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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Newron
Sponsor:
Information provided by (Responsible Party):
Newron
ClinicalTrials.gov Identifier:
NCT02790034
First received: May 24, 2016
Last updated: March 13, 2017
Last verified: March 2017
  Purpose
This study evaluates the safety, tolerability and efficacy of Sarizotan in reducing respiratory abnormalities in Rett Syndrome. A third of equally randomised patients in to will be treated with 5 mg BID, another third with 10 mg BID and the remaining third with placebo BID over a course of 24 weeks.

Condition Intervention Phase
Rett Syndrome
Drug: Sarizotan
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Newron:

Primary Outcome Measures:
  • 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:
  • 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.

  • 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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.


  • 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.

  • 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.

  • 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.

  • 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.


Estimated Enrollment: 129
Study Start Date: August 2016
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Sarizotan 5 mg
Patients will receive 1 capsule of 5 mg Sarizotan BID for 24 weeks.
Drug: Sarizotan
5 mg or 10 mg per day of Sarizotan followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
Other Names:
  • sarizotan hydrochloride
  • EMD128130
Active Comparator: Sarizotan 10 mg
Patients will receive 1 capsule of 10 mg Sarizotan BID for 24 weeks.
Drug: Sarizotan
5 mg or 10 mg per day of Sarizotan followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
Other Names:
  • sarizotan hydrochloride
  • EMD128130
Placebo Comparator: Placebo
Patients will receive 1 capsule of placebo BID for 24 weeks.
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

Detailed Description:

A minimum of 43 patients per arm will be treated in this study. Patients in the two groups that receive sarizotan will all start with single dose of 5 mg on Day 1 (Dose level 1). The dose will be increased to 5 mg BID on Day 2 for these 86 patients until Day 7 (Dose level 2). On Day 8, patients that are assigned for treatment with 10 mg BID will receive a single dose of 10 mg (Dose level 3), and 10 mg BID from Day 9 until Day 14. Patients to be treated with 5 mg BID or placebo continue with the same dose until Day 14.

On Day 14, all patients will return for scheduled visits for safety and selected efficacy evaluations. The tolerability of the current dose of study medication will be evaluated, and the patient will be housed overnight, if necessary.

On Day 15, if there are no safety or tolerability issues that would require a dose reduction, patients will be given the morning dose of Dose Level 4 (5 mg sarizotan, 10 mg sarizotan or placebo, bid). Prior to administering the dose, a PK blood sample for assessing steady state trough levels of sarizotan at Dose Level 4 will be taken, and PK blood samples will be collected at 1 and 4 hr post-dose following the dose. Post-dose safety assessments will be performed, and if there are no tolerability issues, patients will be released from the hospital after the last PK sample, and will be provided with a supply of Dose Level 4 (or a lower dose if Dose Level 4 was not tolerated) for dosing on Days 15 [PM] to 56 (Week 8). Home respiratory monitoring will be attempted for 6 hours each day on the 3 days prior to each of the scheduled office visits at Weeks 8, 16 and 24.

On Weeks 8 and 16 patients return for safety and efficacy evaluations. In addition, plasma ACTH and cortisol measurements, and an ophthalmological examination will be done at Week 16. At each of these visits, the patient will be dispensed an 8-week supply of their current dose level of study medication for dosing during the period until the next scheduled visit, provided there are no safety or tolerability issues that would require a dose reduction.

  Eligibility

Ages Eligible for Study:   13 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Body weight ≥ 25 kg
  • Diagnostic:

    1. Diagnosis of Rett syndrome based on consensus clinical criteria (Neul et al, 2010). 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 contingent on the results of the MECP2 test. Patients with MECP2 duplications will not be eligible
    2. 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.
    3. Patient meets all of the following criteria related to breathing abnormalities:
  • Parent report of 10 episodes or more of breathing abnormality per day during wakefulness in the week prior to the screening visit;
  • 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);
  • 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).
  • Stable medication regimen for 4 weeks prior to beginning the study (if receiving services for physical, occupational, or speech therapy - subjects must be on a stable regimen of these services for 3 months prior to beginning the study).
  • Procedural

    1. 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.
    2. Ability to swallow study medication provided either as capsules or combined with food/drink.
    3. Patient is cooperative, willing to complete all aspects of the study, and capable of doing so with assistance of a caregiver.
    4. Caregiver is able to understand the instructions and fully participate.

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 or has taken an investigational drug within one month or 5 half-lives (whichever is longer) prior to screening;
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02790034

Contacts
Contact: Ravi Anand, MD +39 026103461 ravi@anand.ch

Locations
United States, Alabama
University of Alabama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Jane Lane    205-934-1130    jlane@uab.edu   
Principal Investigator: Alan Percy, MD         
United States, California
University of California Recruiting
San Diego, California, United States, 92093
Contact: Karen Ditslear    858-246-2288    kditslear@ucsd.edu   
Principal Investigator: Jeffrey Neul, MD         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Susan Rhode    312-942-0079    susan_rohde@rush.edu   
Principal Investigator: Peter Heydeman, MD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Mohammad Naqvi    832-824-3634    mfnaqvi@texaschildrens.org   
Principal Investigator: Daniel Glaze, MD         
India
All India Institute of Medical Sciences Not yet recruiting
Ansari Nagar, New Delhi, India, 110 029
Contact: Sheffali Gulati    +91 986 839 7532    sheffaligulati@gmail.com   
Principal Investigator: Sheffali Gulati, MD         
Apollo Gleneagles Hospitals Not yet recruiting
Kolkata, West Bengal, India, 700054
Contact: Arijit Chattopadhyay, MD    +919830133133    arijitchatto@hotmail.com   
Principal Investigator: Arijit Chattopadhyay, MD         
Amrita Institute of Medical Sciences Not yet recruiting
Kerala, India, 682041
Contact: Vinayan KP, MD    +91 9447800303    vinayankp@aims.amrita.edu   
Principal Investigator: Vinayan KP, MD         
P.D. Hinduja National Hospital and Medical Research Centre Not yet recruiting
Mumbai, India, 400 016
Contact: Vrajesh Udani, MD    +9819596661    vrajesh.udani@gmail.com   
Principal Investigator: Vrajesh Udani, MD         
Jaslok Hospital and Research centre Recruiting
Mumbai, India, 400 026
Contact: Anaita Hegde, MD    +91 982 018 6155    docanaita@rediffmail.com   
Principal Investigator: Anaita Hedge, MD         
Italy
A.O.U. Senese Policlinico Santa Maria alle Scotte Recruiting
Siena, Tuscany, Italy, 53100
Contact: Silvia Leoncini    +390577234010    s.leonicini74@gmail.com   
Principal Investigator: Jousef Hayek, MD         
United Kingdom
King's College Hospital Recruiting
Denmark Hill, London, United Kingdom, SE5 8AF
Contact: Asimina Tsirka    440207 848 0690    asimina.tsirka@kcl.ac.uk   
Contact: Efisia Saia    4402078480358    Efisia.Sais@nhs.net   
Principal Investigator: Santosh Paramala, MD         
Sponsors and Collaborators
Newron
Investigators
Study Director: Ravi Anand, MD Newron
  More Information

Publications:
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, May 28, 2009 (v4.03 June 14, 2010), U.S. Department of Health and Human Services.
Guy W (Ed). Clinical Global Impressions. In ECDEU Assessment Manual for Psychopharmacology, revised, U.S. Department of Health, Education and Welfare Pub. No. (ADM) 76-338. Rockville, MD: NIMH, 1976, 217-222.
Landon C. Respiratory monitoring: Advantages of inductive plethysmography over impedance pneumograpy. VivoMetrics, VMLA-039-02, 2003.

Responsible Party: Newron
ClinicalTrials.gov Identifier: NCT02790034     History of Changes
Other Study ID Numbers: Sarizotan/001/II/2015
Study First Received: May 24, 2016
Last Updated: March 13, 2017

Additional relevant MeSH terms:
Rett Syndrome
Syndrome
Signs and Symptoms, Respiratory
Disease
Pathologic Processes
Signs and Symptoms
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System

ClinicalTrials.gov processed this record on March 28, 2017