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    Clinical Trial Results:
    Efficacy, Safety and Tolerability Study of 1 mg Rasagiline in Patients with Amyotrophic Lateral Sclerosis (ALS) Receiving Standard Therapy (Riluzole)

    Summary
    EudraCT number
    		 2011-004482-32
    Trial protocol
    		 DE  
    Global end of trial date
    28 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2021
    First version publication date
    03 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RAS-ALS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01879241
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Ulm
    Sponsor organisation address
    Albert-Einstein-Alle 29, Ulm, Germany, 89081
    Public contact
    Prof. Dr. A.C. Ludolph, Universitätsklinikum Ulm, 0049 07311771200, albert.ludolph@rku.de
    Scientific contact
    Prof. Dr. A.C. Ludolph, Universitätsklinikum Ulm, 0049 07311771200, albert.ludolph@rku.de
    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
    15 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy of rasagiline as add-on therapy to standard therapy with riluzole in patients with ALS compared to placebo in terms of survival (mortality exclusively defined as death).
    Protection of trial subjects
    The study intervention was provided add on to standard therapy with riluzole. The frequency of study visits was in line with the number of visits under standard therapy. Hence, no additional burden to standard health care was constituted.
    Background therapy
    		 The study intervention was provided add on to standard therapy with riluzole. Trial subjects were stable on standard therapy (100 mg riluzole per day) for at least 3 months before inclusion.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2013
    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
    Germany: 251
    Worldwide total number of subjects
    251
    EEA total number of subjects
    251
    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)
    164
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 02 July 2013, and 11 November 2014, trial subjects were recruited at at 15 study centres of the German ALS/MND-NET.

    Pre-assignment
    Screening details
    		 273 patients with amyotrophic lateral sclerosis were screened, 20 did not meet inclusion criteria, 1 withdrew consent during screening process. Hence, 252 patients were randomly assigned to receive either placebo (n=125) or rasagiline (n=127). One patient assigned to rasagiline did not take any treatment and was hence excluded from FAS.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rasagiline
    Arm description
    		 1 mg rasagiline (study intervention) plus standard therapy (100 mg riluzole), per day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rasagiline mesilate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg rasagiline per day

    Arm title
    		 Placebo
    Arm description
    		 Non-active substance (placebo) plus standard therapy (100 mg riluzole), per day
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Non-active substance (placebo), 1 tablet per day plus standard therapy (100 mg riluzole)

    Number of subjects in period 1
    		Rasagiline Placebo
    Started
    126
    125
    Completed
    108
    111
    Not completed
    18
    14
         Consent withdrawn by subject
    10
    9
         Physician decision
    3
    2
         Adverse event, non-fatal
    2
    -
         did not comply with treatment
    1
    3
         Non-amyotrophic lateral sclerosis death
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rasagiline
    Reporting group description
    		 1 mg rasagiline (study intervention) plus standard therapy (100 mg riluzole), per day

    Reporting group title
    Placebo
    Reporting group description
    		 Non-active substance (placebo) plus standard therapy (100 mg riluzole), per day

    Reporting group values
    		 Rasagiline Placebo Total
    Number of subjects
    		 126 125 251
    Age categorical
    Units: Subjects
    Age continuous
    252 patients with ALS at the age of 30.7-81.8 years were randomly assigned to receive either placebo (n=125) or rasagiline (n=127). In the rasagiline group, one patient left study participation before starting the intervention since he did not take the assigned intervention as to why only 126 patients were included in the primary analysis.
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ± 11.2 60.4 ± 10.2 -
    Gender categorical
    251 patients with ALS were assigned to receive either placebo (n=125) or rasagiline (n=126). 99 (39%) of them were female, 152 (61%) were male.
    Units: Subjects
        Female
    		 58 41 99
        Male
    		 68 84 152
    ALSFRS-R
    Physical functioning of the patients before randomisation was measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). A maximum score of 48 indicates unimpaired functioning status.
    Units: Score
        arithmetic mean (standard deviation)
    		 37.9 ± 5.6 38.3 ± 5.3 -
    Slow vital capacity
    Respiratory functioning before randomisation was assessed by slow vital capacity (SVC). A best-sitting SVC of at least 50% was required for inclusion in the trial.
    Units: Percent
        arithmetic mean (standard deviation)
    		 84.1 ± 19.2 85.4 ± 17.0 -
    SEIQoL
    Individual quality of life before randomisation was measured according to the Schedule for Evaluation of Individual Quality of Life (SEIQoL). In an interview the five most important areas of life are extracted, their weight is calculated and they are evaluated in terms of satisfaction for each subject.
    Units: Score
        arithmetic mean (standard deviation)
    		 67.1 ± 19.5 68.3 ± 20.6 -

    End points

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    End points reporting groups
    Reporting group title
    Rasagiline
    Reporting group description
    		 1 mg rasagiline (study intervention) plus standard therapy (100 mg riluzole), per day

    Reporting group title
    Placebo
    Reporting group description
    		 Non-active substance (placebo) plus standard therapy (100 mg riluzole), per day

    Primary: Survival probability

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    End point title
    		 Survival probability
    End point description
    The primary objective of this trial was to investigate survival to evaluate the efficacy of rasagiline as add-on therapy to riluzole. Hence, the time from randomization until death or the end of trial was compared between the group receiving rasagiline and the placebo group. Reported is the survival probability (95% CI).
    End point type
    Primary
    End point timeframe
    Time from baseline (date of randomization) until date of death or end of whole trial (last patient's last visit plus a 14-days safety follow-up.)
    End point values
    		 Rasagiline Placebo
    Number of subjects analysed
    126
    125
    Units: Probability
        number (confidence interval 95%)
    0.43 (0.25 to 0.59)
    0.53 (0.43 to 0.62)
    Statistical analysis title
    		 Survival
    Statistical analysis description
    As a primary efficacy endpoint survival in terms of time to death or end of trial was assessed. The study population was analysed according to the intention-to-treat principle. The two treatment groups were compared using a one-sided unstratified log-rank test.
    Comparison groups
    Rasagiline v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.34
    Notes
    [1] - The primary efficacy endpoint survival at the end of the study did not show a significant difference between the group receiving treatment with rasagiline and the placebo group.

    Secondary: Change in ALSFRS-R

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    End point title
    		 Change in ALSFRS-R
    End point description
    Changes in the ALSFRS-R were assessed and compared between the two groups to evaluate the benefit of rasagiline on physical functioning.
    End point type
    Secondary
    End point timeframe
    Baseline (date of randomization) until end of participation (18 months or death)
    End point values
    		 Rasagiline Placebo
    Number of subjects analysed
    126
    125
    Units: Points/month
        median (inter-quartile range (Q1-Q3))
    0.95 (0.41 to 1.28)
    1.02 (0.48 to 1.53)
    Statistical analysis title
    		 Change in ALSFRS-R
    Statistical analysis description
    Change in physical functioning in terms of ALSFRS-R, measured in points per month was evaluated by a Wilcoxon rank-sum test. No significant difference was found between the group receiving treatment with rasagiline and the placebo group (p=0.32).
    Comparison groups
    Rasagiline v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.32 [2]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - The difference in change of ALSFRS-R score was not found significant between the rasagiline and the placebo group.

    Secondary: Change in SVC

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    End point title
    		 Change in SVC
    End point description
    Changes in the slow vital capacity (SVC) were assessed in %/month to evaluate the benefit of rasagiline on respiratory function.
    End point type
    Secondary
    End point timeframe
    Baseline (date of randomization) until end of trial participation (18 months after baseline)
    End point values
    		 Rasagiline Placebo
    Number of subjects analysed
    126
    125
    Units: percent/month
        median (inter-quartile range (Q1-Q3))
    2.07 (0.65 to 4.08)
    1.78 (0.49 to 4.23)
    Statistical analysis title
    		 Change in SVC
    Statistical analysis description
    To evaluate the benefit of rasagiline on respiratory function changes in slow vital capacity (SVC) were assessed in % per months as a secondary endpoint. No significant difference was found between the two groups.
    Comparison groups
    Rasagiline v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.82 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - The difference in change of SVC was found not significant between the group receiving rasagiline as treatment and the placebo group.

    Secondary: Time to tracheostomy or death

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    End point title
    		 Time to tracheostomy or death
    End point description
    The time to tracheostomy or death was assessed as a secondary objective to evaluate the benefit of rasagiline. During their participation in this trial 9 patients in the rasagiline group (7%) and 8 patients in the placebo group (6%) underwent a tracheostomy. Reported is the survival probability for a tracheostomy or death (95% CI).
    End point type
    Secondary
    End point timeframe
    Baseline until end of study participation (18 months after baseline)
    End point values
    		 Rasagiline Placebo
    Number of subjects analysed
    126
    125
    Units: Probability
        number (confidence interval 95%)
    0.37 (0.20 to 0.55)
    0.48 (0.38 to 0.58)
    Statistical analysis title
    		 Survival until tracheostomy or death
    Statistical analysis description
    The survival probability for a tracheostomy during the study period or death was calculated and compared between the group receiving rasagiline as treatment and the placebo group.
    Comparison groups
    Rasagiline v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.65
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval

    Secondary: Change in SEIQoL

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    End point title
    		 Change in SEIQoL
    End point description
    Changes in SEIQoL score were assessed as % per months to evaluate benefit of rasagiline on the individual quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (date of randomization) until end of participation (18 months or death)
    End point values
    		 Rasagiline Placebo
    Number of subjects analysed
    126
    125
    Units: Percent/month
        median (inter-quartile range (Q1-Q3))
    0.03 (-0.67 to 0.95)
    0.24 (-0.27 to 1.22)
    Statistical analysis title
    		 Change in SEIQoL
    Statistical analysis description
    To evaluate the benefit of rasagiline for the individual quality of life changes in sum score of the SEIQoL were assessed in % per months as a secondary endpoint of the trial. No significant difference was found between the two groups. The analysis however shows nearly constant values over time with similar results for both groups.
    Comparison groups
    Rasagiline v Placebo
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2 [4]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - The difference in change of SEIQoL was found not significant between the group receiving treatment with rasagiline and the placebo group.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time from baseline to final visit (18 months) plus additional 14 days safety follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Rasagiline
    Reporting group description
    		 1 mg rasagiline (study intervention) plus standard therapy (100 mg riluzole), per day

    Reporting group title
    Placebo
    Reporting group description
    		 Non-active substance (placebo) plus standard therapy (100 mg riluzole), per day

    Serious adverse events
    		 Rasagiline Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    77 / 126 (61.11%)
    85 / 125 (68.00%)
         number of deaths (all causes)
    34
    41
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 126 (3.17%)
    5 / 125 (4.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    30 / 126 (23.81%)
    24 / 125 (19.20%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 24
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 126 (19.05%)
    31 / 125 (24.80%)
         occurrences causally related to treatment / all
    0 / 26
    0 / 35
         deaths causally related to treatment / all
    0 / 10
    0 / 19
    Dyspnoea
         subjects affected / exposed
    21 / 126 (16.67%)
    16 / 125 (12.80%)
         occurrences causally related to treatment / all
    1 / 23
    0 / 20
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Pneumonia
         subjects affected / exposed
    8 / 126 (6.35%)
    6 / 125 (4.80%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Hypoventilation
         subjects affected / exposed
    7 / 126 (5.56%)
    4 / 125 (3.20%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2.39%
    Non-serious adverse events
    		 Rasagiline Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 126 (60.32%)
    73 / 125 (58.40%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 126 (9.52%)
    16 / 125 (12.80%)
         occurrences all number
    16
    23
    Contusion
         subjects affected / exposed
    9 / 126 (7.14%)
    5 / 125 (4.00%)
         occurrences all number
    9
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 126 (7.14%)
    8 / 125 (6.40%)
         occurrences all number
    10
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    9 / 126 (7.14%)
    6 / 125 (4.80%)
         occurrences all number
    9
    7
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    3 / 126 (2.38%)
    0 / 125 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    6 / 126 (4.76%)
    7 / 125 (5.60%)
         occurrences all number
    6
    7
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 125 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 125 (0.80%)
         occurrences all number
    2
    2
    Pneumonia
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 125 (1.60%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 126 (5.56%)
    1 / 125 (0.80%)
         occurrences all number
    7
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    6 / 126 (4.76%)
    10 / 125 (8.00%)
         occurrences all number
    6
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 126 (1.59%)
    7 / 125 (5.60%)
         occurrences all number
    2
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 126 (7.14%)
    10 / 125 (8.00%)
         occurrences all number
    11
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2013
    The initial study protocol (version 1.0, 26 November 2012) excluded the intake of any antidepressants. To avoid unnecessary medical and ethical conflicts, this exclusion criterion was revised (protocol version 2.0, 02 October 2013) and only antidepressants contraindicated by the summary of product characteristics of rasagiline were prohibited.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29934198
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