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    Clinical Trial Results:
    ENVISION: A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study with an Open-label Extension to Evaluate the Efficacy and Safety of Givosiran in Patients with Acute Hepatic Porphyrias

    Summary
    EudraCT number
    2017-002432-17
    Trial protocol
    GB   DE   ES   DK   CZ   SE   BG   FI   BE   FR   PL   NL   IT  
    Global end of trial date
    31 May 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Jun 2022
    First version publication date
    16 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALN-AS1-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03338816
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND: 126094
    Sponsors
    Sponsor organisation name
    Alnylam Pharmaceuticals, Inc.
    Sponsor organisation address
    300 Third Street, Cambridge, United States, 02142
    Public contact
    Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc., +1 8772569526, clinicaltrials@alnylam.com
    Scientific contact
    Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc., +1 8772569526, 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
    31 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the effect of subcutaneous givosiran (ALN-AS1), compared to placebo, on the rate of porphyria attacks in patients with Acute Hepatic Porphyrias (AHP).
    Protection of trial subjects
    The Investigators were to ensure that the patients’ confidentiality was maintained. On the CRFs or other documents submitted to the Sponsor or designees, patients were not identified by their names, but by the assigned patient number and initials. If patient names were included on copies of documents submitted to the Sponsor or designees, the names (except for initials) were obliterated and the assigned patient number was added to the document. Documents not for submission to the Sponsor (eg, signed ICFs) were maintained by the Investigator in strict confidence.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Nov 2017
    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
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    94
    EEA total number of subjects
    38
    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)
    93
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients with acute hepatic porphyrias (AHP) were enrolled at thirty-six sites in Australia, Bulgaria, Canada, Germany, Denmark, Spain, Finland, France, United Kingdom, Italy, Japan, Korea (the Republic of), Mexico, Netherlands, Poland, Sweden, Taiwan and the United States.

    Pre-assignment
    Screening details
    Patients who met all eligibility criteria were randomized in a 1:1 ratio to receive 2.5 mg/kg givosiran or placebo once monthly for a 6-month double-blind treatment period.

    Period 1
    Period 1 title
    6-Month Double-blind Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo 6-Month DB
    Arm description
    Matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo (normal saline [0.9% NaCl]) by SC

    Arm title
    Givosiran 2.5 mg/kg 6-Month DB
    Arm description
    Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period. 1 subject discontinued treatment during the 6-month DB period but completed the 6-month DB Visit.
    Arm type
    Experimental

    Investigational medicinal product name
    Givosiran
    Investigational medicinal product code
    Other name
    GIVLAARI, ALN-AS1
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Givosiran by SC

    Number of subjects in period 1
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Started
    46
    48
    Completed
    46
    48
    Period 2
    Period 2 title
    6-Month DB + Open-Label Extension Period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Givosiran
    Arm description
    Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo (normal saline [0.9% NaCl]) by SC

    Investigational medicinal product name
    Givosiran
    Investigational medicinal product code
    Other name
    GIVLAARI, ALN-AS1
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Givosiran by SC

    Arm title
    Givosiran/Givosiran
    Arm description
    Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.
    Arm type
    Experimental

    Investigational medicinal product name
    Givosiran
    Investigational medicinal product code
    Other name
    GIVLAARI, ALN-AS1
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Givosiran by SC

    Number of subjects in period 2 [1]
    Placebo/Givosiran Givosiran/Givosiran
    Started
    46
    47
    Completed
    38
    41
    Not completed
    8
    6
         Patient Desired Lower Dose
    -
    1
         Death
    -
    1
         Withdrawal by Subject
    3
    3
         Physician decision
    1
    -
         Pregnancy
    1
    1
         Adverse event, non-fatal
    2
    -
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 subject discontinued treatment during the 6-month DB period due to an adverse event but completed the 6-month DB Visit

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo 6-Month DB
    Reporting group description
    Matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.

    Reporting group title
    Givosiran 2.5 mg/kg 6-Month DB
    Reporting group description
    Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period. 1 subject discontinued treatment during the 6-month DB period but completed the 6-month DB Visit.

    Reporting group values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB Total
    Number of subjects
    46 48 94
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    46 47 93
        From 65-84 years
    0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.4 ± 10.5 40.1 ± 12.1 -
    Gender categorical
    Units: Subjects
        Female
    41 43 84
        Male
    5 5 10
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    3 5 8
        Not Hispanic or Latino
    42 42 84
        Unknown or Not Reported
    1 1 2
    Ethnicity
    Units: Subjects
        Asian
    7 8 15
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    1 0 1
        White
    34 39 73
        More than One Race
    1 0 1
        Unknown or Not Reported
    2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo 6-Month DB
    Reporting group description
    Matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.

    Reporting group title
    Givosiran 2.5 mg/kg 6-Month DB
    Reporting group description
    Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period. 1 subject discontinued treatment during the 6-month DB period but completed the 6-month DB Visit.
    Reporting group title
    Placebo/Givosiran
    Reporting group description
    Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.

    Reporting group title
    Givosiran/Givosiran
    Reporting group description
    Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.

    Primary: Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)

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    End point title
    Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)
    End point description
    Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant’s usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home. This endpoint analyzed AIP patients in the Full Analysis Set (FASAIP): All randomized AIP participants (with identified mutation in the hydroxymethylbilane synthase [HMBS] gene) who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: annualized attack rate
        arithmetic mean (confidence interval 95%)
    12.52 (9.35 to 16.76)
    3.22 (2.25 to 4.59)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Negative binomial regression model with treatment group and stratification factors (prior hemin prophylaxis status and historical attack rates) as fixed effects and the logarithm of the follow-up time as an offset variable.
    Comparison groups
    Placebo 6-Month DB v Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Negative binomial regression model
    Parameter type
    Rate ratio
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.16
         upper limit
    0.41
    Notes
    [1] - P=6.040E-09

    Secondary: The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP

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    End point title
    The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP
    End point description
    The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    3 and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: mmol/mol creatinine (Cr)
    least squares mean (standard error)
        Month 3
    19.965 ± 1.475
    1.756 ± 1.413
        Month 6
    23.150 ± 2.534
    4.013 ± 2.352
    No statistical analyses for this end point

    Secondary: The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP

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    End point title
    The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP
    End point description
    The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: mmol/mol Cr
        least squares mean (standard error)
    49.110 ± 4.959
    12.906 ± 4.642
    No statistical analyses for this end point

    Secondary: Annualized Rate of Hemin Administration in Participants With AIP

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    End point title
    Annualized Rate of Hemin Administration in Participants With AIP
    End point description
    Annualized rate of hemin doses was evaluated as annualized days of hemin use. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: annualized rate of use
        arithmetic mean (confidence interval 95%)
    29.71 (18.41 to 47.94)
    6.77 (4.20 to 10.92)
    No statistical analyses for this end point

    Secondary: Annualized Rate of Porphyria Attacks in Participants With AHP

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    End point title
    Annualized Rate of Porphyria Attacks in Participants With AHP
    End point description
    Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant’s usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home. This endpoint analyzed AIP patients in the Full Analysis Set (FAS): All randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    46
    48
    Units: annualized attack rate
        arithmetic mean (confidence interval 95%)
    12.26 (9.22 to 16.29)
    3.35 (2.37 to 4.74)
    No statistical analyses for this end point

    Secondary: Area Under the Curve (AUC) of the Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP

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    End point title
    Area Under the Curve (AUC) of the Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP
    End point description
    Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale*week
        median (inter-quartile range (Q1-Q3))
    5.286 (-23.048 to 11.145)
    -11.514 (-29.181 to 3.040)
    No statistical analyses for this end point

    Secondary: Average Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory- Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP

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    End point title
    Average Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory- Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP
    End point description
    Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale
        median (inter-quartile range (Q1-Q3))
    0.245 (-1.020 to 0.470)
    -0.506 (-1.309 to 0.143)
    No statistical analyses for this end point

    Secondary: AUC of the Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP

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    End point title
    AUC of the Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP
    End point description
    Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale*week
        least squares mean (standard error)
    -4.208 ± 4.689
    -11.148 ± 4.501
    No statistical analyses for this end point

    Secondary: Average Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP

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    End point title
    Average Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP
    End point description
    Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale
        least squares mean (standard error)
    -0.182 ± 0.209
    -0.502 ± 0.200
    No statistical analyses for this end point

    Secondary: AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP

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    End point title
    AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP
    End point description
    Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale
        least squares mean (standard error)
    -4.011 ± 3.453
    1.481 ± 3.310
    No statistical analyses for this end point

    Secondary: Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP

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    End point title
    Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP
    End point description
    Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale
        least squares mean (standard error)
    -0.181 ± 0.154
    0.067 ± 0.147
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP

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    End point title
    Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP
    End point description
    The SF-12 is a survey designed for use in patients with multiple chronic conditions. This 12-item scale can be used to assess the physical and mental health of respondents. 10 of the 12 questions are answered on a 5 point likert scale and 2 are answered on a 3 point likert scale. The questions are then scored and weighted into 2 subscales, physical health and mental health. Respondents can have a score that ranges from 0-100 with 100 being the best score and indicating high physical or mental health. A 3 point change in SF-12 score reflects a meaningful difference. A higher score indicates improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB
    Number of subjects analysed
    43
    46
    Units: score on a scale
        least squares mean (standard error)
    1.431 ± 1.220
    5.369 ± 1.169
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug through completion of the OLE Period (up to 39 months).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo 6-Month DB
    Reporting group description
    Matching placebo (normal saline [0.9% NaCl]) was administered SC, QM, for 6 months during the 6-Month DB Period.

    Reporting group title
    Givosiran 2.5 mg/kg 6-Month DB
    Reporting group description
    Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.

    Reporting group title
    Placebo/Givosiran
    Reporting group description
    Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly. MedDRA (23.0) was used for this reporting group.

    Reporting group title
    Givosiran/Givosiran
    Reporting group description
    Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly. MedDRA (23.0) was used for this reporting group.

    Reporting group title
    All Givosiran
    Reporting group description
    All participants treated with any amount of givosiran. MedDRA (23.0) was used for this reporting group.

    Serious adverse events
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB Placebo/Givosiran Givosiran/Givosiran All Givosiran
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 46 (8.70%)
    10 / 48 (20.83%)
    17 / 46 (36.96%)
    20 / 48 (41.67%)
    37 / 94 (39.36%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic dissection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Deep vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein occlusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hysterosalpingo-oophorectomy
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intrathecal pump insertion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain management
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon neoplasm
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Administration site extravasation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug withdrawal syndrome
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug dependence
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic attack
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fractured sacrum
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural fever
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood homocysteine increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    0 / 48 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    1 / 3
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic vein thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral venous sinus thrombosis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine with aura
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 48 (4.17%)
    0 / 46 (0.00%)
    2 / 48 (4.17%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    1 / 48 (2.08%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Trismus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    1 / 48 (2.08%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter bacteraemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Helicobacter gastritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 48 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    1 / 48 (2.08%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 48 (2.08%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo 6-Month DB Givosiran 2.5 mg/kg 6-Month DB Placebo/Givosiran Givosiran/Givosiran All Givosiran
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 46 (80.43%)
    43 / 48 (89.58%)
    44 / 46 (95.65%)
    47 / 48 (97.92%)
    91 / 94 (96.81%)
    Vascular disorders
    Hypertension
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    3 / 48 (6.25%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    4
    3
    7
    Immune system disorders
    Drug hypersensitivity
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    7
    1
    8
    General disorders and administration site conditions
    Asthenia
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    4 / 46 (8.70%)
    3 / 48 (6.25%)
    4 / 46 (8.70%)
    5 / 48 (10.42%)
    9 / 94 (9.57%)
         occurrences all number
    7
    7
    11
    13
    24
    Fatigue
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    5 / 48 (10.42%)
    13 / 46 (28.26%)
    12 / 48 (25.00%)
    25 / 94 (26.60%)
         occurrences all number
    0
    6
    14
    21
    35
    Influenza like illness
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    5 / 48 (10.42%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    1
    8
    9
    Injection site pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    3 / 94 (3.19%)
         occurrences all number
    0
    0
    0
    3
    3
    Injection site reaction
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    8 / 48 (16.67%)
    14 / 46 (30.43%)
    16 / 48 (33.33%)
    30 / 94 (31.91%)
         occurrences all number
    0
    15
    77
    52
    129
    Oedema peripheral
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    2 / 48 (4.17%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    4
    2
    6
    Pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    3 / 48 (6.25%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    9
    5
    14
    Pyrexia
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    5 / 46 (10.87%)
    0 / 48 (0.00%)
    6 / 46 (13.04%)
    6 / 48 (12.50%)
    12 / 94 (12.77%)
         occurrences all number
    6
    0
    7
    9
    16
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 94 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Depression
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    3 / 48 (6.25%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    4
    4
    8
    Injury, poisoning and procedural complications
    Contusion
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    5 / 46 (10.87%)
    2 / 48 (4.17%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    5
    5
    10
    Fall
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    1 / 48 (2.08%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    6
    1
    7
    Ligament sprain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    3 / 48 (6.25%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    4
    3
    7
    Investigations
    Alanine aminotransferase increased
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 48 (8.33%)
    4 / 46 (8.70%)
    4 / 48 (8.33%)
    8 / 94 (8.51%)
         occurrences all number
    0
    6
    5
    7
    12
    Amylase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    4 / 48 (8.33%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    3
    6
    9
    Aspartate aminotransferase increased
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    3 / 46 (6.52%)
    4 / 48 (8.33%)
    7 / 94 (7.45%)
         occurrences all number
    0
    4
    4
    5
    9
    Blood creatinine increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    5 / 48 (10.42%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    6
    7
    13
    Blood homocysteine increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    1
    3
    4
    Gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    3 / 48 (6.25%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    3
    5
    8
    Glomerular filtration rate decreased
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    2 / 46 (4.35%)
    5 / 48 (10.42%)
    7 / 94 (7.45%)
         occurrences all number
    0
    3
    7
    8
    15
    Lipase increased
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 48 (0.00%)
    6 / 46 (13.04%)
    7 / 48 (14.58%)
    13 / 94 (13.83%)
         occurrences all number
    3
    0
    10
    12
    22
    Weight increased
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    2
    3
    5
    Cardiac disorders
    Palpitations
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    6
    1
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    1
    4
    5
    Dyspnoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    1
    3
    4
    Oropharyngeal pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    4 / 48 (8.33%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    4
    4
    8
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    3
    1
    4
    Nervous system disorders
    Dizziness
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences all number
    3
    0
    1
    4
    4
    Headache
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    7 / 46 (15.22%)
    6 / 48 (12.50%)
    7 / 46 (15.22%)
    13 / 48 (27.08%)
    20 / 94 (21.28%)
         occurrences all number
    9
    9
    15
    26
    41
    Hypoaesthesia
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 94 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Migraine
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    6 / 48 (12.50%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    1
    10
    11
    Paraesthesia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    1 / 48 (2.08%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    4
    1
    5
    Tremor
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    3 / 48 (6.25%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    2
    3
    5
    Eye disorders
    Eye pruritus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    3 / 94 (3.19%)
         occurrences all number
    0
    0
    0
    4
    4
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 48 (8.33%)
    8 / 46 (17.39%)
    6 / 48 (12.50%)
    14 / 94 (14.89%)
         occurrences all number
    5
    4
    9
    8
    17
    Abdominal pain upper
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    4 / 48 (8.33%)
    8 / 94 (8.51%)
         occurrences all number
    0
    0
    6
    4
    10
    Constipation
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    4 / 46 (8.70%)
    6 / 48 (12.50%)
    10 / 94 (10.64%)
         occurrences all number
    0
    3
    4
    7
    11
    Diarrhoea
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    7 / 46 (15.22%)
    8 / 48 (16.67%)
    15 / 94 (15.96%)
         occurrences all number
    0
    0
    7
    9
    16
    Dyspepsia
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 94 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    3 / 48 (6.25%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    4
    3
    7
    Nausea
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    5 / 46 (10.87%)
    13 / 48 (27.08%)
    12 / 46 (26.09%)
    22 / 48 (45.83%)
    34 / 94 (36.17%)
         occurrences all number
    6
    15
    21
    34
    55
    Vomiting
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    5 / 46 (10.87%)
    0 / 48 (0.00%)
    8 / 46 (17.39%)
    7 / 48 (14.58%)
    15 / 94 (15.96%)
         occurrences all number
    5
    0
    18
    16
    34
    Renal and urinary disorders
    Chronic kidney disease
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    1 / 46 (2.17%)
    5 / 48 (10.42%)
    6 / 94 (6.38%)
         occurrences all number
    0
    3
    2
    6
    8
    Skin and subcutaneous tissue disorders
    Eczema
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    2 / 48 (4.17%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    4
    2
    6
    Pruritus
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    5 / 46 (10.87%)
    3 / 48 (6.25%)
    8 / 94 (8.51%)
         occurrences all number
    0
    0
    5
    3
    8
    Rash
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    5 / 48 (10.42%)
    5 / 94 (5.32%)
         occurrences all number
    0
    3
    0
    5
    5
    Product issues
    Device occlusion
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    1 / 46 (2.17%)
    5 / 48 (10.42%)
    6 / 94 (6.38%)
         occurrences all number
    0
    3
    1
    7
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    5 / 48 (10.42%)
    8 / 94 (8.51%)
         occurrences all number
    0
    0
    3
    5
    8
    Back pain
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    4 / 46 (8.70%)
    0 / 48 (0.00%)
    6 / 46 (13.04%)
    7 / 48 (14.58%)
    13 / 94 (13.83%)
         occurrences all number
    4
    0
    7
    9
    16
    Muscle spasms
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    4 / 48 (8.33%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    4
    6
    10
    Myalgia
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    3 / 48 (6.25%)
    7 / 94 (7.45%)
         occurrences all number
    3
    0
    4
    3
    7
    Neck pain
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    5 / 48 (10.42%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    1
    5
    6
    Pain in extremity
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    5 / 48 (10.42%)
    7 / 94 (7.45%)
         occurrences all number
    0
    0
    2
    6
    8
    Metabolism and nutrition disorders
    Hyperhomocysteinaemia
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    6 / 46 (13.04%)
    3 / 48 (6.25%)
    9 / 94 (9.57%)
         occurrences all number
    0
    0
    6
    3
    9
    Iron overload
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    3 / 48 (6.25%)
    4 / 94 (4.26%)
         occurrences all number
    0
    0
    1
    3
    4
    Infections and infestations
    Bronchitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    4 / 46 (8.70%)
    2 / 48 (4.17%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    7
    3
    10
    COVID-19
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    2 / 46 (4.35%)
    3 / 48 (6.25%)
    5 / 94 (5.32%)
         occurrences all number
    0
    0
    2
    3
    5
    Conjunctivitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    3 / 94 (3.19%)
         occurrences all number
    0
    0
    0
    8
    8
    Cystitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    3 / 48 (6.25%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    4
    4
    8
    Gastroenteritis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    5 / 46 (10.87%)
    3 / 48 (6.25%)
    8 / 94 (8.51%)
         occurrences all number
    0
    0
    7
    3
    10
    Influenza
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    5 / 46 (10.87%)
    4 / 48 (8.33%)
    9 / 94 (9.57%)
         occurrences all number
    0
    0
    6
    5
    11
    Nasopharyngitis
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 48 (8.33%)
    11 / 46 (23.91%)
    14 / 48 (29.17%)
    25 / 94 (26.60%)
         occurrences all number
    3
    4
    14
    23
    37
    Pharyngitis
    alternative dictionary used: MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    0 / 48 (0.00%)
    3 / 46 (6.52%)
    3 / 48 (6.25%)
    6 / 94 (6.38%)
         occurrences all number
    0
    0
    3
    3
    6
    Tooth infection
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    4 / 48 (8.33%)
    4 / 94 (4.26%)
         occurrences all number
    0
    3
    0
    6
    6
    Upper respiratory tract infection
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 48 (8.33%)
    12 / 46 (26.09%)
    7 / 48 (14.58%)
    19 / 94 (20.21%)
         occurrences all number
    4
    4
    13
    17
    30
    Urinary tract infection
    Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
         subjects affected / exposed
    6 / 46 (13.04%)
    3 / 48 (6.25%)
    10 / 46 (21.74%)
    9 / 48 (18.75%)
    19 / 94 (20.21%)
         occurrences all number
    6
    4
    14
    16
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2018
    This amendment was issued as part of the response to a single case of anaphylactic reaction reported in Study 002 as described above. The following changes were made to the protocol in light of these results: • Provided details of an anaphylactic reaction reported in Study 002 • Added anaphylactic reaction to givosiran potential risks • Provided guidance on monitoring and management of potential anaphylactic reactions due to study drug • Added guidance and procedures for management of potential cases of anaphylactic reaction • Added anaphylactic reactions to list of AEs of Clinical Interest • Added guidance for diagnosing anaphylactic reactions • In addition, the following changes were made: • Addition of 2 QOL measures: − PGIC at Months 6 and 12 − PPEQ at Months 6, 12, 18, and 24 • Updated guidance and procedures on patient withdrawal from study • Clarified that ALA/PBG levels measured during Screening are acceptable for use as entry criteria • Provided the following additional clarifications: − predose samples (not restricted to 60 minutes before dosing) − interim analysis for sample size reassessment is blinded − definition of sexual abstinence − contraception with an intrauterine hormone-releasing system also requires use of a barrier method
    26 Jul 2018
    This protocol amendment was generated in response to liver transaminase elevations observed during the study. The primary purpose for this amendment was to: • Require Investigators to review predose LFTs prior to study drug administration • Implement a standard hepatic assessment panel if patients develop significant ALT elevation • Provide specific guidance for rechallenge using a lower dose in patients whose ALT resolves after study drug dosing has been withheld due to ALT elevation • Expand the medical history collection to include a specific inquiry into iron overload and other liver disease
    21 Sep 2018
    In light of liver transaminase elevations observed in the study, a lower givosiran dose of 1.25 mg/kg once monthly was introduced in protocol Amendment 2 as a rechallenge dose for patients who resume dosing after resolution of liver transaminase elevations. In order to generate additional data at this dose level, evaluation of the 1.25 mg/kg once monthly dose was proposed for patients crossing over to the OLE period under this amendment, after their completion of the DB period. The primary purpose for this protocol amendment was to: • Implement the inclusion of an additional, lower dose of givosiran (1.25 mg/kg once monthly) during the OLE period • Provide specific guidance for increasing dose from 1.25 mg/kg once monthly to 2.5 mg/kg once monthly in patients who tolerate 1.25 mg/kg once monthly dose but who are experiencing inadequate disease control. • Add statistical analyses to evaluate the durability of the treatment effect.
    28 May 2019
    The primary purpose for this protocol amendment was to update information from a completed drug-drug interaction study (ALN-AS1-004). The results of the study indicated that givosiran treatment resulted in moderate reduction in CYP1A2 and CYP2D6 activity, weak reduction in CYP3A4 and CYP2C19 activity, and no change in the activity of CYP2C9. Investigators were provided guidance to review concomitant medications that are primarily metabolized by these enzymes and monitor the patient's clinical response and to select medications not primarily metabolized by CYP2D6 or CYP1A2 for patients requiring new medications. Additional updates included: • Clarification that patients may continue to receive givosiran until it is commercially available in the patient’s territory, • Addition of guidance for serious breaches of protocol
    12 Feb 2020
    The primary purpose for this protocol amendment was to increase the dose of givosiran for patients receiving 1.25 mg/kg givosiran SC once monthly to the recommended dose of 2.5 mg/kg givosiran SC once monthly. Additional updates included: • Allow patients who developed a transaminase elevation meeting protocol-defined dose-holding rules while receiving 2.5 mg/kg givosiran SC once monthly to resume dosing at either the 1.25 or 2.5 mg/kg givosiran SC once monthly dose after resolution of ALT to ≤2×ULN (or ≤2×baseline for patients who had elevated baseline ALT) per the Investigator’s judgement and after discussion with the medical monitor • Discontinuation of monitoring by the DMC after all patients completed at least 6 months during the OLE period • Removal of the requirement to test and review the results for INR within 14 days prior to dosing
    23 Apr 2020
    The main purpose of this protocol amendment was to incorporate changes related to USMs that were communicated to Investigators in a Dear Investigator Letter dated 07 April 2020 to assure the safety of study participants while minimizing risks to study integrity amid the COVID-19 pandemic. In addition, study administration-related text was updated to provide clarification on Investigator responsibilities regarding communication of new study information to patients and IRBs/IECs. With the implementation of changes in Amendment 6, the global amendment became aligned with prior country-specific amendments for Sweden; therefore, a country-specific amendment was no longer required.
    29 Mar 2021
    This protocol amendment was generated based on the observation that blood homocysteine levels increased during the study compared to levels before givosiran treatment; the clinical relevance of blood homocysteine increases is unknown. The purpose of the amendment was to recommend the following: • measuring blood homocysteine levels • that patients with increased blood homocysteine levels receive a supplement containing vitamin B6

    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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