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    Clinical Trial Results:
    Open-Label Phase Ib, Dose-Ranged, Single and Multiple Dose Study to Assess Safety and Pharmacokinetics of TRO19622 in 6-25 Year Old Spinal Muscular Atrophy (SMA) Patients

    Summary
    EudraCT number
    2006-006845-14
    Trial protocol
    FR  
    Global end of trial date
    06 Nov 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Feb 2016
    First version publication date
    13 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WP29845
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trophos Study ID: CL E Q 1115-1
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    20 Apr 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was an open-label, single and multiple dose, dose-ranged study in participants aged 6-25 years with spinal muscular atrophy (SMA) type Ib, II, or III; to assess the safety, tolerability, and pharmacokinetic of single and multiple oral doses of olesoxime.
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practices (GCP) based on guidelines of the European Economic Community and French law and with the principles of the Declaration of Helsinki as revised in Edinburgh, Scotland, October 2000, "note of clarification on paragraph 29 added by the World Medical Association (WMA) General Assembly, Washington 2002" and "Note of clarification on paragraph 30 added by the WMA General Assembly, Tokyo 2004". In accordance with French law, the sponsor had subscribed an insurance that covered the liability of the sponsor, the investigator and other persons involved in the study (Gerling France Police N [1680] 90712). In order to protect anonymity and confidentiality, a code (five digits) was assigned to each participant enrolled in the study and was composed of the participant number, the first two letters of the last name and the first two letters of the first name. All study documents bore this code.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    5
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Study was planned to evaluate 2 doses of olesoxime: 125 milligrams (mg) once a day (QD) and 250 mg QD; however, due to difficulties in recruitment the study was stopped after the inclusion of the 8th participant. Only the first dose (125 mg QD) was studied.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Olesoxime 125 mg
    Arm description
    Participants received single oral dose of olesoxime 125 mg capsule on Day 1 followed by olesoxime 125 mg capsule orally once a day (QD) from Day 16 to Day 25.
    Arm type
    Experimental

    Investigational medicinal product name
    Olesoxime
    Investigational medicinal product code
    TRO19622
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Olesoxime 125 mg capsule with 200 milliliters (mL) of water after standard breakfast on Day 1 and with 200 mL of water just before the noon meal from Day 16 to Day 25.

    Number of subjects in period 1
    Olesoxime 125 mg
    Started
    8
    Completed
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Olesoxime 125 mg
    Reporting group description
    Participants received single oral dose of olesoxime 125 mg capsule on Day 1 followed by olesoxime 125 mg capsule orally once a day (QD) from Day 16 to Day 25.

    Reporting group values
    Olesoxime 125 mg Total
    Number of subjects
    8 8
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.63 ± 7.37 -
    Gender categorical
    Units: Subjects
        Female
    4 4
        Male
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Olesoxime 125 mg
    Reporting group description
    Participants received single oral dose of olesoxime 125 mg capsule on Day 1 followed by olesoxime 125 mg capsule orally once a day (QD) from Day 16 to Day 25.

    Primary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as AEs. AEs included SAEs as well as non-SAEs. An SAE was any experience that suggests a significant hazard, contraindication, side effect or precaution that: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically significant. Analysis was performed on all enrolled participants.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 65
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this single arm study.
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    8
    Units: participants
        Participants with AEs
    5
        Participants with SAEs
    1
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Olesoxime

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    End point title
    Maximum Plasma Concentration (Cmax) of Olesoxime
    End point description
    Analysis was performed on all enrolled participants. Among the population, 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged less than (<) 18 years were considered as children and participants aged greater than or equal to (≥) 18 years were considered as adults.
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Days 2, 3, 5, and 10, pre-dose on Day 15; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Days 26, 27, 29, 34, and 65
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    8 [2]
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1, Adults (n = 3)
    209 ± 25.2
        Day 1, Children (n = 5)
    373 ± 201
        Day 25, Adults (n = 3)
    594 ± 149
        Day 25, Children (n = 3)
    1190 ± 1070
    Notes
    [2] - Number of participants (n) = participants evaluable for specified category.
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Curve From Administration to 24 Hours (AUC0-24) of Olesoxime

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    End point title
    Area Under the Plasma Concentration Curve From Administration to 24 Hours (AUC0-24) of Olesoxime
    End point description
    AUC0-24 = Area under the plasma concentration-time curve from time 0 to 24 hours post dose. Analysis was performed on all enrolled participants. Among the population, 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged <18 years were considered as children and participants aged ≥18 years were considered as adults.
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Day 2; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Day 26
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    8 [3]
    Units: hour*nanograms/milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Day 1, Adults (n = 3)
    3191.85 ± 979.39
        Day 1, Children (n = 5)
    4427.16 ± 1760.54
        Day 25, Adults (n = 3)
    12359.69 ± 4344.54
        Day 25, Children (n = 3)
    26232.49 ± 24381.78
    Notes
    [3] - Number of participants (n) = participants evaluable for specified category.
    No statistical analyses for this end point

    Secondary: Time Passed Since Administration at Which the Cmax Occurred (tmax) of Olesoxime

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    End point title
    Time Passed Since Administration at Which the Cmax Occurred (tmax) of Olesoxime
    End point description
    Analysis was performed on all enrolled participants. Among the population, 1 participant who had an outlier value during single dose period, was excluded from analysis on Day 1 and 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged <18 years were considered as children and participants aged ≥18 years were considered as adults.
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Days 2, 3, 5, and 10, pre-dose on Day 15; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Days 26, 27, 29, 34, and 65
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    7 [4]
    Units: hours
    median (full range (min-max))
        Day 1, Adults (n = 3)
    12 (8 to 12)
        Day 1, Children (n = 4)
    18 (8 to 24)
        Day 25, Adults (n = 3)
    8 (8 to 12)
        Day 25, Children (n = 3)
    8 (4 to 24)
    Notes
    [4] - n = participants evaluable for specified category.
    No statistical analyses for this end point

    Secondary: Plasma Concentration Half-Life (t1/2) of Olesoxime

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    End point title
    Plasma Concentration Half-Life (t1/2) of Olesoxime
    End point description
    Plasma concentration half-life is the time measured for the plasma concentration to decrease by one half. Analysis was performed on all enrolled participants. Among the population, 1 participant who had a bad fitting in the terminal phase during single dose period, was excluded from analysis on Day 1 and 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged <18 years were considered as children and participants aged ≥18 years were considered as adults.
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Days 2, 3, 5, and 10, pre-dose on Day 15; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Days 26, 27, 29, 34, and 65
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    7 [5]
    Units: hours
    arithmetic mean (standard deviation)
        Day 1, Adults (n = 3)
    53.79 ± 6.87
        Day 1, Children (n = 4)
    55.74 ± 6.46
        Day 25, Adults (n = 3)
    69.08 ± 3.79
        Day 25, Children (n = 3)
    68.78 ± 24.2
    Notes
    [5] - n = participants evaluable for specified category.
    No statistical analyses for this end point

    Secondary: Dose and Weight Normalized Cmax of Olesoxime

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    End point title
    Dose and Weight Normalized Cmax of Olesoxime
    End point description
    Analysis was performed on all enrolled participants. Among the population, 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged <18 years were considered as children and participants aged ≥18 years were considered as adults. Dose and weight normalized cmax was reported in nanograms/milliliter/milligram/kilogram ([ng/mL]/mg/kg).
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Days 2, 3, 5, and 10, pre-dose on Day 15; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Days 26, 27, 29, 34, and 65
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    8 [6]
    Units: (ng/mL)/mg/kg
    arithmetic mean (standard deviation)
        Day 1, Adults (n = 3)
    87.7 ± 6.56
        Day 1, Children (n = 5)
    96.1 ± 72
        Day 25, Adults (n = 3)
    256 ± 88.5
        Day 25, Children (n = 3)
    352 ± 293
    Notes
    [6] - n = participants evaluable for specified category.
    No statistical analyses for this end point

    Secondary: Dose and Weight Normalized AUC0-24 of Olesoxime

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    End point title
    Dose and Weight Normalized AUC0-24 of Olesoxime
    End point description
    AUC0-24 = Area under the plasma concentration-time curve from time 0 to 24 hours post dose. Analysis was performed on all enrolled participants. Among the population, 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged <18 years were considered as children and participants aged ≥18 years were considered as adults. Dose and weight normalized AUC0-24 was reported in hour*nanograms/milliliter/milligram/kilogram ([h*ng/mL]/mg/kg).
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Day 2; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Day 26
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    8 [7]
    Units: (h*ng/mL)/mg/kg
    arithmetic mean (standard deviation)
        Day 1, Adults (n = 3)
    1315.89 ± 208.25
        Day 1, Children (n = 5)
    1037.8 ± 461.38
        Day 25, Adults (n = 3)
    5369.42 ± 2325.92
        Day 25, Children (n = 3)
    7694.38 ± 6664.91
    Notes
    [7] - n = participants evaluable for specified category.
    No statistical analyses for this end point

    Secondary: Weight Normalized Apparent Oral Clearance (CL/F) of Olesoxime

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    End point title
    Weight Normalized Apparent Oral Clearance (CL/F) of Olesoxime
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Analysis was performed on all enrolled participants. Among the population, 2 participants who had stopped the treatment during repeated dose period, were excluded from the analysis on Day 25. For analysis, 2 sub-populations were defined: children and adults. Participants aged <18 years were considered as children and participants aged ≥18 years were considered as adults.
    End point type
    Secondary
    End point timeframe
    Single dose (Day 1): Pre-dose, 4, 8, and 12 hours after post-dose on Day 1, Days 2, 3, 5, and 10, pre-dose on Day 15; Multiple dose (Day 25): pre-dose, 4, 8, and 12 hours post-dose on Day 25, Days 26, 27, 29, 34, and 65
    End point values
    Olesoxime 125 mg
    Number of subjects analysed
    8 [8]
    Units: liters/hour/kilogram (L/h/kg)
    arithmetic mean (standard deviation)
        Day 1, Adults (n = 3)
    0.18 ± 0.02
        Day 1, Children (n = 5)
    0.21 ± 0.14
        Day 25, Adults (n = 3)
    0.22 ± 0.11
        Day 25, Children (n = 3)
    0.22 ± 0.19
    Notes
    [8] - n = participants evaluable for specified category.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Day 65
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Olesoxime 125 mg
    Reporting group description
    Participants received single oral dose of olesoxime 125 mg capsule on Day 1 followed by olesoxime 125 mg capsule orally QD from Day 16 to Day 25.

    Serious adverse events
    Olesoxime 125 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Olesoxime 125 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 8 (50.00%)
    Respiratory, thoracic and mediastinal disorders
    Pharyngolaryngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2007
    To recruit 2 additional sites and to modify the list of investigators.
    15 May 2008
    To recruit 2 additional sites and to modify the list of investigators.

    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.
    None reported
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