Rett Syndrome
Conditions
Keywords
MECP2, RTT, Retts, ketamine
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.
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.
Interventions
DRUGKetamine
oral ketamine dosed twice daily for 5 days
Sponsors
Vanderbilt University Medical Center
Rett Syndrome Research Trust
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
double-blind
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.
Eligibility
Sex/Gender
FEMALE
Age
6 Years to 12 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Limiting Adverse Events | 6 weeks | The Number of Participants with Treatment-emergent adverse events on ketamine compared to placebo will be summarized |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression of Improvement | 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 | 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 | 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 | 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. |
| Continuous Biosensor Data | 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. |
| Children's Sleep Habits Questionnaire | 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 | 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 | Day 1, Day 15 | ketamine EEG alpha, beta, gamma, delta and theta waveform signatures compared to placebo to indicate target engagement |
| Parent Domain Likert Scale | 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. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 7 sites in the US with active participants between 12Mar2019 and 22Nov2021.
Pre-assignment details
24 participants were screened, 23 were enrolled. 23 patients were included in the safety analysis. 21 were included in the efficacy analysis (1 was withdrawn, and 1 was excluded from analysis for study ineligibility).
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants - 0.75 mg/kg Ketamine Female patients with Rett syndrome, aged 6-12 years inclusive, who had not achieved menarche. | 11 |
| All Study Participants - 1.5 mg/kg Ketamine Female patients with Rett syndrome, aged 6-12 years inclusive, who had not achieved menarche. | 12 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants - 1.5 mg/kg Ketamine | All Study Participants - 0.75 mg/kg Ketamine | Total |
|---|---|---|---|
| Age, Continuous | 7.6 years STANDARD_DEVIATION 1.93 | 8.6 years STANDARD_DEVIATION 2.2 | 8.1 years STANDARD_DEVIATION 2.09 |
| BMI | 15.4 kg/m^2 STANDARD_DEVIATION 1.89 | 15.1 kg/m^2 STANDARD_DEVIATION 3.06 | 15.2 kg/m^2 STANDARD_DEVIATION 2.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 11 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 117.5 cm STANDARD_DEVIATION 9.41 | 126.0 cm STANDARD_DEVIATION 11.84 | 121.7 cm STANDARD_DEVIATION 11.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 9 Participants | 20 Participants |
| Region of Enrollment United States | 12 participants | 11 participants | 23 participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 21.5 kg STANDARD_DEVIATION 4.62 | 24.4 kg STANDARD_DEVIATION 7.33 | 22.9 kg STANDARD_DEVIATION 6.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 2 / 11 | 4 / 11 | 7 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Dose-Limiting Adverse Events
The Number of Participants with Treatment-emergent adverse events on ketamine compared to placebo will be summarized
Time frame: 6 weeks
Population: The Safety Population consisted of all patients who received at least 1 dose of study treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0.75 mg/kg Ketamine | Dose-Limiting Adverse Events | AEs leading to dose interruption | 0 Participants |
| 0.75 mg/kg Ketamine | Dose-Limiting Adverse Events | SAEs | 0 Participants |
| 0.75 mg/kg Ketamine | Dose-Limiting Adverse Events | No TEAEs reported | 9 Participants |
| 0.75 mg/kg Ketamine | Dose-Limiting Adverse Events | AEs leading to discontinuation | 0 Participants |
| 0.75 mg/kg Ketamine | Dose-Limiting Adverse Events | TEAEs | 2 Participants |
| 0.75 mg/kg Placebo | Dose-Limiting Adverse Events | AEs leading to discontinuation | 0 Participants |
| 0.75 mg/kg Placebo | Dose-Limiting Adverse Events | AEs leading to dose interruption | 0 Participants |
| 0.75 mg/kg Placebo | Dose-Limiting Adverse Events | TEAEs | 4 Participants |
| 0.75 mg/kg Placebo | Dose-Limiting Adverse Events | No TEAEs reported | 7 Participants |
| 0.75 mg/kg Placebo | Dose-Limiting Adverse Events | SAEs | 0 Participants |
| 1.5 mg/kg Ketamine | Dose-Limiting Adverse Events | AEs leading to discontinuation | 1 Participants |
| 1.5 mg/kg Ketamine | Dose-Limiting Adverse Events | SAEs | 0 Participants |
| 1.5 mg/kg Ketamine | Dose-Limiting Adverse Events | TEAEs | 6 Participants |
| 1.5 mg/kg Ketamine | Dose-Limiting Adverse Events | AEs leading to dose interruption | 0 Participants |
| 1.5 mg/kg Ketamine | Dose-Limiting Adverse Events | No TEAEs reported | 5 Participants |
| 1.5 mg/kg Placebo | Dose-Limiting Adverse Events | AEs leading to dose interruption | 0 Participants |
| 1.5 mg/kg Placebo | Dose-Limiting Adverse Events | SAEs | 0 Participants |
| 1.5 mg/kg Placebo | Dose-Limiting Adverse Events | TEAEs | 3 Participants |
| 1.5 mg/kg Placebo | Dose-Limiting Adverse Events | AEs leading to discontinuation | 0 Participants |
| 1.5 mg/kg Placebo | Dose-Limiting Adverse Events | No TEAEs reported | 9 Participants |
Other Pre-specified
Children's Sleep Habits Questionnaire
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.
Time frame: 4 weeks
Other Pre-specified
Clinical Global Impression of Improvement
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
Time frame: 4 weeks
Other Pre-specified
Clinician Domain Likert Scale
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.
Time frame: 4 weeks
Other Pre-specified
Continuous Biosensor Data
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.
Time frame: 6-8 weeks
Other Pre-specified
EEG Signature
ketamine EEG alpha, beta, gamma, delta and theta waveform signatures compared to placebo to indicate target engagement
Time frame: Day 1, Day 15
Other Pre-specified
Motor Behavioral Assessment
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.
Time frame: 4 weeks
Other Pre-specified
Parent Domain Likert Scale
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.
Time frame: 4 weeks
Other Pre-specified
Rett Caregiver Burden Inventory Assessment
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.
Time frame: 4 weeks
Other Pre-specified
Rett Syndrome Behaviour Questionnaire
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.
Time frame: 4 weeks