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Trial registered on ANZCTR


Registration number
ACTRN12617000853347
Ethics application status
Approved
Date submitted
7/06/2017
Date registered
9/06/2017
Date last updated
7/06/2021
Date data sharing statement initially provided
21/12/2018
Date results information initially provided
26/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Platelet rich plasma for knee osteoarthritis - the RESTORE trial
Scientific title
platelet-Rich plasma as a symptom- and disEaSe-modifying Treatment fOR knee ostEoarthritis - the RESTORE trial
Secondary ID [1] 292131 0
None
Universal Trial Number (UTN)
Trial acronym
RESTORE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee osteoarthritis 303557 0
Condition category
Condition code
Musculoskeletal 302966 302966 0 0
Osteoarthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Platelet-rich plasma (PRP) injections into the knee joint.

PRP injections are made from withdrawing and centrifuging the participant’s own blood on the day of treatment. An injection of PRP will be administered to participant’s study knee by a qualified doctor under ultrasound guidance once per week for three weeks.

Approximately 20mL of blood from the participant’s arm will be drawn. A research nurse will prepare the injection, and both the participant and injecting doctor will not be told which treatment group the participant is allocated to.

The whole blood sample will be centrifuged in a separate room to allow extraction of the PRP. A portion of the PRP will be withdrawn and saved for analysis, and approximately 5mL withdrawn into a syringe. The syringe will then be covered with a patient label, such that the injecting doctor will not know or be able to tell whether the syringe has PRP or placebo (saline). The doctor will then inject local anaesthetic superficially (which is optional for the participant), and then perform the PRP injection in to the knee joint under ultrasound guidance.

Participants will return to the site radiology clinic for their second injection of PRP approximately one week later, and again for a third and final injection approximately one week after that. The injection process will be the same as the first injection.
Intervention code [1] 298273 0
Treatment: Other
Comparator / control treatment
Placebo injections are the same volume of saline as the PRP injection.

An injection of saline solution will be administered into the participant’s knee under ultrasound guidance once per week for three weeks.

Approximately 20mL of blood from the participant’s arm will be drawn. A research nurse will prepare the injection, and both the participant and injecting doctor will not be told which treatment group the participant is allocated to.

The research nurse will prepare a syringe with a saline solution (approximately 5mL) in a separate room, a patient label will be placed over the syringe, such that the injecting doctor will not know or be able to tell whether the syringe has PRP or saline. The doctor will then inject local anaesthetic superficially (which is optional for the participant) and then perform the saline injection in to the participant’s knee joint under ultrasound guidance.

Participants will return to the site radiology clinic for their second saline injection approximately one week later, and again for a third and final injection one week after that. The injection process will be the same as the first injection.
Control group
Placebo

Outcomes
Primary outcome [1] 302354 0
Overall knee pain.

Scored on an 11-point numerical rating scale for average overall pain in the last week where 0=no pain and 10=worst pain possible.
Timepoint [1] 302354 0
Baseline plus 2 months (secondary time point) and 12 months (primary time point) after baseline.

*Additionally will be asked at 6 and 9 months to identify pattern of pain trajectory.
Primary outcome [2] 302355 0
Medial tibial cartilage volume.

A MRI will be performed of the study knee using a 3T whole body system with dedicated extremity coil and a T1-weighted fat suppressed 3D gradient recall acquisition sequence.
Timepoint [2] 302355 0
Baseline plus 12 months after baseline.
Secondary outcome [1] 335683 0
Walking knee pain.

Scored on an 11-point numerical rating scale for average pain on walking in the last week where 0=no pain and 10=worst pain possible.
Timepoint [1] 335683 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [2] 335684 0
Knee Osteoarthritis Outcome Score (KOOS) Pain.

Scored from 9 questions regarding knee pain in the last week. Ranges from 0 to 100; lower scores indicate worse pain.
Timepoint [2] 335684 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [3] 335685 0
KOOS Other Symptoms.

Scored from 7 questions regarding knee symptoms in the last week. Ranges from 0 to 100; lower scores indicate worse symptoms.
Timepoint [3] 335685 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [4] 335686 0
KOOS Function in Daily Living.

Scored from 17 questions regarding knee function in the last week. Ranges from 0 to 100; lower scores indicate worse function.
Timepoint [4] 335686 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [5] 335687 0
KOOS Function in Sport and Recreation.

Scored from 5 questions regarding knee function in the last week. Ranges from 0 to 100; lower scores indicate worse function.
Timepoint [5] 335687 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [6] 335688 0
KOOS Knee-related Quality of Life.

Scored from 4 questions regarding knee related quality of life in the last week. Ranges from 0 to 100; lower scores indicate worse quality of life.
Timepoint [6] 335688 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [7] 335689 0
Global change in pain.

Scored from a 7-point Likert scale from “much worse” to “much better” when compared to baseline. Those “moderately better” or “much better” will be classified as improved.
Timepoint [7] 335689 0
2 months and 12 months after baseline.
Secondary outcome [8] 335690 0
Global change in physical function.

Scored from a 7-point Likert scale from “much worse” to “much better” when compared to baseline. Those “moderately better” or “much better” will be classified as improved.
Timepoint [8] 335690 0
2 months and 12 months after baseline.
Secondary outcome [9] 335691 0
Global change overall.

Scored from a 7-point Likert scale from “much worse” to “much better” when compared to baseline. Those “moderately better” or “much better” will be classified as improved.
Timepoint [9] 335691 0
2 months and 12 months after baseline.
Secondary outcome [10] 335692 0
Quality of life (AQoL-8D).

Health-related quality of life evaluated with the 35-item Assessment of Quality of Life Instrument (8D version). Ranges from -0.04 to 1.00; higher scores indicate better quality of life.
Timepoint [10] 335692 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [11] 335693 0
Intermittent and Constant Osteoarthritis Pain (ICOAP) Constant knee pain.

Scored from 5-items regarding constant knee pain in the previous week. Ranges from 0 to 100; higher scores indicate worse pain.
Timepoint [11] 335693 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [12] 335694 0
ICOAP Intermittent knee pain.

Scored from 6-items regarding intermittent knee pain in the previous week. Ranges from 0 to 100; higher scores indicate worse pain.
Timepoint [12] 335694 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [13] 335695 0
Physical Activity Scale for the Elderly (PASE).

Physical activity levels in the last week will be assessed using the PASE. Ranges from 0 to 400+; higher scores indicate greater levels of physical activity.
Timepoint [13] 335695 0
Baseline plus 2 months and 12 months after baseline.
Secondary outcome [14] 335696 0
MRI Osteoarthritis Knee Score (MOAKS) Meniscal Morphology sub-score.

Any regions with worsening at 12 months compared to baseline. Yes or No.
Timepoint [14] 335696 0
12 months after baseline.
Secondary outcome [15] 335697 0
MOAKS Inter-Condylar Synovitis sub-score.

Worsening in inter-condylar synovitis at 12 months compared to baseline. Yes or No.
Timepoint [15] 335697 0
12 months after baseline.
Secondary outcome [16] 335698 0
MOAKS Cartilage Morphology sub-score.

Number of areas with worsening in thickness at 12 months compared to baseline: Categorised as 0, 1, 2, or 3+.
Timepoint [16] 335698 0
12 months after baseline.
Secondary outcome [17] 335699 0
MOAKS Whole Knee Effusion.

Change in Whole Knee Effusion at 12 months compared to baseline: Categorised as Worsened, No Change or Improved.
Timepoint [17] 335699 0
12 months after baseline.
Secondary outcome [18] 335700 0
Bone marrow lesions (BML) score in the medial tibiofemoral compartment.

Assessed from the MRIs using Categorical scoring (range 0-3 per region). Range 0-6. Medial tibia and medial femoral condyle region BML scores are added.
Timepoint [18] 335700 0
Baseline plus 12 months after baseline.
Secondary outcome [19] 335701 0
Cartilage defects score in the medial tibiofemoral compartment.

Assessed from the MRIs using Categorical scoring (range 0-4 per region). Range 0-8. Medial tibia and medial femoral condyle region cartilage defect scores are added.
Timepoint [19] 335701 0
Baseline plus 12 months after baseline.

Eligibility
Key inclusion criteria
1) aged greater than or equal to 50 years;
2) knee pain on most days in the last month;
3) tibiofemoral osteophytes on x-ray; and
4) A minimum pain score of 4 on an 11-point numeric rating scale for the last week.
Minimum age
50 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Kellgren and Lawrence (KL) grade 1 indicating questionable disease or grade 4 indicating severe disease;
2) predominant lateral tibiofemoral disease;
3) Hyaluronic acid injection in past 6 months, corticosteroid injection in past 3 months or autologous blood product in the past;
4) knee surgery on their most painful knee within past 12 months;
5) systemic or inflammatory joint disease;
6) history of crystalline or neuropathic arthropathy;
7) knee joint replacement or high tibial osteotomy on their most painful knee;
8) plan for joint surgery in next 12 months;
9) other muscular, joint or neurological condition affecting lower limb function;
10) needle phobia;
11) immunosuppression or acute infective processes;
12) cancer or other tumour-like lesions;
13) bleeding disorder or receiving anti-coagulation therapy;
14) presence of a warm tense joint effusion;
15) platelet count greater than or equal to 150,000/microlitre;
16) any other medical condition precluding participation in the study including contraindication to MRI such as pregnancy;
17) be unwilling to discontinue NSAID and other analgesic usage for knee pain, with the exception of paracetamol for rescue pain relief, from 2 weeks prior to baseline assessment until the 12 month follow up assessment;
18) Body mass index (BMI) >40kg/m2 because of problems fitting in to the MRI machine knee coil; and
19) Inability to understand written/spoken English.

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 will be concealed via the use of a central randomization service (NHMRC Clinical Trial Centre).

At each of the injecting sites, the research nurse will firstly withdraw blood from the participant’s arm. The research nurse will then contact the central service by telephone where group allocation will be revealed via an established automated service.

The research nurse will prepare all injections in a separate room, and a patient label will be placed over the syringe to occlude the contents. The nurse will then give the syringe to the injecting doctor who will not know or be able to tell whether the syringe contains PRP 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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will occur according to a 1: 1 allocation and will be stratified according to site (Melbourne or Sydney) and radiographic disease severity (Kellgren & Lawrence grades 2 or 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
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All participants will be included in the study in the group to which they were randomised. Analysis will be conducted by a biostatistician blinded to treatment group, with two-sided hypothesis tests and p-values < 0.05 significant. Missing data will be imputed using multiple imputation methodology, and sensitivity to the missing at random assumption will be investigated. Changes from baseline will be presented for each group at each time point using the mean change and 95% confidence intervals. For continuous outcomes (eg pain, cartilage volume, physical function), longitudinal analyses will be conducted, with differences in mean change (follow-up minus baseline) compared between the groups using mixed linear regression models with the baseline value, stratifying variables (KL grade and injecting doctor) and an interaction between month and treatment group as covariates, including random effects for participants. Models including baseline cartilage volume, age, gender, body mass index and bone size will also be fit. Appropriate transformations of outcome measures will be considered if needed to meet statistical assumptions (eg. linearity, normality and homogeneity of residuals) as assessed using diagnostic plots. Binary outcomes will be compared between groups using risk differences calculated after fitting longitudinal regression models for binary outcomes, adjusted for stratification variables and accounting for clustering of measurements within participants. The MRI-derived measurements (MOAKS, BML size and cartilage defects) will be compared between groups using appropriate models, adjusting for age, gender, BMI, and the stratifying variables of KL grade and injecting site (doctor). The model for cartilage defects will also be adjusted for bone area. If appropriate, the effect of PRP on primary outcomes under hypothetical full adherence to assigned treatment will be investigated. Success of blinding will be assessed using the James Blinding Index.

Sensitivity Analysis:
Due to a change in centrifuge speed from 3500RPM to 3300RPM (equivalent to 1500g with the study centrifuge) at the Melbourne site, implemented on the 7th of December 2017, we plan to do a sensitivity analysis excluding participants randomized and treated before this date. By the 7th of December 2017, 31 participants across the two recruitment sites had been randomized.

Recruitment
Recruitment status
Completed
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,VIC
Recruitment hospital [1] 8289 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 16349 0
3010 - University Of Melbourne
Recruitment postcode(s) [2] 16350 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 296669 0
Government body
Name [1] 296669 0
National Health and Medical Research Council
Address [1] 296669 0
GPO Box 1421
Canberra ACT 2601
Country [1] 296669 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Centre for Health Exercise and Sports Medicine
Department of Physiotherapy
School of Health Sciences
Level 7, Alan Gilbert Building
University of Melbourne VIC 3010
Country
Australia
Secondary sponsor category [1] 295628 0
None
Name [1] 295628 0
Address [1] 295628 0
Country [1] 295628 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297894 0
Northern Sydney Local health District Human Research Ethics Committee
Ethics committee address [1] 297894 0
Research Office
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 297894 0
Australia
Date submitted for ethics approval [1] 297894 0
27/10/2016
Approval date [1] 297894 0
27/03/2017
Ethics approval number [1] 297894 0
RESP/16/286

Summary
Brief summary
Knee osteoarthritis is a common condition that affects the cartilage lining of the knee joint and causes pain and stiffness. It is therefore important to find effective treatments that improve people’s symptoms and quality of life, and also slow down the loss of joint cartilage that happens in osteoarthritis. One such therapy that may be effective is platelet-rich plasma (PRP) injections. This treatment involves an injection of the person’s own PRP, which is made from blood taken from their arm and injected into their knee. Blood contains plasma, red blood cells, white blood cells and platelets that release chemicals which can stimulate the healing process. This may give rise to improvements in symptoms and slowing of the disease process.

This study aims to find out whether a series of three PRP injections (one per week for three weeks) into the knee joint is effective in reducing pain and slowing loss of cartilage in the knee joint. To do this, we will compare outcomes over 12 months in a group of patients with knee osteoarthritis who receive three PRP injections and a group who receive three injections of inactive sterile salt injections (saline).

We will recruit 288 people with mild to moderately severe knee osteoarthritis from the community. Measurements will be taken at baseline, 2 months and 12 months and will comprise questionnaires and magnetic resonance imaging. Participants will be randomly allocated to either the PRP or saline injection group and neither the participant, nor the injecting doctor or the assessor will know which injection the participant will receive.
Trial website
http://healthsciences.unimelb.edu.au/research-groups/physiotherapy-research/chesm/restore
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75390 0
Prof Kim Bennell
Address 75390 0
Centre for Health, Exercise & Sports Medicine
Department of Physiotherapy
School of Health Sciences
University of Melbourne, Vic, 3010
Country 75390 0
Australia
Phone 75390 0
+61383444135
Fax 75390 0
Email 75390 0
k.bennell@unimelb.edu.au
Contact person for public queries
Name 75391 0
Mr Ben Metcalf
Address 75391 0
Centre for Health, Exercise & Sports Medicine
Department of Physiotherapy
School of Health Sciences
University of Melbourne, Vic, 3010
Country 75391 0
Australia
Phone 75391 0
+61383448127
Fax 75391 0
Email 75391 0
b.metcalf@unimelb.edu.au
Contact person for scientific queries
Name 75392 0
Prof Kim Bennell
Address 75392 0
Centre for Health, Exercise & Sports Medicine
Department of Physiotherapy
School of Health Sciences
University of Melbourne, Vic, 3010
Country 75392 0
Australia
Phone 75392 0
+61383444135
Fax 75392 0
Email 75392 0
k.bennell@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary