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

Primary Purpose

Rett Syndrome

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sarizotan low dose
Sarizotan high dose
Placebo
Sponsored by
Newron Pharmaceuticals SPA
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rett Syndrome

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama
  • University of California
  • Rush University Medical Center
  • Gillette Children's Specialty Healthcare
  • Baylor College of Medicine
  • South Metropolitan Health Service Fiona Stanley Hospital
  • Amrita Institute of Medical Sciences
  • Vijaya Health Centre
  • P.D. Hinduja National Hospital and Medical Research Centre
  • Jaslok Hospital and Research centre
  • All India Institute of Medical Sciences
  • A.O.U. Senese Policlinico Santa Maria alle Scotte
  • U.O. Neuropsichiatria Infantile
  • King's College Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Sarizotan low dose

Sarizotan high dose

Placebo

Arm Description

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)

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)

Placebo bid for 24 wks DB age 4 and above

Outcomes

Primary Outcome Measures

Reduction in Respiratory Abnormality in Patients With Rett Syndrome
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
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)

Full Information

First Posted
May 24, 2016
Last Updated
November 22, 2021
Sponsor
Newron Pharmaceuticals SPA
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1. Study Identification

Unique Protocol Identification Number
NCT02790034
Brief Title
Evaluation of the Efficacy, Safety, and Tolerability of Sarizotan in Rett Syndrome With Respiratory Symptoms
Acronym
STARS
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

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Terminated
Why Stopped
The study did not demonstrate evidence of efficacy on the primary or secondary efficacy variables
Study Start Date
October 26, 2016 (Actual)
Primary Completion Date
August 6, 2019 (Actual)
Study Completion Date
May 4, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Newron Pharmaceuticals SPA

4. Oversight

Data Monitoring Committee
Yes

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rett Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
129 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sarizotan low dose
Arm Type
Experimental
Arm Description
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)
Arm Title
Sarizotan high dose
Arm Type
Experimental
Arm Description
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)
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo bid for 24 wks DB age 4 and above
Intervention Type
Drug
Intervention Name(s)
Sarizotan low dose
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Sarizotan high dose
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
Primary Outcome Measure Information:
Title
Reduction in Respiratory Abnormality in Patients With Rett Syndrome
Description
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.
Time Frame
Baseline up to week 24
Secondary Outcome Measure Information:
Title
Efficacy of Sarizotan Assessed by the Caregiver-rated Impression of Change
Description
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)
Time Frame
24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ravi Anand, MD
Organizational Affiliation
Newron Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
University of California
City
San Diego
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Gillette Children's Specialty Healthcare
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55101
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
South Metropolitan Health Service Fiona Stanley Hospital
City
Murdoch
State/Province
Western Australia
ZIP/Postal Code
6961
Country
Australia
Facility Name
Amrita Institute of Medical Sciences
City
Kochi
State/Province
Kerala
ZIP/Postal Code
682041
Country
India
Facility Name
Vijaya Health Centre
City
Chennai
State/Province
Tamilnadu
ZIP/Postal Code
600 026
Country
India
Facility Name
P.D. Hinduja National Hospital and Medical Research Centre
City
Mumbai
ZIP/Postal Code
400 016
Country
India
Facility Name
Jaslok Hospital and Research centre
City
Mumbai
ZIP/Postal Code
400 026
Country
India
Facility Name
All India Institute of Medical Sciences
City
New Delhi
ZIP/Postal Code
110 029
Country
India
Facility Name
A.O.U. Senese Policlinico Santa Maria alle Scotte
City
Siena
State/Province
Tuscany
ZIP/Postal Code
53100
Country
Italy
Facility Name
U.O. Neuropsichiatria Infantile
City
Milano
ZIP/Postal Code
20142
Country
Italy
Facility Name
King's College Hospital
City
London
ZIP/Postal Code
SE5 8AF
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
20921395
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.
Results Reference
background
PubMed Identifier
24910619
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.
Results Reference
background
PubMed Identifier
24351104
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.
Results Reference
background
PubMed Identifier
8265274
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.
Results Reference
background
PubMed Identifier
9072988
Citation
Bloch KE, Li Y, Sackner MA, Russi EW. Breathing pattern during sleep disruptive snoring. Eur Respir J. 1997 Mar;10(3):576-86.
Results Reference
background
PubMed Identifier
3625404
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.
Results Reference
background
PubMed Identifier
16263320
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.
Results Reference
background
PubMed Identifier
1395758
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.
Results Reference
background
PubMed Identifier
16162719
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.
Results Reference
background
PubMed Identifier
18198809
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.
Results Reference
background
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.
Results Reference
background
PubMed Identifier
2388636
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.
Results Reference
background
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.
Results Reference
background
PubMed Identifier
7792119
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.
Results Reference
background
PubMed Identifier
9487980
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.
Results Reference
background
PubMed Identifier
11420195
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.
Results Reference
background
PubMed Identifier
18555901
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.
Results Reference
background
PubMed Identifier
19394452
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.
Results Reference
background
PubMed Identifier
9452925
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.
Results Reference
background
PubMed Identifier
24623853
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.
Results Reference
background
PubMed Identifier
4225383
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.
Results Reference
background
Citation
Landon C. Respiratory monitoring: Advantages of inductive plethysmography over impedance pneumograpy. VivoMetrics, VMLA-039-02, 2003.
Results Reference
background
PubMed Identifier
11152021
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.
Results Reference
background
PubMed Identifier
10334149
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.
Results Reference
background
PubMed Identifier
18337588
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.
Results Reference
background
PubMed Identifier
21154482
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.
Results Reference
background
PubMed Identifier
25895911
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.
Results Reference
background
PubMed Identifier
2917945
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.
Results Reference
background
PubMed Identifier
22192257
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.
Results Reference
background
PubMed Identifier
33862302
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.
Results Reference
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Evaluation of the Efficacy, Safety, and Tolerability of Sarizotan in Rett Syndrome With Respiratory Symptoms

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