Evidence synthesis in neuromyelitis optica spectrum disorders: modeling a clinical trial based on published data

   Relevance. Optic neuromyelitis spectrum disorders are a severe orphan nosology for which the search for new highly effective therapeutic options is a priority area of medical care. At the same time, due to the nature of this group of diseases, conducting new clinical trials (CT) is significantly complicated not only by the long and complex recruitment of patients and the unethical nature of using a parallel control group without treatment, but also by conducting comparisons with a historical control group or indirect comparisons, for which planning the sample size in the CT for a new therapy option is a separate methodological task.

   Objective. The aim of this study was to estimate the power for the analysis of the primary endpoint in the single-arm BCD-132-6/AQUARELLE trial, which was planned to be performed using an adjusted indirect comparison (AIC) of the study drug divosilimab with published data on the placebo group in the randomized N-MOmentum trial.

   Materials and methods. Using the data of the studies identified using a systematic search, a meta-regression model was estimated for the dependence of the average annual relapse rate (ARR) on therapy (anti-CD20 or placebo), the assessment horizon, and baseline patient characteristics. According to its results, for the expected BCD-132-6/AQUARELLE population, a 6-month ARR of 0.116 (95 % CI: 0.030–0.212) was predicted for anti-CD20 therapy. Next, a stepwise effective sample size (ESS) simulation was performed in the divosilimab group with power assessment.

   Results. The expected ratio of the ARR of divosilimab and placebo at 6 months was 0.117 (90 % CI: 0.045–0.214) with-out weighting and 0.156 (90% CI: 0.050–0.315) after weighting (ESS). The minimum EES required to achieve a power of 90 % when testing the hypothesis of superiority in the ARR at 6 months for divosilimab therapy compared with placebo with a one-sided type I error probability of 0.05 is 35 people.

   Conclusion. The obtained results can be used to support the statistical inference of the BCD-132-6/AQUARELLE study.

1. Bruscolini A, Sacchetti M, La Cava M, Gharbiya M, Ralli M, Lambiase A, De Virgilio A, Greco A. Diagnosis and management of neuromyelitis optica spectrum disorders - An update. Autoimmun Rev. 2018 Mar;17(3):195-200. doi: 10.1016/j.autrev.2018.01.001.

2. Whittam D, Wilson M, Hamid S, Keir G, Bhojak M, Jacob A. What's new in neuromyelitis optica? A short review for the clinical neurologist. J Neurol. 2017 Nov;264(11):2330-2344. doi: 10.1007/s00415-017-8445-8.

3. Papp V, Magyari M, Aktas O, Berger T, Broadley SA, Cabre P, Jacob A, Kira JI, Leite MI, Marignier R, Miyamoto K, Palace J, Saiz A, Sepulveda M, Sveinsson O, Illes Z. Worldwide Incidence and Prevalence of Neuromyelitis Optica : A Systematic Review. Neurology. 2021 Jan 12;96(2):59-77. doi: 10.1212/WNL.0000000000011153.

4. Simaniv TO, Kochergin IA, Zakharova MN, Korobko DS, Zaslavsky LG, Zelenova OV, Abramov SI. Clinical and epidemiological aspects of neuromyelitis optic spectrum diseases in the russian population. S.S. Korsakov Journal of Neurology and Psychiatry. 2021;121(7):96-103. (In Russ.) doi: 10.17116/jnevro202112107196.

5. Jayasundara K, Hollis A, Krahn M, Mamdani M, Hoch JS, Grootendorst P. Estimating the clinical cost of drug development for orphan versus non-orphan drugs. Orphanet J Rare Dis. 2019 Jan 10;14(1):12. doi: 10.1186/s13023-018-0990-4.

6. Friede T, Posch M, Zohar S, Alberti C, Benda N, Comets E, Day S, Dmitrienko A, Graf A, Günhan BK, Hee SW, Lentz F, Madan J, Miller F, Ondra T, Pearce M, Röver C, Toumazi A, Unkel S, Ursino M, Wassmer G, Stallard N. Recent advances in methodology for clinical trials in small populations: the InSPiRe project. Orphanet J Rare Dis. 2018 Oct 25;13(1):186. doi: 10.1186/s13023-018-0919-y.

7. Phillippo DM, Ades AE, Dias S, Palmer S, Abrams KR, Welton NJ. Methods for Population-Adjusted Indirect Comparisons in Health Technology Appraisal. Med Decis Making. 2018 Feb; 38(2):200-211. doi: 10.1177/0272989X17725740.

8. Zierhut ML, Chen Y, Pithavala YK, Nickens DJ, Valota O, Amantea MA. Clinical Trial Simulations From a Model-Based Meta-Analysis of Studies in Patients With Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy. CPT Pharmacometrics Syst Pharmacol. 2016 May;5(5):274-82. doi: 10.1002/psp4.12078.

9. Bennett JL, Aktas O, Rees WA, Smith MA, Gunsior M, Yan L, She D, Cimbora D, Pittock SJ, Weinshenker BG, Paul F, Marignier R, Wingerchuk D, Cutter G, Green A, Hartung HP, Kim HJ, Fujihara K, Levy M, Katz E, Cree BAC; N-MOmentum study investigators. Association between B-cell depletion and attack risk in neuromyelitis optica spectrum disorder: An exploratory analysis from N-MOmentum, a double-blind, randomised, placebo-controlled, multicentre phase 2/3 trial. EBioMedicine. 2022 Dec;86:104321. doi: 10.1016/j.ebiom.2022.104321.

10. Aungsumart S, Youngkong S, Dejthevaporn C, Chaikledkaew U, Thadanipon K, Tansawet A, Khieukhajee J, Attia J, McKay GJ, Thakkinstian A. Efficacy and safety of monoclonal antibody therapy in patients with neuromyelitis optica spectrum disorder : A systematic review and network meta-analysis. Front Neurol. 2023 Apr 4;14:1166490. doi: 10.3389/fneur.2023.1166490.

11. Cree BAC, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM, Fujihara K, Paul F, Cutter GR, Marignier R, Green AJ, Aktas O, Hartung HP, Lublin FD, Drappa J, Barron G, Madani S, Ratchford JN, She D, Cimbora D, Katz E; N-MOmentum study investigators. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019 Oct 12;394(10206):1352-1363. doi: 10.1016/S0140-6736(19)31817-3.

12. Traboulsee A, Greenberg BM, Bennett JL, Szczechowski L, Fox E, Shkrobot S, Yamamura T, Terada Y, Kawata Y, Wright P, Gianella-Borradori A, Garren H, Weinshenker BG. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol. 2020 May;19(5):402-412. doi: 10.1016/S1474-4422(20)30078-8.

13. Yamamura T. et al. Efficacy of satralizumab (SA237) in subgroups of patients in SAkuraSky: a Phase III double-blind, placebo-controlled, addon study in patients with neuromyelitis optica spectrum disorder (NMOSD) (S43.008). Neurology. 2019;15(92):S43.008.

14. Nikoo Z, Badihian S, Shaygannejad V, Asgari N, Ashtari F. Comparison of the efficacy of azathioprine and rituximab in neuromyelitis optica spectrum disorder: a randomized clinical trial. J Neurol. 2017 Sep;264(9):2003-2009. doi: 10.1007/s00415-017-8590-0.

15. Tahara M, Oeda T, Okada K, Kiriyama T, Ochi K, Maruyama H, Fukaura H, Nomura K, Shimizu Y, Mori M, Nakashima I, Misu T, Umemura A, Yamamoto K, Sawada H. Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020 Apr;19(4):298-306. doi: 10.1016/S1474-4422(20)30066-1.

16. Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, Nakashima I, Terzi M, Totolyan N, Viswanathan S, Wang KC, Pace A, Fujita KP, Armstrong R, Wingerchuk DM. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019 Aug 15;381(7):614-625. doi: 10.1056/NEJMoa1900866.

17. Zhang C, Zhang M, Qiu W, Ma H, Zhang X, Zhu Z, Yang CS, Jia D, Zhang TX, Yuan M, Feng Y, Yang L, Lu W, Yu C, Bennett JL, Shi FD; TANGO Study Investigators. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020 May;19(5): 391-401. doi: 10.1016/S1474-4422(20)30070-3.

18. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions. 2^nd Edition. Chichester (UK): John Wiley & Sons, 2019.

19. Dias S. et al. Heterogeneity: Subgroups, Meta-Regression, Bias And Bias-Adjustment / S. Dias, A. J. Sutton, N. J. Welton, A. E. Ades, London: National Institute for Health and Care Excellence (NICE), 2012.

20. Viechtbauer W. Conducting meta-analyses in R with the metafor package. Journal of Statistical Software. 2010;36(3):1-48. doi: 10.18637/jss.v036.i03

21. Li H. Q., Tang M. L., Wong W. K. Confidence intervals for ratio of two Poisson rates using the method of variance estimates recovery. Computational Statistics. 2014;29:869-889.