A Study to Evaluate Ketamine for the Treatment of Rett Syndrome

• ClinicalTrials.gov Identifier: NCT03633058
• Recruitment Status: Completed
• First Posted: August 16, 2018
• Last Update Posted: April 22, 2022
• Sponsor: Rett Syndrome Research Trust
• Collaborator: Vanderbilt University Medical Center
• Information provided by (Responsible Party): Rett Syndrome Research Trust

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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 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

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 :

1. Dose-Limiting Adverse Events [ Time Frame: 6 weeks ]
   the incidence of treatment-emergent adverse events will be summarized compared to placebo

Secondary Outcome Measures :

1. 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
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.

Other Outcome Measures:

1. 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

• 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

Locations

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

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

More Information

• Responsible Party: Rett Syndrome Research Trust
• ClinicalTrials.gov Identifier: NCT03633058
• Other Study ID Numbers: Ket-101-RSRT
• First Posted: August 16, 2018
• Last Update Posted: April 22, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Rett Syndrome Research Trust:

MECP2; RTT; Retts; ketamine

Additional relevant MeSH terms:

Rett Syndrome; Syndrome; Ketamine; 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; 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