Trial registered on ANZCTR


Trial ID
ACTRN12614000814673
Ethics application status
Approved
Date submitted
20/07/2014
Date registered
31/07/2014
Date last updated
16/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of mesenchymal stem cells in the treatment of knee osteoarthritis – A randomised Controlled Trial
Scientific title
The effectiveness of autologous adipose derived mesenchymal stem cells versus accepted conservative management as treatment for symptomatic knee osteoarthritis on pain, function and cartilage volume in osteoarthritis patients.
Secondary ID [1] 285017 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoarthritis 292531 0
Condition category
Condition code
Musculoskeletal 292837 292837 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will look to assess the response of symptomatic medial knee compartment osteoarthritis to different dosing and injection protocols of mesenchymal stem cells in comparison to accepted conservative management. 30 participants will be enrolled in the study and randomly separated into 3 study groups.
- Group 1. Single intra-articular injecton of 100million stem cells at 0months.
- Group 2. Intra-articular injection of 100million stem cells at 0 and 6 months (total of 200million cells)
- Group 3. Control Group - conservative management.

Autologous adipose derived mesenchymal stem cells will be used due to the ease of harvest (liposuction) and safety in comparison to allogeneic cells.
Intervention code [1] 289851 0
Treatment: Other
Comparator / control treatment
Conservative management of symptomatic osteoarthritis. This includes :
- simple analgesia
- weight loss education
- regular exercise
- biomechanical adjustment

The control group will be offered cross over to the most successful treatment protocol at no charge after completion of 12 months follow-up. Timing of this treatment will be determined by time of completion of data collection for all patients and when the most successful treatment protocol has been clearly determined. This would be anticipated to be within 2months of completion of data collection.
Control group
Active

Outcomes
Primary outcome [1] 292702 0
Knee Injury and Osteoarthritis Outcome Score -
consists of 5 subscales being pain, other symptoms, function in daily living, function in sport and recreation and knee related quality of life. It is reliable and valid for the population of people with osteoarthritis.
Timepoint [1] 292702 0
Assessed at 0,1,3,6 and 12months post commencement of study.
Primary outcome [2] 292703 0
0-10 Numerical Pain Rating Scale (NPRS) - The NPRS has been validated for use in people with knee osteoarthritis
Timepoint [2] 292703 0
Assessed at 0,1,3,6 and 12months post commencement of study.
Primary outcome [3] 292704 0
MRI quantitative data including mapping of cartilage volume.
Timepoint [3] 292704 0
Assessed at commencement of study and again at 12months.
Secondary outcome [1] 309524 0
Global perceived effect scale. Measures of global effect are a recommended outcome measure for clinical trials
Timepoint [1] 309524 0
Assessed at 1,3,6 and 12months post commencement of study.
Secondary outcome [2] 309525 0
Pain Treatment Satisfaction Scale - a validated questionnaire
Timepoint [2] 309525 0
Assessed at 1,3,6 and 12months post commencement of study.
Secondary outcome [3] 309527 0
The Orebro Musculoskeletal Pain Questionnaire will also be completed. This questionnaire has been to shown to be reliable and valid for detecting individuals at risk of developing persistent pain. This questionnaire will be used in the current study to assess the potential impact of psychosocial factors on participants’ outcome.
Timepoint [3] 309527 0
Assessed at commencement of study

Eligibility
Key inclusion criteria
1. Radiological diagnosis of osteoarthritis using the American College of Rheumatology criteria (Altman, 1986).
2. Radiological grading of Grade II-III OA of the knee as determined by a qualified radiologist using the Kellgren and Lawrence system (Kellgren and Lawrence 1957).
3. Medial Compartment OA as determined above.

4. Primary OA treatment already undertaken defined as: analgesia/anti-inflammatory medication, supplements approved by the treating clinician (eg glucosamine sulphate), an attempted exercise program prescribed by a physiotherapist or medical practitioner for at least 8 weeks (Petrella 2000), weight loss and nutritional management as prescribed by a dietitian or medical practitioner for at least 8 weeks, and biomechanical management including bracing if appropriate as prescribed by a physiotherapist, podiatrist or medical practitioner. Autologous MSC is an invasive treatment and guidelines recommend trialling conservative measures as the first line of treatment in knee OA (Thompson, Gordon et al. 2009).

5. A minimum pain score of 5 on an 11-point numerical rating scale.


6. Single symptomatic knee osteoarthritis.

8. Less than 5 degrees varus or valgus knee deformity as measured by the long mechanical axis of the knee on X-Ray.
9. Sufficient English skills to complete the questionnaires required for the study, as well as to understand the instructions given by the study doctors. This is required as no funding is available for translation or interpreters, and the outcome questionnaires to be used have only been validated in English language.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18yrs. OA does not commonly occur in people under 18.

2. Pregnancy (accepted contra-indication as no safety data on this population).

3. Breastfeeding (accepted contra-indication as no safety data on this population).

4. 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.

5. Blood disorder (accepted contra-indication as no safety data on this population)
6. Anti-coagulant therapy that cannot safely be ceased.
7. MRI confirmed displaced meniscial tear.

8. MRI Confirmed Grade IV chondral loss

9. Previous meniscectomy/significant partial meniscectomy or other knee related surgery within the last 12 months.

10. Previous intra-articular injectable therapies within the last 6months.

11. Lateral Compartment and/or Patellofemoral compartment Grade 2-4 osteoarthritis.

12. History of cancer.

13. History of systemic illness or significant organ impairment/failure (ie. renal failure).

14. History of an atypical pain syndrome.

15. History of infective or inflammatory joint disorders, or suspected infective or inflammatory joint disease

16. Plans at the time of enrolment to undergo surgery in the following 12 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.
17. History of allergy to any substances used within the treatments.
18. History of other musculoskeletal or neurological condition that effects lower limb function.
19. Patients may not participate in any other clinical study of an investigational drug or investigational treatment at any time while participating in this study

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)
The trial will be advertised to both allied health and medical groups. Google ads will also be used to gather attention within the general community.

After direct enquiry from a possible participant and after an initial phone based screen, participants will be invited to attend for a formal assessment to ascertain their suitability for the trial. If suitable they will be invited to enrol in the study and then complete a formal informed consent.

Formally enrolled participants will then be randomly allocated to a study group/arm by the study administrator using a randomisation computer program (www.randomizer.org)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be allocated a participant number from 0-30 that was randomly generated by research randomiser online program ww.randomizer.org

Treatment Arm 1. Participant No. 1-10
Treatment Arm 2. Participant No. 11-20
Control Arm. Participant No. 21-30
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Those participants allocated to the control group will be offered a crossover to the most successful treatment protocol after completion of study data collection. This will be at no charge.
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 measurement. 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
Active, not 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
Recruitment postcode(s) [1] 8453 0
3128 - Box Hill

Funding & Sponsors
Funding source category [1] 289629 0
Commercial sector/Industry
Name [1] 289629 0
Magellan Stem Cells
Address [1] 289629 0
Level 2, 116-118 Thames St
Box Hill Nth 3128
Victoria
Country [1] 289629 0
Australia
Funding source category [2] 289630 0
Commercial sector/Industry
Name [2] 289630 0
Melbourne Stem Cell Centre
Address [2] 289630 0
Level 2, 116-118 Thames St
Box Hill Nth 3128
Victoria
Country [2] 289630 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Magellan Stem Cells
Address
Level 2, 116-118 Thames St
Box Hill Nth 3128
Victoria
Country
Australia
Secondary sponsor category [1] 288316 0
Commercial sector/Industry
Name [1] 288316 0
Melbourne Stem Cell Centre
Address [1] 288316 0
Level 2, 116-118 Thames St
Box Hill Nth 3128
Victoria
Country [1] 288316 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291370 0
Monash University Humam Research Ethics Committee
Ethics committee address [1] 291370 0
Human Ethics
Monash Research Office
Monash University
Level 1, Building 3e, Clayton Campus
Wellington Rd
Clayton VIC 3800, Australia
Ethics committee country [1] 291370 0
Australia
Date submitted for ethics approval [1] 291370 0
Approval date [1] 291370 0
25/06/2014
Ethics approval number [1] 291370 0
CF14/1013 - 2014000415

Summary
Brief summary
Osteoarthritis is a major cause of pain and disability world wide. This study aims to explore the effectiveness of autologous mesenchymal stem cell (MSC) injections in treating OA. This study involves the use of autologous MSC, autologous meaning that the cells are taken from and injected back into the same person. Based on previous animal studies and initial human patients, these MSCs are expected reduce pain and assist in bone and cartilage tissue repair, supporting their potential in the treatment of osteoarthritis.
Trial website
http://www.melbournestemcellcentre.com/research/
Trial related presentations / publications
Public notes
Attachments [1] 130 130 0 0
http://www.anzctr.org.au/AnzctrAttachments/366755-Research Trial advertisment.pdf

Contacts
Principal investigator
Name 50078 0
Prof Richard Boyd
Address 50078 0
Department of Anatomy and Developmental Biology, School of Biological Sciences
Monash University
Clayton, Victoria 3800
Australia
Country 50078 0
Australia
Phone 50078 0
+6139905 0630
Fax 50078 0
Email 50078 0
richard.boyd@monash.edu.au
Contact person for public queries
Name 50079 0
Dr Julien Freitag
Address 50079 0
Melbourne Stem Cell Centre
Level 2, 116-118 Thames St
Box Hill Nth
Victoria 3128
Country 50079 0
Australia
Phone 50079 0
+61392708000
Fax 50079 0
Email 50079 0
julien.freitag@mscc.com.au
Contact person for scientific queries
Name 50080 0
Prof Richard Boyd
Address 50080 0
Department of Anatomy and Developmental Biology, School of Biological Sciences
Clayton, Victoria 3800
Monash University
Australia
Country 50080 0
Australia
Phone 50080 0
+6139905 0630
Fax 50080 0
Email 50080 0
richard.boyd@monash.edu.au