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

• ClinicalTrials.gov Identifier: NCT02790034
• Recruitment Status: Terminated
• First Posted: June 3, 2016
• Results First Posted: December 21, 2021
• Last Update Posted: December 21, 2021
• Sponsor: Newron Pharmaceuticals SPA
• Information provided by (Responsible Party): Newron Pharmaceuticals SPA

Tracking Information

• First Submitted Date: May 24, 2016
• First Posted Date: June 3, 2016
• Results First Submitted Date: October 12, 2021
• Results First Posted Date: December 21, 2021
• Last Update Posted Date: December 21, 2021
• Actual Study Start Date: October 26, 2016
• Actual Primary Completion Date: August 6, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 22, 2021)

Reduction in Respiratory Abnormality in Patients With Rett Syndrome [ Time Frame: 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.

Original Primary Outcome Measures (submitted: May 30, 2016)

• 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.
• 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.

Current Secondary Outcome Measures (submitted: November 22, 2021)

Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change [ 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. 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)

Original Secondary Outcome Measures (submitted: May 30, 2016)

• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of the Efficacy, Safety, and Tolerability of Sarizotan in Rett Syndrome With Respiratory Symptoms
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Rett Syndrome

Intervention

• Drug: 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). Assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
• Drug: 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) Assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients
• Drug: Placebo
  Placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

Study Arms

• Experimental: 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)
  Intervention: Drug: Sarizotan low dose
• Experimental: 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)
  Intervention: Drug: Sarizotan high dose
• Placebo Comparator: Placebo
  Placebo bid for 24 wks DB age 4 and above
  Intervention: Drug: Placebo

Publications *

• Abdala AP, Dutschmann M, Bissonnette JM, Paton JF. Correction of respiratory disorders in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18208-13. doi: 10.1073/pnas.1012104107. Epub 2010 Oct 4.
• Abdala AP, Bissonnette JM, Newman-Tancredi A. Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists. Front Physiol. 2014 May 30;5:205. doi: 10.3389/fphys.2014.00205. eCollection 2014.
• 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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• Byard RW. Forensic issues and possible mechanisms of sudden death in Rett syndrome. J Clin Forensic Med. 2006 Feb;13(2):96-9. doi: 10.1016/j.jcfm.2005.08.013. Epub 2005 Nov 2.
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• Collop NA, Anderson WM, Boehlecke B, Claman D, Goldberg R, Gottlieb DJ, Hudgel D, Sateia M, Schwab R; Portable Monitoring Task Force of the American Academy of Sleep Medicine. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2007 Dec 15;3(7):737-47.
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• 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.
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• Julu PO, Kerr AM, Hansen S, Apartopoulos F, Jamal GA. Immaturity of medullary cardiorespiratory neurones leading to inappropriate autonomic reactions as a likely cause of sudden death in Rett's syndrome. Arch Dis Child. 1997 Nov;77(5):464-5. doi: 10.1136/adc.77.5.463c. No abstract available.
• Julu PO, Kerr AM, Apartopoulos F, Al-Rawas S, Engerstrom IW, Engerstrom L, Jamal GA, Hansen S. Characterisation of breathing and associated central autonomic dysfunction in the Rett disorder. Arch Dis Child. 2001 Jul;85(1):29-37. doi: 10.1136/adc.85.1.29.
• Julu PO, Engerstrom IW, Hansen S, Apartopoulos F, Engerstrom B, Pini G, Delamont RS, Smeets EE. Cardiorespiratory challenges in Rett's syndrome. Lancet. 2008 Jun 14;371(9629):1981-3. doi: 10.1016/S0140-6736(08)60849-1. No abstract available.
• Katz DM, Dutschmann M, Ramirez JM, Hilaire G. Breathing disorders in Rett syndrome: progressive neurochemical dysfunction in the respiratory network after birth. Respir Physiol Neurobiol. 2009 Aug 31;168(1-2):101-8. doi: 10.1016/j.resp.2009.04.017. Epub 2009 Apr 24.
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• Khwaja OS, Ho E, Barnes KV, O'Leary HM, Pereira LM, Finkelstein Y, Nelson CA 3rd, Vogel-Farley V, DeGregorio G, Holm IA, Khatwa U, Kapur K, Alexander ME, Finnegan DM, Cantwell NG, Walco AC, Rappaport L, Gregas M, Fichorova RN, Shannon MW, Sur M, Kaufmann WE. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4596-601. doi: 10.1073/pnas.1311141111. Epub 2014 Mar 12.
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• Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK; RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010 Dec;68(6):944-50. doi: 10.1002/ana.22124.
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Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 30, 2016): 129
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: May 4, 2020
• Actual Primary Completion Date: August 6, 2019 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, India, Italy, United Kingdom, United States

Administrative Information

• NCT Number: NCT02790034
• Other Study ID Numbers: Sarizotan/001/II/2015
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Newron Pharmaceuticals SPA
• Original Responsible Party: Same as current
• Current Study Sponsor: Newron Pharmaceuticals SPA
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ravi Anand, MD; Newron Pharmaceuticals

• PRS Account: Newron Pharmaceuticals SPA
• Verification Date: November 2021