Rett Syndrome
Conditions
Brief summary
This study evaluates the safety, tolerability and efficacy of Sarizotan in reducing respiratory abnormalities in Rett Syndrome in an initial double blind 24 week period followed by an open label treatment phase of up to 168 weeks (the latter for patients with no safety and tolerability issues).
Detailed description
This is a randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and efficacy of multiple doses of sarizotan in patients with Rett syndrome with respiratory abnormalities. The study participants will be randomized to either sarizotan between 2 and 10 mg bid or placebo bid, based on age and weight criteria. All patients who have completed the final evaluations at Week 24 (Day 168) and have no safety or tolerability issues that would preclude continuing on the study medication and have been compliant with the trial requirements will have the option of continuing open-label treatment with Sarizotan for up to 168 weeks.
Interventions
DRUGSarizotan low dose
2 mg or 5 mg bid based on age and weight criteria for 24 wks DB 2 mg bid (4 to \<13 years; ≥13 years of age and weighing \<25 kg; 5 mg bid (≥13 years of age and weighing ≥25 kg). Assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
DRUGSarizotan high dose
5 mg or 10 mg bid based on age and weight criteria for 24 wks DB 5 mg bid (4 to \<13 years; ≥13 years of age and weighing \<25 kg; 10 mg bid (≥13 years of age and weighing ≥25 kg) Assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients
DRUGPlacebo
Placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
Sponsors
Newron Pharmaceuticals SPA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Body weight ≥ 10 kg * Age ≥ 4 years * Diagnosis of Rett syndrome based on consensus clinical criteria and patients with MECP2 duplications will not be eligible. * Has at least 10 episodes of breathing dysrhythmia, defined by episodes ≥10 seconds of breath holding (apnea), per hour during cardiorespiratory monitoring * Ability to take study medication provided either as capsules or combined with food/drink. * Patient is cooperative, willing to complete all aspects of the study, and capable of doing so with assistance of a caregiver.
Exclusion criteria
* Meets any of the diagnostic
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Respiratory Abnormality in Patients With Rett Syndrome | Baseline up to week 24 | Measured as the percent change in the number of apnea episodes per hour during awake time, calculated using an ambulatory data acquisition system (BioRadioTM) as part of home monitoring procedure. BioRadioTM record specific respiratory and cardiac parameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change | 24 weeks | Caregiver-rated Impression of Change (CIC): 7-point scale requiring the caregiver to rate how much the patient's illness has improved or worsened relative to the baseline state. 7-point Likert-type scale for which ratings range from 1 = very much improved to 7 = very much worse, with 4 = no change. This caregiver-rated measure considered activities, behavior, mood and functioning. This rating was performed in consultation with the study Investigator but was based largely on the caregivers' evaluation during the reporting period. The single rating of the CIC was to be based on changes in the following domains: • Activities (watching TV, interest in conversations around her, cooperation during toileting, dressing/bathing, etc.), • Communication (verbal or by eye movements, hand movements, or head movements), • Behavior (agitation, refusal to feed, scratching, social avoidance), • Participation in family/outdoor/social events) |
Countries
Australia, India, Italy, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 14 sites in 5 countries. Enrollment occurred from 26-Oct-2016 through February 2019 . An analysis was planned when the primary efficacy data at Week 24 were available for all patients (06 August 2019 - last patient last visit for double-blind part of the study). Patients without safety and tolerability issues continued in the open label with sarizotan for an additional 24 weeks and then another 48 weeks if no safety issues were present.
Pre-assignment details
A total of 198 patients were screened, of which 69 (34.8%) patients were screen failures. A total of 129 patients were randomized in the study. A total of 128 patients were exposed to at least one dose of IMP, with placebo ITT group (40) vs safety pop (39).
Participants by arm
| Arm | Count |
|---|---|
| Sarizotan Low Dose 2 mg or 5 mg bid based on age and weight criteria for 24 wks DB
2 mg bid (4 to \<13 years; ≥13 years of age and weighing \<25 kg
5 mg bid (≥13 years of age and weighing ≥25 kg) | 33 |
| Sarizotan High Dose 5 mg or 10 mg bid based on age and weight criteria for 24 wks DB
5 mg bid (4 to \<13 years; ≥13 years of age and weighing \<25 kg
10 mg bid (≥13 years of age and weighing ≥25 kg) | 56 |
| Placebo Placebo BID | 40 |
| Total | 129 |
Baseline characteristics
| Characteristic | Sarizotan Low Dose | Total | Placebo | Sarizotan High Dose |
|---|---|---|---|---|
| Age, Categorical <=18 years | 23 Participants | 85 Participants | 27 Participants | 35 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 44 Participants | 13 Participants | 21 Participants |
| Age, Continuous | 13.23 years STANDARD_DEVIATION 7.195 | 14.51 years STANDARD_DEVIATION 8.78 | 14.13 years STANDARD_DEVIATION 9.155 | 15.55 years STANDARD_DEVIATION 9.362 |
| Duration of Rett syndrome | 87.90 months STANDARD_DEVIATION 72.536 | 87.94 months STANDARD_DEVIATION 70.696 | 73.94 months STANDARD_DEVIATION 65.8 | 97.18 months STANDARD_DEVIATION 72.922 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 13 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 116 Participants | 36 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 37 Participants | 13 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 23 Participants | 82 Participants | 22 Participants | 37 Participants |
| Region of Enrollment Australia | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Region of Enrollment India | 8 Participants | 34 Participants | 12 Participants | 14 Participants |
| Region of Enrollment Italy | 8 Participants | 30 Participants | 9 Participants | 13 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 21 Participants | 6 Participants | 10 Participants |
| Region of Enrollment United States | 11 Participants | 41 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Female | 33 Participants | 129 Participants | 40 Participants | 56 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 56 | 0 / 39 |
| other Total, other adverse events | 25 / 33 | 46 / 56 | 30 / 39 |
| serious Total, serious adverse events | 2 / 33 | 10 / 56 | 5 / 39 |
Outcome results
Primary
Reduction in Respiratory Abnormality in Patients With Rett Syndrome
Measured as the percent change in the number of apnea episodes per hour during awake time, calculated using an ambulatory data acquisition system (BioRadioTM) as part of home monitoring procedure. BioRadioTM record specific respiratory and cardiac parameters.
Time frame: Baseline up to week 24
Population: The ITT population included all patients who were randomized to treatment. This population was used for all efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sarizotan Low Dose | Reduction in Respiratory Abnormality in Patients With Rett Syndrome | 1.54 % of change in mean counts per hr | Standard Error 10.1228 |
| Sarizotan High Dose | Reduction in Respiratory Abnormality in Patients With Rett Syndrome | 13.211 % of change in mean counts per hr | Standard Error 7.5075 |
| Placebo | Reduction in Respiratory Abnormality in Patients With Rett Syndrome | 18.503 % of change in mean counts per hr | Standard Error 8.441 |
Comparison: Primary inferential comparison between treatment groups used a restricted maximum likelihood (REML)-based, mixed-effects repeated measures model approach (MMRM) with 95% CI for the difference between treatment groups for % change from baseline in the number of apnea episodes. Model included % change from baseline as response, the fixed, categorical effects of treatment group, visit, treatment group-by-visit interaction, and the continuous terms age and baseline value as covariate.p-value: 0.641195% CI: [-27.741, 17.157]Mixed Models Analysis
Comparison: Primary inferential comparison between treatment groups used a restricted maximum likelihood (REML)-based, mixed-effects repeated measures model approach (MMRM) with 95% CI for the difference between treatment groups for % change from baseline in the number of apnea episodes. Model included % change from baseline as response, the fixed, categorical effects of treatment group, visit, treatment group-by-visit interaction, and the continuous terms age and baseline value as covariate.p-value: 0.201195% CI: [-43.119, 9.186]Mixed Models Analysis
Secondary
Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change
Caregiver-rated Impression of Change (CIC): 7-point scale requiring the caregiver to rate how much the patient's illness has improved or worsened relative to the baseline state. 7-point Likert-type scale for which ratings range from 1 = very much improved to 7 = very much worse, with 4 = no change. This caregiver-rated measure considered activities, behavior, mood and functioning. This rating was performed in consultation with the study Investigator but was based largely on the caregivers' evaluation during the reporting period. The single rating of the CIC was to be based on changes in the following domains: • Activities (watching TV, interest in conversations around her, cooperation during toileting, dressing/bathing, etc.), • Communication (verbal or by eye movements, hand movements, or head movements), • Behavior (agitation, refusal to feed, scratching, social avoidance), • Participation in family/outdoor/social events)
Time frame: 24 weeks
Population: The ITT population included all patients who were randomized to treatment. This population was used for all efficacy analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sarizotan Low Dose | Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change | 3.6 score on a scale | Standard Deviation 0.67 |
| Sarizotan High Dose | Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change | 3.5 score on a scale | Standard Deviation 1.12 |
| Placebo | Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change | 3.4 score on a scale | Standard Deviation 0.79 |