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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02790034




Registration number
NCT02790034
Ethics application status
Date submitted
24/05/2016
Date registered
3/06/2016
Date last updated
4/02/2019

Titles & IDs
Public title
Evaluation of the Efficacy, Safety, and Tolerability of Sarizotan in Rett Syndrome With Respiratory Symptoms
Scientific 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
Secondary ID [1] 0 0
Sarizotan/001/II/2015
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rett Syndrome 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Neurological 0 0 0 0
Other neurological disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sarizotan
Treatment: Drugs - Placebo

Active Comparator: Sarizotan - Between 2 to 10 mg bid based on age and weight criteria.

Placebo Comparator: Placebo - Placebo bid respectively


Treatment: Drugs: Sarizotan
2 to 10 mg per day of Sarizotan followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

Treatment: Drugs: Placebo
placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Reduction in respiratory abnormality in patients with Rett syndrome - 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.
Timepoint [1] 0 0
3 days prior to Baseline up to week 24
Secondary outcome [1] 0 0
Efficacy of sarizotan assessed by the caregiver - 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.
Timepoint [1] 0 0
24 weeks
Secondary outcome [2] 0 0
Safety and tolerability of sarizotan in patients with Rett syndrome with respiratory symptoms. - 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
Timepoint [2] 0 0
24 weeks
Secondary outcome [3] 0 0
Respiratory symptoms - Percent time spent with breathing dysrhythmia per hour - 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.
Timepoint [3] 0 0
24 weeks
Secondary outcome [4] 0 0
Respiratory symptoms - Number of hyperventilation episodes - Number of hyperventilation episodes. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
Timepoint [4] 0 0
24 weeks
Secondary outcome [5] 0 0
Respiratory symptoms - Oxygen saturation - Oxygen saturation. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
Timepoint [5] 0 0
24 weeks
Secondary outcome [6] 0 0
Respiratory symptoms - Respiratory Distress Index; - Respiratory Distress Index; These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
Timepoint [6] 0 0
24 weeks
Secondary outcome [7] 0 0
Respiratory symptoms - Incidence of breathing dysrhythmia episodes - Incidence of breathing dysrhythmia episodes. These respiratory outcomes will be determined by assessment of changes in intra-subject values and group mean change values.
Timepoint [7] 0 0
24 weeks
Secondary outcome [8] 0 0
Motor behaviour - 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.
Timepoint [8] 0 0
24 weeks
Secondary outcome [9] 0 0
Global change from baseline - 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.
Timepoint [9] 0 0
24 weeks
Secondary outcome [10] 0 0
Caregiver burden - 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.
Timepoint [10] 0 0
24 weeks
Secondary outcome [11] 0 0
Overall assessment of symptoms of Rett syndrome - 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.
Timepoint [11] 0 0
24 weeks
Secondary outcome [12] 0 0
Pharmacokinetics profile of sarizotan and its comparison with the profile in adults - measurement of plasma levels of Sarizotan and its major metabolites from blood samples collected from the patients at the specified time points.
Timepoint [12] 0 0
Baseline, 1 and 4 hr post-dose on Day 1, and 1 and 4 hr post-dose on Day 15

Eligibility
Key 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.
Minimum age
4 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
South Metropolitan Health Service Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 0 0
6961 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Minnesota
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
India
State/province [6] 0 0
Kerala
Country [7] 0 0
India
State/province [7] 0 0
Tamilnadu
Country [8] 0 0
India
State/province [8] 0 0
West Bengal
Country [9] 0 0
India
State/province [9] 0 0
Mumbai
Country [10] 0 0
India
State/province [10] 0 0
New Delhi
Country [11] 0 0
Italy
State/province [11] 0 0
Tuscany
Country [12] 0 0
Italy
State/province [12] 0 0
Milano
Country [13] 0 0
United Kingdom
State/province [13] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Newron Pharmaceuticals SPA
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This study evaluates the safety, tolerability and efficacy of Sarizotan in reducing
respiratory abnormalities in Rett Syndrome.
Trial website
https://clinicaltrials.gov/show/NCT02790034
Trial related presentations / 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.
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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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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.
Public notes

Contacts
Principal investigator
Name 0 0
Ravi Anand, MD
Address 0 0
Newron Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications