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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects with Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension

    Summary
    EudraCT number
    		 2017-002447-15
    Trial protocol
    		 GB   DK   DE   HU   IT  
    Global end of trial date
    10 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 May 2021
    First version publication date
    01 May 2021
    Other versions
    Summary report(s)
    		 SPIMM-301 CSR Sumamry

    Trial information

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    Trial identification
    Sponsor protocol code
    SPIMM-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03323749
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Stealth BioTheraeputics Inc.
    Sponsor organisation address
    140 Kendrick Street Building C-West, Needham, United States, MA 02494
    Public contact
    Chief Clinical Development Officer, Stealth BioTherapeutics Inc., +1 6177622503, Jim.Carr@stealthbt.com
    Scientific contact
    Chief Clinical Development Officer, Stealth BioTherapeutics Inc., +1 6177622503, Jim.Carr@stealthbt.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
    10 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Feb 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of PART 1 is to evaluate the effect of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks on the: • Distance Walked on the 6MWT • Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment© (PMMSA) The PART 2 objective is to assess the long-term safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for up to 144 weeks.
    Protection of trial subjects
    This pivotal trial was conducted in strict accordance with the current versions of the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki, and all applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Oct 2017
    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
    United States: 118
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Italy: 41
    Worldwide total number of subjects
    218
    EEA total number of subjects
    72
    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)
    7
    Adults (18-64 years)
    193
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Multicenter trial: 27 sites in Canada, Denmark, Germany, Hungary, Italy, the United Kingdom, and the United States. 09 Oct 2017 (First subject’s informed consent date) Part 1: 03 Nov 2017 (First subject’s dose date) to 04 Nov 2019 (Last subject’s last visit or contact) Part 2: 30 Apr 2018 (First subject’s dose date) to 10 Feb 2020

    Pre-assignment
    Screening details
    		 Subjects were ≥16 and ≤80 years of age (≥18 years of age in Germany), diagnosed with PMM (adjudicated molecular genetic abnormality of the mitochondrial respiratory chain and subject reported symptoms). Subjects who walked <100 m or >450 m during the 6MWT at the Screening Visit or the Baseline Visit were not eligible for the trial.

    Period 1
    Period 1 title
    Double-Blind 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
    		 Double-Blind Elamipretide Then Open-Label Elamipretide
    Arm description
    		 Patients in this arm have been initially randomised to elamipretide (in the double-blind period) followed by elamipretide in the open-label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    elamipretide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg (0.5 mL) elamipretide subcutaneous (SC) daily

    Arm title
    		 Double-Blind Placebo, Then Open-Label Elamipretide
    Arm description
    		 Patients in this arm have been initially randomised to placebo (in the double-blind period) followed by elamipretide in the open-label period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mL placebo subcutaneous (SC) daily

    Number of subjects in period 1
    		Double-Blind Elamipretide Then Open-Label Elamipretide Double-Blind Placebo, Then Open-Label Elamipretide
    Started
    109
    109
    Completed
    102
    103
    Not completed
    7
    6
         Adverse event, non-fatal
    3
    1
         Lost to follow-up
    4
    5
    Period 2
    Period 2 title
    Open Label
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double-Blind Elamipretide, Then Open Label Elamipretide
    Arm description
    		 Patients in this arm have been initially randomised to elamipretide (in the double-blind period) followed by elamipretide in the open-label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    elamipretide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg (0.5 mL) elamipretide subcutaneous (SC) daily

    Arm title
    		 Double-Blind Placebo Then Open-Label Elamipretide
    Arm description
    		 Patients in this arm have been initially randomised to placebo (in the double-blind period) followed by elamipretide in the open-label period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    elamipretide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    40 mg (0.5 mL) elamipretide subcutaneous (SC) daily

    Number of subjects in period 2 [1]
    		Double-Blind Elamipretide, Then Open Label Elamipretide Double-Blind Placebo Then Open-Label Elamipretide
    Started
    93
    103
    Completed
    0
    0
    Not completed
    93
    103
         Termination due Sponsor decision
    93
    103
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 9 subjects did not wish to continue from Part 1 to Part 2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double-Blind Elamipretide Then Open-Label Elamipretide
    Reporting group description
    		 Patients in this arm have been initially randomised to elamipretide (in the double-blind period) followed by elamipretide in the open-label period.

    Reporting group title
    Double-Blind Placebo, Then Open-Label Elamipretide
    Reporting group description
    		 Patients in this arm have been initially randomised to placebo (in the double-blind period) followed by elamipretide in the open-label period.

    Reporting group values
    		 Double-Blind Elamipretide Then Open-Label Elamipretide Double-Blind Placebo, Then Open-Label Elamipretide Total
    Number of subjects
    		 109 109 218
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.5 ± 15.7 44.3 ± 14.3 -
    Gender categorical
    Units: Subjects
        Female
    		 67 73 140
        Male
    		 42 36 78

    End points

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    End points reporting groups
    Reporting group title
    Double-Blind Elamipretide Then Open-Label Elamipretide
    Reporting group description
    		 Patients in this arm have been initially randomised to elamipretide (in the double-blind period) followed by elamipretide in the open-label period.

    Reporting group title
    Double-Blind Placebo, Then Open-Label Elamipretide
    Reporting group description
    		 Patients in this arm have been initially randomised to placebo (in the double-blind period) followed by elamipretide in the open-label period.
    Reporting group title
    Double-Blind Elamipretide, Then Open Label Elamipretide
    Reporting group description
    		 Patients in this arm have been initially randomised to elamipretide (in the double-blind period) followed by elamipretide in the open-label period.

    Reporting group title
    Double-Blind Placebo Then Open-Label Elamipretide
    Reporting group description
    		 Patients in this arm have been initially randomised to placebo (in the double-blind period) followed by elamipretide in the open-label period.

    Primary: Six-minute Walk Test (6MWT)

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    End point title
    		 Six-minute Walk Test (6MWT)
    End point description
    Change From Baseline in Distance Walked (meters) on the Six-Minute Walk Test by Visit
    End point type
    Primary
    End point timeframe
    Baseline to 24 weeks
    End point values
    		 Double-Blind Elamipretide Then Open-Label Elamipretide Double-Blind Placebo, Then Open-Label Elamipretide
    Number of subjects analysed
    100
    102
    Units: meters
        arithmetic mean (standard deviation)
    15.33 ± 61.48
    17.38 ± 51.69
    Statistical analysis title
    		 Efficacy analyses
    Statistical analysis description
    The distance walked (meters) during the 6MWT and Total Fatigue score on the PMMSA constituted the primary endpoint family. A family-wise alpha level of 0.05 was maintained for the primary endpoint family, using Hochberg’s procedure at the primary time point of 24 weeks. If both primary endpoints were significantly different from placebo at the 0.05 (two-sided) level of significance (in favor of treatment), then both were considered statistically significant.
    Comparison groups
    Double-Blind Elamipretide Then Open-Label Elamipretide v Double-Blind Placebo, Then Open-Label Elamipretide
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.025
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [1] - two-sided

    Primary: Total Fatigue Score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA)

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    End point title
    		 Total Fatigue Score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA)
    End point description
    Change from Baseline in Total fatigue score on the on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) by visit. Each individual item score ranges from 1 (none) to 4 (severe). The total fatigue score ranges from 4-16. Lower values represent a better outcome. The total fatigue score is the sum of question 1 through question 4 on the Primary Mitochondrial Myopathy Symptom Assessment.
    End point type
    Primary
    End point timeframe
    Baseline to 24 weeks
    End point values
    		 Double-Blind Elamipretide Then Open-Label Elamipretide Double-Blind Placebo, Then Open-Label Elamipretide
    Number of subjects analysed
    98
    101
    Units: Score
        arithmetic mean (standard deviation)
    -1.18 ± 2.13
    -1.09 ± 2.44
    Statistical analysis title
    		 Efficacy analyses
    Statistical analysis description
    The distance walked (meters) during the 6MWT and Total Fatigue score on the PMMSA constituted the primary endpoint family. A family-wise alpha level of 0.05 was maintained for the primary endpoint family, using Hochberg’s procedure at the primary time point of 24 weeks. If both primary endpoints were significantly different from placebo at the 0.05 (two-sided) level of significance (in favor of treatment), then both were considered statistically significant.
    Comparison groups
    Double-Blind Elamipretide Then Open-Label Elamipretide v Double-Blind Placebo, Then Open-Label Elamipretide
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.025
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [2] - two-sided significance

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Period 1 and Period 2
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Double-Blind Elamipretide
    Reporting group description
    		 Double-blind period: elamipretide: 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system.

    Reporting group title
    Double-Blind Placebo
    Reporting group description
    		 Double-blind period: placebo comparator: Placebo administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system.

    Reporting group title
    Open-Label Elamipretide
    Reporting group description
    		 Double blind period: elamipretide: 40mg (0.5mL) of elamipretide administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system, then elamipretide open-label treatment: 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for up to 144 weeks using the elamipretide delivery system.

    Reporting group title
    Open-Label Placebo
    Reporting group description
    		 Double-blind period: placebo comparator: Placebo administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system. Open-label period: 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for up to 144 weeks using the elamipretide delivery system.

    Serious adverse events
    		 Double-Blind Elamipretide Double-Blind Placebo Open-Label Elamipretide Open-Label Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 109 (4.59%)
    3 / 109 (2.75%)
    12 / 93 (12.90%)
    9 / 103 (8.74%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labile blood pressure
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal laceration
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    MELAS syndrome
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery dissection
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 109 (0.92%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychogenic seizure
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 109 (0.92%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 109 (0.92%)
    0 / 93 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral sinusitis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Double-Blind Elamipretide Double-Blind Placebo Open-Label Elamipretide Open-Label Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 109 (98.17%)
    83 / 109 (76.15%)
    88 / 93 (94.62%)
    102 / 103 (99.03%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    4 / 93 (4.30%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    4
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    2
    2
    Blood lactic acid increased
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    2
    2
    Eosinophil count increased
         subjects affected / exposed
    7 / 109 (6.42%)
    0 / 109 (0.00%)
    7 / 93 (7.53%)
    7 / 103 (6.80%)
         occurrences all number
    7
    0
    7
    7
    Weight decreased
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    3 / 103 (2.91%)
         occurrences all number
    0
    0
    2
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 109 (5.50%)
    3 / 109 (2.75%)
    8 / 93 (8.60%)
    7 / 103 (6.80%)
         occurrences all number
    6
    3
    8
    7
    Skin abrasion
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    3 / 103 (2.91%)
         occurrences all number
    0
    0
    1
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    3 / 103 (2.91%)
         occurrences all number
    0
    0
    2
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 109 (5.50%)
    3 / 109 (2.75%)
    1 / 93 (1.08%)
    3 / 103 (2.91%)
         occurrences all number
    6
    3
    1
    3
    Headache
         subjects affected / exposed
    8 / 109 (7.34%)
    4 / 109 (3.67%)
    5 / 93 (5.38%)
    6 / 103 (5.83%)
         occurrences all number
    8
    4
    5
    6
    Hypoaesthesia
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    3 / 103 (2.91%)
         occurrences all number
    0
    0
    1
    3
    Migraine
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    2
    2
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    9 / 103 (8.74%)
         occurrences all number
    0
    0
    1
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    3 / 93 (3.23%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    3
    2
    Fatigue
         subjects affected / exposed
    4 / 109 (3.67%)
    4 / 109 (3.67%)
    4 / 93 (4.30%)
    4 / 103 (3.88%)
         occurrences all number
    4
    4
    4
    4
    Injection site erythema
         subjects affected / exposed
    94 / 109 (86.24%)
    31 / 109 (28.44%)
    66 / 93 (70.97%)
    87 / 103 (84.47%)
         occurrences all number
    94
    31
    66
    87
    Injection site induration
         subjects affected / exposed
    31 / 109 (28.44%)
    6 / 109 (5.50%)
    25 / 93 (26.88%)
    41 / 103 (39.81%)
         occurrences all number
    31
    6
    25
    41
    Injection site injury
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    1 / 93 (1.08%)
    4 / 103 (3.88%)
         occurrences all number
    0
    0
    1
    4
    Injection site pain
         subjects affected / exposed
    43 / 109 (39.45%)
    20 / 109 (18.35%)
    32 / 93 (34.41%)
    37 / 103 (35.92%)
         occurrences all number
    43
    20
    32
    37
    Injection site pruritus
         subjects affected / exposed
    82 / 109 (75.23%)
    10 / 109 (9.17%)
    57 / 93 (61.29%)
    81 / 103 (78.64%)
         occurrences all number
    82
    10
    57
    81
    Injection site swelling
         subjects affected / exposed
    42 / 109 (38.53%)
    7 / 109 (6.42%)
    29 / 93 (31.18%)
    20 / 103 (19.42%)
         occurrences all number
    42
    7
    29
    20
    Pyrexia
         subjects affected / exposed
    2 / 109 (1.83%)
    3 / 109 (2.75%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Injection site bruising
         subjects affected / exposed
    9 / 109 (8.26%)
    18 / 109 (16.51%)
    5 / 93 (5.38%)
    15 / 103 (14.56%)
         occurrences all number
    9
    18
    5
    15
    Injection site haematoma
         subjects affected / exposed
    0 / 109 (0.00%)
    7 / 109 (6.42%)
    0 / 93 (0.00%)
    0 / 103 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Injection site haemorrhage
         subjects affected / exposed
    7 / 109 (6.42%)
    10 / 109 (9.17%)
    2 / 93 (2.15%)
    8 / 103 (7.77%)
         occurrences all number
    7
    10
    2
    8
    Injection site mass
         subjects affected / exposed
    9 / 109 (8.26%)
    2 / 109 (1.83%)
    4 / 93 (4.30%)
    4 / 103 (3.88%)
         occurrences all number
    9
    2
    4
    4
    Injection site nodule
         subjects affected / exposed
    11 / 109 (10.09%)
    2 / 109 (1.83%)
    8 / 93 (8.60%)
    8 / 103 (7.77%)
         occurrences all number
    11
    2
    8
    8
    Injection site urticaria
         subjects affected / exposed
    14 / 109 (12.84%)
    0 / 109 (0.00%)
    12 / 93 (12.90%)
    8 / 103 (7.77%)
         occurrences all number
    14
    0
    12
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    3 / 93 (3.23%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    3
    1
    Constipation
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    3 / 93 (3.23%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    3
    2
    Nausea
         subjects affected / exposed
    5 / 109 (4.59%)
    8 / 109 (7.34%)
    4 / 93 (4.30%)
    2 / 103 (1.94%)
         occurrences all number
    5
    8
    4
    2
    Diarrhoea
         subjects affected / exposed
    3 / 109 (2.75%)
    9 / 109 (8.26%)
    3 / 93 (3.23%)
    6 / 103 (5.83%)
         occurrences all number
    3
    9
    3
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 109 (3.67%)
    1 / 109 (0.92%)
    3 / 93 (3.23%)
    3 / 103 (2.91%)
         occurrences all number
    4
    1
    3
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    3 / 93 (3.23%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    3
    2
    Back pain
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    4 / 93 (4.30%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    4
    2
    Muscle spasms
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    4 / 93 (4.30%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Muscular weakness
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    3 / 93 (3.23%)
    1 / 103 (0.97%)
         occurrences all number
    0
    0
    3
    1
    Pain in extremity
         subjects affected / exposed
    1 / 109 (0.92%)
    5 / 109 (4.59%)
    2 / 93 (2.15%)
    5 / 103 (4.85%)
         occurrences all number
    1
    5
    2
    5
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    2 / 103 (1.94%)
         occurrences all number
    0
    0
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    8 / 109 (7.34%)
    2 / 109 (1.83%)
    6 / 93 (6.45%)
    2 / 103 (1.94%)
         occurrences all number
    8
    2
    6
    2
    Pneumonia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 109 (0.00%)
    2 / 93 (2.15%)
    2 / 103 (1.94%)
         occurrences all number
    1
    0
    2
    2
    Sinusitis
         subjects affected / exposed
    2 / 109 (1.83%)
    3 / 109 (2.75%)
    2 / 93 (2.15%)
    4 / 103 (3.88%)
         occurrences all number
    2
    3
    2
    4
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 109 (6.42%)
    7 / 109 (6.42%)
    7 / 93 (7.53%)
    7 / 103 (6.80%)
         occurrences all number
    7
    7
    7
    7
    Urinary tract infection
         subjects affected / exposed
    0 / 109 (0.00%)
    0 / 109 (0.00%)
    4 / 93 (4.30%)
    0 / 103 (0.00%)
         occurrences all number
    0
    0
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2017
    Main changes include but are not limited to: Added language to provide additional clarity to sites with regard to the 6MWT, QTc prolongation and the virus (HIV), hepatitis B, or hepatitis C infection. Added additional analytes that will be analyzed.
    22 Dec 2017
    Main changes include but are not limited to: Updated language to align with summary nonclinical study safety findings from the Investigator’s Brochure v10.0 (Sections 1.2. and 1.5.), which was updated on 22 December 2017; Removed the maximum number of subjects since the risk:benefit does not change at exactly 222 participants. The study will still enroll approximately 202 subjects; Updated text to provide clarity that the decision for a subject to continue into PART 2 requires the Investigator’s review of the PART 2 Continuation Criteria; Updated text to provide guidance that the C-SSRS Baseline/Screening should be completed at the Screening Visit; Added text to provide guidance of what constitutes enrollment in SPIMM-300; Updated text to provide guidance that the repeat ECGs must occur during the same visit; Added section to provide background information on the elamipretide pen injector and its classification status in multiple countries/regions; Added language to provide guidance if an Investigator wishes to rechallange a subject on the IMP.
    15 Jun 2018
    Main changes include but are not limited to: To provide clarity about planned analyses; To provide an option for subjects who did not participate in SPIMM-300 to enroll in SPIMM-301 and to note their screening period may be longer than 28 days; To clarify subjects who do not continue in PART 2 will not be administered IMP at the Week 24 visit and those who do continue will be administered PART 2 drug supply; To clarify the order of assessments performed; To note the collection of genetic testing results from subjects not previously enrolled in SPIMM-300 and assessment of pre-treatment events; To clarify study conduct and IMP administration; To provide the blood sample for assessing the immunogenicity potential of the IMP; To note the review of genetic testing results from subjects not previously enrolled in SPIMM-300 and to note genetic testing will not be provided as part of the SPIMM-301 trial; To clarify the additional ISR assessments performed during the extended study duration; To define the study subject population and to provide clarification; To clarify eligibility criteria for PART 2; To provide examples of situations that an Investigator may consider subject discontinuation; To update text about the elamipretide pen injector; To provide instruction regarding IMP administration for subjects receiving concomitant therapy SC injections; To clarify how IMP is to be dispensed and stored; To clarify the definition of ADE and SADE; To clarify eGFR is being calculated from the safety laboratory tests.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Feb 2020
    At the completion of Part 1, the database for Part 1 was locked and the final analyses for Part 1 conducted, while Part 2 remained ongoing. Following review of the final analyses for Part 1, Stealth BioTherapeutics decided to terminate the open trials evaluating elamipretide in subjects with PMM. Due to this, Part 2 of the trial was terminated early. Therefore, trial visits and phone calls occurred until trial termination, and the Part 2 Follow-up Period for each active subject began after they were discontinued early due to trial termination.
    -

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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