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Accelerated intermittent theta burst stimulation targeting personalized fronto-parietal control network improves core symptoms of autism spectrum disorder: a double-blind, randomized controlled trial
Molecular Psychiatry
(2026)<br>- Comments
doi: 10.1038/s41380-026-03596-2<br>pubmed: 41986743<br>issn: 1359-4184<br>issn: 1476-5578
Qi Liu, Jiawei Zhang, Xinyu Duan, Ping Zhang, Yang Yang, Guanzhong Yao, Bulideerqing Jiaerheng, Xiao-Jing Shou, Yong He, Kaiyue Han, Meixiang Jia, Lifang Wang, Weijun Gong, Wuxiang Xie, Kai Sun, Danhong Wang, Xiao-Dan Wu, Hua Cao, Hao Zhang, Hesheng Liu
Retrospective Registration and Post-Hoc Trial Redesign Questions\nThis paper presents a randomized, double-blind clinical trial (NCT05890846) published under Nature\/ICMJE clinical-trial standards[4], which require pre-specified study designs and prospectively defined primary endpoints.\nHowever, the publicly archived ClinicalTrials.gov history appears difficult to reconcile with a prospectively fixed confirmatory trial design. According to the registry history :\n\n\n\nVersion\nDate\nRegistry Status \/ Changes\n\n\n\n\nV1\n2023-05-26\nFirst registration submitted. Status listed as \u201cNot yet recruiting\u201d. Start date listed as June 2023. Protocol described a 4-arm, 8-week design with continuous outcome measures. Xuanwu Hospital listed as trial site.\n\n\nV2\n2023-09-04\nStatus still listed as \u201cNot yet recruiting\u201d. HPPH replaces Xuanwu Hospital as the trial site.\n\n\nV3\n2024-02-02\nMajor redesign introduced: 4 arms \u2192 2 arms; 8 weeks \u2192 12 weeks; continuous outcomes replaced with composite endpoints (ADOS-2 SA + SCQ). CRRC added as study site.\n\n\nV4\n2024-04-01\nSubmitted after reported completion of data collection. Primary endpoint modified again: SCQ removed; ADOS-2 SA retained as sole primary endpoint.\n\n\n\nMeanwhile, the paper states that:\n\nparticipation recruitment and data collection began in June 2022,\nand data collection ended in March 2024.\n\nThus:\n\nrecruitment allegedly began approximately 11 months before initial registration,\nthe study reportedly remained \u201cNot yet recruiting\u201d long after recruitment allegedly began,\nand major protocol\/endpoint modifications reportedly occurred during or immediately after data collection.\n\nSeveral questions therefore appear critical for evaluating this trial:\n\nWas any participant enrolled before the V1 registration on 2023-05-26?\nIf recruitment had already begun before V1 registration, how does the study satisfy ICMJE registration requirements[4]?\nWhen exactly was the final primary endpoint (ADOS-2 SA alone) prospectively fixed relative to:\n\nparticipant enrollment,\ninterim analyses,\nknowledge of treatment outcomes,\ndatabase lock,\nand completion of data collection?\n\n\nDoes a timestamped Statistical Analysis Plan (SAP) exist that predates:\n\nparticipant enrollment,\ndatabase lock,\nand any knowledge of treatment outcomes?\n\n\n\nBecause the registry history appears to show substantial redesign of study structure and primary endpoints during or after trial execution \u2014 including endpoint modification following reported completion of data collection \u2014 clarification of when the final confirmatory design and primary endpoint were prospectively fixed would be important.\nReferences\n\nMolecular Psychiatry paper , https:\/\/www.nature.com\/articles\/s41380-026-03596-2\nClinicalTrials.gov record: NCT05890846 , https:\/\/clinicaltrials.gov\/study\/NCT05890846\nClinicalTrials.gov archived history for NCT05890846\n\nV1 (2023-05-26)\nV2 (2023-09-04)\nV3 (2024-02-02)\nV4 (2024-04-01) \n\n\nICMJE requirements on clinical trial registrations, https:\/\/www.icmje.org\/recommendations\/browse\/publishing-and-editorial-issues\/clinical-trial-registration.html\n","markdown":"### Retrospective Registration and Post-Hoc Trial Redesign Questions\n\nThis paper presents a randomized, double-blind clinical trial (**NCT05890846**) published under Nature\/ICMJE clinical-trial standards[4], which require pre-specified study designs and prospectively defined primary endpoints.\nHowever, the publicly archived ClinicalTrials.gov history appears difficult to reconcile with a prospectively fixed confirmatory trial design. According to the registry history :\n\n| Version | Date | Registry Status \/ Changes |\n|---|:---|---|\n| **V1** | 2023-05-26 | First registration submitted. Status listed as **\u201cNot yet recruiting\u201d**. Start date listed as **June 2023**. Protocol described a **4-arm**, **8-week** design with continuous outcome measures. Xuanwu Hospital listed as trial site. |\n| **V2** | 2023-09-04 | Status still listed as **\u201cNot yet recruiting\u201d**. **HPPH** replaces Xuanwu Hospital as the trial site.|\n| **V3** | 2024-02-02 | Major redesign introduced: **4 arms \u2192 2 arms**; **8 weeks \u2192 12 weeks**; continuous outcomes...