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Clinical Trial
. 2025 Jan 24;17(1):4.
doi: 10.1186/s11689-025-09591-y.

A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome

Kathleen Campbell #  1 , Jeffrey L Neul #  2 , David N Lieberman  3 , Elizabeth Berry-Kravis  4 , Tim A Benke  5 , Cary Fu  6 , Alan Percy  7 , Bernhard Suter  8 , David Morris  9 , Randall L Carpenter  10 , Eric D Marsh #  11 , Jana von Hehn #  12
Affiliations
Clinical Trial

A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome

Kathleen Campbell et al. J Neurodev Disord. .

Abstract

Background: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.

Design: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.

Methods: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity.

Results: Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019-11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine.

Conclusions: Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT.

Trial registration: Registered at clinicaltrials.gov NCT03633058.

Keywords: Clinical trial; Electroencephalography; Ketamine; Rett syndrome.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was reviewed and approved by the Food and Drug Administration, by the institutional review boards at each participating site, and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Appropriate written informed consent for study participation was obtained prior to completing any study procedures. Consent for publication: Not applicable. Competing interests: KC has no competing interests. EBK has no competing interests. DNL has acted as a consultant for Acadia Pharmaceuticals, Neurogene, and Taysha Gene Therapies. He has been a Site PI for industry sponsored trials from Acadia Pharmaceuticals, GW Pharmaceuticals, Anavex Life Sciences, and Neurogene. He has received research support from RSRT. TAB has received research funding from GRIN2B Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation; consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, Takeda Pharmaceutical Company Limited and Taysha; clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Rett Syndrome Research Trust; all remuneration has been made to his department. CF has been a site investigator for industry sponsored clinical trials from Zogenix pharmaceuticals, Acadia pharmaceuticals, GW pharmaceuticals, Neurogene, and Taysha. AP was a site investigator for Acadia Pharmaceuticals and is a consultant for Acadia, Neurogene, and Taysha Gene Therapies. BS has received research funding from the NIH, IRSF, and the Blue Bird Circle; he has provided consultancy for IONIS pharmaceuticals, Neurogene, and Taysha; clinical trials with Acadia Pharmaceuticals Inc., Marinus Pharmaceuticals, Neurogene, and the Rett Syndrome Research Trust. EDM has acted as a consultant for Stoke therapeutics, Acadia Pharmaceuticals, and Novartis Pharmaceuticals. He has been a Site PI for industry sponsored trials for Stoke Theraputics, Acadia Pharmaceuticals, GW Pharmaceuticals, Zogenix Pharmaceuticals, Marinus Pharmaceuticals, Takeda Pharmaceuticals and Epygenic Pharmaceuticals. He has received research support from the NIH, Penn Orphan Disease center, RettSyndrome.org, RSRT, and International CDKL5 Research Foundation. DM has no competing interests. RLC has no competing interests. JLN has acted as a consultant for Acadia Pharmaceuticals, Alycone Pharmaceuticals, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, IONIS Pharmaceuticals, Neurogene, Newron Pharmaceuticals, Ovid Therapeutics, Taysha Gene Therapies, and Ultragenyx. He has been a site PI for industry sponsored clinical research for Acadia Pharmaceuticals, GW Pharmaceuticals, IONIS Pharmaceuticals, Newron Pharmaceuticals. He has received research support from the National Institutes of Health, International Rett Syndrome Foundation, and RSRT. JvH has no competing interests.

Figures

Fig. 1
Fig. 1
Study activities and safety monitoring
Fig. 2
Fig. 2
CONSORT diagram of study procedure and participant flow [29, 30]
Fig. 3
Fig. 3
Change in EEG measures after administration of drug compared with placebo. Black solid horizontal lines represent means, black dashed line represents zero change, gray solid lines connect paired samples from the same participants
Fig. 4
Fig. 4
Correlation between alpha/delta power ratio and MBA at baseline. Overlayed text shows Pearson correlation and p-value. Blue line represents linear model, shaded area represents 95% confidence interval of linear model
See this image and copyright information in PMC

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