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    Clinical Trial Results:
    An Open-Label Study To Evaluate The Efficacy And Safety Of Revusiran In Patients With Transthyretin-Mediated Familial Amyloidotic Polyneuropathy With Disease Progression Post Orthotopic Liver Transplant

    Summary
    EudraCT number
    		 2015-002603-29
    Trial protocol
    		 SE   PT   ES   GB  
    Global end of trial date
    06 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Feb 2018
    First version publication date
    21 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-TTRSC-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02595983
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alnylam Pharmaceuticals, Inc.
    Sponsor organisation address
    300 Third Street, Cambridge, United States, 02142
    Public contact
    Investor Relations and Corporate Communications, Alnylam Pharmaceuticals Inc, Investors@alnylam.com
    Scientific contact
    Chief Medical Officer, 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
    02 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assess the efficacy of revusiran in patients with transthyretin (TTR)-amyloidosis (hATTR amyloidosis) with polyneuropathy, with disease progression post-orthotopic liver transplant (OLT) by evaluating the reduction in serum TTR level compared to baseline.
    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
    28 Dec 2015
    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
    Portugal: 3
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 2
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    10
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 12 patients with hATTR amyloidosis with polyneuropathy who had neuropathy progression following OLT were enrolled and treated in this study.

    Pre-assignment period milestones
    Number of subjects started
    		 12
    Number of subjects completed
    		 12

    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
    		 All patients who received at least 1 dose of the study drug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Revusiran
    Investigational medicinal product code
    ALN-TTRSC
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received 5 daily doses of 500 mg revusiran (Days 0 through 4) and a dose of 500 mg on Day 7, followed by once weekly 500 mg doses for the duration of the study, until termination of dosing

    Number of subjects in period 1
    		All Patients
    Started
    12
    Completed
    8
    Not completed
    4
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 12 12
    Age categorical
    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)
    		 10 10
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.8 ± 8.65 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least a single dose of study drug.

    Subject analysis sets values
    		 Safety
    Number of subjects
    12
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    10
        From 65-84 years
    2
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.8 ± 8.65
    Gender categorical
    Units: Subjects
        Female
    3
        Male
    9

    End points

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    End points reporting groups
    Reporting group title
    All Patients
    Reporting group description
    		 All patients who received at least 1 dose of the study drug

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least a single dose of study drug.

    Primary: Serum TTR over 6 months

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    End point title
    		 Serum TTR over 6 months [1]
    End point description
    Percent reduction from baseline in serum TTR level at 6 months.
    End point type
    Primary
    End point timeframe
    6 months
    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: Limited collection of data due to the Sponsor's decision to terminate the study.
    End point values
    		 Safety
    Number of subjects analysed
    0 [2]
    Units: Percentage
    Notes
    [2] - Limited collection of data due to the Sponsor’s decision to terminate the study.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs that occurred after the start of study drug administration on Day 0 (Baseline) up to 90 days post modified early termination visit (End of Study)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 All patients who received at least 1 dose of study drug

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 12 (66.67%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Investigations
    Blood immunoglobulin M increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercapnic coma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
         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
    11 / 12 (91.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    6
    Injection site erythema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    Injection site haematoma
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gait disturbance
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Generalised oedema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Injection site bruising
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Secretion discharge
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Asthenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dysphonia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Prothrombin level decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood lactic acid increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood pyruvic acid increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood pressure abnormal
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Tooth fracture
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eschar
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Wound
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Cardiomyopathy
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    4
    Hypoaesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    Syncope
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Speech disorder
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Aphasia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Polyneuropathy
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Macrocytosis
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Retinal vein occlusion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Aerophagia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    4
    Dysuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Joint stiffness
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    4
    Cystitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Hyperuricaemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2016
    The primary purpose for the protocol amendment is to allow for more intensive monitoring of liver function in response to adverse events (AEs) in ongoing and completed studies with revusiran in patients with transthyretin-mediated cardiac amyloidosis.
    12 Oct 2016
    The primary purpose of Protocol Amendment 3 is to provide guidance for follow-up of patients enrolled in the study following the Sponsor's decision to discontinue study drug dosing in all ongoing revusiran studies as previously communicated to the investigators, ethics committees, and health authorities.

    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.
    Safety and efficacy conclusions are limited due to Sponsor’s decision to terminate the study.
    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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