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    Clinical Trial Results:
    External Natural History Controlled, open-Label Intervention Study to Assess the Efficacy and Safety of Long-Term Treatment with Raxone® in Leber’s Hereditary Optic Neuropathy (LHON)

    Summary
    EudraCT number
    2015-004405-16
    Trial protocol
    AT   DE   BE   PT   ES   BG   PL   IT  
    Global end of trial date
    29 Mar 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Aug 2022
    First version publication date
    28 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SNT-IV-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02774005
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Santhera Pharmaceuticals (Switzerland) Ltd
    Sponsor organisation address
    Hohenrainstrasse 24, Pratteln, Switzerland, 4133
    Public contact
    Regulatory Affairs Manager, Santhera Pharmaceuticals (Switzerland) Ltd, 41 79 811 01 98, julien.gaudias@santhera.com
    Scientific contact
    Regulatory Affairs Manager, Santhera Pharmaceuticals (Switzerland) Ltd, 41 79 811 01 98, julien.gaudias@santhera.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
    13 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess efficacy of Raxone® in the promotion of recovery or stabilization of visual acuity in patients treated with Raxone® ≤1 year after the onset of symptoms, compared to an external natural history control group of idebenone naïve patients
    Protection of trial subjects
    This study was conducted according to the guidelines of Good Clinical Practice (GCP), ICH E3 (CPMP/ICH/135/95), the US Code of Federal Regulations governing Protection of Human Subjects (21 CFR 50), Financial Disclosure by Clinical Investigators (21 CFR 54), Institutional Review Boards (21 CFR 56), Investigational New Drug Application (21 CFR 312), and Applications for FDA Approval to Market a New Drug (21 CFR 314), in compliance with the World Medical Assembly Declaration of Helsinki and its most recent amendments and applicable local regulatory requirements and laws
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Mar 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
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 70
    Worldwide total number of subjects
    199
    EEA total number of subjects
    129
    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)
    0
    Adolescents (12-17 years)
    29
    Adults (18-64 years)
    164
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    214 patients were assessed for eligibility. 15 patients were excluded because they did not meet the inclusions criteria. A total of 199 patients were enrolled in the study (198 received treatment and were included in the Safety Population). There were 196 patients in the ITT population.

    Pre-assignment
    Screening details
    214 patients were assessed for eligibility. 15 patients were excluded because they did not meet the inclusions criteria. A total of 199 patients were enrolled in the study (198 received treatment and were included in the Safety Population). There were 196 patients in the ITT population.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    not blinded

    Arms
    Arm title
    Idebenone 300mg TiD
    Arm description
    All patients received Raxone® study drug at the same dose; there was no randomization procedure. Patients received 900 mg Raxone® (2 tablets 3 times daily (TiD) with meals) for 24 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Raxone
    Investigational medicinal product code
    Other name
    idebenone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 900 mg Raxone® (2 tablets 3 times daily with meals) for 24 months.

    Number of subjects in period 1
    Idebenone 300mg TiD
    Started
    199
    Completed
    138
    Not completed
    61
         another study
    1
         subject is enrolling in a different LHON study tha
    1
         Due to Covid 19 lockdown V9 was not completed
    1
         Pt not willing to perform onsiteV9.didnt withdraw
    1
         cardiologist imposed travel restriction
    1
         Adverse event, serious fatal
    1
         Adverse event, non-fatal
    8
         Lack of compliance with study medication
    4
         Consent withdrawn by subject
    23
         Genetic diagnosis reveals that a patient does not
    12
         Pt unable to return for visits. Sent medicati
    1
         Lost to follow-up
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    199 199
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    29 29
        Adults (18-64 years)
    164 164
        From 65-84 years
    6 6
        85 years and over
    0 0
    Age continuous
    Age continuous entry numbers are based on the Safety Population n=198.
    Units: years
        median (standard deviation)
    34.2 ± 15.2 -
    Gender categorical
    Gender categorical entry numbers are based on the safety Population n=198.
    Units: Subjects
        Female
    53 53
        Male
    146 146
    Subject analysis sets

    Subject analysis set title
    External natural history control group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Natural History (NH) comparator group: Eligible subjects/eyes for matching (n=372 pts/731eyes), Natural History comparator Group matched to LEROS mITT used for Evaluation of 12months endpoints, NH matched N=106

    Subject analysis sets values
    External natural history control group
    Number of subjects
    106
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    372
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age continuous entry numbers are based on the Safety Population n=198.
    Units: years
        median (standard deviation)
    ±
    Gender categorical
    Gender categorical entry numbers are based on the safety Population n=198.
    Units: Subjects
        Female
    88
        Male
    18

    End points

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    End points reporting groups
    Reporting group title
    Idebenone 300mg TiD
    Reporting group description
    All patients received Raxone® study drug at the same dose; there was no randomization procedure. Patients received 900 mg Raxone® (2 tablets 3 times daily (TiD) with meals) for 24 months.

    Subject analysis set title
    External natural history control group
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Natural History (NH) comparator group: Eligible subjects/eyes for matching (n=372 pts/731eyes), Natural History comparator Group matched to LEROS mITT used for Evaluation of 12months endpoints, NH matched N=106

    Primary: Proportion of eyes that achieved CRB at M12 in those pts that started treatment with Raxone ≤1 year after onset of symptoms, compared to eyes in matching external NH control group

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    End point title
    Proportion of eyes that achieved CRB at M12 in those pts that started treatment with Raxone ≤1 year after onset of symptoms, compared to eyes in matching external NH control group
    End point description
    PEP was the proportion of eyes that achieved a Clinically Relevant Benefit (CRB) (that is, in which there was either a Clinically Relevant Recovery [CRR] of VA from Baseline or a Clinically Relevant Stabilization [CRS]) at Month 12 in those patients that started treatment with Raxone® ≤1 year after the onset of symptoms, compared to eyes in the matching external NH control group.
    End point type
    Primary
    End point timeframe
    at Month 12
    End point values
    Idebenone 300mg TiD External natural history control group
    Number of subjects analysed
    80 [1]
    106 [2]
    Units: eyes
        number (not applicable)
    60
    40
    Notes
    [1] - Overall Number of Eyes Analyzed for PEP:142
    [2] - Overall Number of Eyes Analyzed for PEP: 193 Natural history group matched to mITT LEROS: N=106
    Statistical analysis title
    primary endpoint
    Comparison groups
    Idebenone 300mg TiD v External natural history control group
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021 [3]
    Method
    Wald-Chi-Squares
    Confidence interval
    Notes
    [3] - P-values for Type 3 Tests are based on Wald Chi-Squares

    Secondary: SEP1:Components of the primary endpoint: proportion of eyes with CRR of VA from Baseline at Month 12 compared to matching external NH control group

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    End point title
    SEP1:Components of the primary endpoint: proportion of eyes with CRR of VA from Baseline at Month 12 compared to matching external NH control group
    End point description
    End point type
    Secondary
    End point timeframe
    at Month 12
    End point values
    Idebenone 300mg TiD
    Number of subjects analysed
    80 [4]
    Units: eyes
    number (not applicable)
        eyes with CRR
    47
    Notes
    [4] - Overall Number of eyes Analyzed:142
    No statistical analyses for this end point

    Secondary: SEP2: Components of the primary endpoint: proportion of eyes in which Baseline VA better than 1.0 logMAR was maintained at Month 12 (CRS) compared to matching external NH control group

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    End point title
    SEP2: Components of the primary endpoint: proportion of eyes in which Baseline VA better than 1.0 logMAR was maintained at Month 12 (CRS) compared to matching external NH control group
    End point description
    End point type
    Secondary
    End point timeframe
    at Month 12
    End point values
    Idebenone 300mg TiD
    Number of subjects analysed
    22 [5]
    Units: eyes
    number (not applicable)
        eyes with CRS
    20
    Notes
    [5] - Overall Number of eyes Analyzed:31
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    >24 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Raxone 300mg TiD
    Reporting group description
    -

    Serious adverse events
    Raxone 300mg TiD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 198 (13.64%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Social circumstances
    Miscarriage of partner
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease Reoccurance
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic behaviour
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urobilinogen urine increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Ketoacidosis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis intestinal perforated
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Trichomoniasis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vulvovaginitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Raxone 300mg TiD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    148 / 198 (74.75%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Orthostatic hypotension
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    6
    Social circumstances
    Orthosis user
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Chills
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Cyst
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    8 / 198 (4.04%)
         occurrences all number
    8
    Influenza like illness
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    5
    Malaise
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    5
    Medical device pain
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Polyp
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Anger
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Confusional state
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Depressed mood
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    8 / 198 (4.04%)
         occurrences all number
    8
    Depressive symptom
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hallucination
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hallucination, visual
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Irritability
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Mood altered
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Mood swings
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Panic attack
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Restlessness
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Suicidal behaviour
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Suicidal ideation
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Glycosuria
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Dysmenorrhoea
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    9
    Testicular pain
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Arthropod sting
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Contusion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Corneal abrasion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Foot fracture
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Foreign body in eye
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Head injury
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Heat stroke
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Lower limb fracture
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Overdose
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Product administration error
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Radius fracture
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Skin laceration
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tendon rupture
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Thermal burn
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Wound
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 198 (7.58%)
         occurrences all number
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 198 (6.57%)
         occurrences all number
    13
    Bacterial test positive
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Blood bicarbonate decreased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Blood bilirubin increased
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    4
    Blood cholesterol increased
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Blood creatine phosphokinase
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    14 / 198 (7.07%)
         occurrences all number
    15
    Blood creatinine increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Blood phosphorus decreased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Blood triglycerides increased
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    6
    Blood urea decreased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Blood urea increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Blood uric acid increased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Eosinophil count increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 198 (4.55%)
         occurrences all number
    9
    Gastric pH decreased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Haematocrit decreased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Haemoglobin decreased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Liver function test increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Lymphocyte count increased
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Mean cell volume increased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Monocyte count decreased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Monocyte count increased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    3
    Neutrophil count decreased
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Neutrophil count increased
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Protein urine present
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    5
    Red blood cell count decreased
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Transaminases increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Urinary sediment present
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Urine ketone body present
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Weight increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    White blood cell count increased
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    White blood cells urine positive
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Hereditary optic atrophy
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Allergic bronchitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Asthma
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    10
    Cough
         subjects affected / exposed
    12 / 198 (6.06%)
         occurrences all number
    14
    Dysphonia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    7
    Oropharyngeal pain
         subjects affected / exposed
    14 / 198 (7.07%)
         occurrences all number
    22
    Pulmonary congestion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Respiratory acidosis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Sinus congestion
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Splenomegaly
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    5
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    37 / 198 (18.69%)
         occurrences all number
    131
    Hyperaesthesia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Ophthalmic migraine
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Presyncope
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Seizure
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Sinus headache
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    4
    Syncope
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Eye haemorrhage
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Eye pain
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    5
    Eyelid pain
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Photophobia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Photopsia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Pupils unequal
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Visual acuity reduced
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Excessive cerumen production
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hypoacusis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Motion sickness
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    4
    Abdominal migraine
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Abdominal pain
         subjects affected / exposed
    8 / 198 (4.04%)
         occurrences all number
    10
    Abdominal pain upper
         subjects affected / exposed
    13 / 198 (6.57%)
         occurrences all number
    14
    Constipation
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Dental caries
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Dental necrosis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    19 / 198 (9.60%)
         occurrences all number
    28
    Dyspepsia
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    9
    Eosinophilic oesophagitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Food poisoning
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    10
    Gastrointestinal pain
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Infrequent bowel movements
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Malpositioned teeth
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    15 / 198 (7.58%)
         occurrences all number
    20
    Salivary hypersecretion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tooth disorder
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tooth impacted
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    7 / 198 (3.54%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    6 / 198 (3.03%)
         occurrences all number
    7
    Pyrexia
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    6
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    6
    Haematuria
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Nephrolithiasis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Urine abnormality
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Prostatitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pregnancy of partner
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Acne
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    3
    Alopecia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Ingrown hair
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Psoriasis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    6 / 198 (3.03%)
         occurrences all number
    7
    Rash pruritic
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Scab
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Skin fissures
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Skin irritation
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    4
    Arthritis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    9 / 198 (4.55%)
         occurrences all number
    13
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    5
    Neck pain
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Osteoporosis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Pain in jaw
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Periarthritis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Synovial cyst
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tendonitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Thyroiditis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Dehydration
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Fluid retention
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hyperlipidaemia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    4
    Hyponatraemia
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Periostitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Infections and infestations
    Bacterial abdominal infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Bacteriuria
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    6
    Bronchitis viral
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Candida infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Cellulitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Enterobiasis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Eye infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Fungal skin infection
         subjects affected / exposed
    2 / 198 (1.01%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    5
    Gastroenteritis viral
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    3
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hepatitis C
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Hordeolum
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    8 / 198 (4.04%)
         occurrences all number
    9
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 198 (1.52%)
         occurrences all number
    5
    Nasopharyngitis
         subjects affected / exposed
    33 / 198 (16.67%)
         occurrences all number
    51
    Oral herpes
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Pulpitis dental
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    7 / 198 (3.54%)
         occurrences all number
    8
    Skin infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 198 (2.53%)
         occurrences all number
    7
    Urinary tract infection
         subjects affected / exposed
    4 / 198 (2.02%)
         occurrences all number
    5
    Viral infection
         subjects affected / exposed
    1 / 198 (0.51%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2017
    Amendment 1: 1.Amendment to the Study Administrative Structure to update the study team details after changes at Santhera. 2. Amendment to the Synopsis and Section 3.1 to reflect plans to expand the study to the Rest of the World. 3. Amendment to the Synopsis, Sections 6 and 6.5.1 to clarify that only patients that do not have a known LHON-specific DNA mutation will be withdrawn from the study. 4. Amendment to Section 1.1 to update the percentage of individuals with LHON that harbor one of three point mutations in mitochondrial DNA to more than 90%. 5. Amendment to Synopsis, Study flow chart, Sections 6.2, 6.2.1, 8.5.1 and 8.6.1 to update study assessment instructions. 6. Amendment to Section 8.2.2 to state where reference safety information can be found. 7. Addition of Section 8.2.5 to describe the reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) by the Sponsor. 8. Amendment to Section 10.15 to clarify under which circumstances access to study drug would be possible after a patient completes
    06 Mar 2019
    Amendment 2: 1. Amendment to the Study Administrative Structure to update Santhera study team changes and change of the CRO name. 2. Amendment to the Signature page after change in protocol signature process and changes in the study team. 3. Amendment to Sections 4.4 and 11 to clarify that the reference guideline on contraception for this trial is the Clinical Trial Facilitation Group Guidance on Contraception 2014. 4. Amendment to Section 6.3.2 to update information on interaction with other medicinal products. 5. Amendment to Section 8.1.2 to add guidance on the definition and reporting of Adverse Events of Special Interest (AESI). 6. Amendment to Sections 8.1.6 and 8.2.3 to clarify the definition of related/unrelated AE and SAEs. 7. Amendment to Section 9.3.1 to better define the Intent-To-Treat population. 8. Amendment to Section 9.5 and the synopsis to update timelines on the preparation of the statistical analysis plan. 9. Amendment to Section 3.1, 3.2 and 9.6 and synopsis to update the number of patients to be enrolled to the LEROS study based on sample size re-calculation. 10. Amendment to Section 10.1 to clarify the notification of Urgent Safety Measures by the Investigator to the Sponsor and IRB/IEC. 11. Amendment to Section 10.4 to clarify that Quality Risk Assessment for the trial will be performed according to Santhera SOPs. 12. Amendment to Section 10 to add Section 10.18 referring to the registration of the Clinical Trial in a Publicly Accessible Database. 13. Minor editorial changes.

    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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