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Trial registered on ANZCTR


Registration number
ACTRN12620000870954
Ethics application status
Approved
Date submitted
18/06/2020
Date registered
31/08/2020
Date last updated
31/08/2020
Date data sharing statement initially provided
31/08/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Stem cell therapy in knee osteoarthritis.
Scientific title
Evaluating the efficacy and cost-effectiveness of stem cell injections in people with mild to moderate knee osteoarthritis: a randomised placebo-controlled trial (The SCUlpTOR trial)
Secondary ID [1] 301858 0
None
Universal Trial Number (UTN)
U1111-1234-4897
Trial acronym
The SCUlpTOR trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis 317275 0
Condition category
Condition code
Musculoskeletal 315398 315398 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
- The dose administered: 2.5 x 10^7 cell culture-expanded allogeneic mesenchymal stem cells (MSCs) suspended in 5 ml excipient solution.
- The frequency and duration of administration: three knee intra-articular injections of allogeneic MSCs performed at baseline, week 3 and 52 (12-months).
- The mode of administration: ultrasound-guided intra-articular injections applied to the study knee delivered by an experienced radiologist.
- Strategies used to monitor adherence to the intervention: the number of injections delivered will be recorded in the participants' notes on REDCap - Study visit form.
Intervention code [1] 317458 0
Treatment: Drugs
Intervention code [2] 318150 0
Treatment: Other
Comparator / control treatment
Saline solution containing 0.9% sodium chloride
Control group
Placebo

Outcomes
Primary outcome [1] 323645 0
The proportion of participants achieving patient-acceptable symptom state (PASS) for knee pain.
Timepoint [1] 323645 0
24 months post-treatment allocation (first intervention dose).
Primary outcome [2] 323646 0
Central medial femorotibial (cMFT) cartilage thickness loss in µm. The cMFT cartilage thickness will be measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee. The MRI will use a 3.0T whole-body system with dedicated extremity coil and a T1-weighted fat-suppressed 3D gradient recall acquisition sequence.
Timepoint [2] 323646 0
24 months post-treatment allocation (first intervention dose) in comparison to baseline
Secondary outcome [1] 382472 0
Knee pain intensity measured by the visual analogue scale (VAS).
Timepoint [1] 382472 0
3, 6, 9, 12, 15, 18, 21 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [2] 382473 0
Knee pain intensity measured by the Wong-Baker FACES Pain Rating Scale.
Timepoint [2] 382473 0
3, 6, 9, 12, 15, 18, 21 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [3] 382474 0
Physical activity levels measured by the Physical Activity Scale for the Elderly (PASE).
Timepoint [3] 382474 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [4] 382475 0
Health-related quality of life measured using the total score of the Assessment of Quality of Life - 8 domains (AQoL-8D) instrument (composite).
Timepoint [4] 382475 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [5] 385957 0
Knee pain intensity measured by the Knee Injury and Osteoarthritis Outcome Score (KOOS)' Pain subscale.
Timepoint [5] 385957 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [6] 385958 0
Knee function in daily living measured by the KOOS' Function in daily living subscale.
Timepoint [6] 385958 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [7] 385960 0
Sport- and recreation-related knee function measured by the KOOS' Function in sport and recreation subscale.
Timepoint [7] 385960 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [8] 385961 0
Knee-related quality of life measured by the KOOS' knee-related quality of life subscale.
Timepoint [8] 385961 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [9] 385969 0
Other knee symptoms, measured by the KOOS' other Symptoms subscale.
Timepoint [9] 385969 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [10] 385983 0
KOOS total score using all five subscales: pain, other symptoms, function in daily living, function in sport and recreation and knee-related quality of life.
Timepoint [10] 385983 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [11] 385993 0
Change of cartilage thickness in total femorotibial plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [11] 385993 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [12] 385994 0
Change of cartilage thickness in lateral femorotibial plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [12] 385994 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [13] 385995 0
Change of cartilage thickness in medial femorotibial plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [13] 385995 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [14] 385996 0
Change of cartilage thickness in medial tibial plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [14] 385996 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [15] 385997 0
Change of cartilage thickness in medial femoral plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [15] 385997 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [16] 385998 0
Change of cartilage thickness in lateral tibial plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [16] 385998 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [17] 385999 0
Change of cartilage thickness in lateral femoral plate measured by drawing disarticulation contours around the cartilage edges, section by section in all MRI slices of the study knee.
Timepoint [17] 385999 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [18] 386000 0
Change in the number of areas with worsening in cartilage thickness using the MRI Osteoarthritis Knee Scores (MOAKS).
Timepoint [18] 386000 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [19] 386001 0
Change in osteophytes score in each location according to size using the MOAKS.
Timepoint [19] 386001 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [20] 386002 0
Change in bone marrow lesions (BMLs) using the MOAKS.
Timepoint [20] 386002 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [21] 386003 0
Change in meniscal morphology features using MOAKS.
Timepoint [21] 386003 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [22] 386004 0
Change in whole knee effusion, using MOAKS.
Timepoint [22] 386004 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [23] 386005 0
Change in infra-patellar fat pad synovitis (Hoffa’s synovitis), using MOAKS.
Timepoint [23] 386005 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [24] 386007 0
Quality-adjusted-life-years (QALY) based on measures obtained from the AQoL-8D and
transformed into a utility index using weights derived from the Australian population.
Timepoint [24] 386007 0
24 months post-treatment allocation in comparison to baseline.
Secondary outcome [25] 386008 0
Healthcare-related costs will be based on MBS and PBS data in combination the healthcare usage monthly surveys.
Timepoint [25] 386008 0
From baseline (treatment allocation) for the duration of the study (24 months).
Secondary outcome [26] 386012 0
Blinding success measured by asking which treatment participants believe they received, also asking the injecting doctors which treatment they believe they have given to the participants.
Timepoint [26] 386012 0
After each injection (baseline, week 3 and week 52).
Secondary outcome [27] 386019 0
Health-related quality of life: Independent living, senses and pain using the Physical Super Dimensions of the Assessment of Quality of Life (AQoL-8D) instrument (composite).
Timepoint [27] 386019 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [28] 386020 0
Health-related quality of life: mental health, happiness, self-worth, coping and relationships using the Psycho-Social Super Dimensions of the AQoL-8D instrument (composite).
Timepoint [28] 386020 0
3, 6, 12 and 24 months post-treatment allocation in comparison to baseline.
Secondary outcome [29] 386044 0
Perceived improvement in knee pain intensity assessed by the global rating of change
Timepoint [29] 386044 0
3, 6, 12 and 24-months post-treatment allocation.
Secondary outcome [30] 386045 0
Perceived improvement in knee function assessed by the global rating of change.
Timepoint [30] 386045 0
3, 6, 12 and 24-months post-treatment allocation.
Secondary outcome [31] 386046 0
Perceived overall improvement assessed by the global rating of change
Timepoint [31] 386046 0
3, 6, 12 and 24-months post-treatment allocation.

Eligibility
Key inclusion criteria
• Ability and willingness to participate and complete the study
• Having internet access and an active email account
• Having functional English
• Australian Citizen or Permanent resident
• Male or Female >=40 years of age.
• Knee OA as defined by the clinical and radiographic American College of Rheumatology (ACR) criteria.
• Presence of pain in the study knee for at least half of the days in the previous month
• Pain intensity >= 40 and <= 90 on a 0-100 visual analogue scale (VAS).
• Kellgren-Lawrence grade (KLG) 2 or 3 of the study knee based on knee radiograph.
• Minimal medial joint space width (mJSW) between 1mm and 4mm of the study knee based on radiographs.
• Willingness to undergo a new knee X-ray and MRI
• Female of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation.
• Willingness to stop or maintain a routine (on the same dosage and frequency) of conservative treatments
• Willingness to stop or minimise the use of anti-inflammatory drugs and other analgesics (except paracetamol for rescue pain relief) for the duration of the study
• Willingness to not start a new treatment for knee OA during the study.
• Willingness and ability to travel for the study required physical visits
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Incomplete online screening surveys;
• Participants that are non-responders after completing the screening survey but before being enrolled;
• Radiological evidence of predominant patellofemoral or lateral tibiofemoral disease;
• Bilateral symptomatic knee OA if the patient-reported pain intensity in the contralateral knee is <= 30 on a 0-100 VAS;
• Significant injury in the study knee that led to substantial loss of function or surgeries within the past 6 months;
• Prior knee joint replacement or high tibial osteotomy in the study knee;
• Surgery on the study knee within the past 12 months;
• Planned surgery for the study knee in the next 24 months;
• Systemic or inflammatory joint disease;
• History of crystalline arthropathy, autoimmune arthritis, hemochromatosis or fibromyalgia;
• Signs of undiagnosed crystal arthritis or joint infection (i.e., knee that is red, swollen and hot);
• Any painful muscular or neurological condition of the lower limb;
• Immunosuppression or acute infective processes;
• Cancer or other tumour-like lesions, except for non-melanoma skin cancer which has been removed and not active within the past 3 years;
• Hyaluronic acid (HA) injection within the past 6 months;
• Autologous blood product or stem cell injection in the study knee within the past 12 months;
• Steroid injections in any joint within the past 6 months;
• Regularly taking centrally acting analgesics (e.g., opioid analgesics, duloxetine and pregabalin);
• Participation in another knee OA clinical trial and/or treatment received with any investigational agent within 30 days before enrolment;
• Any unstable concurrent clinically significant acute, chronic medical conditions or abnormal laboratory findings that would jeopardise the safety of the participant, interfere with study objectives or affect the participant’s compliance;
• Needle phobia;
• Contraindications to MRI

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 study coordinator at each site will contact the site unblinded researcher just prior to administration of the first injection who will then reveal the participant’s group allocation using the REDCap randomisation module. The randomisation survey in REDCap will be made available only to the unblinded researchers via user rights. The subject enrolment log containing participant’s group allocation will be available to the unblinded researchers only through file encryption.
The injecting doctors, study coordinators, study physician, imaging readers and study statistician will remain blinded to the treatment allocation until the main results are analysed. Participants will not be told until the end of the study (24 months after baseline) which group they were allocated to. The unblinded researcher will prepare the injection in a separate room, and a patient label will be placed over the syringe to occlude the contents. The researcher will then give the syringe to the injecting doctor who will not know or be able to tell whether the syringe has stem cells or saline. The study participants will be blinded to group allocation. All clinical and MRI assessments will be conducted by an assessor blinded to treatment allocation.
The same preparation process will be in place for injection appointment 2 and 3, which will help blinding of participants to their group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Individuals who qualify and consent to take part in the study will be assigned to either active or placebo group with a 1:1 allocation rate as per computer-generated randomisation scheduled using random permuted block sizes and stratified by study site and radiographic disease severity (KLG 2 vs 3).
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The statistical analysis will be performed by a qualified biostatistician who will be blinded to the group allocation. Subjects will be analysed according to the intention-to-treat (ITT) principle.
Demographic characteristics and baseline scores summarised as mean (SD) for continuous variables or medians (quartiles) if the distribution is skewed. Counts with percentages will be presented for categorical variables.
The primary outcome will be the difference in the proportion of patients achieving 1) a VAS pain score <= 32 (0-100 scale) at 24 months and 2) with 0.15 mm cartilage loss at 24 months in the two groups based on a two-sided significance level of 0.05. The difference in proportion between groups will be presented alongside the corresponding confidence intervals. The mean cartilage loss in each treatment group will be summarised as mean (SD) and compared using a t-test, if appropriate.
Secondary outcomes will be summarised as mean (SD) by treatment group at each time point of interest. Generalised estimating equations (GEE) will be used to assess the effect of treatment over time. Results will be presented with corresponding 95% confidence intervals (CIs) and p-value.
To assist with the interpretation of the results, we will calculate the minimal clinically important improvement (MCII) for pain using the Global Rating of Change (GRC) scale. The average score for the pain of the people who answered the GRC as “slightly better” will be the cut-off value for MCII. We will also calculate the minimal clinically important difference (MCID) between groups by using the GRC scale. The difference between the mean scores for the pain of the people who answered the GRC as “no change” and “slightly better” will be the cut-off value for the MCID. Covariables of interest will include age, gender and BMI. Progression of symptoms, BMLs, synovitis, effusion, cartilage lesions, osteophytes and meniscal damage will also be examined. Results will be presented with appropriate estimates together with 95% CIs.

Recruitment
Recruitment status
Not yet 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,TAS

Funding & Sponsors
Funding source category [1] 305594 0
Government body
Name [1] 305594 0
National Health and Medical Research Council
Address [1] 305594 0
16 Marcus Clarke St, Canberra ACT 2601
Country [1] 305594 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 306010 0
None
Name [1] 306010 0
Address [1] 306010 0
Country [1] 306010 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305892 0
The University of Sydney Human Research Ethics Committee (HREC)
Ethics committee address [1] 305892 0
Camperdown NSW 2006
Ethics committee country [1] 305892 0
Australia
Date submitted for ethics approval [1] 305892 0
24/01/2020
Approval date [1] 305892 0
10/06/2020
Ethics approval number [1] 305892 0
2020/119

Summary
Brief summary
SCUlpTOR is a 24-month research study from the Institute of Bone and Joint Research (IBJR) at the University of Sydney, evaluating the efficacy and cost-effectiveness of stem cell injections compared with placebo in people with knee OA. Currently, the medical opinion about stem cell therapy for treating osteoarthritis remains highly controversial, given the considerable cost of treatment and very limited scientific evidence of efficacy and safety. Therefore, we aim to conduct this trial to ascertain whether or not intra-articular stem cell injections improve symptoms and slow disease progression in people with mild to moderate knee OA. The stem cells that we used was originally sourced from a healthy donor/master cell bank following standard manufacturing process and release tests to optimise safety and batch to batch reproducibility.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101962 0
Prof David Hunter
Address 101962 0
Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney.
Rheumatology Department, Lv 10 Kolling Building, Reserve Road, St Leonards, NSW 2065, Australia.
Country 101962 0
Australia
Phone 101962 0
+61 02 9463 1887
Fax 101962 0
Email 101962 0
david.hunter@sydney.edu.au
Contact person for public queries
Name 101963 0
Dr Sarah Robbins
Address 101963 0
Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney.
Rheumatology Department, Lv 10 Kolling Building, Reserve Road, St Leonards, NSW 2065, Australia.
Country 101963 0
Australia
Phone 101963 0
+61 02 9463 1855
Fax 101963 0
Email 101963 0
sarah.robbins@sydney.edu.au
Contact person for scientific queries
Name 101964 0
Prof David Hunter
Address 101964 0
Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney.
Rheumatology Department, Lv 10 Kolling Building, Reserve Road, St Leonards, NSW 2065, Australia.
Country 101964 0
Australia
Phone 101964 0
+61 02 9463 1887
Fax 101964 0
Email 101964 0
david.hunter@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
A de-identified dataset containing individual participant data (of those who consented to have their anonymised data used in future studies) will be published in an open-access Data Repository by the Coordinating Principal Investigator three years after study close-out.
When will data be available (start and end dates)?
Three years after study close-out with no end date.
Available to whom?
Anyone who wishes to access it, since it will be published in an open-access Data Repository.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Data will be published in an open-access Data Repository (link to be provided once data has been published).
What supporting documents are/will be available?
No other documents available
Summary results
No Results