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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Six-Month Study to Evaluate the Efficacy, Safety and Tolerability of Sarizotan in Patients with Rett Syndrome with Respiratory Symptoms

    Summary
    EudraCT number
    		 2015-004448-20
    Trial protocol
    		 GB   IT  
    Global end of trial date
    04 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 May 2021
    First version publication date
    28 May 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Sarizotan/001/II/2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02790034
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Newron Pharmaceuticals S.p.A.
    Sponsor organisation address
    Via Meucci 3, Bresso (MI) , Italy, 20091
    Public contact
    Ravi Anand, Newron Pharmaceuticals S.p.A., +41 793741364, ravi@anand.ch
    Scientific contact
    Ravi Anand, Newron Pharmaceuticals S.p.A., +41 793741364, ravi@anand.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001808-PIP03-17
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the effect of sarizotan high dose (5 and 10 mg bid), compared to placebo, on reducing the number of apnea episodes, during awake time, in patients with RTT with respiratory abnormalities.
    Protection of trial subjects
    There was no specific patient support therapy implemented by the sponsor.
    Background therapy
    		 No background therapy was involved.
    Evidence for comparator
    		 There are currently no approved treatments for the key symptoms, including respiratory dysfunction, in RTT patients; therefore, a placebo control, rather than an active control, was used in this study.
    Actual start date of recruitment
    26 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    India: 34
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    129
    EEA total number of subjects
    30
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    58
    Adolescents (12-17 years)
    27
    Adults (18-64 years)
    44
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 5 countries (Italy, UK, India, Australia, US) with recruitment period October 2016 to February 2019 - for the double-blind period. Patients without safety and tolerability issues continued with open label sarizotan for up to an additional 168 weeks.

    Pre-assignment
    Screening details
    		 198 patients were screened; 69 (34.8%) were screen failures Reason for SF: Did not meet entry criteria - 53 (76.8%) Major protocol deviation - 0 Pretreatment Event/Adverse Event - 1 (1.4%) Lost to follow-up - 1 (1.4%) Voluntary withdrawal - 14 (20.3%) Study termination - 0 Other reason; specify - 0

    Period 1
    Period 1 title
    Double Blind Low dose/ High Dose/Placebo (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sarizotan Low Dose
    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) Assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sarizotan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Gastric use, Oral use
    Dosage and administration details
    • Patients of age 4 to <13 years were randomized to 1:1:1 sarizotan 2 mg bid (low dose sarizotan group), sarizotan 5 mg bid (high dose sarizotan group), or placebo bid. • Patients of age ≥13 years and weight <25 kg were randomized to 1:1:1 sarizotan 2 mg bid (low dose sarizotan group), sarizotan 5 mg bid (high dose sarizotan group), or placebo bid.

    Arm title
    		 Sarizotan High Dose
    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) Assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sarizotan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Gastric use, Oral use
    Dosage and administration details
    • Patients of age ≥13 years and weight ≥25 kg were randomized to 1:1:1 sarizotan 5 mg bid (low dose sarizotan group), sarizotan 10 mg bid (high dose sarizotan group), or placebo bid.

    Arm title
    		 Placebo
    Arm description
    		 Placebo bid for 24 wks DB age 4 and above Placebo: placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Gastric use, Oral use
    Dosage and administration details
    • Patients of age 4 to <13 years were randomized to 1:1:1 sarizotan 2 mg bid (low dose sarizotan group), sarizotan 5 mg bid (high dose sarizotan group), or placebo bid. • Patients of age ≥13 years and weight <25 kg were randomized to 1:1:1 sarizotan 2 mg bid (low dose sarizotan group), sarizotan 5 mg bid (high dose sarizotan group), or placebo bid. • Patients of age ≥13 years and weight ≥25 kg were randomized to 1:1:1 sarizotan 5 mg bid (low dose sarizotan group), sarizotan 10 mg bid (high dose sarizotan group), or placebo bid.

    Number of subjects in period 1
    		Sarizotan Low Dose Sarizotan High Dose Placebo
    Started
    33
    56
    40
    Completed
    27
    46
    36
    Not completed
    6
    10
    4
         Consent withdrawn by subject
    1
    4
    1
         Adverse event, non-fatal
    4
    6
    2
         No matching reasons found
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sarizotan Low Dose
    Reporting group 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.

    Reporting group title
    Sarizotan High Dose
    Reporting group 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.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo bid for 24 wks DB age 4 and above Placebo: placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

    Reporting group values
    		 Sarizotan Low Dose Sarizotan High Dose Placebo Total
    Number of subjects
    		 33 56 40 129
    Age categorical
    All the patients enrolled in the study were female. The mean (SD) age was 14.51 (8.780) years and ranged between 3.7 years to 44.4 years. Approximately half of the patients (67 [51.9%]) were 4 to 12 years of age and 44 (34.1%) patients were adults (≥18 years). 18 (14.0%) were in the 13-17 years old category.
    Units: Subjects
        Children (4-12 years)
    		 17 26 24 67
        Adolescents (13-17 years)
    		 6 9 3 18
        Adults (>=18 years)
    		 10 21 13 44
    Gender categorical
    All the patients enrolled in the study were female.
    Units: Subjects
        Female
    		 33 56 40 129
        Male
    		 0 0 0 0
    Race
    The majority of patients (82 [63.6%]) were White, and most (89.9%) were not Hispanic or Latino. Overall, 37 (28.7%) patients were Asian.
    Units: Subjects
        Black or African American
    		 1 1 3 5
        Native Hawaiian or other Pacific Islanders
    		 0 1 0 1
        White
    		 23 37 22 82
        Asian
    		 8 16 13 37
        Other
    		 0 1 2 3
        Multiple
    		 1 0 0 1
    Baseline disease characteristic
    Summary of duration of Rett syndrome by treatment group: The mean (SD) duration of Rett syndrome was numerically higher in sarizotan groups (87.90 [72.536] months in low dose sarizotan group and 97.18 [72.922] months in high dose sarizotan group) compared with placebo group (73.94 [65.800] months).
    Units: Months
        arithmetic mean (standard deviation)
    		 87.90 ± 72.536 97.18 ± 72.922 73.94 ± 65.800 -

    End points

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    End points reporting groups
    Reporting group title
    Sarizotan Low Dose
    Reporting group 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.

    Reporting group title
    Sarizotan High Dose
    Reporting group 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.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo bid for 24 wks DB age 4 and above Placebo: placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

    Primary: Percent reduction (change) from baseline in the number of apnea episodes (each ≥10 seconds in duration) per hour, during awake time

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    End point title
    		 Percent reduction (change) from baseline in the number of apnea episodes (each ≥10 seconds in duration) per hour, during awake time
    End point description
    The primary efficacy outcome was the percent reduction (change) from baseline in the number of apnea episodes (each ≥10 seconds in duration) per hour, during awake time obtained from the BioRadioTM. The percent change from baseline was calculated as follows: %Change from Baseline at Visit X = ([Value at Post-baseline Visit X – Baseline Value]/Baseline value)*100.
    End point type
    Primary
    End point timeframe
    24 Weeks
    End point values
    		 Sarizotan Low Dose Sarizotan High Dose Placebo
    Number of subjects analysed
    33
    56
    40
    Units: percentage change in mean counts per hr
        least squares mean (standard error)
    1.54 ± 10.1228
    13.211 ± 7.5075
    18.503 ± 8.441
    Statistical analysis title
    		 Primary efficacy analysis
    Statistical analysis description
    Primary inferential comparison between treatment groups used a restricted maximum likelihood (REML)-based, mixed-effects repeated measures model approach (MMRM) with 95% CI for the difference between treatment groups for % change from baseline in the number of apnea episodes. Model included % change from baseline as response, the fixed, categorical effects of treatment group, visit, treatment group-by-visit interaction, and the continuous terms age and baseline value as covariate.
    Comparison groups
    Sarizotan High Dose v Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.292
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.741
         upper limit
    		 17.157
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.3184

    Secondary: Difference between sarizotan and placebo on the mean rating of the CIC at Week 24/endpoint

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    End point title
    		 Difference between sarizotan and placebo on the mean rating of the CIC at Week 24/endpoint
    End point description
    The key secondary efficacy outcome was the difference between sarizotan and placebo on the CIC from baseline, a 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 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, etc.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Sarizotan Low Dose Sarizotan High Dose Placebo
    Number of subjects analysed
    33
    56
    40
    Units: number
        arithmetic mean (standard deviation)
    3.6 ± 0.67
    3.5 ± 1.12
    3.4 ± 0.79
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs will be collected, from the time of signing of Informed Consent to the end of the safety follow-up period (14 days after last dose of study medication). In addition, all subjects will be followed up for 30 days after last dose for SAEs.
    Adverse event reporting additional description
    Analysis population = safety Classification of the Event: Classify the event as either serious or non-serious Description of Signs or Symptoms: Whenever possible, record a specific diagnosis for the event Start/stop date Intensity (mild, moderate, severe) Causality Action taken with IMP
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Sarizotan Low Dose
    Reporting group 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.

    Reporting group title
    Sarizotan High Dose
    Reporting group 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.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo bid for 24 wks DB (age 4 to <13 years; age ≥13 years and weight <25 kg; age ≥13 years and weight ≥25 kg) Placebo: placebo BID followed by assessment of safety, tolerability and efficacy on reducing the respiratory symptoms in patients.

    Serious adverse events
    		 Sarizotan Low Dose Sarizotan High Dose Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 33 (6.06%)
    10 / 56 (17.86%)
    5 / 39 (12.82%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Medication error
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 56 (0.00%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 56 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 56 (3.57%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Change in seizure presentation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 56 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gingival hypertrophy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 56 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 56 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 56 (1.79%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sarizotan Low Dose Sarizotan High Dose Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 33 (75.76%)
    46 / 56 (82.14%)
    30 / 39 (76.92%)
    Nervous system disorders
    Seizure
         subjects affected / exposed
    8 / 33 (24.24%)
    15 / 56 (26.79%)
    5 / 39 (12.82%)
         occurrences all number
    8
    15
    5
    Somnolence
         subjects affected / exposed
    2 / 33 (6.06%)
    10 / 56 (17.86%)
    6 / 39 (15.38%)
         occurrences all number
    2
    10
    6
    Psychomotor hyperactivity
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 56 (1.79%)
    3 / 39 (7.69%)
         occurrences all number
    4
    1
    3
    Dystonia
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 56 (5.36%)
    1 / 39 (2.56%)
         occurrences all number
    3
    3
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 56 (5.36%)
    0 / 39 (0.00%)
         occurrences all number
    4
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 56 (7.14%)
    4 / 39 (10.26%)
         occurrences all number
    2
    4
    4
    Constipation
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 56 (8.93%)
    2 / 39 (5.13%)
         occurrences all number
    2
    5
    2
    Vomiting
         subjects affected / exposed
    5 / 33 (15.15%)
    2 / 56 (3.57%)
    2 / 39 (5.13%)
         occurrences all number
    5
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 56 (5.36%)
    4 / 39 (10.26%)
         occurrences all number
    1
    3
    4
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 56 (7.14%)
    1 / 39 (2.56%)
         occurrences all number
    3
    4
    1
    Insomnia
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 56 (3.57%)
    2 / 39 (5.13%)
         occurrences all number
    3
    2
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 56 (5.36%)
    3 / 39 (7.69%)
         occurrences all number
    2
    3
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    5 / 56 (8.93%)
    1 / 39 (2.56%)
         occurrences all number
    1
    5
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2017
    The 24-week, double blind, extension treatment period of the study was converted into an open-label, extension period. Appropriate changes were made throughout the protocol related to the conversion of the double-blind extension treatment period into an open-label period, including modification of the schedule of evaluations and revision of the dose titration paradigm.
    29 Mar 2017
    • Allowed inclusion of RTT patients who were 6 to <13 years of age and weigh at least 10 kg. • Implemented a weight-based dosing paradigm for these younger patients (6 to <13 years of age) in the initial double-blind treatment period. • Allowed inclusion of patients ≥13 years of age and weighing <25 kg in the study. These patients were included with the younger patients and randomized (2:1) to sarizotan 5 mg bid (High Dose) or placebo. • Implemented a weight-based dosing paradigm for younger patients (6 to <13 years of age), as well as patients ≥13 years of age and weighing <25 kg, in the open-label extension treatment period.
    02 Oct 2017
    • The randomization scheme for patients 6 to <13 years of age was modified, to balance the randomization (1:1:1) across the 3 treatment groups (sarizotan 2 mg bid, sarizotan 5 mg bid, or placebo bid). • The CIC was modified to eliminate the inclusion of respiratory symptoms in the overall assessment of the change in the patient’s condition from baseline.
    02 Nov 2017
    The primary purpose of this amendment was to allow patients who were benefitting from open label treatment with sarizotan to continue to benefit long-term. This amendment extended open-label treatment by an additional 48 weeks, for a total of 72 weeks of open label treatment.
    11 Feb 2018
    The purpose of this amendment was to allow patients older than 4 years of age, and weighing at least 10 kg, to be enrolled in the study. Previously, the lower age limit for inclusion was set at 6 years.
    29 Nov 2018
    The primary purpose of this amendment was to allow patients benefitting from open-label treatment with sarizotan for up to 72 weeks under the current protocol, to extend the treatment by another 48 weeks to a total of 120 weeks of open-label treatment.
    10 Dec 2019
    The primary purpose of this amendment was to allow patients who were benefitting from treatment with sarizotan for up to 144 weeks to continue to benefit with longer-term treatment. This amendment extended open-label treatment of 120 weeks by an additional 48 weeks, to have a total of 168 weeks of open-label treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    109 patients completed the initial 24 week double-blind placebo-controlled phase; 97 patients entered the open-label extension study. The extension period was later terminated, as the primary efficacy endpoint in the initial phase was not met
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