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    Clinical Trial Results:
    Daclatasvir plus Sofosbuvir for chronic HCV-infected renal transplant patients – a pilot study of efficacy and safety

    Summary
    EudraCT number
    		 2014-004551-32
    Trial protocol
    		 DE  
    Global end of trial date
    22 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Sep 2022
    First version publication date
    08 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AI444-314
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité - University Hospital of Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Clinical Trial Information, Charité Universitätsmedizin Berlin, +49 030450514001, michael.duerr@charite.de
    Scientific contact
    Clinical Trial Information, Charité Universitätsmedizin Berlin, +49 030450514001, michael.duerr@charite.de
    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
    23 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the rate of sustained virologic resonse (SVR) in all treated renal transplant patients at week 12 after the end of treatment.
    Protection of trial subjects
    Potential trial participants agreed to participate in the study by providing written informed consent after approval by German health authorities and an independent Ethic committee. The study was conducted according the Declaration of Helsinki, the International Conference on Harmonization and Good Clinical Practice guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    15
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started on the 1st of July 2015 at the Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin.

    Pre-assignment
    Screening details
    		 1365 Patients were screened. Drop outs: 1349 Enrolled: 16

    Period 1
    Period 1 title
    Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 DCV and SOF Arm
    Arm description
    		 In total, 16 KTR with chronic HCV infection received a 12-weeks course of DCV 60 mg and SOF 400 mg orally once daily given
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCV
    Investigational medicinal product code
    Other name
    Daklinza
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60mg daily

    Investigational medicinal product name
    SOF
    Investigational medicinal product code
    Other name
    Sovaldi
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg daily

    Number of subjects in period 1
    		DCV and SOF Arm
    Started
    16
    Completed
    16
    Period 2
    Period 2 title
    Observation Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 DCV and SOF
    Arm description
    		 observational follow-up period for 24-week
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		DCV and SOF
    Started
    16
    Completed
    15
    Not completed
    1
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 16 16
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 51.5 (34 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 8 8
    Number of previous renal transplantations
    Units: Subjects
        1st
    		 4 4
        2nd
    		 11 11
        3rd
    		 0 0
        4th
    		 1 1
    Cause of end-stage renal disease
    Units: Subjects
        Chronic Glomerulonephritis
    		 5 5
        Polycystic Kidney Disease
    		 3 3
        Alport-Syndrome
    		 4 4
        Interstitial Nephritis
    		 3 3
        Unknown
    		 1 1
    CMV antibody status
    (Donor (D+/-)/Recipient (R+/-);
    Units: Subjects
        Low-risk (D - / R +)
    		 4 4
        Intermediate risk (D + / R +)
    		 10 10
        High-risk (D + / R -)
    		 2 2
    EBV antibody status
    Units: Subjects
        (D unknown /R +)
    		 16 16
    HCV genotype
    Units: Subjects
        Ia
    		 1 1
        Ib
    		 15 15
    Median time since kidney transplantation (range), y
    Units: years
        median (full range (min-max))
    		 12.8 (2.3 to 25.8) -
    Renal Transplant function Creatinine
    Units: mg/dl
        median (full range (min-max))
    		 1.27 (0.95 to 2.3) -
    Renal Transplant function eGFR
    Median eGFR, ml/min per 1.73 m2
    Units: ml/min
        median (full range (min-max))
    		 60 (25 to 87) -
    Median body mass index (range)
    Units: kg/m²
        median (full range (min-max))
    		 21.47 (16.43 to 31.25) -

    End points

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    End points reporting groups
    Reporting group title
    DCV and SOF Arm
    Reporting group description
    		 In total, 16 KTR with chronic HCV infection received a 12-weeks course of DCV 60 mg and SOF 400 mg orally once daily given
    Reporting group title
    DCV and SOF
    Reporting group description
    		 observational follow-up period for 24-week

    Subject analysis set title
    TAC treatment
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    To further specify the drug metabolism we assessed the C/D ratio of TAC was assesed

    Subject analysis set title
    CyA treatment
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    To further specify the drug metabolism we assessed the C/D ratio of CyA

    Primary: Sustained virological response at SVR 12

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    End point title
    		 Sustained virological response at SVR 12 [1]
    End point description
    these “responders”, we noticed early viral response, defined as a rapid virus clearance already after a median of 4 weeks after initiating DCV/SOF therapy. One patient achieved negative HCV PCR at EOT but had early viral relapse 4 weeks after EOT.
    End point type
    Primary
    End point timeframe
    12 weeks after EOT
    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: This is an explorative proof of concept study with a calculated sample size of n = 14 patients (power 90% with a type I error of 5% (type II error = 10%) for an estimated efficacy of 79% SVR12. During the course of the study it was decided to enroll 2 additional patients, which even further increases the power of this study to demonstrate adequate efficacy in this population.
    End point values
    		 DCV and SOF Arm DCV and SOF
    Number of subjects analysed
    16
    16
    Units: Patients
    16
    15
    No statistical analyses for this end point

    Secondary: Sustained virological response SVR 4 and 24

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    End point title
    		 Sustained virological response SVR 4 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks after EOT
    End point values
    		 DCV and SOF Arm
    Number of subjects analysed
    16
    Units: Patients
        SVR4
    15
        SVR24
    15
    No statistical analyses for this end point

    Secondary: Calcineurin inhibitor assessment: C/D Scores

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    End point title
    		 Calcineurin inhibitor assessment: C/D Scores
    End point description
    Metabolism rate of tacrolimus (TAC) or ciclosporin A (CyA) treated patients were determined at predefined study visits by dividing the drug blood trough concentration (C) to the daily TAC or CyA dose (D) respectively. To further specify the drug metabolism we assessed the C/D ratio of TAC-(n = 7) and CyA-(n = 8) treated patients.
    End point type
    Secondary
    End point timeframe
    Screening, baseline, week (w) 1, 2, 4, 6, 8, 10, EOT, SVR4, − 12 and − 24
    End point values
    		 TAC treatment CyA treatment
    Number of subjects analysed
    7
    8
    Units: ng/ml x 1/mg
    arithmetic mean (standard deviation)
        BL
    4.33 ( 1.5 )
    1.31 ( 0.71 )
        EOT
    2.85 ( 0.84 )
    0.89 ( 0.23 )
        SVR12
    2.49 ( 0.76 )
    0.79 ( 0.21 )
        SVR24
    3.12 ( 2.19 )
    0.57 ( 0.23 )
    No statistical analyses for this end point

    Secondary: Change of the Hepatic function : Liver parameters

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    End point title
    		 Change of the Hepatic function : Liver parameters
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 DCV and SOF
    Number of subjects analysed
    14
    Units: U/l
    arithmetic mean (standard deviation)
        ALT Baseline
    48.31 ( 31.71 )
        ALT EOT
    20.56 ( 10.52 )
        ALT SVR12
    19.06 ( 7.88 )
        AST Baseline
    42.06 ( 16.78 )
        AST EOT
    27.75 ( 12.37 )
        AST SVR12
    23.0 ( 12.37 )
    No statistical analyses for this end point

    Secondary: Change of the Hepatic function : Ferritin levels

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    End point title
    		 Change of the Hepatic function : Ferritin levels
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 DCV and SOF
    Number of subjects analysed
    14
    Units: µg/l
    arithmetic mean (standard deviation)
        Baseline
    253.38 ( 163.37 )
        EOT
    124.11 ( 64.37 )
        SVR12
    127.33 ( 6.3 )
    No statistical analyses for this end point

    Secondary: Change of the Hepatic function: APRI

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    End point title
    		 Change of the Hepatic function: APRI
    End point description
    APRI: AST to-platelet ratio index;
    End point type
    Secondary
    End point timeframe
    32weeks
    End point values
    		 DCV and SOF
    Number of subjects analysed
    14
    Units: ratio index U/l x 10^9l
    arithmetic mean (standard deviation)
        Baseline
    0.47 ( 0.22 )
        SVR 24
    0.25 ( 0.11 )
    No statistical analyses for this end point

    Secondary: Change of the Hepatic function: FIB-4 score

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    End point title
    		 Change of the Hepatic function: FIB-4 score
    End point description
    End point type
    Secondary
    End point timeframe
    36 weeks
    End point values
    		 DCV and SOF
    Number of subjects analysed
    14
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    1.45 ( 0.63 )
        SVR24
    1.19 ( 0.53 )
    No statistical analyses for this end point

    Secondary: Change of the Glucose tolerance

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    End point title
    		 Change of the Glucose tolerance
    End point description
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    		 DCV and SOF
    Number of subjects analysed
    15
    Units: mg/dl
    arithmetic mean (standard deviation)
        Baseline
    141 ( 77 )
        EOT
    132 ( 52 )
        SVR12
    117 ( 77 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    36 Weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    DCV + SOF
    Reporting group description
    		 -

    Serious adverse events
    		 DCV + SOF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Liverbiopsie (Lymphom)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pituitary Adenoma
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infections
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Relapse (HCV-PCR positive after Therapy)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    C difficile infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 DCV + SOF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    Nervous system disorders
    Problems with concentration
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Edema/swelling foot
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoe
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cold
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences all number
    10
    Dyspnoe/asthma episode
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Pain shoulder/arm
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Lower back pain
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    2
    Infections and infestations
    Bronchitis/ pneumonia
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    2
    Urinary tract infections
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Anemia / iron deficiency
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The number of 16 treated patients is still relatively small. In addition, further follow-up will have to proof sustained viral clearance and functional improvement. decided to implement an un-controlled open-label design.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30717681
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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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