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    Clinical Trial Results:
    A Phase 2, Open Label Study to Evaluate The Safety and Efficacy of Ledipasvir/Sofosbuvir (LDV/SOF) Fixed Dose Combination (FDC) Tablet for 12 or 24 Weeks in Kidney Transplant Recipients with Chronic HCV Infection

    Summary
    EudraCT number
    		 2014-002121-35
    Trial protocol
    		 IT   DE   AT  
    Global end of trial date
    16 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2017
    First version publication date
    26 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-337-1406
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02251717
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    16 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to determine the antiviral efficacy of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) as measured by the proportion of participants who attain SVR at 12 weeks after discontinuation of therapy (SVR12) and to evaluate the safety and tolerability of each treatment regimen as assessed by review of the accumulated safety data.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2014
    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
    Austria: 24
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 49
    Worldwide total number of subjects
    114
    EEA total number of subjects
    114
    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)
    99
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Europe. The first participant was screened on 14 October 2014. The last study visit occurred on 16 June 2016.

    Pre-assignment
    Screening details
    		 130 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LDV/SOF 12 Weeks
    Arm description
    		 LDV/SOF for 12 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant
    Arm type
    		 Experimental

    Investigational medicinal product name
    LDV/SOF
    Investigational medicinal product code
    Other name
    Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    90/400 mg FDC tablet administered orally once daily

    Arm title
    		 LDV/SOF 24 Weeks
    Arm description
    		 LDV/SOF for 24 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant
    Arm type
    		 Experimental

    Investigational medicinal product name
    LDV/SOF
    Investigational medicinal product code
    Other name
    Harvoni®, GS-5885/GS-7977
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    90/400 mg FDC tablet administered orally once daily

    Number of subjects in period 1
    		LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Started
    57
    57
    Completed
    56
    56
    Not completed
    1
    1
         Withdrew Consent
    1
    -
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LDV/SOF 12 Weeks
    Reporting group description
    		 LDV/SOF for 12 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant

    Reporting group title
    LDV/SOF 24 Weeks
    Reporting group description
    		 LDV/SOF for 24 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant

    Reporting group values
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks Total
    Number of subjects
    		 57 57 114
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54 ( 8.3 ) 53 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24 48
        Male
    		 33 33 66
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 4 5
        Not Hispanic or Latino
    		 56 53 109
    Race
    Units: Subjects
        Black or African American
    		 2 2 4
        White
    		 54 53 107
        Asian
    		 1 1 2
        Other
    		 0 1 1
    HCV genotype
    Units: Subjects
        Genotype 1
    		 51 53 104
        Genotype 4
    		 6 4 10
    Cirrhosis Status
    Units: Subjects
        No
    		 49 48 97
        Yes
    		 8 9 17
    IL28b Status
    The CC, CT, and TT alleles are different forms of the IL28b gene.
    Units: Subjects
        CC
    		 14 18 32
        CT
    		 34 34 68
        TT
    		 9 5 14
    HCV RNA Category
    Units: Subjects
        < 800,000 IU/mL
    		 11 16 27
        ≥ 800,000 IU/mL
    		 46 41 87
    Prior HCV Treatment Status
    Units: Subjects
        Treatment-Naive
    		 40 39 79
        Treatment- Experienced
    		 17 18 35
    Years From Most Recent Kidney Transplant
    Units: years
        arithmetic mean (standard deviation)
    		 12.1 ( 9.51 ) 14.4 ( 9.66 ) -
    HCV RNA
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 6.3 ( 0.63 ) 6.2 ( 0.53 ) -

    End points

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    End points reporting groups
    Reporting group title
    LDV/SOF 12 Weeks
    Reporting group description
    		 LDV/SOF for 12 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant

    Reporting group title
    LDV/SOF 24 Weeks
    Reporting group description
    		 LDV/SOF for 24 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant

    Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)

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    End point title
    		 Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [1]
    End point description
    SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment.
    End point type
    Primary
    End point timeframe
    Posttreatment Week 12
    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 statistical comparison was planned or performed.
    End point values
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Number of subjects analysed
    57
    57
    Units: percentage of participants
        number (confidence interval 95%)
    100 (93.7 to 100)
    100 (93.7 to 100)
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event

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    End point title
    		 Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event [2]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    Notes
    [2] - 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 statistical comparison was planned or performed.
    End point values
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Number of subjects analysed
    57
    57
    Units: percentage of participants
        number (not applicable)
    1.8
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)

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    End point title
    		 Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
    End point description
    SVR4 and SVR24 were defined as HCV RNA < LLOQ at 4 and 24 weeks after stopping study treatment, respectively.
    End point type
    Secondary
    End point timeframe
    Posttreatment Weeks 4 and 24
    End point values
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Number of subjects analysed
    57
    57
    Units: percentage of participants
    number (confidence interval 95%)
        SVR4
    100 (93.7 to 100)
    100 (93.7 to 100)
        SVR24
    100 (93.7 to 100)
    100 (93.7 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Virologic Failure

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    End point title
    		 Percentage of Participants With Virologic Failure
    End point description
    Virologic failure was defined as: On-treatment virologic failure: • Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), or • Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or • Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) Virologic relapse: • Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last ontreatment visit.
    End point type
    Secondary
    End point timeframe
    Up to Posttreatment Week 24
    End point values
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Number of subjects analysed
    57
    57
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 weeks plus 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    LDV/SOF 12 Weeks
    Reporting group description
    		 LDV/SOF for 12 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant

    Reporting group title
    LDV/SOF 24 Weeks
    Reporting group description
    		 LDV/SOF for 24 weeks in participants with chronic genotype 1 or 4 HCV infection who have had a kidney transplant

    Serious adverse events
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 57 (8.77%)
    8 / 57 (14.04%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous shunt operation
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LDV/SOF 12 Weeks LDV/SOF 24 Weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 57 (40.35%)
    36 / 57 (63.16%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 57 (15.79%)
    13 / 57 (22.81%)
         occurrences all number
    9
    14
    Somnolence
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 57 (5.26%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 57 (5.26%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 57 (14.04%)
    8 / 57 (14.04%)
         occurrences all number
    8
    9
    Fatigue
         subjects affected / exposed
    4 / 57 (7.02%)
    7 / 57 (12.28%)
         occurrences all number
    4
    9
    Oedema peripheral
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 57 (7.02%)
         occurrences all number
    0
    5
    Diarrhoea
         subjects affected / exposed
    3 / 57 (5.26%)
    5 / 57 (8.77%)
         occurrences all number
    3
    5
    Nausea
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 57 (5.26%)
         occurrences all number
    3
    3
    Vomiting
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 57 (1.75%)
         occurrences all number
    3
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    3
    Dyspnoea
         subjects affected / exposed
    1 / 57 (1.75%)
    4 / 57 (7.02%)
         occurrences all number
    1
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 57 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 57 (0.00%)
    3 / 57 (5.26%)
         occurrences all number
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    0 / 57 (0.00%)
    5 / 57 (8.77%)
         occurrences all number
    0
    5
    Urinary tract infection
         subjects affected / exposed
    4 / 57 (7.02%)
    4 / 57 (7.02%)
         occurrences all number
    4
    7
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    5 / 57 (8.77%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2014
    Text was updated to ensure clear direction to investigators on the possible methods to manage study drug in the event that a subject requires treatment adjustments due to changes in creatinine clearance.
    17 Apr 2015
    - A safety update regarding disallowed medication. Amiodarone has been added to the “Agents Disallowed” list based on risk of symptomatic bradycardia with coadministration of amiodarone with ledipasvir/sofosbuvir. Postmarketing cases of symptomatic bradycardia have been reported in patients receiving amiodarone who were coadministered Harvoni® (ledipasvir/sofosbuvir) or Sovaldi® (sofosbuvir) in combination with another direct acting antiviral. - Alignment in Gilead protocols for clarification of requirements for use of abstinence as a form of contraception based on a UK competent authority request - Minor administrative changes made to Italian Amendment 1, dated 29 September 2014 based on request from the competent Italian authority, AIFA.
    19 Jun 2015
    Updated the information related to the interaction of LDV/SOF with dabigatran, in line with the approved SmPC of Harvoni based on request from VHP.

    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.
    There were no limitations affecting the analysis or results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27842383
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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