcome [8] 321570 0
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.
This is assessed by spirometry.
Timepoint [8] 321570 0
Spirometry will be performed and reviewed for rate of FVC decline at Week 3,6,10,14,28,41 and finally week 54.
Secondary outcome [9] 321571 0
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.
This is assessed by a change in distance walked.
Timepoint [9] 321571 0
Change from screening , week 28 and 12 Months.
Secondary outcome [10] 321572 0
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.
The outcome is assessed by a change in the total score once all numbers have been put into the SGRQ score calculator. The SQRQ is a measurment of change in respiratory function.
Timepoint [10] 321572 0
Baseline, week 28 and 12 Months.
Secondary outcome [11] 321573 0
Inpatient bed-days.
This is defined as the aggregate of inpatient bed-days between the screening visit and week 54.
This is assessed by review of medical records or hospital administration operating systems.
Timepoint [11] 321573 0
12 Months
Secondary outcome [12] 321574 0
Freedom from CLAD progression.
CLAD progression is defined as fall in FEV1 > 10% from the baseline (screening visit) FEV1 at 12 months.
This is assessed by spirometry.
Timepoint [12] 321574 0
12 Months

Eligibility
Key inclusion criteria
1. Bilateral lung transplant recipients aged greater or equal to 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 4 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.
6. Provision of written informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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 4 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
10. Allergy to beef products
11. Women who are pregnant, breast-feeding or unwilling to use adequate contraception
12. Patients who are currently participating in another interventional clinical trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation to receive MCS or placebo is random. Randomisation is performed centrally at the lead site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be generated by a statistical software program (Stata) using permuted blocks. We will stratify for site/Clad phenotype and blocks. This means that we have equal numbers in each – this has the benefit that if the trial stops early we will have similar numbers in each arm.
Randomisation will be stratified by site and by CLAD phenotype (R-CLAD vs BOS). To randomise a patient, The site will contact the responsible delegate at The Prince Charles Hospital. The delegate will assign a treatment arm from the sealed randomisation schedule. The randomisation schedule (confidential Excel spreadsheet list) will be provided to the lead site (unblinded staff member) by the manufacture of the cells (Cell and Tissue Therapies (CTTWA)). Cell and Tissue Therapies will use simple allocation. The delegate will review available stored products at treatment site. If stock is available they will then determine which Unique Product Numbers to be used and inform the site. If stock is not available they will liaise with CTTWA to arrange shipment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Stratified by site and CLAD phenotype
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary efficacy outcome is a 50% reduction in the number of patients experiencing CLAD progression (defined as a 10% fall in FEV1 from baseline to the end of the study at 12 months) or death. Currently, >65% of patients with new onset CLAD will suffer a further 10% decline in FEV1 or death in the subsequent 12 months. Assuming a power of 80 % and a two-sided significance level of 5 %, with a 1:1 randomization, then to detect a 50% reduction in the expected 65% of patients meeting the endpoint, 41 patients are required in each of the MSC and placebo arms, giving a total of 82 patients in the study.
Logistical regression will be the statistical test used.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 5386 0
The Prince Charles Hospital - Chermside
Recruitment hospital [2] 5387 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 5388 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 5389 0
The Alfred - Prahran
Recruitment hospital [5] 5390 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 12840 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 12842 0
3004 - Melbourne
Recruitment postcode(s) [3] 12839 0
4032 - Chermside
Recruitment postcode(s) [4] 12843 0
5000 - Adelaide
Recruitment postcode(s) [5] 12841 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 293041 0
Government body
Name [1] 293041 0
National Health and Medical Research Council (NHMRC)
Address [1] 293041 0
GHD Building Level 1, 16 Marcus Clarke St, Canberra ACT 2601
Country [1] 293041 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
St Lucia QLD 4072
Country
Australia
Secondary sponsor category [1] 291818 0
None
Name [1] 291818 0
Address [1] 291818 0
Country [1] 291818 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294556 0
The Prince Charles Hospital Metro North Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 294556 0
Rode Road
CHERMSIDE QLD 4032
Ethics committee country [1] 294556 0
Australia
Date submitted for ethics approval [1] 294556 0
10/03/2016
Approval date [1] 294556 0
11/04/2016
Ethics approval number [1] 294556 0
Ethics committee name [2] 294557 0
Royal Perth Hospital Human Research Ethics Committee
Ethics committee address [2] 294557 0
102 – 118 Murdoch Drive

Murdoch WA 6150

Ethics committee country [2] 294557 0
Australia
Date submitted for ethics approval [2] 294557 0
25/05/2016
Approval date [2] 294557 0
13/07/2016
Ethics approval number [2] 294557 0
Ethics committee name [3] 294558 0
University of Queensland
Ethics committee address [3] 294558 0
St Lucia Qld 4072
Ethics committee country [3] 294558 0
Australia
Date submitted for ethics approval [3] 294558 0
27/04/2016
Approval date [3] 294558 0
26/04/2016
Ethics approval number [3] 294558 0

Summary
Brief summary
This is a phase 2 multi centre randomised study where consented Lung transplant patients that have met the criteria for new onset CLAD (and none of the exclusion criteria) will receive 4 doses of Mesenchymal Stromal Cells (MSC)/placebo intravenous infusions over a period of 2 weeks. Follow up review will be performed at weeks 3,6,10,14,28,41 and 54.
It is hypothesied that MSC treatment will result in a progression free survival of patients with new-onset CLAD experiencing disease progression at 12 months.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64106 0
Prof Daniel Chambers
Address 64106 0
The Prince Charles Hospital
Rode Road
CHERMSIDE QLD 4032
Country 64106 0
Australia
Phone 64106 0
+61731394000
Fax 64106 0
+61731396140
Email 64106 0
daniel.chambers@health.qld.gov.au
Contact person for public queries
Name 64107 0
Prof Daniel Chambers
Address 64107 0
The Prince Charles Hospital
Rode Road
CHERMSIDE QLD 4032
Country 64107 0
Australia
Phone 64107 0
+61731394000
Fax 64107 0
+61731396140
Email 64107 0
daniel.chambers@health.qld.gov.au
Contact person for scientific queries
Name 64108 0
Prof Daniel Chambers
Address 64108 0
The Prince Charles Hospital
Rode Road
CHERMSIDE QLD 4032
Country 64108 0
Australia
Phone 64108 0
+61731394000
Fax 64108 0
+61731396140
Email 64108 0
daniel.chambers@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Study information will be de identified before entering in to the data base and grouped data will be reported.
What supporting documents are/will be available?
No other documents available
Summary results
No Results