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    Clinical Trial Results:
    Effects of oral Levosimendan (ODM-109) on respiratory function in patients with ALS: open label extension for patients completing study 3119002

    Summary
    EudraCT number
    		 2018-004180-31
    Trial protocol
    		 BE   ES   DE   FI   AT   NL   IE   GB   FR   IT  
    Global end of trial date
    18 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2021
    First version publication date
    13 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3119003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03948178
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Orion Corporation
    Sponsor organisation address
    Orionintie 1, Espoo, Finland,
    Public contact
    Clinical Trials Information, Orion Corporation, +358 104261, clinicaltrials@orionpharma.com
    Scientific contact
    Clinical Trials Information, Orion Corporation, +358 104261, clinicaltrials@orionpharma.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
    18 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective, in addition to continuing treatment for subjects in this study, was to evaluate long-term safety of oral levosimendan in amyotrophic lateral sclerosis (ALS) patients.
    Protection of trial subjects
    Adverse events were followed by sponsor and the independent data and safety monitoring board (DSMB). Specific criteria were in place for the withdrawal of patients from study treatment, including uncontrolled increased heart rate, and life threatening supraventricular or ventricular arrhytmias. The investigator could also withdraw the treatment if considered to be in the best interests of the subject. Patients were free to leave the study at any time but were also withdrawn in the event of a safety finding of clinical concern.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 2019
    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
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    227
    EEA total number of subjects
    132
    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)
    0
    Adults (18-64 years)
    160
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patiens participating to REFALS study and completed 48-weeks treatment were recruited to continue with oral levosimendan for long term safety follow-up.

    Pre-assignment
    Screening details
    		 Male or female subjects with written or verbal IC obtained. Subjects who completed 48 weeks of treatment according to the REFALS study protocol. Able to swallow study treatment capsules at the time of completing 48 weeks dosing in the REFALS study.

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

    Arms
    Arm title
    		 Levosimendan
    Arm description
    		 Oral levosimendan 0.5-2 mg daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    levosimendan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The target maintenance dose of oral levosimendan was 2 mg/day taken as 1 mg b.i.d. Levosimendan treatment was started at 1 mg/day. The subject were to be reviewed 2 weeks after initiation of levosimendan at which time the dose was to be increased to 2 mg/day, if considered appropriate and the 1 mg/day dose was well tolerated. It was permitted to use also less frequent dosing than 1 mg once daily (e.g. 1 mg on alternate days) if levosimendan 1 mg/day was not well tolerated. The subject was to be re-assessed 2 weeks after each dose change.

    Number of subjects in period 1
    		Levosimendan
    Started
    227
    Completed
    0
    Not completed
    227
         Adverse event, serious fatal
    5
         Disease progression
    30
         Adverse event, non-fatal
    7
         Personal reason
    14
         Other
    2
         Study terminated by sponsor
    164
         Withdrawal of consent
    2
         Lost to follow-up
    2
         Protocol deviation
    1

    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
    		 227 227
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 160 160
        From 65-84 years
    		 67 67
    Gender categorical
    Units: Subjects
        Female
    		 85 85
        Male
    		 142 142

    End points

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    End points reporting groups
    Reporting group title
    Levosimendan
    Reporting group description
    		 Oral levosimendan 0.5-2 mg daily.

    Primary: Long term safety of oral levosimendan

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    End point title
    		 Long term safety of oral levosimendan [1]
    End point description
    Number of patients with Treatment emergent adverse events (TEAE)s
    End point type
    Primary
    End point timeframe
    After 48 weeks of treatment according to the REFALS study protocol until the end of study. The mean time on treatment (including dose interruptions) was 23.54 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary objective, in addition to continuing treatment for subjects in REFALS study, was to evaluate long-term safety of oral levosimendan in ALS patients. Long term safety, adverse event reporting, vital signs and 12-lead ECG, was evaluated using descriptive statistics only.
    End point values
    		 Levosimendan
    Number of subjects analysed
    227
    Units: number
    161
    No statistical analyses for this end point

    Secondary: Change from baseline, SVC (supine) at 2 weeks

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    End point title
    		 Change from baseline, SVC (supine) at 2 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    2 and 4 weeks and 3 and 6 months after start of study treatment
    End point values
    		 Levosimendan
    Number of subjects analysed
    133
    Units: percent
        arithmetic mean (standard deviation)
    1.2 ± 7.0
    No statistical analyses for this end point

    Secondary: Change from baseline, SVC (supine) at 4 weeks

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    End point title
    		 Change from baseline, SVC (supine) at 4 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    2 and 4 weeks and 3 and 6 months after start of study treatment
    End point values
    		 Levosimendan
    Number of subjects analysed
    89
    Units: percent
        arithmetic mean (standard deviation)
    0.9 ± 9.5
    No statistical analyses for this end point

    Secondary: Change from baseline, SVC (supine) at 3 months

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    End point title
    		 Change from baseline, SVC (supine) at 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    2 and 4 weeks and 3 and 6 months after start of study treatment
    End point values
    		 Levosimendan
    Number of subjects analysed
    62
    Units: percent
        arithmetic mean (standard deviation)
    -2.4 ± 10.6
    No statistical analyses for this end point

    Secondary: Change from baseline, SVC (supine) at 6 months

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    End point title
    		 Change from baseline, SVC (supine) at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    2 and 4 weeks and 3 and 6 months after start of study treatment
    End point values
    		 Levosimendan
    Number of subjects analysed
    30
    Units: percent
        arithmetic mean (standard deviation)
    -3.3 ± 13.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent until the end of study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Levosimendan
    Reporting group description
    		 -

    Serious adverse events
    		 Levosimendan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 227 (19.38%)
         number of deaths (all causes)
    19
         number of deaths resulting from adverse events
    19
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    EUTHANASIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    PYREXIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHOKING
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    RESPIRATORY ARREST
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    RESPIRATORY DEPRESSION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    RESPIRATORY DISTRESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    RESPIRATORY FAILURE
         subjects affected / exposed
    11 / 227 (4.85%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 9
    RHINORRHOEA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    SUICIDE ATTEMPT
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    OXYGEN SATURATION DECREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MENISCUS INJURY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    STOMA SITE PAIN
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    CARDIAC ARREST
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    METASTASES TO LYMPH NODES
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    DIARRHOEA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SALIVA ALTERED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RENAL MASS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CYSTITIS BACTERIAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    SYSTEMIC VIRAL INFECTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Levosimendan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    158 / 227 (69.60%)
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    BLOOD PRESSURE INADEQUATELY CONTROLLED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HAEMATOMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HYPERTENSION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HYPOTENSION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    LYMPHOEDEMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SUPERFICIAL VEIN PROMINENCE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Surgical and medical procedures
    CENTRAL VENOUS CATHETER REMOVAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    CHEST PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CHILLS
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    FACIAL PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    FATIGUE
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    GAIT DISTURBANCE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    OEDEMA PERIPHERAL
         subjects affected / exposed
    8 / 227 (3.52%)
         occurrences all number
    9
    PAIN
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    PARADOXICAL DRUG REACTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PERIPHERAL SWELLING
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences all number
    4
    PYREXIA
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences all number
    5
    Immune system disorders
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    ASPIRATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ATELECTASIS
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    CHOKING
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    COUGH
         subjects affected / exposed
    8 / 227 (3.52%)
         occurrences all number
    8
    DYSPNOEA
         subjects affected / exposed
    13 / 227 (5.73%)
         occurrences all number
    13
    DYSPNOEA AT REST
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HYPOVENTILATION
         subjects affected / exposed
    6 / 227 (2.64%)
         occurrences all number
    8
    HYPOXIA
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    INCREASED BRONCHIAL SECRETION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    LARYNGOSPASM
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    NASAL CONGESTION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    ORTHOPNOEA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    RESPIRATORY FAILURE
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    RHINORRHOEA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SLEEP APNOEA SYNDROME
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    UPPER-AIRWAY COUGH SYNDROME
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    6 / 227 (2.64%)
         occurrences all number
    6
    DEPRESSED MOOD
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DEPRESSION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    INSOMNIA
         subjects affected / exposed
    5 / 227 (2.20%)
         occurrences all number
    5
    MOOD DISORDER DUE TO A GENERAL MEDICAL CONDITION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PANIC ATTACK
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    2
    PANIC REACTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PROCEDURAL ANXIETY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SLEEP DISORDER
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    TEARFULNESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    BLOOD POTASSIUM DECREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    BLOOD PRESSURE SYSTOLIC INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HEART RATE INCREASED
         subjects affected / exposed
    12 / 227 (5.29%)
         occurrences all number
    12
    OXYGEN SATURATION DECREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PULMONARY FUNCTION TEST DECREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    TROPONIN INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    WEIGHT DECREASED
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    WHITE BLOOD CELL COUNT INCREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    ARTHROPOD BITE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CONCUSSION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CONTUSION
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    EYE CONTUSION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    FACE INJURY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    FACIAL BONES FRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    2
    FALL
         subjects affected / exposed
    23 / 227 (10.13%)
         occurrences all number
    40
    FOOT FRACTURE
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    GASTROSTOMY TUBE SITE COMPLICATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HEAD INJURY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    JAW FRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    JOINT DISLOCATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    LIP INJURY
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    NASAL INJURY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    POST LUMBAR PUNCTURE SYNDROME
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    POST-TRAUMATIC PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    RIB FRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SKIN ABRASION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    3
    SKIN LACERATION
         subjects affected / exposed
    6 / 227 (2.64%)
         occurrences all number
    7
    STOMA SITE ERYTHEMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    STOMA SITE HAEMORRHAGE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    STOMA SITE PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    TOOTH FRACTURE
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    WOUND
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    WRIST FRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    LEFT VENTRICLE OUTFLOW TRACT OBSTRUCTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PALPITATIONS
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences all number
    4
    TACHYCARDIA
         subjects affected / exposed
    18 / 227 (7.93%)
         occurrences all number
    20
    TACHYCARDIA PAROXYSMAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Nervous system disorders
    AMYOTROPHIC LATERAL SCLEROSIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CERVICAL RADICULOPATHY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DIZZINESS
         subjects affected / exposed
    6 / 227 (2.64%)
         occurrences all number
    7
    DIZZINESS POSTURAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DYSGEUSIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ENCEPHALOPATHY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HEADACHE
         subjects affected / exposed
    20 / 227 (8.81%)
         occurrences all number
    28
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PARAESTHESIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    POST-TRAUMATIC HEADACHE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SCIATICA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    LUNG NEOPLASM
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    NORMOCHROMIC NORMOCYTIC ANAEMIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SEBORRHOEIC KERATOSIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Ear and labyrinth disorders
    EAR DISCOMFORT
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    MOTION SICKNESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    VERTIGO
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Eye disorders
    BLEPHARITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    ABDOMINAL DISTENSION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ANAL INCONTINENCE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CONSTIPATION
         subjects affected / exposed
    10 / 227 (4.41%)
         occurrences all number
    10
    DIARRHOEA
         subjects affected / exposed
    8 / 227 (3.52%)
         occurrences all number
    8
    DIVERTICULUM
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DYSPEPSIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DYSPHAGIA
         subjects affected / exposed
    10 / 227 (4.41%)
         occurrences all number
    10
    ENTERITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    GINGIVAL BLEEDING
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    IRRITABLE BOWEL SYNDROME
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    NAUSEA
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    SALIVA ALTERED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SALIVARY HYPERSECRETION
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences all number
    4
    TONGUE COATED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    TOOTHACHE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    VOMITING
         subjects affected / exposed
    5 / 227 (2.20%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    DECUBITUS ULCER
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DERMAL CYST
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DRY SKIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DYSHIDROTIC ECZEMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ECZEMA
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    ECZEMA NUMMULAR
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    ERYTHEMA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HYPERHIDROSIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    INGROWING NAIL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    MILIARIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    NAIL BED INFLAMMATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PRURITUS
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    RASH
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    SKIN EXFOLIATION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SKIN LESION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SKIN REACTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Renal and urinary disorders
    INCONTINENCE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    MICTURITION DISORDER
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    NEUROGENIC BLADDER
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    POLYURIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    URINARY RETENTION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    URINE ABNORMALITY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    ARTHRITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    BACK PAIN
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences all number
    5
    BURSITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CHONDROMALACIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    DUPUYTREN'S CONTRACTURE
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    JOINT SWELLING
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    MOBILITY DECREASED
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    MUSCLE SPASMS
         subjects affected / exposed
    6 / 227 (2.64%)
         occurrences all number
    7
    MUSCLE TWITCHING
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    MUSCULAR WEAKNESS
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    MYALGIA
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    NECK PAIN
         subjects affected / exposed
    3 / 227 (1.32%)
         occurrences all number
    3
    PAIN IN EXTREMITY
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    PAIN IN JAW
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    PERIARTHRITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    TENDON PAIN
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Infections and infestations
    BARTHOLIN'S ABSCESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    BRONCHITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CONJUNCTIVITIS BACTERIAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    CYSTITIS
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    FUNGAL SKIN INFECTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    GASTROENTERITIS
         subjects affected / exposed
    4 / 227 (1.76%)
         occurrences all number
    4
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    GINGIVAL ABSCESS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HERPES ZOSTER
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    NASOPHARYNGITIS
         subjects affected / exposed
    10 / 227 (4.41%)
         occurrences all number
    11
    ORAL HERPES
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    RHINITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    SINUSITIS
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    3
    STOMA SITE CELLULITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    STOMA SITE INFECTION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    TONSILLITIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    9 / 227 (3.96%)
         occurrences all number
    10
    VULVOVAGINAL CANDIDIASIS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    DEHYDRATION
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    FOLATE DEFICIENCY
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1
    HYPOKALAEMIA
         subjects affected / exposed
    2 / 227 (0.88%)
         occurrences all number
    2
    TYPE 2 DIABETES MELLITUS
         subjects affected / exposed
    1 / 227 (0.44%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2020
    This amendment was written to describe how to perform baseline or treatment period visits remotely in case visit to the study centre was not possible due to restriction related to COVID-19 pandemic. All arrangements described in this section applied only to the extent that protocol requirements could not be met because of COVID-19 restrictions. Study centre visits had to take place to the extent possible and usual protocol requirements adopted for all subjects as soon as COVID-19 limitations permitted. SVC and weight were not assessed while these arrangements applied. During the remote visits, protocol requirements could be altered as assessments were conducted by phone interviews and for example HR values measured with automate sphygmomanometer were allowed.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Aug 2020
    The study was terminated by the sponsor on 21 August 2020, as the efficacy endpoints of the REFALS study were not met.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    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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