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

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ClinicalTrials.gov Identifier: NCT02790034

Recruitment Status : Terminated (The study did not demonstrate evidence of efficacy on the primary or secondary efficacy variables)

First Posted : June 3, 2016

Results First Posted : December 21, 2021

Last Update Posted : December 21, 2021

View this study on the modernized ClinicalTrials.gov

Sponsor:

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 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).

Condition or disease	Intervention/treatment	Phase
Rett Syndrome	Drug: Sarizotan low dose Drug: Sarizotan high dose 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.

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual 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 :	October 26, 2016
Actual Primary Completion Date :	August 6, 2019
Actual Study Completion Date :	May 4, 2020

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Rett syndrome

MedlinePlus related topics: Rett Syndrome

Genetic and Rare Diseases Information Center resources: Rett Syndrome

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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)	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.
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)	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
Placebo Comparator: Placebo Placebo bid for 24 wks DB age 4 and above	Drug: Placebo Placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

Outcome Measures

Primary Outcome Measures :

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.

Secondary Outcome Measures :

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)

Eligibility Criteria

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02790034

Locations

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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
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

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Study Director:	Ravi Anand, MD	Newron Pharmaceuticals

Study Documents (Full-Text)

Documents provided by Newron Pharmaceuticals SPA:

Study Protocol [PDF] March 17, 2020

Statistical Analysis Plan [PDF] March 30, 2020

More Information

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.

Adams JA, Zabaleta IA, Stroh D, Sackner MA. Measurement of breath amplitudes: comparison of three noninvasive respiratory monitors to integrated pneumotachograph. Pediatr Pulmonol. 1993 Oct;16(4):254-8. doi: 10.1002/ppul.1950160408.

Bloch KE, Li Y, Sackner MA, Russi EW. Breathing pattern during sleep disruptive snoring. Eur Respir J. 1997 Mar;10(3):576-86.

Brouillette RT, Morrow AS, Weese-Mayer DE, Hunt CE. Comparison of respiratory inductive plethysmography and thoracic impedance for apnea monitoring. J Pediatr. 1987 Sep;111(3):377-83. doi: 10.1016/s0022-3476(87)80457-2.

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.

Cantineau JP, Escourrou P, Sartene R, Gaultier C, Goldman M. Accuracy of respiratory inductive plethysmography during wakefulness and sleep in patients with obstructive sleep apnea. Chest. 1992 Oct;102(4):1145-51. doi: 10.1378/chest.102.4.1145.

Clarenbach CF, Senn O, Brack T, Kohler M, Bloch KE. Monitoring of ventilation during exercise by a portable respiratory inductive plethysmograph. Chest. 2005 Sep;128(3):1282-90. doi: 10.1378/chest.128.3.1282.

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.

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.

FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associated movement disorders. Mov Disord. 1990;5(3):195-202. doi: 10.1002/mds.870050303.

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.

Hammer J, Newth CJ, Deakers TW. Validation of the phase angle technique as an objective measure of upper airway obstruction. Pediatr Pulmonol. 1995 Mar;19(3):167-73. doi: 10.1002/ppul.1950190305.

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.

Kerr AM, Armstrong DD, Prescott RJ, Doyle D, Kearney DL. Rett syndrome: analysis of deaths in the British survey. Eur Child Adolesc Psychiatry. 1997;6 Suppl 1:71-4.

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.

Konno K, Mead J. Measurement of the separate volume changes of rib cage and abdomen during breathing. J Appl Physiol. 1967 Mar;22(3):407-22. doi: 10.1152/jappl.1967.22.3.407. No abstract available.

Landon C. Respiratory monitoring: Advantages of inductive plethysmography over impedance pneumograpy. VivoMetrics, VMLA-039-02, 2003.

Leino K, Nunes S, Valta P, Takala J. Validation of a new respiratory inductive plethysmograph. Acta Anaesthesiol Scand. 2001 Jan;45(1):104-11. doi: 10.1034/j.1399-6576.2001.450116.x.

Loube DI, Andrada T, Howard RS. Accuracy of respiratory inductive plethysmography for the diagnosis of upper airway resistance syndrome. Chest. 1999 May;115(5):1333-7. doi: 10.1378/chest.115.5.1333.

Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, Zoghbi H, Percy A, Glaze DG. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008 Apr 15;70(16):1313-21. doi: 10.1212/01.wnl.0000291011.54508.aa. Epub 2008 Mar 12.

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.

Neul JL, Glaze DG, Percy AK, Feyma T, Beisang A, Dinh T, Suter B, Anagnostou E, Snape M, Horrigan J, Jones NE. Improving Treatment Trial Outcomes for Rett Syndrome: The Development of Rett-specific Anchors for the Clinical Global Impression Scale. J Child Neurol. 2015 Nov;30(13):1743-8. doi: 10.1177/0883073815579707. Epub 2015 Apr 20.

Sackner MA, Watson H, Belsito AS, Feinerman D, Suarez M, Gonzalez G, Bizousky F, Krieger B. Calibration of respiratory inductive plethysmograph during natural breathing. J Appl Physiol (1985). 1989 Jan;66(1):410-20. doi: 10.1152/jappl.1989.66.1.410.

Weng SM, Bailey ME, Cobb SR. Rett syndrome: from bed to bench. Pediatr Neonatol. 2011 Dec;52(6):309-16. doi: 10.1016/j.pedneo.2011.08.002. Epub 2011 Nov 6.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gualniera L, Singh J, Fiori F, Santosh P. Emotional Behavioural and Autonomic Dysregulation (EBAD) in Rett Syndrome - EDA and HRV monitoring using wearable sensor technology. J Psychiatr Res. 2021 Jun;138:186-193. doi: 10.1016/j.jpsychires.2021.03.052. Epub 2021 Apr 7.

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Responsible Party:	Newron Pharmaceuticals SPA
ClinicalTrials.gov Identifier:	NCT02790034
Other Study ID Numbers:	Sarizotan/001/II/2015
First Posted:	June 3, 2016 Key Record Dates
Results First Posted:	December 21, 2021
Last Update Posted:	December 21, 2021
Last Verified:	November 2021

Additional relevant MeSH terms:

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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

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