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Trial registered on ANZCTR


Trial ID
ACTRN12614000812695
Ethics application status
Approved
Date submitted
19/07/2014
Date registered
31/07/2014
Date last updated
20/03/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Intra-articular mesenchymal stem cell injections following arthroscopic microfracture versus arthroscopic microfracture alone for knee cartilage defects: a pilot randomised controlled trial
Scientific title
The effect of mesenchymal stem cell injections following arthroscopic microfracture versus microfracture alone on cartilage healing in patients with an isolated knee cartilage defect.
Secondary ID [1] 285014 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee cartilage defect 292528 0
Condition category
Condition code
Musculoskeletal 292832 292832 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will determine the efficacy of autologous adipose derived mesenchymal stem cell injections post arthroscopic microfracture for isolated knee cartilage defects versus arthroscopic microfracture alone. The arthroscopic microfracture will not form part of the study as this is accepted surgical management. The post operative stem cell injections are the sole intervention. 40 participants will be recruited and randomally allocated to a treatment arm/group of 20 participants who receive stem cell injections and a control arm/group of 20 particpants who have no intervention post microfracture. The treatment arm/group will receive injections of 100million mesenchymal stem cells at 1week post microfracture and a 2nd injection of 100Million stem cells at 6months totalling 200Million cells.
Intervention code [1] 289848 0
Treatment: Other
Comparator / control treatment
Non blinded control - microfracture with no post operative intervention. Control participants will be followed up with serial questionnaires and repeat imaging as per the treatment group.
Control group
Active

Outcomes
Primary outcome [1] 292697 0
MRI assessed cartilage volume
Timepoint [1] 292697 0
pre intervention and at 12month follow-up
Primary outcome [2] 292698 0
MRI assessed cartilage quality
Timepoint [2] 292698 0
pre intervention and at 12month follow-up
Primary outcome [3] 292699 0
Knee Injury and Osteoarthritis Outcome Score
Timepoint [3] 292699 0
Pre intervention and assessed at 1, 3, 6 and 12 months post intervention
Secondary outcome [1] 309514 0
0-10 Numerical Pain rating Scale
Timepoint [1] 309514 0
Pre-intervention and at 1, 3, 6 and 12 months post intervention
Secondary outcome [2] 309515 0
Global Rating of Change Scale
Timepoint [2] 309515 0
1, 3, 6 and 12 months post intervention
Secondary outcome [3] 309516 0
Pain Treatment Satisfaction Scale - validated questionnaire
Timepoint [3] 309516 0
1,3,6 and 12 months post intervention
Secondary outcome [4] 309518 0
Orebro Musculoskeletal Pain Questionnaire : This questionnaire will be used in the current study to assess the potential impact of psychosocial factors on participants’ outcome.
Timepoint [4] 309518 0
Preintervention

Eligibility
Key inclusion criteria
1. Aged between 18 – 50 (inclusive). As isolated full thickness chondral defects are often traumatic in nature it is likely that this age restriction represents the majority of patients who undergo microfracture.
2. Pre-operative radiological diagnosis of an isolated full thickness knee cartilage defect of the medial or lateral femoral condyle
3. Planned arthroscopic microfracture/osteoplasty
4. Sufficient English skills to complete the questionnaires required for the study, as well as to understand the instructions given by the study doctors.
5. No plans at the time of enrolment to undergo surgery in the following three months. This criterion is aimed at avoiding co-interventions that may confound the results of the study. While involvement in the project will not strictly prevent participants from undertaking such interventions if required, we will exclude volunteers who already have such procedures scheduled
Minimum age
18 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy (accepted contra-indication as no safety data on this population).
2. Have other causes of their knee symptoms suspected to be due to serious pathology such as tumour or referral from the hip or lumbar spine. These conditions are not under investigation within the current project;
3. Blood disorder (accepted contra-indication as no safety data on this population)
4. MRI confirmed displaced meniscial tear.
5. MRI confirmed Grade II-IV degenerative osteoarthritis
6. History of cancer
7. History of atypical chronic pain syndrome

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)
Participants will be referred directly to the study by orthopaedic surgeons. Surgeons will be made aware of the study through both advertising and presentations. The participants will be undergoing a planned arthroscopic microfracture external to the study for an isolated medial femoral condyle cartilage defect. After referral the potential participants will undergo initial screening and if suitable will be formally enrolled in the study after completing an informed consent. The participants will be randomly allocated by the study administration to the treatment arm or control arm.

Allocation will be concealed :

Allocation will be performed by the study administrator after formal enrolment by the study doctor. The study doctor will not be present at time of allocation. Allocation will be concealed from the study doctor and allocation schedule will only be known by the study administrator using a number randomisation computer program. The study doctor will only be aware of the treatment group allocation after random allocation has been undertaken and not in their presence (this is not a blinded trial)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Use of computer generated Research Randomiser (www.randomizer.org). Participants 1-20 will be within the treatment arm and 21-40 will be within the control arm. Research Randomiser will randomly generate the list of 0-40 in random order. Participants will be sequentially allocated numbers from this randomly generated list.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data analysis will focus on detecting the between-group treatment effect (with 95% confidence intervals) at each of the follow-up points (1-month, 3-months, 6-months and 12-months following randomisation). Analyses will be conducted using SPSS Version 21, with alpha set at 0.05 using a two-tailed hypothesis. Continuous data will be analysed using linear mixed models (with the group x time interaction estimating the treatment effect). These were chosen for their strength in analysing longitudinal biological data and accounting for correlations associated with repeated measurements. The mixed models will adjust for the baseline score of the outcome of interest as recommended by the revised CONSORT statement. Ordinal data will be analysed using the Mann Whitney U test.
At each follow-up point, participants in each group will be dichotomised according to whether they achieved the minimum clinically important difference of the outcome or not, and then the risk ratio, risk difference and number needed to treat will be calculated along with 95% confidence intervals. Statistical significance will be evaluated using Chi square analysis. For these purposes, the minimum clinically important difference will be defined as 10/100 for the KOOS, 2/10 for the NRS pain scales , at least “much improved” on the global rating of change scale and “very satisfied” on the treatment satisfaction scales. It has been argued that these values for minimum clinically important difference may be too low in some contexts, hence we will repeat this analysis using a threshold of 50% reduction in KOOS scores and NRS pain scores based on empirical validation studies suggesting that this may be a more suitable threshold for important differences.
All data will be analysed on an intention to treat basis, in that all participants will be analysed in the treatment group to which they are initially allocated regardless of their compliance with that treatment. All participants who withdraw from treatment for any reason will continue to be contacted for follow-up assessments and informed that their data are still required. Missing data will be handled via restricted maximum likelihood estimation within the linear mixed models. Given the popularity of simple data imputation methods we will undertake a secondary sensitivity analysis to determine whether the results would differ if missing data were replaced using the last observation carried forward method.

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
Current
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 289625 0
Commercial sector/Industry
Name [1] 289625 0
Magellan Stem Cells
Address [1] 289625 0
Magellan Stem Cells
2/116-118 Thames St
Box Hill Nth
Victoria 3128
Australia
Country [1] 289625 0
Australia
Funding source category [2] 289626 0
Commercial sector/Industry
Name [2] 289626 0
Melbourne Stem Cell Centre
Address [2] 289626 0
2/116-118 Thames St
Box Hill Nth
Victoria 3128
Australia
Country [2] 289626 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Magellan Stem Cells
Address
2/116-118 Thames St
Box Hill Nth
Victoria 3128
Australia
Country
Australia
Secondary sponsor category [1] 288313 0
Name [1] 288313 0
Melbourne Stem Cell Centre
Address [1] 288313 0
2/116-118 Thames St
Box Hill Nth
Victoria 3128
Australia
Country [1] 288313 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291367 0
Latrobe University Human Ethics Committee
Ethics committee address [1] 291367 0
Human Ethics
University Human Ethics Committee Research Integrity Unit and Research Services
La Trobe University Bundoora, Victoria 3086
Ethics committee country [1] 291367 0
Australia
Date submitted for ethics approval [1] 291367 0
Approval date [1] 291367 0
28/05/2014
Ethics approval number [1] 291367 0
14-016

Summary
Brief summary
The treatment of isolated knee cartilage defects remains difficult. Research indicates that these isolated lesions lead to later development of generalised osteoarthritis. Traditional and accepted arthroscopic microfracture of these lesions leads to formation of fibrocartilage which unfortunately only causes short to medium term improvement. Use of mesenchymal stem cells injections post micro fracture has shown promise in pre-clinical animal studies and also in initial human trials. We wish to explore the potential of autologous adipose derived mesenchymal stem cell injections post surgery to improve the quality of cartilage repair and prevent later onset development of osteoarthritis.
Trial website
http://www.melbournestemcellcentre.com/research/
Trial related presentations / publications
Public notes
Attachments [1] 128 128 0 0
http://www.anzctr.org.au/AnzctrAttachments/366749-Microfracture Research Trial.pdf

Contacts
Principal investigator
Name 50054 0
Dr Jon Ford
Address 50054 0
Lifecare Sports Medicine
316 Malvern Rd
Prahran
Victoria 3181
Country 50054 0
Australia
Phone 50054 0
+61422244183
Fax 50054 0
Email 50054 0
j.ford@latrobe.edu.au
Contact person for public queries
Name 50055 0
Dr Julien Freitag
Address 50055 0
Melbourne Stem Cell Centre
2/116-118 Thames St
Box Hill Nth 3128
Victoria
Country 50055 0
Australia
Phone 50055 0
+61392708000
Fax 50055 0
Email 50055 0
julien.freitag@mscc.com.au
Contact person for scientific queries
Name 50056 0
Dr Julien Freitag
Address 50056 0
Melbourne Stem Cell Centre
2/116-118 Thames St
Box Hill Nth 3128
Victoria
Country 50056 0
Australia
Phone 50056 0
+61392708000
Fax 50056 0
Email 50056 0
julien.freitag@mscc.com.au