Evaluation of the Efficacy, Safety, and Tolerability of Sarizotan in Rett Syndrome With Respiratory Symptoms

• Sponsor: Newron Pharmaceuticals SPA
• Information provided by (Responsible Party): Newron Pharmaceuticals SPA

Study Description

Brief Summary:

This study evaluates the safety, tolerability and efficacy of Sarizotan in reducing respiratory abnormalities in Rett Syndrome.

Condition or disease	Intervention/treatment	Phase
Rett Syndrome	Drug: Sarizotan; Drug: Placebo	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 129 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-Blind, Placebo-Controlled 6-month Study to Evaluate the Efficacy, Safety, and Tolerability of Sarizotan in Patients With Rett Syndrome With Respiratory Symptoms
• Actual Study Start Date: August 2016
• Estimated Primary Completion Date: April 2019
• Estimated Study Completion Date: April 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Sarizotan; Between 2 to 10 mg bid based on age and weight criteria.	Drug: Sarizotan; 2 to 10 mg per day of Sarizotan followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.; Other Name: sarizotan hydrochloride
Placebo Comparator: Placebo; Placebo bid respectively	Drug: Placebo; placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.; Other Name: Placebo capsules with microcrystalline cellulose

Outcome Measures

Primary Outcome Measures :

1. Reduction in respiratory abnormality in patients with Rett syndrome [ Time Frame: 3 days prior to Baseline up to week 24 ]
   Measured as the percent reduction 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 Outcome Measures :

1. Efficacy of sarizotan assessed by the caregiver [ Time Frame: 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.
2. Safety and tolerability of sarizotan in patients with Rett syndrome with respiratory symptoms. [ Time Frame: 24 weeks ]
   Adverse events (AEs),Vital signs (systolic/diastolic blood pressure, pulse, body weight, body temperature, respiratory rate),Laboratory evaluations (blood chemistry, hematology, urinalysis, plasma ACTH, cortisol and prolactin),Electrocardiogram (ECG) - 12-lead standard,Physical examination Neurological examination, Ophthalmology examination (including OCT if feasible), Tanner staging
3. Respiratory symptoms - Percent time spent with breathing dysrhythmia per hour [ Time Frame: 24 weeks ]
   Percent time spent with breathing dysrhythmia per hour. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
4. Respiratory symptoms - Number of hyperventilation episodes [ Time Frame: 24 weeks ]
   Number of hyperventilation episodes. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
5. Respiratory symptoms - Oxygen saturation [ Time Frame: 24 weeks ]
   Oxygen saturation. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
6. Respiratory symptoms - Respiratory Distress Index; [ Time Frame: 24 weeks ]
   Respiratory Distress Index; These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
7. Respiratory symptoms - Incidence of breathing dysrhythmia episodes [ Time Frame: 24 weeks ]
   Incidence of breathing dysrhythmia episodes. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
8. Motor behaviour [ Time Frame: 24 weeks ]

   Assessed by Motor-Behavioral Assessment Scale:

   I. Behavioral/Social Assessment - 16 items II. Orofacial/Respiratory Assessment - 7 items III. Motor Assessment/Physical Signs - 14 items.

9. Global change from baseline [ Time Frame: 24 weeks ]
   assessed by the Clinical Global Impression of Change (CGI-C): 7-point scale requiring the clinician to rate how much the patient's illness has improved or worsened relative to the baseline state.
10. Caregiver burden [ Time Frame: 24 weeks ]
    Caregiver Top 3 Concerns: Visual Analogue Scale-based evaluation of three priority concerns identified by caregivers related to the patient's RTT syndrome which they would like to see change as a result of treatment. The severity of these concerns is rated by the caregiver at baseline and is evaluated again at subsequent follow-up visits.
11. Overall assessment of symptoms of Rett syndrome [ Time Frame: 24 weeks ]
    Assessed by Rett Syndrome Clinical Severity Scale (RCSS): Frequency and manageability of seizures, respiratory irregularities, scoliosis, ability to walk (gait apraxia), hand use, speech and sleep; yielding total and feature-specific scores.
12. Pharmacokinetics profile of sarizotan and its comparison with the profile in adults [ Time Frame: Baseline, 1 and 4 hr post-dose on Day 1, and 1 and 4 hr post-dose on Day 15 ]
    measurement of plasma levels of Sarizotan and its major metabolites from blood samples collected from the patients at the specified time points.

Eligibility Criteria

• Ages Eligible for Study: 4 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 exclusion criteria for Rett syndrome, Typical (Neul et al, 2010);
• Patient is participating in a clinical trial with another investigational drug
• Hypersensitivity to sarizotan or other 5-HT1a agonists;
• Current clinically significant (as determined by Investigator) 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;
• QTcF interval on the ECG is greater than 450 msec.
• Surgery planned during the study (except for insertion of gastrostomy tube);
• Severe diabetes mellitus or fatty acid oxidation disorder.
• 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.
• Females who are pregnant, breastfeeding, or of childbearing potential and not using a hormonal contraceptive.

Contacts and Locations

Locations

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35233

United States, California

University of California

San Diego, California, United States, 92093

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Minnesota

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, United States, 55101

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

Australia, Western Australia

South Metropolitan Health Service Fiona Stanley Hospital

Murdoch, Western Australia, Australia, 6961

India

Amrita Institute of Medical Sciences

Kochi, Kerala, India, 682041

Vijaya Health Centre

Chennai, Tamilnadu, India, 600 026

Apollo Gleneagles Hospitals

Kolkata, West Bengal, India, 700054

P.D. Hinduja National Hospital and Medical Research Centre

Mumbai, India, 400 016

Jaslok Hospital and Research centre

Mumbai, India, 400 026

All India Institute of Medical Sciences

New Delhi, India, 110 029

Italy

A.O.U. Senese Policlinico Santa Maria alle Scotte

Siena, Tuscany, Italy, 53100

U.O. Neuropsichiatria Infantile

Milano, Italy, 20142

United Kingdom

King's College Hospital

London, United Kingdom, SE5 8AF

Sponsors and Collaborators

Newron Pharmaceuticals SPA

Investigators

• Study Director: Ravi Anand, MD; Newron Pharmaceuticals

More Information

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Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome. Am J Respir Cell Mol Biol. 2014 Jun;50(6):1031-9. doi: 10.1165/rcmb.2013-0372OC.

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• Responsible Party: Newron Pharmaceuticals SPA
• ClinicalTrials.gov Identifier: NCT02790034 History of Changes
• Other Study ID Numbers: Sarizotan/001/II/2015
• First Posted: June 3, 2016
• Last Update Posted: February 4, 2019
• Last Verified: February 2019

Additional relevant MeSH terms:

Rett Syndrome; Syndrome; Signs and Symptoms, Respiratory; 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; Signs and Symptoms