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    Clinical Trial Results:
    APOLLO: A Phase 3 Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Patisiran (ALN-TTR02) in Transthyretin (TTR)-Mediated Polyneuropathy (Familial Amyloidotic Polyneuropathy-FAP)

    Summary
    EudraCT number
    		 2013-002987-17
    Trial protocol
    		 SE   ES   PT   IT   DE   NL   GB  
    Global end of trial date
    17 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Aug 2018
    First version publication date
    23 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-TTR02-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01960348
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alnylam Pharmaceuticals, Inc.
    Sponsor organisation address
    300 Third Street, Cambridge, MA, United States, 02142
    Public contact
    Investor Relations and Corporate Communications, Alnylam Pharmaceuticals, Inc., Investors@alnylam.com
    Scientific contact
    Chief Medical Officer , Alnylam Pharmaceuticals, Inc., medinfo@alnylam.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
    14 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of patisiran-LNP (ALN-TTR02) by evaluating the difference between the patisiran and placebo groups in the change from baseline of mNIS+7 score at 18 months
    Protection of trial subjects
    An independent Data Monitoring Committee was implemented for the study and operated under a prespecified charter. The Data Monitoring Committee was responsible for monitoring the progress of the study and the safety of the participants
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 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
    United States: 42
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Cyprus: 4
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Italy: 8
    Worldwide total number of subjects
    225
    EEA total number of subjects
    110
    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)
    130
    From 65 to 84 years
    95
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 225 patients with hATTR amyloidosis were enrolled and randomized in the study.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Patisiran (ALN-TTR02)
    Arm description
    		 All patients who received at least 1 dose of patisiran (ALN-TTR02)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patisiran
    Investigational medicinal product code
    ALN-TTR02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients who were randomized into the active treatment group received 0.3 mg/kg patisiran (ALN-TTR02) every three weeks (q3w) administered as an approximately 80-minute IV infusion. In the event of a mild or moderate infusion related reaction (IRR), the infusion time may have been extended.

    Arm title
    		 Placebo
    Arm description
    		 All patients who received at least 1 dose of placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Normal saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients who were randomized into the control group received placebo (normal saline 0.9%) every three weeks (q3w) administered as an approximately 80-minute IV infusion. In the event of a mild or moderate infusion related reaction (IRR), the infusion time may have been extended.

    Number of subjects in period 1
    		Patisiran (ALN-TTR02) Placebo
    Started
    148
    77
    Completed
    138
    55
    Not completed
    10
    22
         Adverse event, serious fatal
    6
    5
         Adverse event, not serious
    2
    2
         Consent withdrawn by subject
    1
    11
         Physician decision
    -
    1
         Adverse event, serious non-fatal
    -
    3
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Patisiran (ALN-TTR02)
    Reporting group description
    		 All patients who received at least 1 dose of patisiran (ALN-TTR02)

    Reporting group title
    Placebo
    Reporting group description
    		 All patients who received at least 1 dose of placebo

    Reporting group values
    		 Patisiran (ALN-TTR02) Placebo Total
    Number of subjects
    		 148 77 225
    Age categorical
    Units: Subjects
        Less than 65 years
    		 86 44 130
        65-74 years
    		 53 24 77
        Greater than or equal to 75 years
    		 9 9 18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.6 ( 11.96 ) 62.2 ( 10.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 19 58
        Male
    		 109 58 167
    Baseline NIS
    The Neuropathy Impairment Score is an assessment of motor weakness (NIS-W), sensation (NIS-S) and reflexes (NIS-R) scored based on physical exam findings.
    Units: Subjects
        <50
    		 62 35 97
        ≥50
    		 86 42 128
    Genotype Class
    TTR genotype class, collected at baseline
    Units: Subjects
        Early onset V30M (<50 years of age at onset)
    		 13 10 23
        All other mutations (including late onset V30M)
    		 135 67 202
    Previous Tetramer Stabilizer Use
    Prior use of tafamidis, meglumine or diflunisal
    Units: Subjects
        Yes
    		 78 41 119
        No
    		 70 36 106

    End points

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    End points reporting groups
    Reporting group title
    Patisiran (ALN-TTR02)
    Reporting group description
    		 All patients who received at least 1 dose of patisiran (ALN-TTR02)

    Reporting group title
    Placebo
    Reporting group description
    		 All patients who received at least 1 dose of placebo

    Subject analysis set title
    Modified Intent-to-Treat (mITT) population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients who were randomized and received at least 1 dose of patisiran (ALN-TTR02) or placebo. Patients were analyzed according to the treatment to which they were randomized.

    Subject analysis set title
    Per protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomized patients who received at least 1 dose of patisiran (ALN-TTR02) or placebo, completed baseline and either the 9-month or 18-month mNIS+7 and Norfolk QoL-DN assessments, and did not experience any major protocol deviations that may impact the efficacy results. Patients were analyzed according to treatment received.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least 1 dose of patisiran (ALN-TTR02) or placebo. Patients were analyzed according to the treatment received.

    Subject analysis set title
    Pharmacokinetic (PK) population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All patients in the Safety Population who provided at least 1 pharmacokinetic (PK) concentration measurement.

    Primary: Modified Neuropathy Impairment Score +7 (mNIS+7)

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    End point title
    		 Modified Neuropathy Impairment Score +7 (mNIS+7)
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves.
    End point type
    Primary
    End point timeframe
    18 months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    137
    51
    Units: mNIS+7 points
    least squares mean (standard error)
        Change from Baseline in mNIS+7 at Month 18
    -6.03 ( 1.739 )
    27.96 ( 2.602 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in mNIS+7. The model includes baseline mNIS+7 score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [1]
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -33.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.86
         upper limit
    		 -28.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.974
    Notes
    [1] - P=9.262E-24

    Secondary: Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire

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    End point title
    		 Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function.
    End point type
    Secondary
    End point timeframe
    18 months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    136
    48
    Units: Norfolk QOL-DN points
    least squares mean (standard error)
        Change from Baseline in Norfolk QoL-DN at Month 18
    -6.7 ( 1.77 )
    14.4 ( 2.73 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in Norfolk QOL-DN total score. The model includes baseline Norfolk QOL-DN score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [2]
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -21.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.2
         upper limit
    		 -15
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1
    Notes
    [2] - P=1.103E-10

    Secondary: Neurological Impairment Score-Weakness (NIS-W) score

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    End point title
    		 Neurological Impairment Score-Weakness (NIS-W) score
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments.
    End point type
    Secondary
    End point timeframe
    18 Months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    137
    51
    Units: NIS-W points
    least squares mean (standard error)
        Change from Baseline in NIS-W at Month 18
    0.05 ( 1.306 )
    17.93 ( 1.959 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in NIS-W. The model includes baseline NIS-W score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [3]
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -17.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.32
         upper limit
    		 -13.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.254
    Notes
    [3] - P=1.404E-13

    Secondary: Rasch-built Overall Disability Scale (R-ODS) score

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    End point title
    		 Rasch-built Overall Disability Scale (R-ODS) score
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients.
    End point type
    Secondary
    End point timeframe
    18 Months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    138
    54
    Units: R-ODS points
    least squares mean (standard error)
        Change from Baseline in R-ODS at Month 18
    0.0 ( 0.59 )
    -8.9 ( 0.88 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in R-ODS value. The model includes baseline R-ODS score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [4]
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7
         upper limit
    		 10.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.01
    Notes
    [4] - P=4.066E-16

    Secondary: Timed 10-meter walk test (10-MWT, gait speed)

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    End point title
    		 Timed 10-meter walk test (10-MWT, gait speed)
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted.
    End point type
    Secondary
    End point timeframe
    18 Months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    138
    55
    Units: m/sec
    least squares mean (standard error)
        Change from Baseline in 10-MWT at Month 18
    0.077 ( 0.0242 )
    -0.235 ( 0.0358 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in 10-meter walk test result. The model includes baseline 10-meter walk test result as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [5]
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.311
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.393
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0415
    Notes
    [5] - P=1.875E-12

    Secondary: Modified body mass index (mBMI)

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    End point title
    		 Modified body mass index (mBMI)
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L).
    End point type
    Secondary
    End point timeframe
    18 Months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    133
    52
    Units: kg/m2 x albumin g/L
    least squares mean (standard error)
        Change from Baseline in mBMI at Month 18
    -3.7 ( 9.57 )
    -119.4 ( 14.51 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in mBMI. The model includes baseline mBMI as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.000001 [6]
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    115.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 82.4
         upper limit
    		 149
    Variability estimate
    Standard error of the mean
    Dispersion value
    16.91
    Notes
    [6] - P=8.832E-11

    Secondary: Autonomic symptoms questionnaire (Composite Autonomic Symptom Score [COMPASS 31])

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    End point title
    		 Autonomic symptoms questionnaire (Composite Autonomic Symptom Score [COMPASS 31])
    End point description
    The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor).
    End point type
    Secondary
    End point timeframe
    18 Months
    End point values
    		 Patisiran (ALN-TTR02) Placebo
    Number of subjects analysed
    136
    53
    Units: COMPASS 31 points
    least squares mean (standard error)
        Change from Baseline in COMPASS 31 at Month 18
    -5.29 ( 1.300 )
    2.24 ( 1.940 )
    Statistical analysis title
    		 Placebo vs. Patisiran (ALN-TTR02)
    Statistical analysis description
    In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in COMPASS-31 total score. The model includes baseline COMPASS-31 score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
    Comparison groups
    Patisiran (ALN-TTR02) v Placebo
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Mixed-effect Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -7.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.89
         upper limit
    		 -3.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.213

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs that occurred from the start of study drug administration through End of Study (Day 567), or Follow-up (Day 602) if the patient did not enter open-label extension study.
    Adverse event reporting additional description
    AEs for patients with Rapid Disease Progression at Month 9 who stopped dosing were collected through Day 294 (42 days after last dose).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Patisiran (ALN-TTR02)
    Reporting group description
    		 All patients who received at least 1 dose of patisiran (ALN-TTR02).

    Reporting group title
    Placebo
    Reporting group description
    		 All patients who received at least 1 dose of placebo.

    Serious adverse events
    		 Patisiran (ALN-TTR02) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 148 (36.49%)
    31 / 77 (40.26%)
         number of deaths (all causes)
    7
    6
         number of deaths resulting from adverse events
    7
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Atypical fibroxanthoma
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal oncocytoma
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 148 (1.35%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    3 / 148 (2.03%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Liver transplant
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device battery issue
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         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
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucinations, mixed
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Drug level increased
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hereditary neuropathic amyloidosis
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syringomyelia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 148 (1.35%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    3 / 148 (2.03%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac amyloidosis
         subjects affected / exposed
    2 / 148 (1.35%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 148 (1.35%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 148 (2.03%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 148 (2.03%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular dyssynchrony
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Maculopathy
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous opacities
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 148 (5.41%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 148 (0.68%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 148 (0.68%)
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 148 (2.03%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural cellulitis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 148 (0.00%)
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 148 (0.68%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Patisiran (ALN-TTR02) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    143 / 148 (96.62%)
    75 / 77 (97.40%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    8 / 148 (5.41%)
    5 / 77 (6.49%)
         occurrences all number
    8
    9
    Orthostatic hypotension
         subjects affected / exposed
    7 / 148 (4.73%)
    6 / 77 (7.79%)
         occurrences all number
    7
    7
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    43 / 148 (29.05%)
    17 / 77 (22.08%)
         occurrences all number
    68
    35
    Fatigue
         subjects affected / exposed
    18 / 148 (12.16%)
    8 / 77 (10.39%)
         occurrences all number
    27
    18
    Asthenia
         subjects affected / exposed
    14 / 148 (9.46%)
    8 / 77 (10.39%)
         occurrences all number
    25
    11
    Pyrexia
         subjects affected / exposed
    11 / 148 (7.43%)
    5 / 77 (6.49%)
         occurrences all number
    12
    6
    Peripheral swelling
         subjects affected / exposed
    4 / 148 (2.70%)
    4 / 77 (5.19%)
         occurrences all number
    6
    6
    Immune system disorders
    Infusion related reaction
         subjects affected / exposed
    28 / 148 (18.92%)
    7 / 77 (9.09%)
         occurrences all number
    145
    79
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 148 (10.14%)
    9 / 77 (11.69%)
         occurrences all number
    18
    11
    Dyspnoea
         subjects affected / exposed
    9 / 148 (6.08%)
    0 / 77 (0.00%)
         occurrences all number
    13
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 148 (10.14%)
    7 / 77 (9.09%)
         occurrences all number
    24
    12
    Depression
         subjects affected / exposed
    5 / 148 (3.38%)
    5 / 77 (6.49%)
         occurrences all number
    5
    7
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 148 (4.05%)
    7 / 77 (9.09%)
         occurrences all number
    6
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    25 / 148 (16.89%)
    22 / 77 (28.57%)
         occurrences all number
    47
    42
    Contusion
         subjects affected / exposed
    4 / 148 (2.70%)
    5 / 77 (6.49%)
         occurrences all number
    5
    5
    Thermal burn
         subjects affected / exposed
    4 / 148 (2.70%)
    4 / 77 (5.19%)
         occurrences all number
    7
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    11 / 148 (7.43%)
    5 / 77 (6.49%)
         occurrences all number
    12
    6
    Supraventricular extrasystoles
         subjects affected / exposed
    2 / 148 (1.35%)
    5 / 77 (6.49%)
         occurrences all number
    2
    6
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 148 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 148 (12.84%)
    11 / 77 (14.29%)
         occurrences all number
    24
    37
    Headache
         subjects affected / exposed
    16 / 148 (10.81%)
    9 / 77 (11.69%)
         occurrences all number
    25
    10
    Neuralgia
         subjects affected / exposed
    10 / 148 (6.76%)
    5 / 77 (6.49%)
         occurrences all number
    29
    13
    Balance disorder
         subjects affected / exposed
    8 / 148 (5.41%)
    2 / 77 (2.60%)
         occurrences all number
    10
    2
    Paraesthesia
         subjects affected / exposed
    8 / 148 (5.41%)
    3 / 77 (3.90%)
         occurrences all number
    23
    5
    Somnolence
         subjects affected / exposed
    5 / 148 (3.38%)
    4 / 77 (5.19%)
         occurrences all number
    13
    5
    Hypoaesthesia
         subjects affected / exposed
    4 / 148 (2.70%)
    5 / 77 (6.49%)
         occurrences all number
    6
    5
    Syncope
         subjects affected / exposed
    2 / 148 (1.35%)
    8 / 77 (10.39%)
         occurrences all number
    2
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 148 (2.03%)
    8 / 77 (10.39%)
         occurrences all number
    3
    11
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 148 (5.41%)
    1 / 77 (1.30%)
         occurrences all number
    11
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    8 / 148 (5.41%)
    5 / 77 (6.49%)
         occurrences all number
    10
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    50 / 148 (33.78%)
    28 / 77 (36.36%)
         occurrences all number
    156
    94
    Constipation
         subjects affected / exposed
    22 / 148 (14.86%)
    12 / 77 (15.58%)
         occurrences all number
    29
    17
    Nausea
         subjects affected / exposed
    22 / 148 (14.86%)
    16 / 77 (20.78%)
         occurrences all number
    50
    22
    Vomiting
         subjects affected / exposed
    14 / 148 (9.46%)
    6 / 77 (7.79%)
         occurrences all number
    20
    27
    Dyspepsia
         subjects affected / exposed
    12 / 148 (8.11%)
    3 / 77 (3.90%)
         occurrences all number
    23
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 148 (5.41%)
    5 / 77 (6.49%)
         occurrences all number
    8
    5
    Abdominal pain upper
         subjects affected / exposed
    3 / 148 (2.03%)
    6 / 77 (7.79%)
         occurrences all number
    3
    8
    Haemorrhoids
         subjects affected / exposed
    1 / 148 (0.68%)
    5 / 77 (6.49%)
         occurrences all number
    3
    7
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    10 / 148 (6.76%)
    2 / 77 (2.60%)
         occurrences all number
    51
    2
    Skin ulcer
         subjects affected / exposed
    5 / 148 (3.38%)
    5 / 77 (6.49%)
         occurrences all number
    7
    6
    Skin lesion
         subjects affected / exposed
    2 / 148 (1.35%)
    4 / 77 (5.19%)
         occurrences all number
    2
    4
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    6 / 148 (4.05%)
    7 / 77 (9.09%)
         occurrences all number
    9
    12
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    12 / 148 (8.11%)
    1 / 77 (1.30%)
         occurrences all number
    18
    1
    Arthralgia
         subjects affected / exposed
    11 / 148 (7.43%)
    0 / 77 (0.00%)
         occurrences all number
    13
    0
    Back pain
         subjects affected / exposed
    10 / 148 (6.76%)
    6 / 77 (7.79%)
         occurrences all number
    11
    9
    Pain in extremity
         subjects affected / exposed
    10 / 148 (6.76%)
    8 / 77 (10.39%)
         occurrences all number
    13
    12
    Osteoporosis
         subjects affected / exposed
    7 / 148 (4.73%)
    7 / 77 (9.09%)
         occurrences all number
    7
    7
    Muscular weakness
         subjects affected / exposed
    5 / 148 (3.38%)
    11 / 77 (14.29%)
         occurrences all number
    8
    17
    Myalgia
         subjects affected / exposed
    2 / 148 (1.35%)
    4 / 77 (5.19%)
         occurrences all number
    4
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    19 / 148 (12.84%)
    12 / 77 (15.58%)
         occurrences all number
    40
    18
    Nasopharyngitis
         subjects affected / exposed
    15 / 148 (10.14%)
    6 / 77 (7.79%)
         occurrences all number
    26
    11
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 148 (8.78%)
    5 / 77 (6.49%)
         occurrences all number
    16
    6
    Influenza
         subjects affected / exposed
    11 / 148 (7.43%)
    4 / 77 (5.19%)
         occurrences all number
    13
    4
    Bronchitis
         subjects affected / exposed
    9 / 148 (6.08%)
    2 / 77 (2.60%)
         occurrences all number
    11
    2
    Gastroenteritis
         subjects affected / exposed
    4 / 148 (2.70%)
    4 / 77 (5.19%)
         occurrences all number
    5
    4
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    7 / 148 (4.73%)
    4 / 77 (5.19%)
         occurrences all number
    7
    4
    Decreased appetite
         subjects affected / exposed
    6 / 148 (4.05%)
    5 / 77 (6.49%)
         occurrences all number
    6
    9
    Dehydration
         subjects affected / exposed
    1 / 148 (0.68%)
    5 / 77 (6.49%)
         occurrences all number
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2013
    Reordered secondary endpoints and modified methods of analysis Modified Inclusion Criterion #7 to allow an INR of ≤3 only for patients on warfarin Clarified definition of “highly effective birth control” Modified the premedication regimen to be administered the night prior to study drug administration and on the day of study drug administration
    21 Mar 2014
    Clarified that entry criteria, besides Inclusion Criteria #3 and #4, would continue to be assessed at both the Screening and the Screening/ Baseline visits Modified Inclusion Criterion #1 to allow for enrollment of subjects up to 85 years of age (inclusive) Modified Inclusion Criterion #3: the lower limit of the NIS changed from 10 to 5 Modified Inclusion Criterion #4 to include patients with a NCS sum of the sural sensory nerve action potential, the tibial compound muscle action potential and the peroneal CMAP ≥2 Modified Inclusion Criterion #6: platelet count changed from ≥100,000 cells/mm3 to ≥50000 cells/mm3 Modified Inclusion Criterion #7: INR value changed from ≤3 to ≤3.5 Clarified Exclusion Criterion #1 to exclude patients with vitamin A levels consistent with vitamin A deficiency Removed Exclusion Criterion #18 (removed: Participated in a clinical study with an antisense oligonucleotide for more than 3 months; if in a clinical study with antisense oligonucleotide for ≤3 months, must have completed a 3-month wash-out prior to start of study drug administration in this study) Removed Diflunisal from Exclusion Criterion #19 and added to Exclusion Criterion #20 to clarify that a 3-day washout period prior to start of study drug for this particular agent
    24 Apr 2014
    Expanded the screening window from 28 days to 42 days to accommodate traveling patients
    04 Aug 2014
    Modified Inclusion Criterion #3: the upper limit NIS changed from 100 to 130, and the requirement for having a PND score of ≤3b was added Modified Inclusion Criterion #7 to remove albumin criterion and to increase INR criterion from ≤1.2 to ≤2.0 Modified Inclusion Criterion #8: serum creatinine changed from ≤1.5 to ≤2 × ULN Modified Inclusion Criterion #9 to exclude only patients with an active hepatitis B or hepatitis C infection Modified Inclusion Criterion #1 to change period from 1 month to 75 days after last dose of study drug for women of child-bearing potential Modified Inclusion Criterion #11 to extend the period that males with partners of child-bearing potential must use 1 barrier method and 1 additional method of contraception from 1 month to 75 days after the last dose of study drug Removed Exclusion Criterion #1 (has vitamin A level consistent with vitamin A deficiency) Clarified Exclusion Criterion #16 to state that patients with a history of alcohol abuse within the past 2 years or daily heavy alcohol consumption Modified Exclusion Criterion #17 to exclude patients who participated in a clinical study with antisense oligonucleotide unless there is a 3- month wash-out period Modified Exclusion Criterion #24 to define “under legal protection”
    08 Sep 2015
    Implemented a reduced dose of dexamethasone for the protocol-specified premedication regimen on the day of study drug administration, and removed administration of premedication the night before study drug administration. Specified that patients who are intolerant of 10 mg IV dexamethasone or equivalent on the day of infusion may be considered for further stepwise reduction in dexamethasone or equivalent after consultation with the Medical Monitor Updated the risk benefit assessment to reflect liver function test abnormalities and risk for osteoporosis Modified Inclusion Criterion #4: added ulnar SNAP and ulnar CMAP measurements to the qualifying NCS Modified Inclusion Criterion #7: permitted enrollment of patients with a total bilirubin level elevation to ≤2 x upper limit of normal Modified Exclusion Criterion #14: clarified that patients with any uncontrolled cardiac arrhythmia or unstable angina are not permitted to enroll in the study Included the option for patients to permanently discontinue study treatment and remain on study

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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