Clinical trial NCT02790034: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Rett Syndrome
Lead sponsor: Newron Pharmaceuticals SPA
Sponsor class: INDUSTRY
First posted: 2016-06-03
Enrollment: 129
Sex: ALL
Minimum age (years): 4
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Reduction in Respiratory Abnormality in Patients With Rett Syndrome
timeFrame: Baseline up to week 24
Secondary outcomes:
measure: Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: San Diego
country: United States
facility: University of California
state: California
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Saint Paul
country: United States
facility: Gillette Children's Specialty Healthcare
state: Minnesota
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Murdoch
country: Australia
facility: South Metropolitan Health Service Fiona Stanley Hospital
state: Western Australia
city: Kochi
country: India
facility: Amrita Institute of Medical Sciences
state: Kerala
city: Chennai
country: India
facility: Vijaya Health Centre
state: Tamilnadu
city: Mumbai
country: India
facility: P.D. Hinduja National Hospital and Medical Research Centre
city: Mumbai
country: India
facility: Jaslok Hospital and Research centre
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria alle Scotte
state: Tuscany
city: Milano
country: Italy
facility: U.O. Neuropsichiatria Infantile
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Newron Pharmaceuticals
name: Ravi Anand, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Bloch KE, Li Y, Sackner MA, Russi EW. Breathing pattern during sleep disruptive snoring. Eur Respir J. 1997 Mar;10(3):576-86.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: FitzGerald PM, Jankovic J, Percy AK. Rett syndrome and associated movement disorders. Mov Disord. 1990;5(3):195-202. doi: 10.1002/mds.870050303.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Landon C. Respiratory monitoring: Advantages of inductive plethysmography over impedance pneumograpy. VivoMetrics, VMLA-039-02, 2003.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.