Abstract
Introduction
Cancer is an important outcome in kidney transplantation, but the scope and consistency of how cancer is defined and reported in trials involving kidney transplant recipients has not been evaluated. This study aimed to assess the range and variability of cancer outcomes in trials involving kidney transplant recipients.
Methods
The ClinicalTrials.gov database was searched from February 2000 to July 2021 to identify all randomized controlled trials (RCTs) in adult kidney transplant recipients, and which included cancer as a specified outcome. The definition of cancer, types of cancer (if any), timepoint(s) of measurement and method of aggregation were extracted for each cancer outcome.
Results
Of the 819 trials in kidney transplantation, only 84 (10%) included 1 or more cancer outcomes. Of these, 72 of 84 (86%) trials included cancer as a secondary outcome and 12 of 84 (14%) considered cancer as a primary outcome. The most frequent description of cancer was “malignancy” (n = 44, 43%), without reference to diagnostic criteria, histology, grade, or stage. The 2 most common cancer types were posttransplant lymphoproliferative disorder (PTLD) (n = 20, 20%) and nonmelanoma skin cancer (n = 10, 10%). Several methods of aggregation were identified, including incidence or rate (n = 47, 46%), frequency or proportion (n = 30, 29%), and time to event (n = 5, 5%). Approximately half the cancer outcomes were measured at a single time point (n = 44, 52%).
Conclusion
Cancer is an infrequently reported outcome and is inconsistently defined in trials of kidney transplant recipients. Consistent reporting of cancer outcomes using standardized definitions would provide important information on the impact of cancer in patients after kidney transplantation.
Keywords: cancer, kidney transplant, outcomes, randomized controlled trials
Graphical abstract
Cancer is one of the most important outcomes for patients and health care professionals after kidney transplantation.1 Kidney transplant recipients experience up to 4-fold higher risk of developing cancer, and more than double the risk of mortality because of cancer compared with the age-matched and sex-matched general population.2,3 Cancer is now the leading cause of death among kidney transplant recipients, surpassing cardiovascular disease.4 This increased risk of cancer in kidney transplant recipients is due to a range of factors, including improved graft and overall survival after transplantation, the untoward effects of long-term immunosuppressive medications, and oncogenic viruses.2 Immunosuppressive medications such as azathioprine and cyclosporin have direct effects on impairing DNA repair and can activate oncogenic pathways.5 Kidney transplant recipients have also been found to have reduced tumor surveillance because of the effects of long-term suppression of the immune system.6,7
Trials to reduce the burden of cancer in solid organ transplant recipients are infrequent and transplant recipients are often excluded from contemporary cancer treatment trials, thereby limiting access to therapies.2,8,9 The Standardized Outcomes in Nephrology-Transplantation study has identified cancer to be one of the 6 core outcomes for trials involving kidney transplant recipients, together with graft health, cardiovascular disease, infection, life participation, and mortality.10 A previous systematic review of outcomes reported in clinical trials involving kidney transplant recipients has shown a wide range of different outcome measures and inconsistencies in the measurement and reporting of outcomes.11 Currently, there is no standardized outcome measure for cancer that is used in trials involving patients with a kidney transplant. A standardized outcome measure can ensure consistent outcome measurement and reporting in trials and ensure that outcomes measured are meaningful and important to patients, clinicians, and other stakeholders.12 This study aims to assess the range and variability of all cancer outcomes reported in randomized trials involving kidney transplant recipients.
Methods
Search Strategy, Inclusion and Exclusion Criteria
The ClinicalTrials.gov database was searched from February 29, 2000 to July 12, 2021 to identify eligible trials, using the search terms “kidney,” “renal,” “transplant,” and “transplantation” and the filter for interventional trials. The full text of the record for each potentially eligible trial was reviewed and included if it was an RCT of an intervention involving kidney transplant recipients (including combined organ transplantation), and 1 or more cancer outcomes were included as a primary, secondary, or tertiary outcome of the trial. Trials which focus on pediatric patients (aged <18 years) were excluded, because these trials may have different characteristics and outcomes to trials involving adult patients. All trials, irrespective of their publication and completion status, were included.
Data Extraction and Analysis
For each included trial, data on trial characteristics and cancer outcome(s) were extracted and recorded using the ClinicalTrials.gov record. The trial characteristics extracted included trial registration date, start date, completion date, number of participants (planned or actual), country or region(s), age of participants, interventions, study design, duration of trial, and primary trial outcome(s). For each cancer outcome, the details extracted included the definition of cancer, whether cancer was considered as a primary or secondary or tertiary outcome, description and/or classification of cancer, type(s) of cancer, timepoint of measurement, and method of aggregation. The method of aggregation as originally defined in the trial registration was recorded. The characteristics of trials and cancer outcomes were summarized descriptively as number and proportions for categorical data; and mean and SD for continuous data.
Results
A total of 1506 studies were identified from ClinicalTrials.gov from February 29, 2000 to July 12, 2021 (Figure 1). Of these, 184 studies were excluded because they did not involve kidney transplant recipients, 476 were not RCTs, and 27 were RCTs with a pediatric population. A total of 819 trials involving adult kidney transplant recipients were identified. Of these, cancer was specified as a primary or secondary outcome in 84 (10%). Cancer was considered as the primary outcome in 12 (14%) trials, and secondary outcome in 72 (86%) trials.
Figure 1.
Studies included and excluded in systematic review. RCT, randomized controlled trial.
Trial Characteristics
The characteristics of the 84 trials which included 1 or more cancer outcomes are presented in Table 1. Approximately 40% of these trials were registered between 2006 and 2010 (37, 44%), with fewer trials including a cancer outcome in more recent years. Most trials (63, 75%) were performed in a single country, with the United States (25, 30%), France (11, 13%) and United Kingdom (5, 6%) being the most common.
Table 1.
Characteristics of trials which included a cancer outcome (n = 84)
| Trial characteristic | Number of trials (n, %) |
|---|---|
| Yr of trial registration | |
| 2001–2005 | 13 (15) |
| 2006–2010 | 37 (44) |
| 2011–2015 | 18 (21) |
| 2016–2021 | 16 (19) |
| Country | |
| Single country | |
| United States | 25 (30) |
| France | 11 (13) |
| United Kingdom | 5 (6) |
| Canada | 4 (5) |
| Brazil | 3 (4) |
| Germany | 2 (2) |
| Netherlands | 2 (2) |
| Sweden | 2 (2) |
| Switzerland | 2 (2) |
| Othersa | 7 (8) |
| Multiple countries | 12 (14) |
| Not specified | 9 (11) |
| Transplant population | |
| First kidney transplant only | 29 (35) |
| First or second kidney transplant | 16 (19) |
| Any kidney transplant | 34 (40) |
| Simultaneous kidney-pancreas transplant | 3 (4) |
| Not specified | 2 (2) |
| Intervention type | |
| Immunosuppression | |
| Induction/early posttransplant | 50 (60) |
| Maintenance | 16 (19) |
| Changes in immunosuppression in specific conditions (e.g., cancer) | 6 (7) |
| Treatment of rejection | 2 (2) |
| Other | 10 (12) |
| Number of participants enrolled (actual or planned) | |
| 1–50 | 17 (20) |
| 51–100 | 18 (21) |
| 101–150 | 11 (13) |
| 151–200 | 13 (15) |
| >200 | 25 (30) |
| Trial duration | |
| ≤6 mo | 13 (15) |
| >6–12 mo | 29 (35) |
| >12–24 mo | 27 (32) |
| >24–60 mo | 13 (15) |
| >60 mo | 1 (1) |
| Not specified | 1 (1) |
Others included one trial from each of Australia, Austria, Belgium, Italy, Japan, Spain, Taiwan.
Immunosuppressive therapy was the most common type of intervention in the included trials (74, 88%), with the majority (50, 60%) being trials of induction therapy or early posttransplant immunosuppression. Of the 12 trials with a primary cancer outcome, 7 trials compared the effects of sirolimus to calcineurin-based immunosuppression on graft and patient outcomes, 3 trials were of new experimental treatments, 1 trial compared high dose versus low dose vitamin D supplementation and 1 trial involved nicotinamide. Seven of these trials primarily assessed the effect of the intervention on skin cancer. No study investigated the effect of immunotherapy in kidney transplant recipients. The duration of included trials ranged from less than 6 months to more than 60 months. Most of the trials had a follow-up duration of between 6 months and 12 months (29, 35%) or 12 months and 24 months (27, 32%).
Cancer Outcomes
Cancer outcomes were included a total of 102 times in the 84 included trials as follows: 10 times (10%) as a primary trial outcome, 2 times (2%) as part of a composite primary outcome and 90 times (88%) as a secondary trial outcome. There were a total of 72 different cancer outcome measures, assessed at 20 distinct timepoints. Seven trials included more than 1 cancer outcome.
Definition of Cancer and Cancer Types
Most of the included trials (n = 63, 62%) did not define cancer with reference to diagnostic criteria, cancer type, histology, grade, or cancer stage (Figure 2). The most common description of cancer was “malignancy” or “malignancies” (n = 44, 43%) and “cancer/s” without further specification (n = 12, 11%). Six (6%) trials specified that the diagnosis of cancer required histologic confirmation. Only 1 (1%) study included cancer related death as a trial outcome. This was a study evaluating the effect of sirolimus versus calcineurin inhibitor (cyclosporin or tacrolimus) on nonmelanoma skin cancer in kidney transplant recipients, where death because of nonmelanoma skin cancer was the primary outcome of the trial (NCT00129961).13
Figure 2.
Definitions of cancer.
Of all reported cancer outcomes, 42 (41%) cancer outcomes included mention of 1 or more specific cancer types (Figure 3). This included 14 (14 %) cancer outcomes that encompassed cancer broadly but also included specific mention of certain cancer types, such as “malignancies (including PTLD).” There was no specific mention of cancer types in 56 (55 %) cancer outcomes. The most common cancer types included PTLD (n = 20, 20%) and skin cancer, such as nonmelanoma skin cancer (n = 10, 10%) and squamous cell carcinoma (n = 3, 3%). Nonskin cancers (without further specification) were included in 4 (4%) of cancer outcomes. Melanoma and “solid organ cancer” were each included in 1 cancer outcome (1%) respectively.
Figure 3.
Cancer types specifically included in outcome (n = 102 cancer outcomes).
Method of Aggregation
A range of aggregation methods were used for cancer in the trials identified (Figure 4). A method of aggregation was specified in n = 84 (82%) (Figure 4). The most common method was cancer incidence or rate (47, 46%) and the number or proportion of study participants diagnosed with cancer (30, 29%). Time to event (cancer event) was specified in 5 (5%) cancer outcomes. The cumulative frequency, cumulative incidence, and relative risk of cancer were each used as the method of aggregation in 1 trial respectively.
Figure 4.
Methods of aggregation (n = 102 cancer outcomes).
Timepoint of Measurement
Twenty different distinct timepoints were used for assessing cancer in trials involving kidney transplant recipients (Figure 5). More than half of all trials (n = 44, 52%) reported cancer at only a single timepoint. Eighteen (21%) trials included measurement of cancer at multiple timepoints during the trial. Fifteen (18%) trials specified assessment of the cancer outcome over a defined time period (e.g., up to a certain timepoint or between predetermined timepoints). The most common timepoints were at 12 months (n = 36, 43%) and 2 years (n = 28, 33%) from the start of randomization.
Figure 5.
Timepoints of measurement (n = 84 trials).
Discussion
In this study of 819 randomized trial protocols involving kidney transplant recipients published in ClinicalTrials.gov over the past 20 years, cancer outcomes were identified in only 10%. Cancer outcomes were poorly defined and were highly variable, with over 70 different cancer definitions measured at 20 different timepoints. Most cancer outcomes did not make any specific reference to diagnostic criteria, histology, grade, or cancer stage. In studies where cancer type was included in the outcome, the most common cancer types were PTLD and nonmelanoma skin cancers. Six different methods of aggregation were used for cancer, with more than half of all cancer outcomes measured at a single timepoint at the end of each study. This study demonstrates the lack of a clear and well-defined cancer outcome in trials of kidney transplant recipients, with great variability in the types of cancer measured, timepoints of measurement, and methods of aggregation.
Cancer is a critically important outcome in patients after kidney transplantation.1,10 It is the most common cause of death in kidney transplant recipients, and affects up to 10% of kidney transplant recipients at 10 years after kidney transplantation.3,4 In the Standardized Outcomes in Nephrology-Transplantation study, cancer was rated among the top 5 outcome domains for trials on kidney transplant recipients for both patients or caregivers and health professionals through a 3-round Delphi survey and consensus workshops.10,14 Given the prevalence of cancer in the kidney transplant population and the critical importance of this outcome to patients, clinicians, and other stakeholders, the accurate assessment and recording of cancer in clinical trials is important to ensure that all cancer events are measured and reported in trials of kidney transplant recipients. Despite the devastating impacts of cancer in patients after kidney transplantation, this study found that over a 20-year period, only 12 trials had been planned or conducted to evaluate an intervention where cancer was a primary outcome of the trial, with most of these studies evaluating interventions for skin cancers. More research is sorely needed to assess possible interventions to reduce the burden of cancer in this at-risk population, including interventions such as cancer screening, specific therapies to reduce the risk of cancers, and cancer-specific treatment strategies in kidney transplant recipients who develop cancers.
Conducting clinical trials with cancer as a primary outcome in kidney transplant recipients can be challenging. Apart from skin cancer, most cancers generally develop over a period of years. Therefore, trials need to be of sufficient duration to allow cancer events to be observed. Solid organ cancers such as colorectal cancer and lung cancer are uncommon diseases, with relatively low rates of cancer events compared with other outcomes such as graft failure and overall mortality.3 For example, the overall incidence of all solid organ cancers is approximately 5% in kidney transplant recipients in the first 5 years posttransplant, with incidence rates of 174 per 100,000 patient-years for colorectal cancer and 202 per 100,000 patient-years for lung cancer. The low absolute rate of any individual cancer type in kidney transplant recipients can therefore create difficulties in designing an adequately powered clinical trial on cancer outcomes. Completed RCTs where cancer is a primary outcome have largely focused on interventions for reducing the incidence of skin cancers and in at-risk patients such as those with a prior history of nonmelanoma skin cancers.13,15 Future studies of cancer in kidney transplant recipients would therefore require consideration of novel trial designs, such as registry-based randomized trials where comprehensive data collection can occur over an extended period of time, and innovative ways to identify individuals at higher risk of developing cancer such as through risk stratification and risk prediction strategies.16
Despite the relatively short duration of trials involving kidney transplant recipients, several previous trials have revealed an association between immunosuppressive interventions and cancer as a secondary end point,17, 18, 19 highlighting the importance of accurate reporting of cancer outcomes in all clinical trials. In the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression (BENEFIT) Trial that compared a more intensive and a less intensive regimen of belatacept with cyclosporine in adult kidney transplant recipients, a higher rate of PTLD was found in transplant recipients who received belatacept. Similarly in the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT) trial, a higher incidence of PTLD was observed in extended criteria donor kidney transplant recipients who received belatacept-based immunosuppression, compared with transplant recipients who received cyclosporin-based immunosuppression.18 These studies highlight the importance of cancer outcome recording to capture the potential impact of interventions on the risk of cancer in kidney transplant recipients, even when cancer is not the intended primary outcome of the trial. Therefore, a well-defined, standardized cancer outcome for trials in kidney transplantation is important to ensure that the impact of interventions such as new immunosuppressive regimens on cancer risk are reported, even when cancer may not be an intended outcome of the trial intervention.
This study found great heterogeneity in the assessment of cancer in current clinical trials of kidney transplant recipients, with poor definition of cancer and variability in cancer types, timepoints of measurement, and methods of aggregation. In the CONsolidated Standards of Reporting Trials (CONSORT) 2010 statement on the transparent reporting of RCTs, it is recommended that all primary and secondary outcome measures be prespecified and completely defined, including the timepoints of measurement and method of assessment.20 The World Health Organization Trial Registration Data Set also requires as a minimum the specification of key elements of primary and secondary outcome measures, including the name of the outcome, specific outcome metrics, and the timepoints of interest.21 Clear and detailed specification of outcome measures before commencement of a clinical trial ensures that important trials outcomes are measured consistently and are comparable between trials, and encourages the complete and transparent reporting of trial findings.20,21 This is particularly important for cancer in trials of kidney transplant recipients because the relatively short duration of 6 months to 24 months in most RCTs of kidney transplant recipients may result in only small numbers of cancer events in each individual clinical trial. It is possible that the lack of cancer outcome specification and measurement in some of the included trial registrations may be due to the short duration (<6 months) of some trials, and trials of surgical and perioperative interventions such as surgical or anesthetic techniques, which are unlikely to have effects on longer term outcomes such as cancer. Nonetheless, the assessment and reporting of cancer in trials of immunosuppression and other interventions in kidney transplant recipients would ensure that the potential impact of these interventions on cancer risk in kidney transplant recipients can be accurately evaluated and reported. An ideal standardized cancer outcome measure should have a clear definition of cancer, with a specific outcome metric measured at predetermined timepoint(s) and should be consistently assessed and reported in all trials of kidney transplant recipients. This would enable comparison and synthesis of results from multiple trials of similar interventions, such as through meta-analyses, and provide patients and clinicians with a better understanding of the impact of these interventions on cancer risk.
This study has several limitations. This study assessed cancer outcomes in clinical trials of kidney transplant recipients through reports of trial registration. Trial registration information may not fully reflect the actual conduct of a trial and the data that are collected and subsequently reported as part of these trials. Given the relatively few occurrences of cancer within the short duration of most clinical trials and the variability of reporting, we were not able to ascertain the range and variability of cancer outcome assessment in clinical trials through the evaluation of published papers, because relatively few published studies in kidney transplant recipients reported cancer events.11 This study was also limited to trial registrations recorded at ClinicalTrials.gov because of feasibility reasons and did not assess trials that were registered only through other trial registries, such as the European Union Clinical Trials Register and the Australian New Zealand Clinical Trials Registry, and trials that were not registered. This may have resulted in a small number of trials that were not included in this study.
In conclusion, despite cancer being a major cause of morbidity and mortality in kidney transplant recipients, few studies have been conducted to examine interventions on cancer outcomes in these patients. Furthermore, this study demonstrated the considerable variability in cancer outcomes in trials involving kidney transplant recipients. Consistent incorporation and reporting of cancer outcomes in clinical trials for kidney transplantation using standardized definitions would provide important information on the impact of cancer in patients after kidney transplantation.
Disclosure
KDJ is a consultant for Secretome, PMV Pharmaceuticals and Calliditas. He receives honoraria from the American Society of Nephrology, International Society of Nephrology and UpToDate.com. Christopher Blosser is a consultant for Natera, LLC. The authors have no other disclosures.
Acknowledgments
Funding
EHA is supported by an Australian National Health and Medical Research Council (NHMRC) Postgraduate Scholarship (APP1168606) and Royal Australasian College of Physicians Jacquot NHMRC Award for Excellence.
Author Contributions
Conception and design: EHA, GW, AT, JCC. Data acquisition: EHA. Data analysis: EHA. Data interpretation: all authors. Writing and editing of manuscript: all authors.
References
- 1.Howell M., Tong A., Wong G., Craig J.C., Howard K. Important outcomes for kidney transplant recipients: a nominal group and qualitative study. Am J Kidney Dis. 2012;60:186–196. doi: 10.1053/j.ajkd.2012.02.339. [DOI] [PubMed] [Google Scholar]
- 2.Au E., Wong G., Chapman J.R. Cancer in kidney transplant recipients. Nat Rev Nephrol. 2018;14:508–520. doi: 10.1038/s41581-018-0022-6. [DOI] [PubMed] [Google Scholar]
- 3.Au E.H., Chapman J.R., Craig J.C., et al. Overall and site-specific cancer mortality in patients on dialysis and after kidney transplant. J Am Soc Nephrol. 2019;30:471–480. doi: 10.1681/asn.2018090906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.42nd report, Chapter 3: Mortality in end stage kidney disease. Australia and New Zealand Dialysis and Transplant Registry. https://www.anzdata.org.au/wp-content/uploads/2019/09/c03_mortality_2018_ar_2019_v1.0_20191202.pdf
- 5.Guba M., Graeb C., Jauch K.W., Geissler E.K. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation. 2004;77:1777–1782. doi: 10.1097/01.tp.0000120181.89206.54. [DOI] [PubMed] [Google Scholar]
- 6.Morteau O., Blundell S., Chakera A., et al. Renal transplant immunosuppression impairs natural killer cell function in vitro and in vivo. PLoS One. 2010;5 doi: 10.1371/journal.pone.0013294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Peraldi M.N., Berrou J., Venot M., et al. Natural killer lymphocytes are dysfunctional in kidney transplant recipients on diagnosis of cancer. Transplantation. 2015;99:2422–2430. doi: 10.1097/tp.0000000000000792. [DOI] [PubMed] [Google Scholar]
- 8.Garon E.B., Rizvi N.A., Hui R., et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–2028. doi: 10.1056/NEJMoa1501824. [DOI] [PubMed] [Google Scholar]
- 9.Schmid P., Cortes J., Pusztai L., et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810–821. doi: 10.1056/NEJMoa1910549. [DOI] [PubMed] [Google Scholar]
- 10.Tong A., Gill J., Budde K., et al. Toward establishing core outcome domains for trials in kidney transplantation: report of the standardized outcomes in nephrology-kidney transplantation consensus workshops. Transplantation. 2017;101:1887–1896. doi: 10.1097/TP.0000000000001774. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Sautenet B., Tong A., Chapman J.R., et al. Range and consistency of outcomes reported in randomized trials conducted in kidney transplant recipients: a systematic review. Transplantation. 2018;102:2065–2071. doi: 10.1097/tp.0000000000002278. [DOI] [PubMed] [Google Scholar]
- 12.Clarke M. Standardising outcomes for clinical trials and systematic reviews. Trials. 2007;8:39. doi: 10.1186/1745-6215-8-39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Campbell S.B., Walker R., Tai S.S., Jiang Q., Russ G.R. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant. 2012;12:1146–1156. doi: 10.1111/j.1600-6143.2012.04004.x. [DOI] [PubMed] [Google Scholar]
- 14.Sautenet B., Tong A., Manera K.E., et al. Developing consensus-based priority outcome domains for trials in kidney transplantation: a multinational Delphi survey with patients, caregivers, and health professionals. Transplantation. 2017;101:1875–1886. doi: 10.1097/TP.0000000000001776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Euvrard S., Morelon E., Rostaing L., et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med. 2012;367:329–339. doi: 10.1056/NEJMoa1204166. [DOI] [PubMed] [Google Scholar]
- 16.Dansie K., Viecelli A.K., Pascoe E.M., et al. Novel trial strategies to enhance the relevance, efficiency, effectiveness, and impact of nephrology research. Kidney Int. 2020;98:572–578. doi: 10.1016/j.kint.2020.04.050. [DOI] [PubMed] [Google Scholar]
- 17.Lim W.H., Russ G.R., Wong G., Pilmore H., Kanellis J., Chadban S.J. The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine. Kidney Int. 2017;91:954–963. doi: 10.1016/j.kint.2016.11.008. [DOI] [PubMed] [Google Scholar]
- 18.Durrbach A., Pestana J.M., Pearson T., et al. A Phase III study of Belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study) Am J Transplant. 2010;10:547–557. doi: 10.1111/j.1600-6143.2010.03016.x. [DOI] [PubMed] [Google Scholar]
- 19.Vincenti F., Charpentier B., Vanrenterghem Y., et al. A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study) Am J Transplant. 2010;10:535–546. doi: 10.1111/j.1600-6143.2009.03005.x. [DOI] [PubMed] [Google Scholar]
- 20.Schulz K.F., Altman D.G., Moher D., CONSORT Group CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. doi: 10.1136/bmj.c332. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.WHO trial registration data set (version 1.3.1). World Health Organization. 2021. https://www.who.int/clinical-trials-registry-platform/network/who-data-set Published.