Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry

Christian Patry, Lukas D Sauer, Anja Sander, Kai Krupka, Alexander Fichtner, Jolanda Brezinski, Yvonne Geissbühler, Elodie Aubrun, Anna Grinienko, Luca Dello Strologo, Dieter Haffner, Jun Oh, Ryszard Grenda, Lars Pape, Rezan Topaloğlu, Lutz T Weber, Antonia Bouts, Jon Jin Kim, Agnieszka Prytula, Jens König, Mohan Shenoy, Britta Höcker, Burkhard Tönshoff, Christian Patry, Lukas D Sauer, Anja Sander, Kai Krupka, Alexander Fichtner, Jolanda Brezinski, Yvonne Geissbühler, Elodie Aubrun, Anna Grinienko, Luca Dello Strologo, Dieter Haffner, Jun Oh, Ryszard Grenda, Lars Pape, Rezan Topaloğlu, Lutz T Weber, Antonia Bouts, Jon Jin Kim, Agnieszka Prytula, Jens König, Mohan Shenoy, Britta Höcker, Burkhard Tönshoff

Abstract

Background: Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far.

Methods: In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554).

Results: Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable.

Conclusions: In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Clinical trial design; Emulated cohorts; Pediatric kidney transplantation; Real-World Data.

Conflict of interest statement

B.T. is a consultant of Bristol-Myers Squibb, Chiesi, CSL Behring Biotherapies for Life, Novartis, and Vifor Pharma. L.T.W. is consultant of Alexion, Chiesi. He received lecture fees from Novartis, Chiesi and a reimbursement of travel cost from Astellas. The other authors declare that they have nothing to disclose and that there is no conflict of interest.

© 2022. The Author(s).

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9584233/bin/467_2022_5777_Figa_HTML.jpg
A higher resolution version of the Graphical abstract is available as Supplementary information
Fig. 1
Fig. 1
Study flow chart showing inclusion and exclusion criteria applied on the CERTAIN Registry data on October 20, 2020 to generate the CERTAIN cohort for comparison with the CRADLE control cohort. Exclusion criteria in the CRADLE trial, which were not applicable to the CERTAIN Registry, are shown Supplemental Table 2. CS, corticosteroids; KTx, kidney transplantation; MMF, mycophenolate mofetil; TAC, tacrolimus
Fig. 2
Fig. 2
Comparisons of efficacy and safety endpoints between the CRADLE control cohort and the CERTAIN cohort. a Patient and donor age at time of kidney transplantation. b Patients with at least one biopsy-proven acute rejection episode and occurrence of the composite efficacy failure endpoint (BPAR, graft loss or death) at year 1 posttransplant (shown by Kaplan–Meier estimates). c eGFR and proteinuria at year 1 posttransplant. d Patients with at least one infection and with at least one urinary tract infection at year 1 posttransplant. eGFR, estimated glomerular filtration rate; KTx, kidney transplantation

References

    1. Speich B, von Niederhäusern B, Schur N, Hemkens LG, Fürst T, Bhatnagar N, Alturki R, Agarwal A, Kasenda B, Pauli-Magnus C, Schwenkglenks M, Briel M. Systematic review on costs and resource use of randomized clinical trials shows a lack of transparent and comprehensive data. J Clin Epidemiol. 2018;96:1–11. doi: 10.1016/j.jclinepi.2017.12.018.
    1. Kostis JB, Dobrzynski JM. Limitations of randomized clinical trials. Am J Cardiol. 2020;129:109–115. doi: 10.1016/j.amjcard.2020.05.011.
    1. Eichler HG, Pignatti F, Schwarzer-Daum B, Hidalgo-Simon A, Eichler I, Arlett P, Humphreys A, Vamvakas S, Brun N, Rasi G. Randomized controlled trials versus real world evidence: neither magic nor myth. Clin Pharmacol Ther. 2021;109:1212–1218. doi: 10.1002/cpt.2083.
    1. Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16:495. doi: 10.1186/s13063-015-1023-4.
    1. Ramagopalan SV, Simpson A, Sammon C. Can real-world data really replace randomised clinical trials? BMC Med. 2020;18:13. doi: 10.1186/s12916-019-1481-8.
    1. Paraskevas KI, de Borst GJ, Veith FJ. Why randomized controlled trials do not always reflect reality. J Vasc Surg. 2019;70:607–614.e3. doi: 10.1016/j.jvs.2019.01.052.
    1. Lilli C, Biggeri A, Zingaretti C, Vertogen B et al (2021) Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine. Epidemiol Prev 45:28–36. 10.19191/EP21.1-2.P028.036
    1. Food and Drug Administration (2018) Framework for FDA’s real-world evidence. PROGRAM. . Accessed 2 Feb 2022
    1. Kim HS, Lee S, Kim JH. Real-world evidence versus randomized controlled trial: Clinical research based on electronic medical records. J Korean Med Sci. 2018;33:e213. doi: 10.3346/jkms.2018.33.e213.
    1. Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, Pawar A, Bessette LG, Lee H, Garry EM, Gautam N, Schneeweiss S. Emulating randomized clinical trials with nonrandomized real-world evidence studies first results from the RCT DUPLICATE Initiative. Circulation. 2021;143:1002–1013. doi: 10.1161/CIRCULATIONAHA.120.051718.
    1. Abdel-Kader K, Jhamb M. EHR-based clinical trials: the next generation of evidence. Clin J Am Soc Nephrol. 2020;15:1050–1052. doi: 10.2215/CJN.11860919.
    1. Thompson AM, Southworth MR. Real world data and evidence: support for drug approval: applications to kidney diseases. Clin J Am Soc Nephrol. 2019;14:1531–1532. doi: 10.2215/CJN.02790319.
    1. Lentine KL, Smith JM, Hart A, Miller JM, Skeans MA, Larkin L, Robinson A, Gauntt K, Israni AK, Hirose R, Snyder JJ. OPTN/SRTR 2020 Annual Data Report:Kidneye. Am J Transplant. 2022;22:1–647. doi: 10.1111/ajt.16982.
    1. FDA (2018) E10 choice of control group and related issues in clinical trials. . Accessed 2 Feb 2022
    1. Plotnicki L, Kohl CD, Höcker B, Krupka K, Rahmel A, Pape L, Hoyer P, Marks SD, Webb NJA, Söylemezoglu O, Topaloglu R, Szabo AJ, Seeman T, Marlies Cornelissen EA, Knops N, Grenda R, Tönshoff B. The CERTAIN registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe. Transplant Proc. 2013;45:1414–1417. doi: 10.1016/j.transproceed.2013.01.007.
    1. Köster L, Krupka K, Höcker B, Rahmel A, Samuel U, Zanen W, Opelz G, Süsal C, Döhler B, Plotnicki L, Kohl CD, Knaup P, Tönshoff B. Integrating data from multiple sources for data completeness in a web-based registry for pediatric renal transplantation-the CERTAIN Registry. Stud Health Technol Inform. 2015;216:1049. doi: 10.3233/978-1-61499-564-7-1049.
    1. Höcker B, Schneble L, Murer L, Carraro A, et al. Epidemiology of and risk factors for BK polyomavirus replication and nephropathy in pediatric renal transplant recipients: an international CERTAIN registry study. Transplantation. 2019;103:1224–1233. doi: 10.1097/TP.0000000000002414.
    1. Tönshoff B, Ettenger R, Dello Strologo L, Marks SD, Pape L, Tedesco-Silva H, Bjerre A, Christian M, Meier M, Martzloff ED, Rauer B, Ng J, Lopez P. Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: results of a randomized trial. Am J Transplant. 2019;19:811–822. doi: 10.1111/ajt.15081.
    1. Avery L, Rotondi M. More comprehensive reporting of methods in studies using respondent driven sampling is required: a systematic review of the uptake of the STROBE-RDS guidelines. J Clin Epidemiol. 2020;117:68–77. doi: 10.1016/j.jclinepi.2019.09.024.
    1. Chen Z, Zhang H, Guo Y, George TJ, Prosperi M, Hogan WR, He Z, Shenkman EA, Wang F, Bian J. Exploring the feasibility of using real-world data from a large clinical data research network to simulate clinical trials of Alzheimer’s disease. NPJ Digit Med. 2021;4:84. doi: 10.1038/s41746-021-00452-1.
    1. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629–637. doi: 10.1681/ASN.2008030287.
    1. Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, Balk E, Lau J, Levin A, Kausz AT, Eknoyan G, Levey AS. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: Evaluation, classification, and stratification. Pediatrics. 2003;111:1416–1421. doi: 10.1542/peds.111.6.1416.
    1. Schaffrath Rosario A, Schienkiewitz A, Neuhauser H. German height references for children aged 0 to under 18 years compared to WHO and CDC growth charts. Ann Hum Biol. 2011;38:121–130. doi: 10.3109/03014460.2010.521193.
    1. Rosario AS, Kurth BM, Stolzenberg H, Ellert U, Neuhauser H. Body mass index percentiles for children and adolescents in Germany based on a nationally representative sample (KiGGS 2003–2006) Eur J Clin Nutr. 2010;64:341–349. doi: 10.1038/ejcn.2010.8.
    1. Centers for Disease Control and Prevention Percentile Data Files with LMS values. . Accessed on 03/12/2022
    1. Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time. Stat Med. 2007;26:4505–4519. doi: 10.1002/sim.2864.
    1. Offner G, Toenshoff B, Höcker B, et al. Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids. Transplantation. 2008;86:1241–1248. doi: 10.1097/TP.0b013e318188af15.
    1. Grenda R, Watson A, Vondrak K, Webb NJA, Beattie J, Fitzpatrick M, Saleem MA, Trompeter R, Milford DV, Moghal NE, Hughes D, Perner F, Friman S, Van Damme-Lombaerts R, Janssen F. A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation. Am J Transplant. 2006;6:1666–1672. doi: 10.1111/j.1600-6143.2006.01367.x.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren