Call to action: RIAT restoration of a misreported clinical trial on Plasma Rich in Growth Factors
We write to issue a call to action to restore the reporting of a randomized clinical trial on Plasma Rich in Growth Factors (PRGF-Endoret®) sponsored by BTI Biotechnology Institute. The concerned trial has been cited as follows:
Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A randomized Clinical trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-8.
This high impact publication, totaling 167 citations as of March 25th, 2019 according to Scopus (https://www.scopus.com), reports the results of a clinical trial of PRGF-Endoret® compared to hyaluronic acid that enrolled 176 patients with knee osteoarthritis. Furthermore, this study was highly influential to the Spanish Medicines Agency (AEMPS) since platelet-rich plasma and derivatives were granted the human medicine category last May 2013 based on the results of the above-mentioned trial.
However, according to the pre-planned authorized protocol, this trial publication has misreported several key methodological issues, which substantially affects the final results and conclusions, and thereby correction of the record is warranted.
We intend to restore the written record for this trial in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative (1).
Our rationale for correcting the record
According to the study protocol (page 5), the primary efficacy outcome is set up as a significant clinical improvement in the pain Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) subscale. In addition, in Section 6.2.3 (page 20) a ‘significant clinical improvement’ is defined as a minimum of 40% decrease in the pain WOMAC subscale compared to the basal estimate (2). The study final report is coherent with the protocol on this issue (page 11) and does not find statistically significant differences between both interventions (pages 15 and 18). However, the corresponding publication (3) does not report the 40% decrease in the pain WOMAC subscale but the 50% decrease in the pain WOMAC subscale. Assuming this new outcome, statistically significant differences were found and publicly reported.
Also, results from several pre-planned secondary outcomes [>40% decrease in pain Visual Analogue Scale (VAS) and Lequesne scales, level of articular mobility (pages 28-29)] are presented in the study final report (pages 21, 24, 34) but not in the published article. Other pre-planned secondary outcomes [≥30% increase in physical function measured by Lequesne and WOMAC scales, quality of life, markers and indicators as C - reactive protein, metalloproteinases, etc. (pages 28-29)] are not provided in the final report or in the publication. Finally, the publication informs about some secondary outcomes, not previously included in the protocol as pre-planned outcomes: Outcome Measures In Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, 20% decrease in WOMAC pain score, percentage of change in the score of WOMAC subscales and global scale, percentage of change in Lequesne scale) (3).
On the other hand, in the ‘Results analysis’ section of the protocol (page 41) it is defined that a per-protocol analysis will be carried out. The study final report is also coherent with the protocol on this issue. However, the corresponding publication reports an intention-to-treat analysis instead of a per-protocol analysis (3).
Some other non-justified minor incoherencies have also been identified between the protocol and the final publication, namely the age range for elegibility, Body Mass Index (BMI) inclusion criteria and sample size calculation. Finally, the publication states that ‘all adverse events disappeared in 48 hours’ but, according to Table 4, it appears to be at least two patients in the hyaluronic arm and five patients in the PRGF arm with persistent adverse events (3).
No evidence of any significant amendment to the protocol has been proved to justify these methodological changes.
The authors report in the publication that they have no conflicts of interest in the authorship and publication of this article. However one of the authors is the Scientific Director of the BTI Biotechnology Institute, manufacturer of the PRGF-Endoret®, and others are employees of the company (3). In our view this is a strong conflict of interest that needs to be declared.
Scope of our restoration
Given the important differences between the final report and the publication in terms of interpretation and conclusions, a thorough correction should be done using the pre-specified primary and secondary outcomes, as well as the original per-protocol analysis. Potential conflicts of interest of the authors should also be stated. Any other detected incoherence should also be dealt with. In a second stage, this restoration should lead to revise in-depth other publications directly affected by this misreported trial, such as a meta-analysis published by the same research team (4).
Our sources
Our background material include the trial protocol, study final report and ethics committee approval letter, all of them facilitated by the study contact author on January 14th, 2019. We will conduct a RIAT re-analysis in adherence to the original protocol and the results included in the study final report.
Questions our restoration aims to answer
1. What is the efficacy of PRGF versus hyaluronic acid in the primary outcome preespecified in the protocol according to the data in the original final report?
2. What is the efficacy of PRGF versus hyaluronic acid in the secondary outcomes preespecified in the protocol according to the data in the original final report?
3. What are the results on the primary and secondary outcomes according to a per-protocol analysis instead of an intention-to-treat analysis?
4. What other kind of incoherencies between protocol, final report and publication need to be corrected in the publication to gain in accuracy? After restoring the Methods and Results sections, how should be re-written the Abstract, Discussion and Conclusions sections?
References
1. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ. 2013 Jun 13;346:f2865.
2. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of Clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis and Cartilage 1996;4:217-43.
3. Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A randomized Clinical trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-8.
4. Anitua E, Sánchez M, Aguirre JJ, Prado R, Padilla S, Orive G. Efficacy and safety of Plasma Rich in Growth Factors intra-articular infiltrations in the treatment of knee osteoarthritis. Arthroscopy 2014;30(8):1006-17.
Competing interests:
No competing interests
27 March 2019
Luis Carlos Saiz
Researcher
Juan Erviti, Leire Leache. Unit of Innovation and Organization, Navarre Health Service
Unit of Innovation and Organization, Navarre Health Service
Rapid Response:
Call to action: RIAT restoration of a misreported clinical trial on Plasma Rich in Growth Factors
We write to issue a call to action to restore the reporting of a randomized clinical trial on Plasma Rich in Growth Factors (PRGF-Endoret®) sponsored by BTI Biotechnology Institute. The concerned trial has been cited as follows:
Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A randomized Clinical trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-8.
This high impact publication, totaling 167 citations as of March 25th, 2019 according to Scopus (https://www.scopus.com), reports the results of a clinical trial of PRGF-Endoret® compared to hyaluronic acid that enrolled 176 patients with knee osteoarthritis. Furthermore, this study was highly influential to the Spanish Medicines Agency (AEMPS) since platelet-rich plasma and derivatives were granted the human medicine category last May 2013 based on the results of the above-mentioned trial.
However, according to the pre-planned authorized protocol, this trial publication has misreported several key methodological issues, which substantially affects the final results and conclusions, and thereby correction of the record is warranted.
We intend to restore the written record for this trial in accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative (1).
Our rationale for correcting the record
According to the study protocol (page 5), the primary efficacy outcome is set up as a significant clinical improvement in the pain Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) subscale. In addition, in Section 6.2.3 (page 20) a ‘significant clinical improvement’ is defined as a minimum of 40% decrease in the pain WOMAC subscale compared to the basal estimate (2). The study final report is coherent with the protocol on this issue (page 11) and does not find statistically significant differences between both interventions (pages 15 and 18). However, the corresponding publication (3) does not report the 40% decrease in the pain WOMAC subscale but the 50% decrease in the pain WOMAC subscale. Assuming this new outcome, statistically significant differences were found and publicly reported.
Also, results from several pre-planned secondary outcomes [>40% decrease in pain Visual Analogue Scale (VAS) and Lequesne scales, level of articular mobility (pages 28-29)] are presented in the study final report (pages 21, 24, 34) but not in the published article. Other pre-planned secondary outcomes [≥30% increase in physical function measured by Lequesne and WOMAC scales, quality of life, markers and indicators as C - reactive protein, metalloproteinases, etc. (pages 28-29)] are not provided in the final report or in the publication. Finally, the publication informs about some secondary outcomes, not previously included in the protocol as pre-planned outcomes: Outcome Measures In Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, 20% decrease in WOMAC pain score, percentage of change in the score of WOMAC subscales and global scale, percentage of change in Lequesne scale) (3).
On the other hand, in the ‘Results analysis’ section of the protocol (page 41) it is defined that a per-protocol analysis will be carried out. The study final report is also coherent with the protocol on this issue. However, the corresponding publication reports an intention-to-treat analysis instead of a per-protocol analysis (3).
Some other non-justified minor incoherencies have also been identified between the protocol and the final publication, namely the age range for elegibility, Body Mass Index (BMI) inclusion criteria and sample size calculation. Finally, the publication states that ‘all adverse events disappeared in 48 hours’ but, according to Table 4, it appears to be at least two patients in the hyaluronic arm and five patients in the PRGF arm with persistent adverse events (3).
No evidence of any significant amendment to the protocol has been proved to justify these methodological changes.
The authors report in the publication that they have no conflicts of interest in the authorship and publication of this article. However one of the authors is the Scientific Director of the BTI Biotechnology Institute, manufacturer of the PRGF-Endoret®, and others are employees of the company (3). In our view this is a strong conflict of interest that needs to be declared.
Scope of our restoration
Given the important differences between the final report and the publication in terms of interpretation and conclusions, a thorough correction should be done using the pre-specified primary and secondary outcomes, as well as the original per-protocol analysis. Potential conflicts of interest of the authors should also be stated. Any other detected incoherence should also be dealt with. In a second stage, this restoration should lead to revise in-depth other publications directly affected by this misreported trial, such as a meta-analysis published by the same research team (4).
Our sources
Our background material include the trial protocol, study final report and ethics committee approval letter, all of them facilitated by the study contact author on January 14th, 2019. We will conduct a RIAT re-analysis in adherence to the original protocol and the results included in the study final report.
Questions our restoration aims to answer
1. What is the efficacy of PRGF versus hyaluronic acid in the primary outcome preespecified in the protocol according to the data in the original final report?
2. What is the efficacy of PRGF versus hyaluronic acid in the secondary outcomes preespecified in the protocol according to the data in the original final report?
3. What are the results on the primary and secondary outcomes according to a per-protocol analysis instead of an intention-to-treat analysis?
4. What other kind of incoherencies between protocol, final report and publication need to be corrected in the publication to gain in accuracy? After restoring the Methods and Results sections, how should be re-written the Abstract, Discussion and Conclusions sections?
References
1. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ. 2013 Jun 13;346:f2865.
2. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of Clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis and Cartilage 1996;4:217-43.
3. Sánchez M, Fiz N, Azofra J, Usabiaga J, Aduriz Recalde E, Garcia Gutierrez A, Albillos J, Gárate R, Aguirre JJ, Padilla S, Orive G, Anitua E. A randomized Clinical trial evaluating Plasma Rich in Growth Factors (PRGF-Endoret) versus hyaluronic acid in the short-term treatment of symptomatic knee osteoarthritis. Arthroscopy 2012;28(8):1070-8.
4. Anitua E, Sánchez M, Aguirre JJ, Prado R, Padilla S, Orive G. Efficacy and safety of Plasma Rich in Growth Factors intra-articular infiltrations in the treatment of knee osteoarthritis. Arthroscopy 2014;30(8):1006-17.
Competing interests: No competing interests