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    Clinical Trial Results:
    A Phase 2, Open-Label Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Exploratory Clinical Activity of ALN-TTRSC in Patients with Transthyretin (TTR) Cardiac Amyloidosis

    Summary
    EudraCT number
    		 2013-002856-33
    Trial protocol
    		 GB  
    Global end of trial date
    05 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2016
    First version publication date
    09 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-TTRSC-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01981837
    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 & Corporate Communication, Alnylam Pharmaceuticals, Inc., investors@alnylam.com
    Scientific contact
    Senior Vice President, Clinical Development, 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
    09 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of multiple doses of ALN-TTRSC (revusiran) in patients with ATTR cardiac amyloidosis.
    Protection of trial subjects
    A Safety Review Committee (SRC) was in place for this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jan 2014
    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
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    26
    EEA total number of subjects
    10
    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)
    7
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 26 patients who met all inclusion criteria and none of the exclusion criteria were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALN-TTRSC (revusiran) 5.0 mg/kg
    Arm description
    		 Patients received 5.0 mg/kg of ALN-TTRSC (revusiran) for a total of 10 doses
    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
    5.0 mg/kg of ALN-TTRSC (revusiran) for a total of 10 doses. Patients received a daily dose of ALN-TTRSC (revusiran) over 5 consecutive days (Days 0, 1, 2, 3, and 4) and then they received once weekly doses of ALN-TTRSC (revusiran) for 5 weeks (Days 7, 14, 21, 28, and 35).

    Arm title
    		 ALN-TTRSC (revusiran) 7.5 mg/kg
    Arm description
    		 Patients received 7.5 mg/kg of ALN-TTRSC (revusiran) for a total of 10 doses
    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
    7.5 mg/kg of ALN-TTRSC (revusiran) for a total of 10 doses. Patients received a daily dose of ALN-TTRSC (revusiran) over 5 consecutive days (Days 0, 1, 2, 3, and 4) and then they received once weekly doses of ALN-TTRSC (revusiran) for 5 weeks (Days 7, 14, 21, 28, and 35).

    Number of subjects in period 1
    		ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Started
    23
    3
    Completed
    23
    3

    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
    		 26 26
    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)
    		 7 7
        From 65-84 years
    		 19 19
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.1 ( 6.36 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 23 23

    End points

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    End points reporting groups
    Reporting group title
    ALN-TTRSC (revusiran) 5.0 mg/kg
    Reporting group description
    		 Patients received 5.0 mg/kg of ALN-TTRSC (revusiran) for a total of 10 doses

    Reporting group title
    ALN-TTRSC (revusiran) 7.5 mg/kg
    Reporting group description
    		 Patients received 7.5 mg/kg of ALN-TTRSC (revusiran) for a total of 10 doses

    Primary: Safety and tolerability of multiple doses of ALN-TTRSC (revusiran) in patients with ATTR cardiac amyloidosis

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    End point title
    		 Safety and tolerability of multiple doses of ALN-TTRSC (revusiran) in patients with ATTR cardiac amyloidosis [1]
    End point description
    The number of patients experiencing adverse events (AEs), serious adverse events (SAEs) and study drug discontinuation (due to any reason)
    End point type
    Primary
    End point timeframe
    Up to 90 days post first 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
    		 ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Number of subjects analysed
    23
    3
    Units: patients
        At least 1 Treatment Emergent Adverse Event (TEAE)
    17
    3
        At least 1 Serious TEAE
    3
    0
        Study Drug Discontinuation For Any Reason
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of ALN-TTRSC (revusiran): AUC

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    End point title
    		 Pharmacokinetic parameters of ALN-TTRSC (revusiran): AUC
    End point description
    Partial area under the plasma concentration-time curve from time 0 to 24 hours (AUC 0-24) and area under the curve from time 0 to the last quantifiable concentration (AUC 0-last) of ALN-TTRSC (revusiran)
    End point type
    Secondary
    End point timeframe
    Up to 90 days post first dose
    End point values
    		 ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Number of subjects analysed
    23
    3
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        AUC 0-24: Day 0
    9523.2 ( 3606.45 )
    16006.2 ( 1728 )
        AUC 0-last: Day 0
    9217.2 ( 3746.44 )
    12684.8 ( 6546.56 )
        AUC 0-24: Day 4
    13364.4 ( 6241.06 )
    29124 ( 6241.55 )
        AUC 0-last: Day 4
    4310.2 ( 1425.93 )
    7547.5 ( 1186.01 )
        AUC 0-24: Day 35
    9960.7 ( 5554.52 )
    27122.5 ( 3826.16 )
        AUC 0-last: Day 35
    7853.3 ( 6398.12 )
    6102.6 ( 989.08 )
    No statistical analyses for this end point

    Secondary: Serum transthyretin (TTR) protein

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    End point title
    		 Serum transthyretin (TTR) protein
    End point description
    Percent lowering of TTR relative to pretreatment/baseline levels
    End point type
    Secondary
    End point timeframe
    Up to 90 days post first dose
    End point values
    		 ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Number of subjects analysed
    23
    3
    Units: percent
    arithmetic mean (standard deviation)
        Mean Percent Change of Serum TTR at Day 21
    -80.208 ( 11.2259 )
    -91.431 ( 4.2603 )
        Mean Percent Change of Serum TTR at Day 42
    -83.593 ( 10.9567 )
    -90.232 ( 5.7909 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of ALN-TTRSC (revusiran): Cmax

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    End point title
    		 Pharmacokinetic parameters of ALN-TTRSC (revusiran): Cmax
    End point description
    Maximum observed plasma concentration (Cmax) of ALN-TTRSC (revusiran)
    End point type
    Secondary
    End point timeframe
    Up to 90 days post first dose
    End point values
    		 ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Number of subjects analysed
    23
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax: Day 0
    814.5 ( 574.57 )
    1043 ( 71.842 )
        Cmax: Day 4
    942.9 ( 322.33 )
    1503 ( 205.99 )
        Cmax: Day 35
    691 ( 394.14 )
    1263 ( 156.95 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of ALN-TTRSC (revusiran): tmax

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    End point title
    		 Pharmacokinetic parameters of ALN-TTRSC (revusiran): tmax
    End point description
    Time of maximum observed plasma concentration (tmax) of ALN-TTRSC (revusiran)
    End point type
    Secondary
    End point timeframe
    Up to 90 days
    End point values
    		 ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Number of subjects analysed
    23
    3
    Units: hours
    arithmetic mean (standard deviation)
        tmax: Day 0
    4.11 ( 2.1618 )
    5.3 ( 1.0833 )
        tmax: Day 4
    2.292 ( 1.8866 )
    3.317 ( 2.3238 )
        tmax: Day 35
    2.879 ( 2.2485 )
    5.272 ( 1.0301 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of ALN-TTRSC (revusiran): CLss/F

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    End point title
    		 Pharmacokinetic parameters of ALN-TTRSC (revusiran): CLss/F
    End point description
    Systemic clearance (CLss/F) of ALN-TTRSC (revusiran)
    End point type
    Secondary
    End point timeframe
    Up to 90 days post first dose
    End point values
    		 ALN-TTRSC (revusiran) 5.0 mg/kg ALN-TTRSC (revusiran) 7.5 mg/kg
    Number of subjects analysed
    23
    3
    Units: L/h/kg
    arithmetic mean (standard deviation)
        CLss/F: Day 4
    0.5034 ( 0.34314 )
    0.2667 ( 0.064487 )
        CLss/F: Day 35
    0.2602 ( 0.16303 )
    0.07163 ( 0.009483 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The Investigator reported all AEs that occurred after the first dose of study drug through the Day 63 or Early Termination visit regardless of their relationship to study drug or clinical significance.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 26 (11.54%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 26 (3.85%)
         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
    		 Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 26 (76.92%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Fall
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Injection site erythema
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    6
    Injection site bruising
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    3
    Injection site rash
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    4
    Abdominal distension
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Dysphonia
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    7 / 26 (26.92%)
         occurrences all number
    8
    Muscle spasms
         subjects affected / exposed
    3 / 26 (11.54%)
         occurrences all number
    4
    Back pain
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 26 (7.69%)
         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
    30 Sep 2013
    Protocol Amendment 1 • The method of acceptable contraception for study participants was revised to reflect MHRA guidelines
    16 Oct 2013
    Protocol Amendment 2 • Increased patient numbers from 12 to 15 • Study drug dose decreased from 7.5 mg/kg to 5.0 mg/kg
    21 Jan 2014
    Protocol Amendment 3 • Changes to timings of pharmacokinetic blood draws • Measurement of vitamin A serum levels added to the Schedule of Assessments for the Day 35 visit
    20 May 2014
    Protocol Amendment 4 • The number of patients was increased to approximately 25 patients • Inclusion Criterion #2 was changed to include only cardiac amyloidosis patients with a TTR mutation • Exclusion Criterion #5 was modified to exclude patients with vitamin A levels consistent with vitamin A deficiency (ie, <20 µg/dL)

    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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    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
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