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    Clinical Trial Results:
    A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of ALN-TTR02 (patisiran) in Patients with TTR Amyloidosis.

    Summary
    EudraCT number
    		 2012-000467-24
    Trial protocol
    		 SE   PT   DE   ES  
    Global end of trial date
    27 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-TTR02-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01617967
    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
    07 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2014
    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-TTR02 (patisiran).
    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
    16 May 2012
    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
    Spain: 3
    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
    Brazil: 1
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Portugal: 9
    Worldwide total number of subjects
    29
    EEA total number of subjects
    27
    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)
    17
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 29 subjects 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
    No

    Arm title
    		 Cohort 1
    Arm description
    		 Patients received 0.010 mg/kg of ALN-TTR02 (patisiran) every four 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
    0.010 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Arm title
    		 Cohort 2
    Arm description
    		 Patients received 0.050 mg/kg of ALN-TTR02 (patisiran) every four 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
    0.050 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Arm title
    		 Cohort 3
    Arm description
    		 Patients received 0.150 mg/kg of ALN-TTR02 (patisiran) every four weeks
    Arm type
    		 Experimental

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

    Arm title
    		 Cohort 4 and 5
    Arm description
    		 Patients received 0.30 mg/kg of ALN-TTR02 (patisiran) every four 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
    0.30 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Arm title
    		 Cohort 6
    Arm description
    		 Patients received 0.30 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
    0.30 mg/kg of ALN-TTR02 (patisiran) every three weeks

    Arm title
    		 Cohort 7, 8, and 9
    Arm description
    		 Patients received 0.30 mg/kg of ALN-TTR02 (patisiran) every three weeks with alternative premedication regimen
    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
    0.30 mg/kg of ALN-TTR02 (patisiran) every three weeks with alternative premedication regimen

    Arm title
    		 Cohort 6, 7, 8 and 9
    Arm description
    		 PK results for Cohorts 6, 7, 8 and 9 have been grouped together.
    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
    0.30 mg/kg of ALN-TTR02 (patisiran) every three weeks

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4 and 5 Cohort 6 Cohort 7, 8, and 9 Cohort 6, 7, 8 and 9
    Started
    4
    3
    3
    7
    3
    9
    12
    Completed
    3
    3
    3
    7
    3
    8
    11
    Not completed
    1
    0
    0
    0
    0
    1
    1
         Consent withdrawn by subject
    1
    -
    -
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    1
    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
    		 29 29
    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)
    		 17 17
        From 65-84 years
    		 12 12
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ± 15.61 -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Patients received 0.010 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Reporting group title
    Cohort 2
    Reporting group description
    		 Patients received 0.050 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Reporting group title
    Cohort 3
    Reporting group description
    		 Patients received 0.150 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Reporting group title
    Cohort 4 and 5
    Reporting group description
    		 Patients received 0.30 mg/kg of ALN-TTR02 (patisiran) every four weeks

    Reporting group title
    Cohort 6
    Reporting group description
    		 Patients received 0.30 mg/kg of ALN-TTR02 (patisiran) every three weeks

    Reporting group title
    Cohort 7, 8, and 9
    Reporting group description
    		 Patients received 0.30 mg/kg of ALN-TTR02 (patisiran) every three weeks with alternative premedication regimen

    Reporting group title
    Cohort 6, 7, 8 and 9
    Reporting group description
    		 PK results for Cohorts 6, 7, 8 and 9 have been grouped together.

    Primary: Safety and tolerability in ATTR patients

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    End point title
    		 Safety and tolerability in ATTR patients [1] [2]
    End point description
    The number of subjects 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 56 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.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics have been reported for all cohorts in the baseline period. Patients in the arm titled ‘Cohort 6’ and the arm titled ‘Cohort 7, 8 and 9’ received 300 μg/kg ALN-TTR02 (patisiran) every 3 weeks. Therefore these two arms have been combined in the statistical analysis of PK parameters and are reported as ‘Cohort 6, 7, 8 and 9’. The arms have not been combined for reporting of other endpoints due to the use of different premedication regimens.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 and 5 Cohort 6 Cohort 7, 8, and 9
    Number of subjects analysed
    4
    3
    3
    7
    3
    9
    Units: subjects
        At least 1 Treatment Emergent Adverse Event
    1
    3
    1
    7
    3
    7
        At least 1 Serious TEAE
    0
    0
    0
    1
    0
    1
        Study Drug Discontinuation For Any Reason
    1
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of ALN-TTR02 (patisiran) - Cmax

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    End point title
    		 Pharmacokinetic parameters of ALN-TTR02 (patisiran) - Cmax [3]
    End point description
    Cmax of ALN-TTR02 (patisiran)
    End point type
    Secondary
    End point timeframe
    Up to 208 days post first dose
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics have been reported for all cohorts in the baseline period. Patients in the arm titled ‘Cohort 6’ and the arm titled ‘Cohort 7, 8 and 9’ received 300 μg/kg ALN-TTR02 (patisiran) every 3 weeks. Therefore these two arms have been combined in the statistical analysis of PK parameters and are reported as ‘Cohort 6, 7, 8 and 9’. The arms have not been combined for reporting of other endpoints due to the use of different premedication regimens.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 and 5 Cohort 6, 7, 8 and 9
    Number of subjects analysed
    4 [4]
    3
    3
    7 [5]
    12 [6]
    Units: ng/ml
    arithmetic mean (standard deviation)
        Cmax - Day 0
    145 ± 23
    672 ± 473
    2560 ± 295
    6053 ± 1326
    4539 ± 1362
        Cmax - Day 21 or 28
    106 ± 37
    683 ± 391
    3243 ± 986
    3782 ± 1259
    3314 ± 1253
    Notes
    [4] - N=3 at Day 28 due to 1 subject not completing study
    [5] - N = 6 at Day 28 as 1 subject excluded from the calculation of descriptive statistics
    [6] - N=11 at Day 21 due to 1 subject not completing study
    No statistical analyses for this end point

    Secondary: Serum transythretin (TTR) protein

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    End point title
    		 Serum transythretin (TTR) protein [7]
    End point description
    Percent lowering of TTR relative to pretreatment/baseline levels
    End point type
    Secondary
    End point timeframe
    Up to 208 days post first dose
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics have been reported for all cohorts in the baseline period. Patients in the arm titled ‘Cohort 6’ and the arm titled ‘Cohort 7, 8 and 9’ received 300 μg/kg ALN-TTR02 (patisiran) every 3 weeks. Therefore these two arms have been combined in the statistical analysis of PK parameters and are reported as ‘Cohort 6, 7, 8 and 9’. The arms have not been combined for reporting of other endpoints due to the use of different premedication regimens.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 and 5 Cohort 6 Cohort 7, 8, and 9
    Number of subjects analysed
    4
    3
    3
    7
    3
    9
    Units: percent
    arithmetic mean (standard deviation)
        Mean Percent TTR Reduction at Day 21 or 28
    -8.9 ± 9.91
    -21.7 ± 1.69
    -51.6 ± 22.84
    -73.9 ± 8.41
    -78 ± 7.55
    -80.7 ± 10.14
        Mean Percent TTR Reduction at Day 42 or 56
    -20.3 ± 20.27
    -14.6 ± 15.8
    -44.7 ± 12.11
    -62.8 ± 25.11
    -78.7 ± 9.77
    -73.3 ± 19.55
    No statistical analyses for this end point

    Secondary: Pharmacokinetic parameters of ALN-TTR02 (patisiran) - AUC

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    End point title
    		 Pharmacokinetic parameters of ALN-TTR02 (patisiran) - AUC [8]
    End point description
    AUC of ALN-TTR02 (patisiran)
    End point type
    Secondary
    End point timeframe
    Up to 208 days post first dose
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics have been reported for all cohorts in the baseline period. Patients in the arm titled ‘Cohort 6’ and the arm titled ‘Cohort 7, 8 and 9’ received 300 μg/kg ALN-TTR02 (patisiran) every 3 weeks. Therefore these two arms have been combined in the statistical analysis of PK parameters and are reported as ‘Cohort 6, 7, 8 and 9’. The arms have not been combined for reporting of other endpoints due to the use of different premedication regimens.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 and 5 Cohort 6, 7, 8 and 9
    Number of subjects analysed
    4 [9]
    3
    3
    7 [10]
    12 [11]
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        AUC 0-last : Day 0
    2738 ± 3159
    9604 ± 10588
    18998 ± 5066
    53724 ± 35814
    39741 ± 33373
        AUC 0-last : Day 21 or Day 28
    2799 ± 2645
    4884 ± 4652
    27748 ± 17081
    30013 ± 15935
    25958 ± 28460
    Notes
    [9] - N=3 at Day 28 due to 1 subject not completing study
    [10] - N = 6 at Day 28 as 1 subject excluded from the calculation of descriptive statistics
    [11] - N=11 at Day 21 due to 1 subject not completing study
    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 observed or reported after the first dose of study drug and through Day 56, regardless of their relationship to study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    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
    2 / 29 (6.90%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
    Additional description: Right arm cellulitis due to extravasation
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
         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
    23 / 29 (79.31%)
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Asthenia
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    6
    Vessel puncture site haematoma
         subjects affected / exposed
    7 / 29 (24.14%)
         occurrences all number
    23
    Pyrexia
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    4
    Immune system disorders
    Infusion related reaction
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Dysphagia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2012
    Protocol Amendment 1.0 • Removed the requirement that the SRC review safety data on all patients within a dose level between the first and second doses of study drug based on favourable single-dose safety data that emerged from the completed Phase 1 studies of ALN-TTR02 (patisiran) at doses greater than or equal to the proposed highest dose in this study. • Extended the postdose on-site observation period from 6 hours to 24 hours post infusion.
    16 Jan 2013
    Protocol Amendment 2.0 • Added alternative dosing regimens

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Jun 2012
    Sponsor notified agencies of a potential safety event in nonclinical toxicology study. Study continued based on human safety and tolerability data from Phase 1 study with ALN-TTR02 (patisiran) and data from other LNP (lipid nanoparticle) based programs.
    26 Jul 2012

    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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