N-of-1 trials in epilepsy: A systematic review and lessons paving the way forward.
antiseizure/therapeutic use
clinical trials methodology
medical care
outcome assessment (healthcare)
precision medicine
single‐case studies
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
10 Sep 2024
10 Sep 2024
Historique:
revised:
28
06
2024
received:
15
02
2024
accepted:
10
07
2024
medline:
10
9
2024
pubmed:
10
9
2024
entrez:
10
9
2024
Statut:
aheadofprint
Résumé
Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy. We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations. Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden. The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies.
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
Références
Fiest KM, Sauro KM, Wiebe S, Patten SB, Dykeman J, Pringsheim T, et al. Prevalence and incidence of epilepsy: a systematic review and meta‐analysis of international studies. Neurology. 2017;88:296–303.
Singh A, Trevick S. The epidemiology of global epilepsy. Neurol Clin. 2016;34(4):837–847.
Symonds JD, Zuberi SM, Stewart K, McLellan A, O'Regan M, MacLeod S, et al. Incidence and phenotypes of childhood‐onset genetic epilepsies: a prospective population‐based national cohort. Brain. 2019;142(8):2303–2318.
Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18(9):898–905.
McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304–316.
Unknown. European Commission – research and innovation. Rare diseases. [cited 2024 Apr 30]. Available from: https://research‐and‐innovation.ec.europa.eu/research‐area/health/rare‐diseases_en
Krey I, von Spiczak S, Johannesen KM, Hikel C, Kurlemann G, Muhle H, et al. L‐serine treatment is associated with improvements in behavior, EEG, and seizure frequency in individuals with GRIN‐related disorders due to null variants. Neurotherapeutics. 2022;19(1):334–341.
Hedrich UBS, Lauxmann S, Wolff M, Synofzik M, Bast T, Binelli A, et al. 4‐aminopyridine is a promising treatment option for patients with gain‐of‐function KCNA2‐encephalopathy. Sci Transl Med. 2021;13(609):eaaz4957.
Guyatt G, Sackett D, Adachi J, Chong J, Rosenbloom D, Pharm D. A clinician's guide for conducting randomized trials in individual patients. CMAJ. 1988;139:497–503.
Mirza RD, Punja S, Vohra S, Guyatt G. The history and development of N‐of‐1 trials. J R Soc Med. 2017;110(8):330–340.
Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n‐of‐1 randomized controlled trial: clinical usefulness. Our three‐year experience. Ann Intern Med. 1990;112(4):293–299.
Lobo MA, Moeyaert M, Cunha AB, Babik I. Single‐case design, analysis, and quality assessment for intervention research. J Neurol Phys Ther. 2017;41(3):187–197.
Nikles J, Mitchel G., editors. The essential guide to N‐of‐1 trials in health. Dordrecht: Springer Netherlands; 2015.
Stunnenberg BC, Raaphorst J, Groenewoud HM, Statland JM, Griggs RC, Woertman W, et al. Effect of mexiletine on muscle stiffness in patients with nondystrophic myotonia evaluated using aggregated N‐of‐1 trials. JAMA. 2018;320(22):2344–2353.
Samuel JP, Bell CS, Samuels JA, Rajan C, Walton AK, Green C, et al. N‐of‐1 trials vs. usual care in children with Hypertension: a pilot randomized clinical trial. Am J Hypertens. 2023;36(2):126–132.
Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n‐of‐1 trials. BMJ. 2021;372:n135.
Zucker DR, Schmid CH, McIntosh MW, D'Agostino RB, Selker HP, Lau J. Combining single patient (N‐of‐1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol. 1997;50(4):401–410.
DEcIDE Methods Center N‐of‐1 Guidance Panel, Duan N, Eslick I, Gabler NB, Kaplan HC, Kravitz RL, et al. Design and implementation of N‐of‐1 trials: a user's guide. No. 13(14). Rockville, MD: Agency for Healthcare Research and Quality; 2014.
Margolis A, Giuliano C. Making the switch: from case studies to N‐of‐1 trials. Epilepsy Behav Rep. 2019;12:100336. https://doi.org/10.1016/j.ebr.2019.100336
Guyatt G, Sackett D, Taylor D, Ghong J, Roberts R, Pugsley S. Determining optimal therapy — randomized trials in individual patients. N Engl J Med. 1986;315(12):767–768.
Nikles CJ, Mitchell GK, Del Mar CB, Clavarino A, McNairn N. An n‐of‐1 trial service in clinical practice: testing the effectiveness of stimulants for attention‐deficit/hyperactivity disorder. Pediatrics. 2006;117(6):2040–2046.
Clough AJ, Hilmer SN, Naismith SL, Kardell LD, Gnjidic D. N‐of‐1 trials for assessing the effects of deprescribing medications on short‐term clinical outcomes in older adults: a systematic review. J Clin Epidemiol. 2018;93:112–119.
Goyal P, Safford M, Hilmer SN, Steinman MA, Matlock D, Maurer MS, et al. N‐of‐1 trials to facilitate evidence‐based deprescribing: rationale and case study. Br J Clin Pharmacol. 2022;88:4460–4473. https://doi.org/10.1111/bcp.15442
Stunnenberg BC, Berends J, Griggs RC, Statland J, Drost G, Nikles J, et al. N‐of‐1 trials in neurology a systematic review. Neurology. 2022;98(2):E174–E185.
Moher D, Liberati A, Tetzlaff J, Altman DG, Antes G, Atkins D, et al. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160.
Salman S, Freund B, Tatum WO. N‐of‐1 trial in epilepsy with fixation‐off sensitivity. Neurol Clin Pract. 2023;13(5):11–14.
Stunnenberg BC, Deinum J, Nijenhuis T, Huysmans F, van der Wilt GJ, van Engelen BGM, et al. N‐of‐1 trials: evidence‐based clinical care or medical research that requires IRB approval? A practical flowchart based on an ethical framework. Healthcare. 2020;8(1):49.
Gabler NB, Duan N, Vohra S, Kravitz RL. N‐of‐1 trials in the medical literature: a systematic review. Med Care. 2011;49(8):761–768.
Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan‐a web and mobile app for systematic reviews. Syst Rev. 2016;5(1):1–10.
Tate RL, Perdices M, Rosenkoetter U, Wakim D, Godbee K, Togher L, et al. Revision of a method quality rating scale for single‐case experimental designs and n‐of‐1 trials: the 15‐item risk of bias in N‐of‐1 trials (RoBiNT) scale. Neuropsychol Rehabil. 2013;23(5):619–638.
Vohra S, Shamseer L, Sampson M, Bukutu C, Schmid CH, Tate R, et al. CONSORT extension for reporting N‐of‐1 trials (CENT) 2015 statement. BMJ. 2015;350:h1738.
Ong KS, Carlin JB, Fahey M, Freeman JL, Scheffer IE, Gillam L, et al. Protocol for a single patient therapy plan: a randomised, double‐blind, placebo‐controlled N‐of‐1 trial to assess the efficacy of cannabidiol in patients with intractable epilepsy. J Paediatr Child Health. 2020;56(12):1918–1923.
Müller AR, den Hollander B, van de Ven PM, Roes KCB, Geertjens L, Bruining H, et al. Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo‐controlled N‐of‐1 trials. BMC Psychiatry. 2024;24(1):23.
Stolarek I, Blacklaw J, Forrest G, Brodie MJ. Vigabatrin and lamotrigine in refractory epilepsy. J Neurol Neurosurg Psychiatry. 1994;57(8):921–924.
Leach JP, Girvan J, Paul A, Brodie MJ, Leach JP, Girvan J, et al. Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy. J Neurol Neurosurg Psychiatry. 1997;62:372–376.
Hart YM, Meinardi H, Sander J, Nutt DJ, Shorvon SD. The effect of intravenous flumazenil on interictal electroencephalographic epileptic activity: results of a placebo‐controlled study. J Neurol Neurosurg Psychiatry. 1991;54:305–309.
Gurrell R, Gorman D, Whitlock M, Ogden A, DSR, DiVentura B, et al. Photosensitive epilepsy: robust clinical efficacy of a selective GABA potentiator. Neurology. 2019;92:e1786–e1795.
Binnie CD, De Beukelaar E, Meijer JWA, Meinardi H, Overweg J, Wauquier A, et al. Open dose‐ranging trial of flunarizine as add‐on therapy in epilepsy. Epilepsia. 1985;6(5):424–428.
Crawford P, Chadwick D. A comparative study of progabide, valproate, and placebo as add‐on therapy in patients with refractory epilepsy. J Neurol Neurosurg Psychiatry. 1986;49:1251–1257.
McKee PJW, Blacklaw J, Friel E, Thompson GG, Gillham RA, Brodie MJ. Adjuvant vigabatrin in refractory epilepsy: a ceiling to effective dosage in individual patients? Epilepsia. 1993;34:937–943.
McKee PJ, Blacklaw J, Carswell A, Gillham RA, Brodie MJ. Double dummy comparison between once and twice daily dosing with modified‐release carbamazepine in epileptic patients. Br J Clin Pharmacol. 1993;36(3):257–261.
Tergau F, Neumann D, Rosenow F, Nitsche MA, Paulus W, Steinhoff B. Can epilepsies be improved by repetitive transcranial magnetic stimulation? – Interim analysis of a controlled study. Suppl Clin Neurophysiol. 2003;56:400–405.
Barkley CM, Hu Z, Fieberg AM, Eberly LE, Birnbaum AK, Leppik IE, et al. An association between resting state EEG parameters and the severity of topiramate‐related cognitive impairment. Epilepsy Behav. 2021;114(Pt A):107598.
Turner RP. The acute effect of music on interictal epileptiform discharges. Epilepsy Behav. 2004;5(5):662–668.
Seynaeve L, Devroye A, Dupont P, Van Paesschen W. Randomized crossover sham‐controlled clinical trial of targeted low‐frequency transcranial magnetic stimulation comparing a figure‐8 and a round coil to treat refractory neocortical epilepsy. Epilepsia. 2016;57(1):141–150.
Koskiniemi M, Van Vleymen B, Hakamies L, Lamusuo S, Taalas J. Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo. J Neurol Neurosurg Psychiatry. 1998;64:344–348.
De Giorgio CM, Miller PR, Harper R, Gornbein J, Schrader L, Soss J, et al. Fish oil (n‐3 fatty acids) in drug resistant epilepsy: a randomised placebo‐controlled crossover study. J Neurol Neurosurg Psychiatry. 2015;86(1):65–70.
Adams J, Alipio‐Jocson V, Katherine Inoyama M, Bartlett V, Saira Sandhu B, Jemima Oso B, et al. Methylphenidate, cognition, and epilepsy a double‐blind, placebo‐controlled, single‐dose study. Neurology. 2016;88:470–476.
Loiseau P, Hardenberg JP, Pestre M, Guyot M, Schechter PJ, Tell GP. Double‐blind, placebo‐controlled study of vigabatrin (gamma‐vinyl GABA) in drug‐resistant epilepsy. Epilepsia. 1986;27(2):115–120.
French JA, Wechsler R, Gelfand MA, Pollard JR, Vazquez B, Friedman D, et al. Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants. Epilepsia. 2019;60(8):1602–1609.
Hughes E, Oates S, Pal DK. Intolerance to quinidine in a n‐of‐1 trial for KCNT1 associated epilepsy of infancy with migrating focal seizures. Seizure. 2022;103:46–50.
Lewis SA, Shetty S, Gamble S, Heim J, Zhao N, Stitt G, et al. Intrathecal magnesium delivery for Mg++−insensitive NMDA receptor activity due to GRIN1 mutation. Orphanet J Rare Dis. 2023;18(1):1–5.
Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam‐induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557–559.
Feely M, Calvert R, Gibson J. Clobazam in catamenial epilepsy. Lancet. 1982;320(8289):71–73.
Hussain SA, Dlugos DJ, Cilio MR, Parikh N, Oh A, Sankar R. Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: a multicenter phase‐2 study. Epilepsy Behav. 2020;102:106826.
Sathananthan N, Dimech‐Betancourt B, Morris E, Vicendese D, Knox L, Gillanders D, et al. A single‐case experimental evaluation of a new group‐based intervention to enhance adjustment to life with acquired brain injury: VaLiANT (valued living after neurological trauma). Neuropsychol Rehabil. 2022;32(8):2170–2202.
FitzGerald A, Main L, Duff U, Foggo J, Rowney F, Haire N, et al. Does amantadine maintain function in long‐established brain injury? A single case experimental design. Brain Inj. 2021;35(11):1443–1450.
Theodore WH, Raubertas RF, Porter RJ, Nice F, Devinsky O, Reeves P, et al. Felbamate: A clinical trial for complex partial seizures. Epilepsia. 1991;32(3):392–397. https://doi.org/10.1111/j.1528‐1157.1991.tb04668.x
Privitera M, Treiman D, Pledger G, Sahlroot J, Handforth A, Linde M, et al. Dezinamide for partial seizures: results of an n‐of‐1 design trial. Neurology. 1994;44(8):1453–1458.
Gordon K, Bawden H, Camfield P, Mann S, Orlik P. Valproic acid treatment of learning disorder and severely epileptiform EEG without clinical seizures. J Child Neurol. 1996;11(1):41–43.
Willoughby JO, Pope KJ, Eaton V. Nicotine as an antiepileptic agent in ADNFLE: an N‐of‐one study. Epilepsia. 2003;44(9):1238–1240.
Willoughby JO, Pope KJ, Eaton V. Erratum: nicotine as an antiepileptic agent in ADNFLE: an N‐of‐one study. Epilepsia. 2003;44:1238–1240.
Tellez‐Zenteno JF, McLachlan RS, Parrent A, Kubu CS, Wiebe S. Hippocampal electrical stimulation in mesial temporal lobe epilepsy. Neurology. 2006;66(10):1490–1494.
Perucca E. From clinical trials of antiepileptic drugs to treatment. Epilepsia Open. 2018;3(S2):220–230.
Seiden LG, Connor GS. The importance of drug titration in the management of patients with epilepsy. Epilepsy Behav. 2022;128:e108517.
Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011;10(5):446–456.
Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta‐analysis of placebo‐controlled randomised trials. Lancet Neurol. 2011;10:961–968.
Perucca E. Designing clinical trials to assess antiepileptic drugs as monotherapy difficulties and solutions. CNS Drugs. 2008;22:917–938.
Samuel JP, Tyson JE, Green C, Bell CS, Pedroza C, Molony D, et al. Treating hypertension in children with n‐of‐1 trials. Pediatrics. 2019;143(4):e20181818.
Nikles CJ, Clavarino AM, Del Mar CB. Using n‐of‐1 trials as a clinical tool to improve prescribing. Br J Gen Pract. 2005;55(512):175–180.
Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, et al. N‐of‐1 trial of a statin, placebo, or No treatment to assess side effects. N Engl J Med. 2020;383(22):2182–2184.
He W, Cui Z, Chen Y, Wang F, Li F. Status of N‐of‐1 trials in chronic pain management: a narrative review. Pain Ther. 2021;10:1013–1028.
Keppel Hesselink JM, Kopsky DJ, Bhaskar AK. Ethical justification of single‐blind and double‐blind placebo‐controlled response tests in neuropathic pain and N‐of‐1 treatment paradigm in clinical settings. J Pain Res. 2019;12:345–352.
Tanious R, Onghena P. Randomized single‐case experimental designs in healthcare research: what, why, and how? Healthcare (Switzerland). 2019;7(4):143.
Karoly PJ, Rao VR, Gregg NM, Worrell GA, Bernard C, Cook MJ, et al. Cycles in epilepsy. Nat Rev Neurol Nat Res. 2021;17:267–284.
Leguia MG, Andrzejak RG, Rummel C, Fan JM, Mirro EA, Tcheng TK, et al. Seizure cycles in focal epilepsy. JAMA Neurol. 2021;78(4):454–463.
Baud MO, Ramantani G. Seizure remissions and cycles in pediatric focal epilepsy. Dev Med Child Neurol. 2023;65(3):308–309.
Karoly PJ, Romero J, Cook MJ, Freestone DR, Goldenholz DM. When can we trust responders? Serious concerns when using 50% response rate to assess clinical trials. Epilepsia. 2019;60(9):e99–e103.
Ebbutt AAF. Three‐period crossover designs for two treatments. Biometrics. 1984;40(1):219–224.
Rowan AJ, Binnie C, Warfield CA, Meinardi H, Meijer JWA. The delayed effect of sodium valproate on the Photoconvulsive response in man. Epilepsia. 1979;20(1):61–68.
McLachlan RS, Pigott S, Tellez‐Zenteno JF, Wiebe S, Parrent A. Bilateral hippocampal stimulation for intractable temporal lobe epilepsy: impact on seizures and memory. Epilepsia. 2010;51(2):304–307.
Buchhalter J, Neuray C, Cheng JY, D'Cruz ON, Datta AN, Dlugos D, et al. EEG parameters as endpoints in epilepsy clinical trials ‐ an expert panel opinion paper. Epilepsy Res. 2022;187:107028.
Sinoo C, de Lange IML, Westers P, Gunning WB, Jongmans MJ, Brilstra EH. Behavior problems and health‐related quality of life in Dravet syndrome. Epilepsy Behav. 2019;90:217–227.
Birbeck GL, Hays RD, Cui X, Vickrey BG. Seizure reduction and quality of life improvements in people with epilepsy. Epilepsia. 2002;43(5):535–538.
Luoni C, Bisulli F, Canevini MP, De Sarro G, Fattore C, Galimberti CA, et al. Determinants of health‐related quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia. 2011;52(12):2181–2191.
Ronen GM, Streiner DL, Rosenbaum P. Health‐related quality of life in childhood epilepsy: moving beyond “seizure control with minimal adverse effects”. Health Qual Life Outcomes. 2003;1(36):1–10.
Müller AR, Brands MMMG, van de Ven PM, Roes KCB, Cornel MC, van Karnebeek CDM, et al. Systematic review of N‐of‐1 studies in rare genetic neurodevelopmental disorders: the power of 1. Neurology. 2021;96(11):529–540.
Zimmerman IL, Woo‐Sam JM. Review of the criterion‐related validity of the WISC‐III: the first five years. Percept Mot Skills. 1997;85:531–546.
Wechsler D. Manual for the Wechsler intelligence scale for children‐revised. San Antonio, TX: Psychological Corp; 1997.
Slade A, Isa F, Kyte D, Pankhurst T, Kerecuk L, Ferguson J, et al. Patient reported outcome measures in rare diseases: a narrative review. Orphanet J Rare Dis. 2018;13(1):1–9.
Donnelly C, Carswell A. Individualized outcome measures: a review of the literature. Can J Occup Ther. 2002;69(2):84–94.
Harpster K, Sheehan A, Foster EA, Leffler E, Schwab SM, Angeli JM. The methodological application of goal attainment scaling in pediatric rehabilitation research: a systematic review. Disabil Rehabil. 2019;41(24):2855–2864.
Brandon Westover M, Cormier J, Bianchi MT, Shafi M, Kilbride R, Cole AJ, et al. Revising the “rule of three” for inferring seizure freedom. Epilepsia. 2012;53(2):368–376.
Punja S, Schmid CH, Hartling L, Urichuk L, Nikles CJ, Vohra S. To meta‐analyze or not to meta‐analyze? A combined meta‐analysis of N‐of‐1 trial data with RCT data on amphetamines and methylphenidate for pediatric ADHD. J Clin Epidemiol. 2016;76:76–81.
Nikles J, Mitchell G, McKinlay L, Waugh MC, Epps A, Carmont SA, et al. A series of n‐of‐1 trials of stimulants in brain injured children. NeuroRehabilitation. 2017;40(1):11–21.
Germini F, Coerezza A, Andreinetti L, Nobili A, Rossi PD, Mari D, et al. N‐of‐1 randomized trials of ultra‐micronized Palmitoylethanolamide in older patients with chronic pain. Drugs Aging. 2017;34(12):941–952. https://doi.org/10.1007/s40266‐017‐0506‐2
Nathan PC, Tomlinson G, Dupuis LL, Greenberg ML, Ota S, Bartels U, et al. A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N‐of‐1 trials design. Support Care Cancer. 2006;14(3):268–276.
Kaplan HC, Opipari‐Arrigan L, Yang J, Schmid CH, Schuler CL, Saeed SA, et al. Personalized research on diet in ulcerative colitis and Crohn's disease: a series of N‐of‐1 diet trials. Am J Gastroenterol. 2022;117(6):902–917.
Mitchell GK, Hardy JR, Nikles CJ, Carmont SAS, Senior HE, Schluter PJ, et al. The effect of methylphenidate on fatigue in advanced cancer: an aggregated N‐of‐1 trial. J Pain Symptom Manag. 2015;50(3):289–296. https://doi.org/10.1016/j.jpainsymman.2015.03.009
Sung L, Tomlinson GA, Greenberg ML, Koren G, Judd P, Ota S, et al. Serial controlled N‐of‐1 trials of topical vitamin E as prophylaxis for chemotherapy‐induced oral mucositis in paediatric patients. Eur J Cancer. 2007;43(8):1269–1275.
Roustit M, Giai J, Gaget O, Khouri C, Mouhib M, Lotito A, et al. On‐demand sildenafil as a treatment for raynaud phenomenon: a series of n‐of‐1 trials. Ann Intern Med. 2018;169(10):694–703.
Ma Y, Fu Y, Tian Y, Gou W, Miao Z, Yang M, et al. Individual postprandial glycemic responses to diet in n‐of‐1 trials: Westlake N‐of‐1 trials for macronutrient intake (WE‐MACNUTR). J Nutr. 2021;151(10):3158–3167.
Ursino M, Stallard N. Bayesian approaches for confirmatory trials in rare diseases: opportunities and challenges. Int J Environ Res Public Health. 2021;18(3):1–9.
Wijeysundera DN, Austin PC, Hux JE, Beattie WS, Laupacis A. Bayesian statistical inference enhances the interpretation of contemporary randomized controlled trials. J Clin Epidemiol. 2009;62(1):13–21.e5. https://doi.org/10.1016/j.jclinepi.2008.07.006
Zucker DR, Ruthazer R, Schmid CH, Feuer JM, Fischer PA, Kieval RI, et al. Lessons learned combining N‐of‐1 trials to assess fibromyalgia therapies. J Rheumatol. 2006;33(10):2069–2077.
Zucker DR, Ruthazer R, Schmid CH. Individual (N‐of‐1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J Clin Epidemiol. 2010;63(12):1312–1323.
Irwig L, Glasziou P, March L. Ethics n‐of‐1 trials. Lancet. 1995;345:469.
Synofzik M, van Roon‐Mom WMC, Marckmann G, van Duyvenvoorde HA, Graessner H, Schüle R, et al. Preparing n‐of‐1 antisense oligonucleotide treatments for rare neurological diseases in Europe: genetic, regulatory, and ethical perspectives. Nucleic Acid Ther. 2021;32:83–94.
Samuel JP, Burgart A, Wootton SH, Magnus D, Lantos JD, Tyson JE. Randomized n‐of‐1 trials: quality improvement, research, or both? Pediatrics. 2016;138(2):1–7.
Kane PB, Bittlinger M, Kimmelman J. Individualized therapy trials: navigating patient care, research goals and ethics. Nat Med. 2021;27(10):1679–1686.
Defelippe VM, J M W van Thiel G, Otte WM, Schutgens REG, Stunnenberg B, Cross HJ, et al. Toward responsible clinical n‐of‐1 strategies for rare diseases. Drug Discov Today. 2023;28(10):103688.
European Medicines Agency. Committee for medicinal products for human use (CHMP) guideline on clinical trials in small populations. London; 2006 Jul [cited 2024 May 22]. Available from: http://www.emea.eu.int
Food and Drug Administration. IND submissions for individualized antisense oligonucleotide drug Products for severely debilitating or life‐threatening diseases: clinical recommendations guidance for sponsor‐investigators. 2021 Dec [cited 2024 May 22]. Available from: https://www.fda.gov/drugs/guidance‐compliance‐regulatory‐information/guidances‐drugs
Nikles J, Onghena P, Vlaeyen JWS, Wicksell RK, Simons LE, McGree JM, et al. Establishment of an international collaborative network for N‐of‐1 trials and single‐case designs. Contemp Clin Trials Commun. 2021;23:103688.
Weinreich SS, Vrinten C, Kuijpers MR, Lipka AF, Schimmel KJM, Van Zwet EW, et al. Aggregated N‐of‐1 trials for unlicensed medicines for small populations: an assessment of a trial with ephedrine for myasthenia gravis. Orphanet J Rare Dis. 2017;12(1):1–18.
Selker HP, Cohen T, D'Agostino RB, Dere WH, Ghaemi SN, Honig PK, et al. A useful and sustainable role for N‐of‐1 trials in the healthcare ecosystem. Clin Pharmacol Ther. 2022;112(2):224–232.