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

• ClinicalTrials.gov Identifier: NCT02790034
• Recruitment Status: Terminated
• First Posted: June 3, 2016
• Last Update Posted: November 9, 2020
• 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)
• 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: August 2016
• Actual Primary Completion Date: August 2019
• Actual Study Completion Date: July 24, 2020

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

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

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.

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.

Byard RW. Forensic issues and possible mechanisms of sudden death in Rett syndrome. J Clin Forensic Med. 2006 Feb;13(2):96-9. 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.

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.

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.

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.

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.

Julu PO, Kerr AM, Apartopoulos F, Al-Rawas S, Engerström IW, Engerström 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.

Julu PO, Engerström IW, Hansen S, Apartopoulos F, Engerström 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.

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. Review.

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.

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.

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.

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.

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. Review.

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.

• Responsible Party: Newron Pharmaceuticals SPA
• ClinicalTrials.gov Identifier: NCT02790034
• Other Study ID Numbers: Sarizotan/001/II/2015
• First Posted: June 3, 2016
• Last Update Posted: November 9, 2020
• Last Verified: November 2020

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