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    Clinical Trial Results:
    A Phase 2, Open-Label Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Activity of Titrating-Dose Lonafarnib in Combination with Ritonavir in Patients Chronically Infected with Hepatitis Delta Virus (LOWR-4)

    Summary
    EudraCT number
    2015-003077-15
    Trial protocol
    DE  
    Global end of trial date
    09 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions
    Summary report(s)
    AASLD 2016 Abstract
    ILC 2017 abstract
    CSR Synopsis
    protocol amendment 01

    Trial information

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    Trial identification
    Sponsor protocol code
    EIG-LNF-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02527707
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Eiger BioPharmaceuticals Inc
    Sponsor organisation address
    2155 Park Boulevard, Palo Alto, United States, CA 94306
    Public contact
    Matthew J. Bys, Senior Director of Operations, , Eiger BioPharmaceuticals, 1-(877) 899-2051, mbys@eigerbio.com
    Scientific contact
    David Apelian MD, PhD, MBA Chief Operating Officer and Executive Medical Officer, , Eiger BioPharmaceuticals, 1-(877) 899-2051, dapelian@eigerbio.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
    08 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) Evaluate the safety and tolerability of the following dose-titration regimen of lonafarnib (LNF) in combination with ritonavir (RTV) over a 24-week treatment period: LNF/RTV starting at 50 mg bid/100 mg bid, escalated to LNF/RTV 75 mg bid/100 mg bid, and then to 100 mg bid/100 mg bid as tolerated 2) Evaluate the pharmacodynamic activity (change in HDV viral load) of the dose-titration regimen of LNF in combination with RTV over a 24-week treatment period
    Protection of trial subjects
    The study was conducted according to GCP, signed ICF was obtained before each patient’s participation in the study. Gastrointestinal (GI) symptoms (diarrhea, nausea, dyspepsia, vomiting, and decreased appetite) are the most common AEs reported with lonafarnib single-agent therapy. Ritonavir may be associated with diarrhea. Occurrence of diarrhea may reduce the absorption of lonafarnib, ritonavir, and other medications from the GI tract. Diarrhea may result in loss of fluids and dehydration, which can be severe, and require hospitalization for supportive care. Patients were requested to receive therapy (antacids, anti-emetics, or anti-diarrheals) for GI symptoms at the earliest signs in order to avoid possible severe complications and prevent and distress associated with these symptoms. Electrolytes were requested to be monitored in cases of diarrhea and volume depletion to prevent further complications which could arise due to electrolyte loss.
    Background therapy
    1) As the Hepatitis Delta patients are also infected with Hepatitis B virus, antivirals for HBV management such as Viread was allowed. 2) Ondansetron was used as a concomitant medication, on need basis, to prevent nausea and vomiting to an does not inhibit or induce enzymes in the CYP system. No interaction is expected with concomitant administration with lonafarnib, therefore it was a safe concomitant medication recommended for use in this trial. 3) Famotidine is a histamine H₂ receptor antagonist that inhibits stomach acid production was allowed to be used as a concomitant medication to prevent symptoms related to stomach acidity and Famotidine not been associated with any clinically significant drug-drug interactions. No significant interference with CYP system has been identified; thus, no interaction is expected with concomitant administration with lonafarnib, therefore it was a safe concomitant medication recommended for use in this trial 4) Omeprazole inhibits CYP2C19 and P-glycoprotein (P-gp) and is completely metabolized, specifically by CYP3A4 and CYP2C19. This medication is another alternative for the reatment of gastrointestinal symptoms. Dose adjustments are typically not required when administering omeprazole with other medications metabolized by CYP2C19; however, dose adjustments are required for omeprazole when administered to patients with hepatic impairment (refer to the Prilosec Product Label for additional information). Therefore the use of this medication was only allowed for some patients who fitted the product label requirement. 4)
    Evidence for comparator
    There was no comparator product used in this trial
    Actual start date of recruitment
    06 Jan 2016
    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: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    14
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was an open label non-randomized trial. Patients were recruited between 06-January-2016 until 09Mar2016

    Pre-assignment
    Screening details
    Patients were screened against the protocol defined inclusion/exclusion criteria. There were 18 patients screened and 15 were eligable and thus enrolled into the study. 2/3 screening failures were due to concomitant use of any prohibited medications or supplements and the remaining one was a screen failure due to significant renal dysfunction

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Study arm
    Arm description
    This is a open label single arm study
    Arm type
    Single Arm

    Investigational medicinal product name
    lonafarnib Capsules, 50 mg, for oral administration
    Investigational medicinal product code
    L262-01A005BOT35
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg bid (1 capsule twice daily) as a starting dose and after 4 weeks if the patients can also tolerate 2 weeks of 75 mg bid (different capsule) 100 mg bid (2 times 50 mg capsules once in the morning and once in the evening) as tolerated in patients - the 50mg capsules were used for 50 mg BID and 100 mg BID

    Investigational medicinal product name
    lonafarnib Capsules, 75 mg, for oral administration
    Investigational medicinal product code
    L262-01A006BOT35
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    After the first 4 weeks of 50mg BID, if the patients could tolerate 50 mg DIB they were escalated for 2 weeks to 75 mg BID. The 75 mg capsule was to be administered once in the morning and once in the evening

    Investigational medicinal product name
    Novir, Ritonavir Tablets, 100 mg
    Investigational medicinal product code
    Lot no: 1039671
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg BID, one 100 mg Tablet twice daily, once morning and once in the evening

    Number of subjects in period 1
    Study arm
    Started
    15
    Completed
    13
    Not completed
    2
         Adverse event, non-fatal
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Reporting group values
    overall trial Total
    Number of subjects
    15 15
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    14 14
        From 65-84 years
    1 1
    Gender categorical
    Units: Subjects
        Female
    4 4
        Male
    11 11
    Ethnic group
    Units: Subjects
        white
    12 12
        black or african american
    1 2
        Asian
    2 1
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis population will consist of all patients who receive at least one dose of study drug.

    Subject analysis set title
    The primary PD/efficacy population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The primary PD/efficacy population will consist of patients who receive study drug throughout the entire 24 week treatment period and for whom viral load data are available from baseline and end-of-treatment (Week 24) study visits

    Subject analysis set title
    The PK population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population will include patients who received at least 2 weeks of study drug at a stable dose level, and in whom a sufficient number of blood samples were collected, plasma samples were analyzed, concentration data were analyzed, and PK parameter values were derived

    Subject analysis sets values
    Safety Population The primary PD/efficacy population The PK population
    Number of subjects
    15
    13
    15
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    14
    12
    14
        From 65-84 years
    1
    1
    1
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    4
    3
    4
        Male
    11
    10
    11
    Ethnic group
    Units: Subjects
        white
    12
    11
    12
        black or african american
    1
    1
    1
        Asian
    2
    1
    2

    End points

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    End points reporting groups
    Reporting group title
    Study arm
    Reporting group description
    This is a open label single arm study

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis population will consist of all patients who receive at least one dose of study drug.

    Subject analysis set title
    The primary PD/efficacy population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The primary PD/efficacy population will consist of patients who receive study drug throughout the entire 24 week treatment period and for whom viral load data are available from baseline and end-of-treatment (Week 24) study visits

    Subject analysis set title
    The PK population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population will include patients who received at least 2 weeks of study drug at a stable dose level, and in whom a sufficient number of blood samples were collected, plasma samples were analyzed, concentration data were analyzed, and PK parameter values were derived

    Primary: Safety Endpoint - Clinical Lab results

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    End point title
    Safety Endpoint - Clinical Lab results [1]
    End point description
    Blood samples were analyzed for hematology, clinical chemistry, and coagulation analytes, and urine samples were analyzed for urinalysis analytes/tests (all analytes/tests are listed in Section 4.1.7 of the study protocol). Laboratory results were summarized using summary statistics (absolute and change-from-baseline values) by dose level and time point. All Grade 3 and Grade 4 laboratory values were summarized categorically by dose level. Liver enzyme results (ALT, AST, total bilirubin, and alkaline phosphatase) were summarized by Common Terminology Criteria for Adverse Events (CTCAE; Version 4.03) grade. All laboratory results were listed by patient, with values outside the normal ranges flagged.
    End point type
    Primary
    End point timeframe
    Enrollment to end of follow up
    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: Clinical laboratory data were summarized at each measurement time point and for eachpatient’s final postbaseline measurement in the following ways: (1) with descriptive statistics (mean, standard deviation, median, and range) for each measurement time point and (2) with descriptive statistics for the change from baseline in the measurements at each postbaseline time point. Summary of the clinical laboratory data are attached.
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: Clinical Laboratory Tests
        number (not applicable)
    0
    0
    Attachments
    Laboratory Summary - Clinical Chemistry 14.4.3.1-1
    No statistical analyses for this end point

    Primary: Safety Endpoint - Vital Signs

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    End point title
    Safety Endpoint - Vital Signs [2]
    End point description
    Actual and change-from-baseline vital sign values (BP, HR, respiration rate, and body temperature) were summarized at each time point by dose level. Vital signs were listed by patient.
    End point type
    Primary
    End point timeframe
    From study enrollment including treatment follow up period
    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: Actual values for vital signs and changes from baseline were summarized for each patient in the attached document Mean vital signs in the safety analysis set did not show any clinically significant changes during the study. Both systolic and diastolic BP (SBP and DBP) showed slight mean reductions from baseline, up to 8.5 and 11.5 mmHg, respectively. Mean HR also showed minor reductions from baseline, up to 5.1 bpm.
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: vital sign units
        number (not applicable)
    0
    0
    Attachments
    Vital Sign
    No statistical analyses for this end point

    Primary: Safety Endpoint - ECG Results

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    End point title
    Safety Endpoint - ECG Results [3]
    End point description
    ECG intervals were summarized by visit and dose level using summary statistics for actual values and change-from-baseline values (average of 3 readings). ECG data and clinical interpretations were listed by patient.
    End point type
    Primary
    End point timeframe
    From study enrollment including study follow up
    Notes
    [3] - 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: Actual values for ECG intervals and changes from baseline were summarized by study visit using descriptive statistics. Clinical interpretation of ECG results are summarized in the attached document.
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: msecs
        number (not applicable)
    0
    0
    Attachments
    QTcF Interval
    No statistical analyses for this end point

    Primary: Safety Endpoint - Concomitant medication use

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    End point title
    Safety Endpoint - Concomitant medication use [4]
    End point description
    Concomitant medications were defined as non-study medications that were used during the study (ie, had a stop date on or after the first dose of study drug). New concomitant medications were those concomitant medications that were started on or after the day of first study drug dose. Prior medications were those non-study medications with a stop date prior to the day of first study drug dose. Prior, concomitant, and new concomitant medications were mapped to drug classes and generic terms using the World Health Organization Drug Dictionary Enhanced (WHO-DD Enhanced), Version WHO2015SEP and summarized by dose level. Prior and concomitant medications were also listed by patient.
    End point type
    Primary
    End point timeframe
    Since study enrollment including follow up
    Notes
    [4] - 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: Concomitant medications were summarized based on mapping to drug classes and generic terms in the World Health Organization Drug Dictionary Enhanced (WHO-DD Enhanced) in the attached document.
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: The amount of conmed used
    0
    0
    Attachments
    Concomitant Medications
    No statistical analyses for this end point

    Primary: Safety Endpoint - Physical Examination Findings

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    End point title
    Safety Endpoint - Physical Examination Findings [5]
    End point description
    Physical examination findings (comprehensive exam at screening, brief exams at each subsequent visit, and genital exams at screening and Week 24 or early termination) were listed by patient
    End point type
    Primary
    End point timeframe
    From screening until end of follow up period
    Notes
    [5] - 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: Actual values for physical examination and changes from baseline were summarized and listed for each patient in the attached document
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: Units used for measuring physical exam
        number (not applicable)
    0
    0
    Attachments
    Physical Exam findings
    No statistical analyses for this end point

    Primary: Safety Endpoint - Ophthalmic Test Results

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    End point title
    Safety Endpoint - Ophthalmic Test Results [6]
    End point description
    Results of the slit lamp and dilated fundus examinations and retinal photography were summarized as normal or abnormal (nonclinically significant or clinically significant) using number (%) of patients by dose level and time point. Results of the visual acuity examination provided number (%) of patients with discrete visual acuity values (eg, 20/15, 20/20) by dose level and time point.
    End point type
    Primary
    End point timeframe
    Screening until end of treatment
    Notes
    [6] - 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: Actual values for ophthalmic examination and changes from baseline were summarized for each patient in the attached document
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: differs for each parameter analysed
        number (not applicable)
    0
    0
    Attachments
    Slip Lamp; Visual Acuity; Dilated Fundus
    No statistical analyses for this end point

    Primary: Efficacy Endpoint - Change in HDV viral load

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    End point title
    Efficacy Endpoint - Change in HDV viral load [7]
    End point description
    Change from baseline to Week 24 in HDV RNA (log10 IU/mL) (viral load).
    End point type
    Primary
    End point timeframe
    From BL to week 24
    Notes
    [7] - 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: The changes from baseline in HDV viral load is presented in the attached document
    End point values
    Study arm The primary PD/efficacy population
    Number of subjects analysed
    15
    13
    Units: log10 IU/mL
        number (not applicable)
    15
    13
    Attachments
    Summary of Hepatitis D RNA (log10 IU/mL) by Dose L
    No statistical analyses for this end point

    Primary: Safety Endpoint - AEs

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    End point title
    Safety Endpoint - AEs [8]
    End point description
    Any AEs that occurred before administration of the first dose of study drug were recorded on the Medical History CRF. AEs that started after administration of the first dose of study drug up to and including 28 days after administration of the last dose of study drug were considered treatment emergent (TEAE). Any AEs that started more than 28 days after the last dose of study drug were considered posttreatment AEs.
    End point type
    Primary
    End point timeframe
    AEs that started after administration of the first dose of study drug up to and including 28 days after administration of the last dose of study drug were considered treatment emergent (TEAE)
    Notes
    [8] - 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 was an open-label single-arm study with no comparator group.
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: number of AEs
    0
    0
    No statistical analyses for this end point

    Primary: Safety Endpoint - Reproductive hormone test results

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    End point title
    Safety Endpoint - Reproductive hormone test results [9]
    End point description
    Results of male and female reproductive hormone tests were summarized by dose and time point and listed by patient.
    End point type
    Primary
    End point timeframe
    From enrollment to the end of follow-up
    Notes
    [9] - 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 was an open-label single-arm study with no comparator group.
    End point values
    Study arm Safety Population
    Number of subjects analysed
    15
    15
    Units: differs for each parameter measured
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Secondary Endpoints - Change in pharmacokinetic parameters

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    End point title
    Secondary Endpoints - Change in pharmacokinetic parameters
    End point description
    Peak plasma concentration as observed, Time of the peak plasma concentration, Area under the plasma concentration versus time curve during the dosing interval calculated by the linear trapezoidal rule, Average plasma drug concentration during multiple-dose administration, Minimum plasma concentration, Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve, Apparent total volume of distribution, Apparent total body clearance and Apparent first-order terminal elimination half-life
    End point type
    Secondary
    End point timeframe
    Collect trough PK blood samples at Weeks 2, 4, 6, 8, 12, and 16. Trough PK sample is collected.At either Week 8, 12, or 16 if the patient is on a stable dose for the prior 2 weeks, full PK sampling should be performed
    End point values
    The PK population
    Number of subjects analysed
    15
    Units: All respective PK paratemeter units
        number (not applicable)
    0
    Attachments
    PK results
    No statistical analyses for this end point

    Secondary: Secondary Endpoint - Change in HBV DNA levels

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    End point title
    Secondary Endpoint - Change in HBV DNA levels
    End point description
    HBV DNA (log10 IU/mL) absolute and change-from-baseline values were summarized using descriptive statistics (mean, SD, median, minimum, and maximum) by dose level at each time point. HBV DNA (log10 IU/mL) mean levels were presented graphically over time. Individual patient plots of HBV DNA over time were also presented graphically.
    End point type
    Secondary
    End point timeframe
    From BL until end of study
    End point values
    The primary PD/efficacy population
    Number of subjects analysed
    13
    Units: log10 IU/mL
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Secondary Endpoint - Change in viral serology

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    End point title
    Secondary Endpoint - Change in viral serology
    End point description
    Viral serology data (HBeAb, HBeAg, HBsAg, and HDV antibody) were listed by patient.
    End point type
    Secondary
    End point timeframe
    From BL at each visit until End of study including study follow up
    End point values
    Study arm The primary PD/efficacy population
    Number of subjects analysed
    13
    13
    Units: IU/L
        number (not applicable)
    0
    0
    Attachments
    Laboratory Results - ALT
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From day 1 until EoT including post treatment follow up
    Adverse event reporting additional description
    Any AEs that occurred before administration of the first dose of study drug were recorded on the Medical History CRF. AEs that started after administration of the first dose of study drug up to and including 28 days after administration of the last dose of study drug were considered treatment emergent (TEAE). Any AEs that started more than 28 day
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Treatment: 50 mg/100 mg
    Reporting group description
    Integral to this study was the titration of the LNF dose from the starting dose of 50 mg bid, up to 75 mg bid, and then to 100 mg bid, if tolerated. LNF/RTV dosing started on Day 1 (baseline, Week 0) at 50 mg bid/100 mg bid. On or after Day 29, if the LNF/RTV dosage of 50 mg bid/100 mg bid had been tolerated for at least 4 weeks and with approval of the investigator, the LNF/RTV dosage could have been escalated to 75 mg bid/100 mg bid. On or after Day 43, if the LNF/RTV dosage of 75 mg bid/100 mg bid had been tolerated for at least 2 weeks and with approval of the investigator, the LNF/RTV dosage could have been escalated to 100 mg bid/100 mg bid

    Reporting group title
    Treatment: 75 mg/100 mg
    Reporting group description
    Integral to this study was the titration of the LNF dose from the starting dose of 50 mg bid, up to 75 mg bid, and then to 100 mg bid, if tolerated. LNF/RTV dosing started on Day 1 (baseline, Week 0) at 50 mg bid/100 mg bid. On or after Day 29, if the LNF/RTV dosage of 50 mg bid/100 mg bid had been tolerated for at least 4 weeks and with approval of the investigator, the LNF/RTV dosage could have been escalated to 75 mg bid/100 mg bid. On or after Day 43, if the LNF/RTV dosage of 75 mg bid/100 mg bid had been tolerated for at least 2 weeks and with approval of the investigator, the LNF/RTV dosage could have been escalated to 100 mg bid/100 mg bid

    Reporting group title
    Treatment: 100 mg/100 mg
    Reporting group description
    Integral to this study was the titration of the LNF dose from the starting dose of 50 mg bid, up to 75 mg bid, and then to 100 mg bid, if tolerated. LNF/RTV dosing started on Day 1 (baseline, Week 0) at 50 mg bid/100 mg bid. On or after Day 29, if the LNF/RTV dosage of 50 mg bid/100 mg bid had been tolerated for at least 4 weeks and with approval of the investigator, the LNF/RTV dosage could have been escalated to 75 mg bid/100 mg bid. On or after Day 43, if the LNF/RTV dosage of 75 mg bid/100 mg bid had been tolerated for at least 2 weeks and with approval of the investigator, the LNF/RTV dosage could have been escalated to 100 mg bid/100 mg bid

    Serious adverse events
    Treatment: 50 mg/100 mg Treatment: 75 mg/100 mg Treatment: 100 mg/100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Jaw fracture/mandibular fracture
    Additional description: This patient was already withdrawn from treatment according to the patients own consent due to decreased appetite. Near the end of the follow-up period, the patient was involved in a fight where the patient sustained a mandibular fracture.
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment: 50 mg/100 mg Treatment: 75 mg/100 mg Treatment: 100 mg/100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    10 / 13 (76.92%)
    9 / 10 (90.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 13 (23.08%)
    4 / 10 (40.00%)
         occurrences all number
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 13 (15.38%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 13 (15.38%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 15 (100.00%)
    5 / 13 (38.46%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    Nausea
         subjects affected / exposed
    6 / 15 (40.00%)
    2 / 13 (15.38%)
    5 / 10 (50.00%)
         occurrences all number
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    5 / 10 (50.00%)
         occurrences all number
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    4 / 15 (26.67%)
    2 / 13 (15.38%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 13 (7.69%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Acne
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 15 (26.67%)
    4 / 13 (30.77%)
    3 / 10 (30.00%)
         occurrences all number
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2015
    As the amendment description is longer than the characters allowed, it is included in the index as a seperate summary attachment
    03 Nov 2015
    - Change in Sponsor Medical monitor - Change in clinical program manager - Addition of inclusion criterion for ALT Inclusion criterion # 7 - Change to exclusion criterion # 8e: From "Prothrombin time >2 seconds" to "Prothrombin time >12 seconds" - Change to exclusion criterion # 19 to include: pegylated interferon alfa-2b - Change to ALT value in management of flares from "ALT of ≥5 × the ULN" to "ALT of ≥10 × the ULN" - Change to description of COBAS test to change wording " The assay can quantitate HBV DNA levels with an upper limit of detection" to say "The assay can quantitate HBV DNA levels with an upper limit of quantification" - Change in SAE reporting information
    22 Dec 2015
    1. Removing prothrombin time (PT): Results for prothrombin time (PT) will vary depending on the method used, with results measured in seconds and compared to the normal range established and maintained by the laboratory that performs the test. This normal range represents an average value of healthy people who live in that area and will vary somewhat from lab to lab. The International Normalized Ratio (INR), provides a consistent way of expressing the prothrombin test results, which had previously suffered from a large degree of variation between centers using different reagents. Therefore, to allow for consistency of results and comparison with other studies, INR will be the test result used for inclusion/exclusion of subjects into the study 2. Changes in thyroid test: Most patients with chronic HDVinfection may have received previous therapy with interferon alfa or peg-interferon alfa. Some patients may have developed hypothyroidism due to interferon therapy and are currently receiving thyroid hormone replacement therapy (THRT). All studies that investigate therapies for chronic HDV allow for inclusion of such patients as long as they are stable on THRT. As it is unnecessary to exclude patients who are stable on THRT, the restriction was removed from the exclusion criteria. 3. Removing the upper limit of BMI: The main concern related to patients with high BMI is the presence of Non-Alcoholic Fatty Liver Disease (NAFLD) in patients with chronic hepatitis Delta. Since liver biopsy is the gold standard for the diagnosis of NAFLD and the eligible patients will have a liver biopsy, the BMI limit is not. 4. Protocol time points are expressed in weeks and not in months 5. The following wording added at follow up: Alpha-interferon treatments will be allowed during the 20 weeks of the FU period (that is, starting 4 weeks after last dose of study treatment) "if considered by the investigatorbe required for patient safety"

    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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