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)
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Summary
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EudraCT number |
2015-003077-15 |
Trial protocol |
DE |
Global end of trial date |
09 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Apr 2022
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First version publication date |
18 Apr 2022
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Other versions |
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Summary report(s) |
AASLD 2016 Abstract ILC 2017 abstract CSR Synopsis protocol amendment 01 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
EIG-LNF-002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02527707 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Eiger BioPharmaceuticals Inc
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Sponsor organisation address |
2155 Park Boulevard, Palo Alto, United States, CA 94306
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Public contact |
Matthew J. Bys, Senior Director of Operations, , Eiger BioPharmaceuticals, 1-(877) 899-2051, mbys@eigerbio.com
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Scientific contact |
David Apelian MD, PhD, MBA Chief Operating Officer and Executive Medical Officer, , Eiger BioPharmaceuticals, 1-(877) 899-2051, dapelian@eigerbio.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 May 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Feb 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 15
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Worldwide total number of subjects |
15
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EEA total number of subjects |
15
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
14
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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Recruitment details |
This was an open label non-randomized trial. Patients were recruited between 06-January-2016 until 09Mar2016 | ||||||||||
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Pre-assignment
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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 | ||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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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
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Investigational medicinal product code |
L262-01A005BOT35
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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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
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Investigational medicinal product name |
lonafarnib Capsules, 75 mg, for oral administration
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Investigational medicinal product code |
L262-01A006BOT35
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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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
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Investigational medicinal product name |
Novir, Ritonavir Tablets, 100 mg
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Investigational medicinal product code |
Lot no: 1039671
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
100 mg BID, one 100 mg Tablet twice daily, once morning and once in the evening
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Population
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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.
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Subject analysis set title |
The primary PD/efficacy population
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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
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Subject analysis set title |
The PK population
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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
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End points reporting groups
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Reporting group title |
Study arm
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Reporting group description |
This is a open label single arm study | ||
Subject analysis set title |
Safety Population
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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.
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Subject analysis set title |
The primary PD/efficacy population
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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
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Subject analysis set title |
The PK population
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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
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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.
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End point type |
Primary
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End point timeframe |
Enrollment to end of follow up
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| 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. |
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Attachments |
Laboratory Summary - Clinical Chemistry 14.4.3.1-1 |
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
From study enrollment including treatment follow up period
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| 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. |
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Attachments |
Vital Sign |
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
From study enrollment including study follow up
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| 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. |
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Attachments |
QTcF Interval |
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Since study enrollment including follow up
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| 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. |
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Attachments |
Concomitant Medications |
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| No statistical analyses for this end point | ||||||||||
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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
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End point type |
Primary
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End point timeframe |
From screening until end of follow up period
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| 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 |
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Attachments |
Physical Exam findings |
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Screening until end of treatment
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| 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 |
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Attachments |
Slip Lamp; Visual Acuity; Dilated Fundus |
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| No statistical analyses for this end point | |||||||||||||
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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).
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End point type |
Primary
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End point timeframe |
From BL to week 24
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| 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 |
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Attachments |
Summary of Hepatitis D RNA (log10 IU/mL) by Dose L |
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| No statistical analyses for this end point | |||||||||||||
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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.
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End point type |
Primary
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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)
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| 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. |
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| No statistical analyses for this end point | ||||||||||
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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.
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End point type |
Primary
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End point timeframe |
From enrollment to the end of follow-up
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| 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. |
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| No statistical analyses for this end point | |||||||||||||
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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
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End point type |
Secondary
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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
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Attachments |
PK results |
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| No statistical analyses for this end point | |||||||||
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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.
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End point type |
Secondary
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End point timeframe |
From BL until end of study
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| No statistical analyses for this end point | |||||||||
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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.
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End point type |
Secondary
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End point timeframe |
From BL at each visit until End of study including study follow up
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Attachments |
Laboratory Results - ALT |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From day 1 until EoT including post treatment follow up
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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
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Treatment: 50 mg/100 mg
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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
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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
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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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Oct 2015 |
As the amendment description is longer than the characters allowed, it is included in the index as a seperate summary attachment |
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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 |
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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" |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
