A Study to Evaluate Ketamine for the Treatment of Rett Syndrome

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ClinicalTrials.gov Identifier: NCT03633058

Recruitment Status : Completed

First Posted : August 16, 2018

Results First Posted : March 27, 2024

Last Update Posted : May 28, 2024

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Sponsor:

Collaborator:

Vanderbilt University Medical Center

Information provided by (Responsible Party):

Jeffrey Neul, Vanderbilt University

Study Description

Brief Summary:

This 2 cohort, sequential, ascending dose study will assess the safety, tolerability and efficacy of oral ketamine dosed in a single 5-day BID regimen in addition to placebo, in a 4-week cross-over design in patients with Rett Syndrome. Approximately 12 patients per cohort are anticipated to participate for approximately 8-10 weeks at approximately 7 US study centers.

Condition or disease	Intervention/treatment	Phase
Rett Syndrome	Drug: Ketamine	Phase 2

Detailed Description:

This study is designed to assess oral ketamine for the treatment of Rett Syndrome and consists of up to 4 ascending dose cohorts, each assessing 1 dose level of ketamine vs placebo. Patients will receive in either order, a 5-day BID regimen of both placebo and the cohort-specified dose level of oral ketamine. Patients may only participate in 1 cohort. Safety and tolerability will be assessed via patient disposition, vital signs, physical examination, adverse events and concomitant medication use. Efficacy will be assessed via physician and caregiver questionnaires and assessments, and continuous, wearable, at-home biosensor data collection. An independent safety committee will review safety data from each cohort to determine if the subsequent ascending dose cohort is warranted. A total of 12 patients per cohort is anticipated at approximately 7 sites. The screening period will last between 2 and 4 weeks, the cross-over treatment period will last 4 weeks, and the safety follow-up period will last 2 weeks. Total patient participation is approximately 8-10 weeks.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	23 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Intervention Model Description:	Patients will receive placebo and ketamine for 5 days BID each, in a double-blind treatment order, and will be assessed for 2 weeks after each treatment.
Masking:	Triple (Participant, Care Provider, Investigator)
Masking Description:	double-blind
Primary Purpose:	Treatment
Official Title:	A Randomized, Double-blind, Placebo-controlled, Cross-over Study to Assess the Safety, Tolerability and Efficacy of Oral Ketamine for Patients With Rett Syndrome
Actual Study Start Date :	March 12, 2019
Actual Primary Completion Date :	November 8, 2021
Actual Study Completion Date :	November 22, 2021

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Rett syndrome

MedlinePlus related topics: Rett Syndrome

Drug Information available for: Ketamine

Genetic and Rare Diseases Information Center resources: Rett Syndrome Oculocerebral Syndrome With Hypopigmentation

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: 0.75 mg/kg ketamine will be dosed orally twice daily for 5 days at 0.75 mg/kg, in addition to 5 days of placebo	Drug: Ketamine oral ketamine dosed twice daily for 5 days Other Name: Ketalar
Experimental: 1.5 mg/kg ketamine will be dosed orally twice daily for 5 days at 0.75 mg/kg, in addition to 5 days of placebo	Drug: Ketamine oral ketamine dosed twice daily for 5 days Other Name: Ketalar

Outcome Measures

Primary Outcome Measures :

Dose-Limiting Adverse Events [ Time Frame: 6 weeks ]
The Number of Participants with Treatment-emergent adverse events on ketamine compared to placebo will be summarized

Other Outcome Measures:

Continuous Biosensor Data [ Time Frame: 6-8 weeks ]
2 different non-invasive, wearable devices will be used in the study to determine changes in physiologic measures for the patient in the home environment. Biosensors will be worn continuously during the screening and treatment period to measure activity, sleep, position, heart rate, and breathing.
Clinical Global Impression of Improvement [ Time Frame: 4 weeks ]
Clinicians will use a 7 point Likert Scale to rate change from baseline symptom severity by addressing the question, "Compared to the patient's condition of Rett syndrome prior to treatment initiation at baseline, the patient's current condition is: 1 very much improved, 2 much improved, 3 minimally improved, 4 no change, 5 minimally worse, 6 much worse, 7 very much worse. No change would be scored a 0, while improvement would be scored at -1, -2, or -3 and worsening would be scored +1, +2 or +3, depending on the degree of perceived change. Negative change indicates improvement while positive change indicates worsening
Motor Behavioral Assessment [ Time Frame: 4 weeks ]
a 37-item questionnaire for clinicians to evaluate current behavioral/social, orofacial/respiratory, and motor/physical symptoms. Each item is rated either 0 (normal or never), 1 (mild or rare), 2 (moderate or occasional), 3 (marked or frequent), 4 (very severe or constant), where higher numbers indicate higher severity. Each subscale is summed for a subscale score, while the total score is a sum of the subscale scores. The behavioral/social subscale score may range from 0 to 64; the orofacial/respiratory subscale may range from 0 to 28, and motor/physical subscale may range from 0 to 56. Total score may range from 0 to 148.
Clinician Domain Likert Scale [ Time Frame: 4 weeks ]
an 8 category (domain) questionnaire to assess current hand function, walking, verbal and non-verbal communication, comprehension, attention, behavior problems, and mood by considering the question, "Considering your experience with the patient at this visit, please rate the level of function in each category". Each domain will be rated on a 7 point Likert Scale where the clinician will select 1 of 7 choices: 1 normal, 2 borderline abnormal, 3 mildly abnormal, 4 moderately abnormal, 5 markedly abnormal, 6 severely abnormal, 7 extremely abnormal. Lower values indicate lesser severity while higher values indicate higher severity.
Rett Syndrome Behaviour Questionnaire [ Time Frame: 4 weeks ]
a 45-item questionnaire for clinicians to evaluate current behavior and emotional features. Each item is rated either 0 (not true or not done), 1 (somewhat or sometimes true) and 2 (very true), where higher numbers indicate higher severity. Total score is summed and may range from 0 to 90.
Parent Domain Likert Scale [ Time Frame: 4 weeks ]
a 9 category (domain) questionnaire to assess current hand function, walking, verbal and non-verbal communication, comprehension, attention, behavior problems, mood, and seizure activity, by considering the question, "Considering your experience with your child over the past 7 days, please rate your child's level of function in each category". Each domain will be rated on a 7 point Likert Scale where the parent/caregiver will select 1 of 7 choices: 1 normal, 2 borderline abnormal, 3 mildly abnormal, 4 moderately abnormal, 5 markedly abnormal, 6 severely abnormal, 7 extremely abnormal. Lower values indicate lesser severity while higher values indicate higher severity.
Children's Sleep Habits Questionnaire [ Time Frame: 4 weeks ]
a 35-item questionnaire for parents to evaluate current sleep and common sleep problems. The parent/caregiver will rate each item as 1 (rarely), 2 (sometimes), or 3 (usually), where higher scores indicate higher severity. The parent/caregiver will also indicate if the item is a problem or not. A total score of the sum of each item and 8 subscale scores (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime sleepiness) are possible. Total scores between 0 and 70 are possible, where higher scores indicate more sleep problems.
Rett Caregiver Burden Inventory Assessment [ Time Frame: 4 weeks ]
a 26-item questionnaire for parents to evaluate the burden of care on their quality of life. The parent/caregiver will rate each item as 0 (never), 1 (rarely), 2 (sometimes), 3 (quite frequently), or 4 (nearly always) where higher scores indicate higher severity. Total scores between 0 and 104 are possible, where higher scores indicate more caregiver burden.
EEG Signature [ Time Frame: Day 1, Day 15 ]
ketamine EEG alpha, beta, gamma, delta and theta waveform signatures compared to placebo to indicate target engagement

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	6 Years to 12 Years (Child)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Female Rett Syndrome patients diagnosed with Rett Syndrome with a confirmed MECP2 mutation
between the ages of 6 and 12, inclusive, who have not achieved menarche
ability to take oral medications
are generally healthy.

Exclusion Criteria:

Patients not on stable medication regimens/other types of behavioral, educational, or dietary interventions for at least 4 weeks,
are taking medications that may interact with ketamine,
have a condition where increased blood pressure, spinal fluid pressure, or ocular pressure may put the patient at increased risk.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03633058

Locations

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United States, Alabama
University of Alabama Birmingham School of Medicine
Birmingham, Alabama, United States, 35294
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37203
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030

Sponsors and Collaborators

Rett Syndrome Research Trust

Vanderbilt University Medical Center

Investigators

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Principal Investigator:	Jeffrey Neul, MD, PhD	Vanderbilt University Medical Center
Study Director:	Jana von Hehn, PhD	Rett Syndrome Research Trust

Study Documents (Full-Text)

Documents provided by Jeffrey Neul, Vanderbilt University:

Study Protocol and Statistical Analysis Plan [PDF] July 1, 2020

More Information

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Responsible Party:	Jeffrey Neul, Director, Vanderbilt Kennedy Center, Annette Schaffer Eskind Chair, Professor of Pediatrics, Pharmacology, and Special Education, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT03633058
Other Study ID Numbers:	Ket-101-RSRT
First Posted:	August 16, 2018 Key Record Dates
Results First Posted:	March 27, 2024
Last Update Posted:	May 28, 2024
Last Verified:	May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Jeffrey Neul, Vanderbilt University:


MECP2 RTT Retts ketamine

Additional relevant MeSH terms:

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Rett Syndrome Syndrome Disease Pathologic Processes Mental Retardation, X-Linked Intellectual Disability Neurobehavioral Manifestations Neurologic Manifestations Nervous System Diseases Genetic Diseases, X-Linked Genetic Diseases, Inborn Heredodegenerative Disorders, Nervous System Ketamine	Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anesthetics, Dissociative Anesthetics, Intravenous Anesthetics, General Anesthetics Central Nervous System Depressants Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action

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