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Trial registered on ANZCTR


Registration number
ACTRN12614001044617
Ethics application status
Submitted, not yet approved
Date submitted
8/09/2014
Date registered
29/09/2014
Date last updated
10/08/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Knee Osteoarthritis and Non-expanded Stem Cell Study
Scientific title
A Randomised, Stratified, Placebo-Controlled, Observer Double-Blind Multicentre Proof of Concept Study of the Safety and Efficacy of Autologous Stromal Vascular Fraction (SVF) With or Without Platelet Rich Plasma (PRP) and Hyaluronic Acid (HA) in Patients with Osteoarthritis of the Knee.
Secondary ID [1] 285182 0
NIL
Universal Trial Number (UTN)
U1111-1160-4996
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Osteoarthritis 292780 0
Condition category
Condition code
Musculoskeletal 293077 293077 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will look to assess the safety and response of knee osteoarthritis to different dosing and injection protocols of stromal vascular fraction (SVF), platelet rich plasma (PRP) and Hyaluronic acid (HA). Sixty four participants will be enrolled in the study and randomly separated into 4 study groups.

Group 1: Placebo Day 0 (Intravenous (IV) + Intra-articular (IA)) and placebo IA at Days 7, 14 and 21
Group 2: SVF + PRP (IA) + placebo (IV) at Day 0, and placebo IA at Days (7, 14 and 21)
Group 3: SVF (IV + IA) + PRP (IA) at Day 0, and placebo (IA Days 7, 14 and 21)
Group 4: SVF (IV +IA) + PRP/HA (IA) at Day 0, and PRP (IA) at Days 7, 14 and 21

Autologous non-expanded SVF from adipose (fat) will be used due to the ease of harvest (liposuction) and safety. On average 100 million cells are injected into the joint and 1.5 million/kg intravenously. Adipose tissue is removed by lipo-aspiration (about 60 minutes). The fat is processed on-site to isolate the cells (this process takes up to 40 mins). The suspension of stem cells is injected into the knee joint under ultrasound guidance, and intravenously (about 60 minutes). The PRP (3ml) process involves separating out platelets with plasma from a small amount of blood taken, and takes about 15 mins. Hyaluronic acid is approved for use in Australia and is routinely used in the treatment of knee osteoarthritis, 1 mL will be injected into the joint.

The harvesting of adipose and the PRP processing will be performed on the same day as the injection of SVF and PRP, respectively.
Intervention code [1] 290045 0
Treatment: Other
Comparator / control treatment
Sterile normal saline will be used for both intra-articular and intravenous injections
Control group
Placebo

Outcomes
Primary outcome [1] 292943 0
Safety will be assessed by monitoring for Adverse Events (including abnormal laboratory test results) over the study interval. Adverse Events will be graded by the Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) and coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology

Adverse events monitoring will consist of blood laboratory tests (complete blood count, comprehensive metabolic panel, coagulation and inflammat), and measurement of vital signs (temperature, heart rate, blood pressure, respiration).

Timepoint [1] 292943 0
Assessed at days 0, 28, 56, 112, 180, 365
Secondary outcome [1] 310359 0
The Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Oxford knee injury score to assess knee pain and function. A validated questionnaire
Timepoint [1] 310359 0
Assessed at commencement of study and days 28, 56, 112, 180 and 365
Secondary outcome [2] 310361 0
Load bearing x-ray and MRI findings will be evaluated for disease modifying activity. Analysis of joint space width will be undertaken in load bearing x-rays. MRI cartilage morphometry (cartilage volume, mean thickness, and surface area) will be also assessed.

The reviewer will indicate whether a participant has improved cartilage volume and the degree or not, or that degeneration has slowed in comparison to the placebo control.
Timepoint [2] 310361 0
Assessed at commencement of study and either days 180 or 365. This will be determined by the Principal Investigator.
Secondary outcome [3] 310362 0
Assessment of Quality of Life (AQoL) and The Short Form (36) Health Survey are patient-reported surveys of patient health and quality life
Timepoint [3] 310362 0
Assessed at commencement of study and days 28,56, 112, 180 and 365
Secondary outcome [4] 310363 0
Concurrent medication will be assessed from patient medical records.
Timepoint [4] 310363 0
Recorded at commencement of study and days 28, 56, 112, 180 and 365
Secondary outcome [5] 310364 0
Assessment of inflammatory blood cytokines by laboratory measurements
Timepoint [5] 310364 0
Assessed at commencement of study and days 28, 56, 112.

Eligibility
Key inclusion criteria
1. X-ray reporting grade 2 or more osteoarthritis of the knee Kellgren and Lawrence scale

2. WOMAC score greater than 50.


3. Greater than 6 months knee pain with the index side (left or right) predominately on one side.

4. Pain worse with activity.

5. An improvement in pain score (>10%) as measured by Numerical Rating scale (NRS, 0-10) within 2 weeks after PRP injection.

6. Sufficient fat present for liposuction

7. Adequate blood chemistry and hematopoietic, renal, cardiovascular, respiratory, immunological function
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants who have received investigational agents within 4 weeks (or 5 half-lives) of treatment.

2. Subjects with significant concurrent or intercurrent illness, psychiatric disorders or alcohol or chemical dependence that would, in the opinion of the Investigator, compromise their safety or compliance or interfere with interpretation of the study.

3. Presence of clinically significant acute or unstable cardiovascular, cerebrovascular (stroke), renal, gastrointestinal, pulmonary, immunological (viral hepatitis, or cirrhosis), endocrine, or central nervous system disorders.

Participants who have had active neoplastic disease (cancer) in the previous 3 years.

4. Presence of active infection (except for colds or minor URTI). History of human immunodeficiency virus or acquired immune deficiency syndrome. Significant peripheral vascular disease.

5. Participants who are pregnant or lactating. Female participants who have positive serum beta HCG pregnancy test taken within 7 days before treatment.

6. Fertile participants who are not using effective contraception (e.g., oral contraceptives, intrauterine devices, double barrier methods such as condoms and diaphragms, abstinence or equivalent measures).

7. Previous treatment with SVF.

8. Conditions/therapies/factors which could confound or interfere with the evaluation of pain/mobility including, but not limited to:
a) Treatments with strong opioid drugs in the previous 4 weeks for other pain rather than knee osteoarthritis
b) Procedures planned during the study period which could interfere with pain assessment (e.g. surgery).
c) Other causes of chronic pain (e.g. low back pain, hip pain).
d) Intrarticular/periarticular therapies in the past 6 weeks.
e) Patients taking glucosamine, unless they have been on a stable dose for at least 2 months. Similarly NSAIDs and COX-2 inhibitor dosing must have been stable for at least a month.
f) Major surgery within the past 3 months.
g) Corticosteroid injection at treatment site within 1 month.
e) Systemic use of corticosteroids within 2 weeks.
f) Consistent use of NSAIDs within 48 hours of procedure.
g) Aspirin (except low dose for cardioprotection), Vitamin E, Fish Oil or anti-inflammatories for one week prior.
h) Knee instability.
i) A varus/valgus deformity of more than 10 degrees, a deformity requiring osteotomy or complex surgery.
J) Gout or pseudogout
k) History of more than one surgical procedure to the knee in question or previous lower extremity amputation
l) Co-existents of inflammatory arthritis (e.g. rheumatoid, psoriatic and ankylosing spondylitis arthritis)

9. Obesity defined as BMI > 35

10. Participants unable to tolerate MRI.

11. Inability to understand the study or complete WOMAC/Oxford/AQoL questionnaires.

12. Inability to provide informed consent.

13. Patients that are allergic to avian proteins, feathers or egg products

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)
Primarily participants will be recruited from the pool currently existing within the Investigator Practices and by posters in each clinic. Other recruitment for the clinical trial will be via referral from other medical practitioners or limited newspaper/website advertisement in the Sydney, Newcastle and Gold Coast regions.

After direct enquiry from a possible participant or 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 1-64 that was randomly generated by (www.randomizer.org)

Group 1. Participant No. 1-16
Group 2. Participant No. 17-32
Group 3. Participant No. 33-48
Group 4. Participant No. 49-64
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
Those participants allocated to the placebo group will be offered the most successful treatment protocol after completion of study data collection using their cryo-preserved cells. This will be at no charge.
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This study is primarily to assess the safety profile of SVF.
However, a sample size estimate was undertaken for the secondary exploratory efficacy endpoint of the WOMAC score.

The chosen sample size of 64 patients allows for 16 patients per treatment cohort which is sufficient to detect a difference between placebo and SVF groups in the mean percentage change over time in WOMAC scores of 20% with a standard deviation of 10% or difference of 10% with a much larger standard deviation of 20%.

All efficacy analyses will be performed using the ITT population. The WOMAC and the AQoL/Oxford questionnaires will be scored according to the author’s instructions. For each post-baseline assessment the change in score from baseline will be calculated. In addition, each patient will be classified as achieving a clinically relevant change in score using the pre-defined cutoffs (30% for WOMAC, and a minimal important clinical difference (MICD) of 0.06 and 5 points for AQol utility score and the Oxford Knee Instrument, respectively). The actual scores and change in scores will be summarised by timepoint and treatment group (overall and by cohort) using descriptive statistical (mean, median, standard deviation, minimum and maximum) whilst achievement of a clinically relevant change will be summarised by treatment group and timepoint (overall and by cohort) using frequencies and percentages.

For WOMAC an exploratory mixed model will be fitted with WOMAC score as the outcome variable and treatment group, cohort, timepoint and baseline score as covariates. Other relevant prognostic factors may be included in the model (to be fully defined in the SAP). The dependence in the data will be addressed through appropriate modelling of the subject covariance matrix (to be fully defined in the SAP). The adjusted mean change in score at each timepoint for each treatment, together with the adjusted mean difference in treatments will be estimated from the model and presented with 95% confidence limits. The comparisons are predefined at 12 months as cohort 2, 3 and 4 vs cohort 1 (SVF IA, SVF (IA + IV) and SVF + PRP + HA vs placebo) and cohorts 3 and 4 vs cohort 2 (SVF (IA + IV) and SVF + PRP + HA vs SVF IA). Due to the exploratory nature of the study no adjustment for multiplicity will be undertaken.

A similar approach will be followed for clinically meaningful change in AQoL/SF-36/Oxford Knee.

For achievement of a clinically meaningful change in WOMAC each patient will be classified as ‘Yes’ or ‘No’, forming a binary outcome variable. A logistic regression model will be fitted with achievement of a clinically relevant change in score during the trial (Yes/No) as the outcome variable and treatment group, cohort, baseline WOMAC score and other relevant prognostic factors (to be defined in the SAP) as covariates. Adjusted odds ratios for SVF IA, SVF (IA + I V) and SVF + PRP + HA vs placebo and SVF (IA +IV) and SVF + PRP + HA vs SVF IA at 12 months will be extracted from the model and presented with 95% confidence limits. In addition the estimated proportion of patients achieving a clinically relevant change in WOMAC will be extracted for each treatment group and presented with 95% confidence limits. As this is an exploratory analysis no adjustment for multiplicity will be undertaken.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Ethics not approved
Date of first participant enrolment
Anticipated
31/01/2015
Actual
Date of last participant enrolment
Anticipated
31/01/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
64
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD

Funding & Sponsors
Funding source category [1] 289918 0
Commercial sector/Industry
Name [1] 289918 0
Cell-Innovations Pty Ltd
Country [1] 289918 0
Australia
Primary sponsor type
Individual
Name
Dr David Mathers
Address
Hunter Regenerative medicine
71 Georgetown Rd
Georgetown
NSW 2298
Country
Australia
Secondary sponsor category [1] 288694 0
Individual
Name [1] 288694 0
Dr John van der Kallen
Address [1] 288694 0
Hunter Regenerative Medicine
71 Georgetown Rd
Georgetown
NSW 2298
Country [1] 288694 0
Australia
Secondary sponsor category [2] 288695 0
Individual
Name [2] 288695 0
Dr Ralph Bright
Address [2] 288695 0
Macquarie Stem Cells
21b Bathurst St
Liverpool
NSW 2170
Country [2] 288695 0
Australia
Secondary sponsor category [3] 288696 0
Individual
Name [3] 288696 0
Dr Nathan Gibbs
Address [3] 288696 0
South Sydney Sports Medicine
111 Anzac Pde
Kensington
NSW 2033
Country [3] 288696 0
Australia
Secondary sponsor category [4] 288697 0
Individual
Name [4] 288697 0
Dr Ken Johnston
Address [4] 288697 0
Southport Central
Suite 12, Level 7, Tower 3,
9 Lawson St, Southport,
Qld 4215
Country [4] 288697 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 291637 0
Bellberry Limited
Ethics committee address [1] 291637 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [1] 291637 0
Australia
Date submitted for ethics approval [1] 291637 0
25/03/2014
Approval date [1] 291637 0
Ethics approval number [1] 291637 0

Summary
Brief summary
The primary objective of this study is to determine the safety and tolerability of autologous stromal vascular
fraction (SVF) compared to placebo in patients with osteoarthritis of the knee.

Secondary objectives are intended to measure differences between placebo and SVF based therapies including improved pain control, improvement of WOMAC, weight bearing x-rays, improvement in the AQoL (Australian Quality of Life) instrument, reduction in rescue medication consumption and MRI to assess disease modifying activity.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46210 0
Dr David Mathers
Address 46210 0
Hunter Regenerative Medicine,
71 Georgetown Rd,
Georgetown
NSW 2298
Country 46210 0
Australia
Phone 46210 0
+61 (2) 49601933
Fax 46210 0
Email 46210 0
[email protected]
Contact person for public queries
Name 46211 0
Jane Young
Address 46211 0
Macquarie Stem Cells
21b Bathurst St
Liverpool
NSW 2071
Country 46211 0
Australia
Phone 46211 0
+61 (2) 9824 2933
Fax 46211 0
Email 46211 0
[email protected]
Contact person for scientific queries
Name 46212 0
Wayne Thomas
Address 46212 0
Cell-Innovations
21b Bathurst St
Liverpool
NSW 2071
Country 46212 0
Australia
Phone 46212 0
+61 (2) 9824 2933
Fax 46212 0
Email 46212 0
[email protected]

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No Supporting Document Provided



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