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    Clinical Trial Results:
    Direct acting antiviral therapy of hepatitis C in Denmark: treatment response, adverse events and resistance associated variants

    Summary
    EudraCT number
    2015-001956-31
    Trial protocol
    DK  
    Global end of trial date
    01 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Nov 2019
    First version publication date
    09 Nov 2019
    Other versions
    Summary report(s)
    Published article

    Trial information

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    Trial identification
    Sponsor protocol code
    2015-001956-31
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre.
    Sponsor organisation address
    Kettegaard Alle´30, Hvidovre, Denmark, 2650
    Public contact
    Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre., 0045 38623514, ninaweis@dadlnet.dk
    Scientific contact
    Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre., 0045 38623514, ninaweis@dadlnet.dk
    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
    01 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study the rate of adverse events and sustanied viral response in a randomized study of patients with chronic hepatitis C, genotype 1 patients, treated for 12 weeks with Viekira PAK® and ribavirin versus Harvoni® and ribavirin. Compare the adverse events- and sustanied viral response rates between the two groups of patients in each treatment arm in relation to demographic, biological and genetic factors.
    Protection of trial subjects
    Close monitoring during treatment to address any adverse events. Reduction of ribavirin if patient experienced severe anemia. To reduce distress during blood sampling were ultra sound used if the patient had experienced difficulties during previous blood sampling.
    Background therapy
    None.
    Evidence for comparator
    Clinical trials with direct acting antivirals (DAA) have shown improved cure rates ≥90% with good tolerability, including difficult to treat patient groups (liver cirrhosis and liver transplantation and previous treatment failure) However, this rapid development has led to few systematic comparisons of different DAA regimens, usually evaluated in cohorts of patients randomized with respect to dosage, addition of ribavirin or treatment duration. This design provides limited information about the rate of adverse events across different DAA regimens. Minimizing adverse events is crucial in relation to adherence to treatment and prevention of prematurely treatment termination due to poor tolerability. The chosen DAA drugs in the study were the DAAs available and approved at the time of initiation of the study.
    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
    Denmark: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    66
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were screened from July 1st 2015 to 1st of April 2017 at six screening sites (departments of infectious diseases and department of hepatology) which covered 4 out of 5 regions in Denmark.

    Pre-assignment
    Screening details
    Eligible patients were 18-70 years and registered with chronic hepatitis C, genotype 1 in the Danish Database for Hepatitis B and C . The patients had to fulfil inclusion criteria defined as: liver biopsy (Metavir score ≥F2), liver stiffness measurement ≥10 kPa, clinical cirrhosis or extra-hepatic manifestations of importance to treat.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    The study was conducted as non-blinded with randomization lists produced electronically in blocks of 4.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm 1, genotype 1.
    Arm description
    Sofosbuvir/ledipasvir/ribavirin
    Arm type
    Active comparator

    Investigational medicinal product name
    Harvoni
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet ledipasvir 90 mg/sofosbuvir 400 mg and tablets ribavirin (according to weight) in the morning. Tablets ribavirin (according to weight) in the evening.

    Investigational medicinal product name
    Rebetol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800-1200 mg depending on weight. Half dose is taken in the morning and half dose is taken in the evening.

    Arm title
    Arm 2, genotype 1
    Arm description
    Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin
    Arm type
    Active comparator

    Investigational medicinal product name
    viekira PAK
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets of paritaprevir/ombitasvir/ritonavir and 1 tablet of dasabuvir and tablet ribavirin (according to weight) in the morning with food. 1 tablet of dasabuvir tablet ribavirin (according to weight) in the evening with food.

    Investigational medicinal product name
    Rebetol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 - 1400 mg depending on weight. Half dose in the morning and half dose in the evening.

    Number of subjects in period 1
    Arm 1, genotype 1. Arm 2, genotype 1
    Started
    34
    38
    Completed
    32
    37
    Not completed
    2
    1
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1, genotype 1.
    Reporting group description
    Sofosbuvir/ledipasvir/ribavirin

    Reporting group title
    Arm 2, genotype 1
    Reporting group description
    Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

    Reporting group values
    Arm 1, genotype 1. Arm 2, genotype 1 Total
    Number of subjects
    34 38 72
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    31 35 66
        From 65-84 years
    3 3 6
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    54 (41 to 66) 51 (27 to 68) -
    Gender categorical
    Units: Subjects
        Female
    10 9 19
        Male
    24 29 53
    Hepatitis C virus subtype
    Units: Subjects
        1b
    9 10 19
        1a
    25 27 52
        unknown
    0 1 1
    Ethnicity
    Units: Subjects
        Caucasian
    33 37 70
        Non-Caucasian
    1 1 2
    Route of infection
    Units: Subjects
        Intravenous drug use
    20 25 45
        Non-intravenous drug use
    7 10 17
        Unknown
    7 3 10
    Liver fibrosis
    Units: Subjects
        Cirrhosis F4, >17 kPa, clinical diagnosed
    13 13 26
        Severe fibrosis F3/12-16.9 kPa
    10 4 14
        Mild-moderate fibrosis F1-F2/<11.9 kPa
    11 21 32
    HIV status
    Units: Subjects
        Negative
    29 31 60
        Positive
    5 7 12
    Hepatitis B status
    Units: Subjects
        Negative
    34 38 72
    Previous treatment
    Units: Subjects
        No
    27 31 58
        Yes
    7 7 14
    Previous response to treatment
    Units: Subjects
        Non-response
    1 1 2
        Relapse
    3 3 6
        Viral breakthrough
    1 0 1
        Termination due to adverse event
    2 3 5
        No previous treatment
    27 31 58
    Fatigue at baseline
    The intensity of fatigue was recorded according to the common terminology criteria for adverse events (CTCAE)
    Units: Subjects
        Grade 1
    11 5 16
        Grade 2
    0 2 2
        None
    23 31 54
    Body-mass index
    Units: numbers
        arithmetic mean (standard deviation)
    25.7 ± 3.16 25.6 ± 4.27 -
    HCV RNA level
    Units: IU/ml
        log mean (standard deviation)
    2.77 ± 3.39 2.35 ± 2.75 -
    Alanine transaminase
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    74 (49 to 124) 86.5 (49 to 137) -
    Platelet count
    x 10^9/liter
    Units: x 10^9/liter
        median (inter-quartile range (Q1-Q3))
    187.5 (126 to 227) 206 (161 to 237) -
    serum albumin
    Units: g/liter
        median (inter-quartile range (Q1-Q3))
    39 (37 to 41) 39 (36 to 42) -

    End points

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    End points reporting groups
    Reporting group title
    Arm 1, genotype 1.
    Reporting group description
    Sofosbuvir/ledipasvir/ribavirin

    Reporting group title
    Arm 2, genotype 1
    Reporting group description
    Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

    Primary: Adverse events

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    End point title
    Adverse events
    End point description
    End point type
    Primary
    End point timeframe
    1 July 2015 - 1 December 2018
    End point values
    Arm 1, genotype 1. Arm 2, genotype 1
    Number of subjects analysed
    34
    38
    Units: number of persons
        Experienced Adverse events
    33
    37
    Attachments
    Statistic analysis
    Statistical analysis title
    Adverse events overall
    Comparison groups
    Arm 2, genotype 1 v Arm 1, genotype 1.
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    ≤ 0.05
    Method
    Fisher exact
    Confidence interval
    Notes
    [1] - A sample size of 50 patients per group with 80% power using 2-sample test for proportions with a 2.sided significance level of 0.05 and the treatment-arm with Viekira PAk/ribavirin set to 30% would detect a difference of 22% giving a proportion of 8% in the other treatment arm. Fisher's exact Test was used.
    Statistical analysis title
    Changes in laboratory results and liver stiffness
    Statistical analysis description
    The Wilcoxon signed-rank and rank-sum tests were applied to estimate changes in laboratory results and liver stiffness measurement from baseline to the end of treatment for all patients and the comparison of treatment groups, respectively.
    Comparison groups
    Arm 2, genotype 1 v Arm 1, genotype 1.
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    ≤ 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (net)
    Confidence interval

    Secondary: Proportion of patients with sustanied virologic response after end of treatment

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    End point title
    Proportion of patients with sustanied virologic response after end of treatment
    End point description
    Hepatitis C virus RNA level measured in a blood sample
    End point type
    Secondary
    End point timeframe
    1 January 2016 - 1 August 2017.
    End point values
    Arm 1, genotype 1. Arm 2, genotype 1
    Number of subjects analysed
    34
    38
    Units: numbers
        Sustanied viral response
    33
    37
    Attachments
    Flowchart Genotype 1
    Statistical analysis title
    Sustanied viral response
    Comparison groups
    Arm 2, genotype 1 v Arm 1, genotype 1.
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    ≤ 0.05
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 July 2015 - 1 December 2018. Adverse events were recorded at baseline and for all patients at weeks 1, 2, 3, 4, 8 and 12 of the study period, and in the post-treatment period at weeks 4, 12 and 24.
    Adverse event reporting additional description
    For all adverse events, start- and end date, intensity (mild, moderate or severe), severity (is recovering, has recovered, recovered with sequelae, still affected), relation to study drug and action taken with study drug was recorded. The severity of adverse events and their relationship to treatment were assessed by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Arm 1, genotype 1.
    Reporting group description
    Sofosbuvir/ledipasvir/ribavirin

    Reporting group title
    Arm 2, genotype 1
    Reporting group description
    Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

    Serious adverse events
    Arm 1, genotype 1. Arm 2, genotype 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 34 (17.65%)
    3 / 38 (7.89%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Cardiac disorders
    Chest pain
    Additional description: Occurred during treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Weakened general condition
    Additional description: Did not occur during treatment.
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastro-intestinal bleeding
    Additional description: Did not occur during treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe stomach pain
    Additional description: Occurred during treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
    Additional description: Occurred during treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    decompensated liver cirrhosis with ascites
    Additional description: Occurred during treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver failure
    Additional description: Suspected Unexpected serious Adverse Reaction (SUSAR).
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Shotness of breath
    Additional description: Occurred during treatment
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign object in throat
    Additional description: Occurred during treatment
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back- and hip pain
    Additional description: Did not occur during treatment.
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
    Additional description: Did not occur during treatment
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Arm 1, genotype 1. Arm 2, genotype 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 34 (97.06%)
    37 / 38 (97.37%)
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 38 (2.63%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 34 (41.18%)
    19 / 38 (50.00%)
         occurrences all number
    14
    19
    Insomnia
         subjects affected / exposed
    8 / 34 (23.53%)
    9 / 38 (23.68%)
         occurrences all number
    8
    9
    Dizziness
         subjects affected / exposed
    3 / 34 (8.82%)
    5 / 38 (13.16%)
         occurrences all number
    3
    5
    Memory impairment/absent minded
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 38 (2.63%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 34 (79.41%)
    29 / 38 (76.32%)
         occurrences all number
    27
    29
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    26 / 34 (76.47%)
    27 / 38 (71.05%)
         occurrences all number
    26
    27
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    0
    3
    Eye disorders
    Affected vision
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 38 (7.89%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Heartburn/abdominal pain/abdominal distention
         subjects affected / exposed
    11 / 34 (32.35%)
    16 / 38 (42.11%)
         occurrences all number
    11
    16
    Nausea/vomiting
         subjects affected / exposed
    11 / 34 (32.35%)
    14 / 38 (36.84%)
         occurrences all number
    11
    14
    Decreased appetite
         subjects affected / exposed
    4 / 34 (11.76%)
    11 / 38 (28.95%)
         occurrences all number
    4
    11
    Diarrhoea
         subjects affected / exposed
    6 / 34 (17.65%)
    8 / 38 (21.05%)
         occurrences all number
    6
    8
    Increased appetite
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 38 (2.63%)
         occurrences all number
    3
    1
    Constipation
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    10 / 34 (29.41%)
    11 / 38 (28.95%)
         occurrences all number
    10
    11
    Skin and subcutaneous tissue disorders
    Pruritus, dry skin or eczema
         subjects affected / exposed
    13 / 34 (38.24%)
    20 / 38 (52.63%)
         occurrences all number
    13
    20
    Psychiatric disorders
    Irritability/mood swings/depression
         subjects affected / exposed
    12 / 34 (35.29%)
    8 / 38 (21.05%)
         occurrences all number
    12
    8
    Musculoskeletal and connective tissue disorders
    Asthenia/malaise/tremor
         subjects affected / exposed
    9 / 34 (26.47%)
    13 / 38 (34.21%)
         occurrences all number
    9
    13
    Arthralgia
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 38 (7.89%)
         occurrences all number
    4
    3
    muscle spams
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 38 (7.89%)
         occurrences all number
    2
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 34 (32.35%)
    13 / 38 (34.21%)
         occurrences all number
    11
    13
    Herpes outbreak
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Fungal infection
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2

    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 treatment-arm, enrolling patients with genotype 3 , was prematurely terminated because national treatment guidelines for genotype 3 patients were altered after approval of Epclusa (velpatasvir/sofosbuvir) in Europe.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/29994874
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