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    Clinical Trial Results:
    Interferon-free Treatment of Acute Genotype 1 Hepatitis C Virus Infection with Ledipasvir/Sofosbuvir Fixed-Dose Combination - The HepNet Acute HCV IV Study

    Summary
    EudraCT number
    		 2013-001081-42
    Trial protocol
    		 DE  
    Global end of trial date
    13 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2023
    First version publication date
    31 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HepNet-aHCV-IV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02309918
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hannover Medical School
    Sponsor organisation address
    Carl-Neuberg-Str. 1, Hannover, Germany, 30625
    Public contact
    Stabsstelle Zentrum für Klinische Studien, Hannover Medical School, EudraCT@mh-hannover.de
    Scientific contact
    Stabsstelle Zentrum für Klinische Studien, Hannover Medical School, EudraCT@mh-hannover.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
    29 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are as follows: • To evaluate the efficacy of treatment with ledipasvir (LDV)/sofosbuvir (SOF) FDC for 6 weeks in patients with acute genotype 1 HCV infection as measured by the proportion of subjects with sustained viral response (HCV RNA < LLOQ TND) 12 weeks after discontinuation of therapy (SVR12) • To evaluate the safety and tolerability of LDV/SOF FDC -containing regimens administered for up to 6 weeks in patients with acute genotype 1 HCV infection
    Protection of trial subjects
    Before study enrolment all subjects got detailed information about study procedures, potential risks and benefits as well as alternative treatment options. The study was approved by regulatory authorities and independent monitoring was conducted to ensure subjects safety. The IMP is an approved drug with extensive data from clinical trials and favorable risk-benefit profile. Safety was assessed throughout the treatment and follow-up periods based on the AEs. Adverse events were documented within one week on the respective AE forms in the (e)CRF. The same documentation responsibilities as described for AEs applied to SAEs. In addition, SAEs were documented on a paper SAE-form and reported to the sponsor. Documentation of SAE was done as complete and detailed as possible. Safety Laboratory assessments were conducted at each single visit. The investigator had the right to withdraw a patient from the study if the patient’s safety or wellbeing was compromised by further study participation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2014
    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: 26
    Worldwide total number of subjects
    26
    EEA total number of subjects
    26
    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)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patints were screened in 10 study centers in Germany. Overall 26 patients were screened for elegibility and signed informed consent. Six patients were ineligible at screening. Recruitment period was between 11/2014 and 11/2015.

    Pre-assignment
    Screening details
    		 Adults (≥18 years) with acute HCV genotype 1 monoinfection. Leading inclusion criteria: HCV RNA > 10.000 IU/mL and documented HCV antibody seroconversion, or known exposure with ALT > 10 ULN within 4 month. Leading exclusion criteria: Liver cirrhosis, hepatic decompensation, systemic drug usage, contraindications against IMP.

    Pre-assignment period milestones
    Number of subjects started
    		 26
    Number of subjects completed
    		 20

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening Failure: 6
    Period 1
    Period 1 title
    Study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single-Arm
    Arm description
    		 Single-arm study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/ Sofosbuvir
    Investigational medicinal product code
    Other name
    Harvoni
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ledipasvir/ Sofosbuvir fixed dose combination. Film-coated tablets containing 90 mg of Ledipasvir (LDV) and 400 mg of Sofosbuvir (SOF). LDV/SOF FDC tablet was administered once daily.

    Number of subjects in period 1 [1]
    		Single-Arm
    Started
    20
    End of treatment
    20
    Follow up week 12
    20
    Completed
    19
    Not completed
    1
         Consent withdrawn by subject
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 26 patients were screened for enrolment and 20 patients finally were enrolled in the study. 11 patients dit not met inclusion-/ exclusion criteria and thus must be excluded as screening failure. The number of patients in the baseline period reflects the number of patients who received at least one dose of study medication (ITT).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study period
    Reporting group description
    		 Single Arm study

    Reporting group values
    		 Study period Total
    Number of subjects
    		 20 20
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 20 20
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 49 (36 to 54) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 12 12
    HCV Genotype
    Units: Subjects
        1a
    		 11 11
        1b
    		 9 9
    HCV RNA
    Units: Subjects
        <= 50.000 IU/ml
    		 12 12
        < 15 IU/ml
    		 1 1
        > 50.000 IU/ml
    		 7 7
    Risk factors for infection
    Units: Subjects
        Sexual transmission
    		 11 11
        Medical procedures/needle stick injury
    		 5 5
        Nail treatment
    		 1 1
        Unspecified
    		 3 3
    HCV RNA
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    		 11000 (140 to 190000) -
    Alanine Aminotransferase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    		 225 (71 to 722) -
    Bilirubin
    Units: µmol/l
        median (inter-quartile range (Q1-Q3))
    		 13.7 (10.2 to 25.1) -
    Aspartate aminotransferase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    		 76.5 (34.5 to 286.5) -
    Gamma GT
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    		 134 (71 to 292) -
    Alkaline phosphatase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    		 104 (80 to 138) -
    Subject analysis sets

    Subject analysis set title
    IIT-Analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The overall population is an ITT population and consists of all patients who received at least one dose ofthe study medication.

    Subject analysis set title
    Per Protocol Analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population comprises of all patients that were complying with the studyprotocol until the end of the observational period, particularly all patients that attended all study visits and have fully observed data for the primary endpoint.

    Subject analysis sets values
    		 IIT-Analysis Per Protocol Analysis
    Number of subjects
    20
    19
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    20
    19
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    49 (36 to 54)
    49 (35 to 54)
    Gender categorical
    Units: Subjects
        Female
    8
    7
        Male
    12
    12
    HCV Genotype
    Units: Subjects
        1a
    11
    11
        1b
    9
    8
    HCV RNA
    Units: Subjects
        <= 50.000 IU/ml
    12
    12
        < 15 IU/ml
    1
    1
        > 50.000 IU/ml
    7
    6
    Risk factors for infection
    Units: Subjects
        Sexual transmission
    11
    11
        Medical procedures/needle stick injury
    5
    4
        Nail treatment
    1
    1
        Unspecified
    3
    3
    HCV RNA
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    11000 (140 to 190000)
    6750 (138 to 250000)
    Alanine Aminotransferase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    225 (71 to 722)
    269 (68 to 766)
    Bilirubin
    Units: µmol/l
        median (inter-quartile range (Q1-Q3))
    13.7 (10.2 to 25.1)
    15.4 (10.1 to 27.4)
    Aspartate aminotransferase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    77 (35 to 287)
    72 (32 to 294)
    Gamma GT
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    134 (71 to 292)
    135 (75 to 292)
    Alkaline phosphatase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    104 (80 to 138)
    108 (84 to 139)

    End points

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    End points reporting groups
    Reporting group title
    Single-Arm
    Reporting group description
    		 Single-arm study

    Subject analysis set title
    IIT-Analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The overall population is an ITT population and consists of all patients who received at least one dose ofthe study medication.

    Subject analysis set title
    Per Protocol Analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population comprises of all patients that were complying with the studyprotocol until the end of the observational period, particularly all patients that attended all study visits and have fully observed data for the primary endpoint.

    Primary: sustained virological response (SVR 12)

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    End point title
    		 sustained virological response (SVR 12)
    End point description
    Proportion of subjects with sustained virological response (SVR 12) 12 weeks after discontinuation of therapy
    End point type
    Primary
    End point timeframe
    Follow up visit 12
    End point values
    		 Single-Arm IIT-Analysis Per Protocol Analysis
    Number of subjects analysed
    20
    20
    19
    Units: Patients
        sustained virological response (SVR 12) week 12
    20
    20
    19
    Statistical analysis title
    		 two-sided 95%-Wilson-confidence interval
    Statistical analysis description
    The two-sided 95%-Wilson-confidence interval for the proportion of subjects with sustained viral response 12 weeks after discontinuation of therapy (SVR 12) was evaluated. Since all patients (ITT or PP) were expected to be HCV-RNA negative, the lower limit of the confidence interval was expected to be above 80%.
    Comparison groups
    Single-Arm v IIT-Analysis v Per Protocol Analysis
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 95%Wilson-confidence interval
    Confidence interval
    Notes
    [1] - 95%Wilson-confidence interval
    [2] - H0: pSVR12 < 0.83 and H1: pSVR12 ≥ 0.83.

    Secondary: sustained virological response (SVR 24)

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    End point title
    		 sustained virological response (SVR 24)
    End point description
    Proportion of subjects with durability of sustained virological response (SVR 24) 24 weeks after discontinuation of therapy
    End point type
    Secondary
    End point timeframe
    Follow up week 24
    End point values
    		 Single-Arm IIT-Analysis Per Protocol Analysis
    Number of subjects analysed
    20
    20
    19 [3]
    Units: patients
        Patients sustained virological response (SVR 24)
    19
    19
    19
    Notes
    [3] - FU24 data were available for 19 patients, 1 patient was lost to follow up
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse event documentation period for this trial begins upon first administration of the IMPs and ends with the end-of-trial visit of the respective patient.
    Adverse event reporting additional description
    Numbers in the non-serious adverse events section reflect all adverse events occurring during the study (non-serious and serious).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    LDV/SOF FDC
    Reporting group description
    		 -

    Serious adverse events
    		 LDV/SOF FDC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 LDV/SOF FDC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    5
    Performance status decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Investigations
    Blood uric acid increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Meniscus injury
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Ligament rupture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Wrist fracture
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Multiple sclerosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Transient global amnesia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Transient ischemic attack
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Diarrhea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Feces discolored
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Oral discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Skin reaction
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Arthralgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Oral herpes
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2015
    Inclusion criterium changed and inclusion of a prohibited concomitant medication
    12 Jun 2015
    secondary objectives were defined more precisely and shipping of samples for the cytokine analysis was changed to the end of the study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28029529
    http://www.ncbi.nlm.nih.gov/pubmed/33517457
    http://www.ncbi.nlm.nih.gov/pubmed/30548086
    http://www.ncbi.nlm.nih.gov/pubmed/34843107
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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