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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-Label, Extension Study to Evaluate the Long-Term Safety, Clinical Activity, and Pharmacokinetics of ALN-TTR02 in Patients With Familial Amyloidotic Polyneuropathy Who Have Previously Received ALN-TTR02

    Summary
    EudraCT number
    		 2013-001644-65
    Trial protocol
    		 PT   SE   ES  
    Global end of trial date
    31 Aug 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Sep 2017
    First version publication date
    14 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-TTR02-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01961921
    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., Alnylam Pharmaceuticals, Inc., Clinicaltrials@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
    24 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety of long-term dosing with patisiran.
    Protection of trial subjects
    The safety assessments included the incidence and severity of adverse events (AEs), clinical laboratory tests (hematology, serum chemistry and urinalysis), electrocardiogram (ECG), vital signs and physical examinations which were assessed throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Brazil: 1
    Worldwide total number of subjects
    27
    EEA total number of subjects
    25
    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)
    14
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 27 subjects who met entry criteria were enrolled.

    Pre-assignment period milestones
    Number of subjects started
    		 27
    Number of subjects completed
    		 27

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

    Arms
    Arm title
    		 All Patients
    Arm description
    		 Patients received 0.3 mg/kg of ALN-TTR02 (patisiran) every three weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patisiran
    Investigational medicinal product code
    ALN-TTR02
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.3 mg/kg of ALN-TTR02 (patisiran) every three weeks

    Number of subjects in period 1
    		All Patients
    Started
    27
    Completed
    25
    Not completed
    2
         Adverse event, serious fatal
    2

    Baseline characteristics

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

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 27 27
    Age categorical
    All patients who received at least one dose of ALN-TTR02 (patisiran)
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 13 13
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ± 15.36 -
    Gender categorical
    All patients who received at least one dose of ALN-TTR02 (patisiran)
    Units: Subjects
        Female
    		 9 9
        Male
    		 18 18
    FAP Stage
    All patients who received at least one dose of ALN-TTR02 (patisiran)
    Units: Subjects
        FAP Stage I: Unimpaired ambulation
    		 24 24
        FAP Stage II: Assistance with ambulation required
    		 3 3
        FAP Stage III: Wheelchair-bound or bedridden
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    All Patients
    Reporting group description
    		 Patients received 0.3 mg/kg of ALN-TTR02 (patisiran) every three weeks.

    Primary: Safety of long-term dosing with ALN-TTR02 (patisiran) in hATTR patients

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    End point title
    		 Safety of long-term dosing with ALN-TTR02 (patisiran) in hATTR patients [1]
    End point description
    The proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs) and study drug discontinuation
    End point type
    Primary
    End point timeframe
    Up to 56 days post last dose
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential analyses were conducted as the primary endpoint was safety and tolerability. Analyses were descriptive in nature.
    End point values
    		 All Patients
    Number of subjects analysed
    27
    Units: Number of subjects
        At least 1 TEAE
    26
        At least 1 SAE
    7
        Study Discontinuation for any reason
    2
    No statistical analyses for this end point

    Secondary: Serum TTR Levels

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    End point title
    		 Serum TTR Levels
    End point description
    TTR levels, measured using the ELISA method
    End point type
    Secondary
    End point timeframe
    Up to 56 days post last dose
    End point values
    		 All Patients
    Number of subjects analysed
    27
    Units: TTR Reduction %
    arithmetic mean (standard deviation)
        Individual Mean TTR (%) Reduction from Baseline ov
    82.06 ± 1.33
        Individual Mean Predose TTR (%) Reduction from Bas
    79.73 ± 1.45
        Individual Maximum TTR (%) Reduction from Baseline
    92.54 ± 0.67
    No statistical analyses for this end point

    Secondary: Neurologic impairment

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    End point title
    		 Neurologic impairment
    End point description
    The mNIS+7 assessment is a composite measure of neurologic impairment that provides a comprehensive measure of large and small fiber function that encompasses the totality of the motor, sensory, and autonomic deficits seen in hATTR amyloidosis patients with polyneuropathy. An increase from baseline in mNIS+7 score suggests worsening of neurological impairment, and a decrease from baseline suggests improvement.
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    End point values
    		 All Patients
    Number of subjects analysed
    27
    Units: mNIS+7
    arithmetic mean (standard deviation)
        mNIS+7 score (Baseline)
    53.02 ± 35.63
        mNIS+7 (Change from baseline at 24 months)
    -6.95 ± 2.03
    No statistical analyses for this end point

    Secondary: Quality of life and disability

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    End point title
    		 Quality of life and disability
    End point description
    Quality of life (EQ-5D and EQ-VAS) and disability (R-ODS). The overall EQ-5D is measured on a scale from 0 to 1, with 0 being worst and 1 best. The EQ-VAS is measured on a scale of 0-100, with 0 being the worst and 100 the best.
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    End point values
    		 All Patients
    Number of subjects analysed
    27
    Units: Score
    arithmetic mean (standard deviation)
        EQ-5D (Baseline)
    0.78 ± 0.14
        EQ-5D (Score change from baseline to 24 months)
    -0.01 ± 0.02
        EQ-VAS (Baseline)
    67.9 ± 17.85
        EQ-VAS (Score change from baseline to 24 months)
    1.7 ± 2.53
        R-ODS (Baseline)
    38.1 ± 8.61
        R-ODS (Score change from baseline to 24 months)
    -1.8 ± 0.83
    No statistical analyses for this end point

    Secondary: Motor function

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    End point title
    		 Motor function
    End point description
    Timed 10-meter walk test and test of grip strength
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    End point values
    		 All Patients
    Number of subjects analysed
    27
    Units: m/sec or kg
    arithmetic mean (standard deviation)
        10-meter Walk Test at Baseline (m/sec)
    1.14 ± 0.79
        10-meter Walk Test Change from baseline at 24 mont
    0.03 ± 0.04
        Hand Grip Strength at Baseline (kg)
    25.81 ± 11.86
        Hand Grip Strength Change from baseline at 24 mont
    1.49 ± 1.23
    No statistical analyses for this end point

    Secondary: Nutritional status (modified body mass index, mBMI)

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    End point title
    		 Nutritional status (modified body mass index, mBMI)
    End point description
    Nutritional status of patients will be evaluated using the mBMI, calculated as BMI (kg/m2) multiplied by albumin (g/L).An increase from baseline in mBMI suggests improvement, and a decrease from baseline suggests worsening
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    End point values
    		 All Patients
    Number of subjects analysed
    27
    Units: kg/m2 x albumin g/L
    arithmetic mean (standard deviation)
        kg/m2 x albumin g/L (Baseline)
    1030.49 ± 168.64
        Kg/m2 x albumin g/L (Change from baseline at 24 mo
    -60.76 ± 34.86
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The investigators reported all AEs that occurred after the start of study drug administration on Day 0 (Baseline) through 21 or 56 days after the last dose of study drug administration (depending on enrollment into the open-label global extension study).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 All patients who received at least one dose of ALN-TTR02 (patisiran)

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 27 (25.93%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac amyloidosis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Surgical and medical procedures
    Arthrodesis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 27 (96.30%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    7 / 27 (25.93%)
         occurrences all number
    93
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    4
    Infusion site extravasation
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Oedema peripheral
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    8
    Early satiety
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Gait disturbance
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Infusion site erythema
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Immune system disorders
    Infusion related reaction
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    30
    Depression
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Investigations
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    10
    Ankle fracture
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Fall
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Foot fracture
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    4
    Ligament rupture
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Hypoaesthesia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    4
    Visual field defect
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    4
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Macular degeneration
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Macular fibrosis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Visual acuity reduced
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    8
    Nausea
         subjects affected / exposed
    5 / 27 (18.52%)
         occurrences all number
    6
    Abdominal pain
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Skin ulcer
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Osteoporosis
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Arthralgia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Osteoarthritis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Osteonecrosis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Osteopenia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    8
    Urinary tract infection
         subjects affected / exposed
    6 / 27 (22.22%)
         occurrences all number
    8
    Bronchitis
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    7
    Cellulitis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Osteomyelitis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Wound infection
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2015
    Protocol Amendment 1.0 Implemented a reduced dose of dexamethasone premedication as part of the protocol-specified premedication regimen

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

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