| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039000 |
| E.1.2 | Term | Rett's disorder |
| E.1.2 | System Organ Class | 100000004850 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of sarizotan (2 to 10 mg bid), compared to placebo, on reducing the number of apnea episodes, during awake time, in patients with RTT with respiratory abnormalities. |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Efficacy Objective: To evaluate the effect of sarizotan (2 to 10 mg bid), compared to placebo, on the Caregiver-rated Impression of Change (CIC) from baseline.
Secondary Objectives:
Safety: To evaluate the safety and tolerability of sarizotan (2 to 10 mg bid).
Efficacy: To evaluate the efficacy of the dose range of sarizotan, compared to placebo, on the following:
- Respiratory symptoms: Percent time spent with breathing dysrhythmia per hour; Number of hyperventilation episodes (≥10 sec each) per hour; Oxygen saturation; Respiratory Distress Index; Incidence of breathing dysrhythmia episodes.
- Motor behavior;
- Global change from baseline;
- Caregiver burden;
- Overall assessment of symptoms of RTT.
To determine the pharmacokinetic (PK) profile of sarizotan at the doses tested and compare with the PK profile in adults. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The patient must meet all of the following inclusion criteria to be eligible for enrolment into the study:
Demographics
1.Female or male ≥ 4 years of age.
2.Body weight ≥ 10 kg, and within the expected range for an RTT patient, based on age and height.
Diagnostic
3.Diagnosis of Rett syndrome based on consensus clinical criteria; a test for MECP2 mutations (Xq28), will be performed at screening if results from an accredited laboratory are not available; selection for the trial is not contigent on the result of MECP2 test. Patients with known MECP2 duplications will not be eligible.
4.One or more of the following breathing dysfunctions: periodic apnea during wakefulness; intermittent hyperventilation; breath holding spells; air swallowing; forced expulsion of air or saliva.
5.Patient meets all of the following criteria related to breathing abnormalities:
a.Parent report of 10 episodes or more of breathing abnormality per day during wakefulness in the week prior to the screening visit;
b.Time per hour spent on normal breathing is less than 90% of the total time per hour of wakefulness (i.e., ≥10% of the time should be abnormal breathing);
c.Has at least 10 episodes of breathing dysrhythmia, defined by episodes ≥10 seconds of breath holding (apnea), per hour during cardiorespiratory monitoring (performed with home/ambulatory monitoring system during screening period).
6.Stable medication regimen for 4 weeks prior to beginning the study (if receiving services - physical, occupational, or speech therapy - subjects must be on a stable regimen of these services for 3 months prior to beginning the study). Female patients of childbearing potential are to use adequate contraception as recommended by their Health Care Provider.
Procedural
7.Parent/legal guardian/representative has provided written consent prior to the patient participating in the study. Where feasible, consent or assent for patients less than 18 years of age, has also been provided by the patient.
8.Ability to take study medication provided either as capsules or combined with food/drink.
9.Patient is cooperative, willing to complete all aspects of the study, and capable of doing so with assistance of a caregiver.
10.Caregiver is able to understand the instructions and fully participate. |
|
| E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a patient from study enrollment:
1.Meets any of the diagnostic exclusion criteria for Rett syndrome, Typical;
2.Patient is participating in a clinical trial with another investigational drug or has taken an investigational drug within one month or 5 half-lives (whichever is longer) prior to screening;
3.Hypersensitivity to sarizotan or other 5-HT1a agonists, [UK only: or to the capsule material gelatin or microcrystalline cellulose used in the placebo capsules];
4.Current clinically significant (as determined by Investigator) a) cardiovascular, respiratory (e.g. severe asthma), gastrointestinal, renal, hepatic, hematologic or other medical disorders, in addition to those directly related to the patient’s Rett syndrome [for US, Italy, India
and Australia];
b) cardiovascular, respiratory (e.g. severe asthma), or gastrointestinal
disease, renal impairment (as indicated by creatinine >2X ULN), hepatic
impairment (as indicated by total bilirubin >2X ULN), history of
moderate or severe hepatic insufficiency or moderate or severe liver cirrhosis, or hematologic or other medical disorders, in addition to those directly related to the patient's Rett syndrome [for UK only];
5.QTcF interval on the ECG is greater than 450 msec.
6.Surgery planned during the study (except for insertion of gastrostomy tube);
7.Severe diabetes mellitus or fatty acid oxidation disorder.
8.Ophthalmologic history including any of the following conditions: albino patients, family history of hereditary retinal disease, retinitis pigmentosa, any active retinopathy or severe diabetic retinopathy.
9.Females who are pregnant, breastfeeding, or of childbearing potential and not using adequate contraception, as recommended by their Health Care Provider.
10.[UK only: Subjects who have an inborn error of metabolism.]
11.Evidence of clinically significant malnutrition.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent reduction in the number of apnea episodes (each ≥10 seconds in duration) per hour, during awake time. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout all the study duration |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Outcome - global assessment performed by the caregiver
Other Secondary Efficacy Outcome - Respiratory Measures; Heart beat variables; Motor-Behavioral Assessment Scale; Clinical Global Impression of Change (CGI-C); Caregiver Top 3 Concerns; Rett Syndrome Clinical Severity Scale (RCSS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For efficacy outcome: Throughout the entire study duration
For PK: prior dosing and at approximately 1 and 4 hr post-dose on Day 1 and on Day 15 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| open label in the extension phase |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| India |
| Italy |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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