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PRIMA trial


- candidate number28992
- NTR NumberNTR7261
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR6-jun-2018
- Secondary IDsABR: NL64160.018.18 
- Public TitlePRIMA trial
- Scientific TitlePlatelet Rich plasma Injection Management for Ankle osteoarthritis study (PRIMA): A multi-center, stratified, block-randomized, double-blind, placebo-controlled trial
- ACRONYMPRIMA
- hypothesisPRP injections are efficacious for symptom reduction and functional improvement compared to placebo injections in the treatment of ankle (talocrural) OA.
- Healt Condition(s) or Problem(s) studiedAnkle, Osteoarthritis
- Inclusion criteria1. Severity of Ankle OA pain on a visual analogue scale (VAS) (0–100 mm) ≥ 40 during daily activities
2. X-rays (AP and lateral view) indicating ≥ grade 2 on the Van Dijk classification[10]
3. Age ≥ 18 years
- Exclusion criteria1. Patient has received injection therapy for ankle OA in the previous 6 months
2. Patient does not want to receive one of the two therapies
3. Patient has clinical signs of concomitant OA of one or more other major joints of the lower extremities that negatively affects their daily activity level
4. Previous ankle surgery for OA or Osteochondral defects (OCD) < 1 year (not including surgery for an ankle fracture in the past)
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingDouble
- controlPlacebo
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-jun-2018
- planned closingdate1-jun-2024
- Target number of participants100
- InterventionsIntra-articular injections of the ankle:
Platelet rich plasma vs Placebo (saline)
- Primary outcomeAmerican Orthopaedic Foot and Ankle Society (AOFAS) score at 26 weeks follow-up,
- Secondary outcome1. Pain scores: (VAS 0-100) during activities of daily living and the pain sub-scale of AOFAS (0-40)
2. Ankle activity score (0-10)
3. Subjective patient satisfaction (4 categories)
4. Health related quality of life (SF-36 scale)
5. The Global Attainment Scaling (GAS)
6. EQ-5D-3L utility score
- TimepointsInclusion: PRP or Saline Injection Proms (AOFAS, VAS, AAS, Subjective patient satisfaction, SF-36, GAS, EQ-5D-3L) PRODISQ, physical examination

6 weeks: PRP or Saline Injection Proms (AOFAS, VAS, AAS, Subjective patient satisfaction, SF-36, GAS, EQ-5D-3L), physical examination

12 weeks: Proms (AOFAS, VAS, AAS, Subjective patient satisfaction, SF-36, GAS, EQ-5D-3L) PRODISQ

26 weeks: Proms (AOFAS, VAS, AAS, Subjective patient satisfaction, SF-36, GAS, EQ-5D-3L) PRODISQ, physical examination

39 weeks: PRODISQ

52 weeks:Proms (AOFAS, VAS, AAS, Subjective patient satisfaction, SF-36, GAS, EQ-5D-3L) PRODISQ

5 years: Proms (AOFAS, VAS, AAS, Subjective patient satisfaction, SF-36, GAS, EQ-5D-3L)

Statistical Analysis
A standard operating procedure will available to logically recode and clean the data. In the event of missing data, we will include multiple imputation for missed data.
All analyses will be performed by an independent statistician, who will be blinded to the allocation. Intervention and placebo group will be coded (allocation will not be revealed at this stage). After final statistical analysis, disclosure and reviewing of the coded results, the authors reached consensus on the interpretation of the results. After unblinding (de-coding of the groups), no changes will be applied to the interpretation of the results. Baseline characteristics will be analyzed between groups using descriptive statistics.

Analysis will be performed using an intention to treat approach.
To test for the effect of treatment on the between-group difference in primary outcome, we will use the repeated measurement general linear model. Changes from baseline to all follow-up time points will be included in the model. Adjustments will be made for those baseline variables that influenced the primary outcome with p < 0.10.

To test for the effect of treatment on the between-group difference in the secondary outcomes, we will use the repeated measurement general linear model. Changes from baseline to all follow-up time points will be included in the model.

In the event of a positive significant outcome, an economic analysis is needed to support a possible change of practice. An economic analysis (costs) will be performed in order to determine cost-effectiveness. Consequently, the amount of symptom reduction may be related to cost-effectivity of PRP injection treatment. The analysis will be based on indirect costs and direct costs and will be determined using the PRODISQ questionnaire. The PRODISQ questionnaire is taken at baseline and every 3 months thereafter up until 1 year. The cost-effectivity analysis occurs at 1 year.
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIESMD L.D.A. Paget
- CONTACT for SCIENTIFIC QUERIESMD L.D.A. Paget
- Sponsor/Initiator Academic Medical Center (AMC), Amsterdam
- Funding
(Source(s) of Monetary or Material Support)
Dutch Arthritis Association (Reumafonds)
- PublicationsChronic achilles tendinopathy by de Vos et al. JAMA 2010 (PRICT-study, registration NTR1420, ABR NL 22805.098.08).

Acute hamstring injuries by Reurink et al. NEJM 2014 (HIT-study registration NTR2771, NL34660.098.10 / 10-163; ABR / METC Zuidwest Holland).[
- Brief summarySummary
Pain is the cardinal symptom of ankle osteoarthritis (OA) and is a complex phenomenon with limited understanding of its pathomechanisms. The main objectives in the clinical management of OA are to reduce inflammation and cartilage degeneration processes as well as relieve pain. Platelet-rich plasma (PRP) is a high concentrate of platelets derived from patient’s whole blood, centrifuged to remove red blood cells. PRP has been used to encourage a healing response across several specialties, in particular dentistry, orthopaedics and dermatology. Growth factors stored in the platelets are assumed to facilitate an anti-inflammatory and analgesic effect.
A recent review concluded that in animal models PRP can diminish multiple inflammatory IL-1 mediated effects, and can also positively influence the collagen network of the cartilage and subsequently reduce pain and improve function.

Our recent and other systematic reviews showed that compared to placebo injections, hyaluronic acid or corticosteroid injections, PRP injections significantly decrease pain and improve function in knee OA patients. Given the clinical effect on pain reduction in knee OA and safety, PRP might serve as a promising non-surgical therapy for ankle OA. PRP might potentially delay the irreversible surgical options like arthrodesis and joint replacement. No significant adverse advents have been reported for any PRP trials regarding acute hamstring injuries, Achilles tendinopathy, knee OA and specifically not ankle OA. Until present, there is no RCT conducted on the efficacy of PRP in the management of ankle OA.

Hypothesis
We hypothesize that:
PRP injections are efficacious for symptom reduction and functional improvement compared to placebo injections in the treatment of ankle (talocrural) OA.

Workplan
Study design
A multi‐center, stratified, block‐randomized, double‐blind, placebo‐controlled trial comparing two treatment groups.

Study population
Patients with ankle (talocrural) OA will be included if they meet the following 3 inclusion criteria:
1. Severity of Ankle OA pain on visual analogue scale (VAS) (0–100 mm) ≥ 40 during daily activities
2. X-rays (AP and lateral view) indicating ≥ grade 2 on the Van Dijk classification
3. Age ≥ 18 years

Intervention
Patients will be randomised into two treatment groups: PRP injection or placebo (saline) injection. Both groups will receive two injections of PRP or placebo at an interval of 6 weeks.

Main study parameter/endpoint
American Orthopaedic Foot and Ankle Society (AOFAS) score at 26 weeks follow-up, validated scale for ankle OA (0-100) measuring three subdomains (pain, function and alignment).
After 26 weeks, the principal investigator will be unblinded after the analysis of the primary outcome. The patients will remain blinded to the therapy until 52 weeks follow-up.
Power analysis Based on previous and ongoing studies, the study protocol of the randomised controlled trial is designed to detect a difference of 12 points (0-100) on the AOFAS score (minimal clinical relevant difference) between the groups. Based on a previous placebo controlled RCT on injection therapy (hyaluronic acid) in ankle OA of DeGroot et al. a standard deviation of 16.3 can be expected. Taking into account a two-sided level of significance of 5%, a power of 90% and a dropout rate of 15%, approximately 50 (40 plus 15%) patients per group will be needed (N=100).

STATISTICAL ANALYSIS
To test for the effect of treatment on the between-group difference in primary outcome, we will use a repeated measurements general linear model. The effect of potential confounders (varus/valgus) will be evaluated and a correction will be performed.

Expected results
We will provide evidence for the (potential) efficacy of PRP for symptom reduction and functional improvement in the treatment of ankle OA. A positive outcome will have an effect on the economical and disease burden. The relatively simple content and widespread availability of the PRP intervention and previously reported good safety will contribute to simple and optimal nationwide implementation.

Conclusion
Our project will provide conclusions on the efficacy of PRP in ankle OA.
- Main changes (audit trail)
- RECORD6-jun-2018 - 20-jun-2018


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