A Double-Blind, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Dose and Multiple Doses of GSK3389404 in Chronic Hepatitis B Subjects
This is a Phase IIa, multicenter, randomized, double-blind (sponsor un-blinded in Part 1), placebo-controlled, 2-part studyto the assess safety, tolerability, PK, and PD profiles of GSK3389404 in subjects with CHB.
This is a Phase IIa,2-part study examining the first administration of GSK3389404 in subjects with chronic hepatitis B (CHB). This study will evaluate safety,tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of GSK3389404 and aim to establish proof-of-mechanism. Part 1 will assess the safety, tolerability, PK, and PD profiles of single ascending subcutaneous (SC) doses of GSK3389404. Part2 will assess thesafety, tolerability, PK, and PD profiles of multiple doses of GSK3389404. In addition, Part 2 will provide an initial evaluation of efficacious dose levels and dosing regimens. Finally, this study will provide an initial evaluation of anydifferences in PD between hepatitis B virus (HBV) e-antigen (HBeAg)-positive and HBeAg-negative subjects with CHB. Data from this studywill support subsequent studies by providing an early assessment of safety and PD in the target patient population when GSK3389404is administered as monotherapy(Part 1) or adjunctive therapy(Part 2).
|Start Date||Duration in Months||Target Completion Date||Actual Completion Date|
|GlaxoSmithKline Research & Development Limited (UK)||Private Business||United Kingdom||N/A|
|GlaxoSmithKline Research & Development Limited (UK)||United Kingdom|
|Name||Institution and Institution Address|
|US GSK Clinical Trials Call Center ; EU GSK Clinical Trials Call Center||GSKClinicalSupportHD@gsk.com||Building 3.3234 5 Moore Drive, PO Box 13398 RTP, NC 27709-3398|
|Name||Institution and Institution Address|
|US GSK Clinical Trials Call Center ; EU GSK Clinical Trials Call Center; PPD Safety Hotline||GSKClinicalSupportHD@gsk.com||Building 3.3234 5 Moore Drive, PO Box 13398 RTP, NC 27709-3398|
|Jose Sollano, Jr., MD||Gastroenterology||Cardinal Santos Medical Center|
|Judy Lao-Tan, MD||Gastroenterology||Cebu Doctors' University Hospital|
|Madalinee Eternity Labio, MD||Gastroenterology and Hepatology||Makati Medical Center|
|Project Location||Institutional Ethics Review Board|
|Cardinal Santos Medical Center||Cardinal Santos Medical Center Ethics Review Committee|
|Cebu Doctors' University Hospital||Cebu Doctors' University Hospital - Institutional Ethics Review Committee|
|Makati Medical Center||Makati Medical Center Institutional Review Board|
Infection with HBV, especially chronic infection, is a significant worldwide medical problem. More than 2 billion of the world’s population has been infected. Of these, an estimated 240 million are chronicallyinfected[WHO,2015].Every year, 650,000 people die from HBV-related disease complications. For those with chronic infection, 20to 30% progress to liver cirrhosis or hepatocellular carcinoma (HCC) [WHO, 2015].
The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated liver disease, end-stage liver disease, HCC, and death. This goal can be achieved if HBV replication is suppressed in a sustained manner thereby decreasing the histological activity of CHB and reducing the risk of cirrhosis and HCC [Liaw,2004; Feld, 2009].In both HBeAg-positive and
HBeAg-negativeCHB, the ultimate treatment endpoint is loss of detectable serum hepatitis B surface antigen (HBsAg) [Lok, 2009;EASL,2012].Loss of HBsAg is preceded by a robust immunological response to HBV infection resulting in sustained suppression of serum HBV deoxyribonucleic acid (DNA) and disease resolution.
· To assess the safety, tolerability, and PK profile of GSK3389404 in single (Part 1) and multiple (Part 2) administration in subjects with CHB.
· To identify one or more efficacious dose(s) anddosing regimen(s) of GSK3389404 over a planned duration of 3 months (Part 2).
· To assess the PD effect of GSK3389404 in subjects with CHB (Part 1 and Part 2).
· To investigate the PK of the metabolite of GSK3389404,alsoknownasISIS 505358, following single and multiple dose administration of GSK3389404(Part 1 and Part2).
· To assess PD differences in HBeAg-positive and HBeAg-negative subjects with CHB (Part 1 and Part 2, if applicable).To describe the seroconversion of subjects, defined as presence of HBV surface antibody (HBsAb) (Part 2 only).
- Hong Kong
Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Subject is able to understand and is capable of giving written informed consent, is willing to complywith protocol requirements, instructions and protocol-stated restrictions, and is likelyto complete the studyas planned.
2. Between 18 and 70years of age, inclusive, at the time of signing the informed consent form.
3. Abodymass index (BMI) between 18 to 30 kg/m2, inclusive.
4. Male or female if theysatisfythe following:
a. Females of reproductive potential are not permitted. Eligible females must meet the following criteria:
i. Non-pregnant (as confirmed bya negative serum human chorionic gonadotrophin [hCG] test); AND
ii. Non-lactating at screening and prior to dosing; AND
iii. Non-reproductive potential as defined byat least one of the following conditions:
1. Premenopausal females without reproductive potential defined by one of the following:
a. Documented salpingectomy;
c. Documented bilateral oophorectomy.
2. Postmenopausal defined as 12 months of spontaneous
3. A blood sample for simultaneous follicle-stimulating hormone (FSH) and estradiol levels maybe collected at the discretion of the investigator or site to confirm non- reproductive potential. Please refer to laboratoryreference ranges for confirmatorylevels for menopause.
b. Male subjects with a female partner of child-bearing potential must agree to meet one of the contraception requirements from the time of first dose ofstudytreatment until the final Follow-up visit.
ii. Male condom plus partner’s use of one of the contraceptive options below that meets the standard operating procedure (SOP) effectiveness criteria including a <1% rate of failure peryear, as stated in the product label:
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive
4. Injectable progestogen [Hatcher, 2011]
5. Contraceptive vaginal ring [Hatcher, 2011]
6. Percutaneous contraceptive patches [Hatcher,2011]
These allowed methods of contraception are onlyeffective when used
consistently,correctlyand in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
5. Documented chronic HBV infection, defined as positive plasma or serum HBsAg
≥6 months prior to screening.
6. Subject with HBV treatment historyas follows:
a. Part 1: Treatment naive or have had prior treatment with interferon (pegylated or non-pegylated) that must have ended at least 12 months prior to the Baseline visit (Day1pre-dose) and/or nucleos(t)ide analogue therapy that must have ended at least 6months prior to the Baseline visit.
b. Part 2: Subjects with CHB receiving stable nucleos(t)ide analogue therapy, defined as no changes to their nucleos(t)ide regimen from at least
6 months prior to screening and with no planned changes to the stable regimen over the duration of thestudy.
7. Plasmaor serum HBV DNA concentration:
a. Part 1:
i. ≥20,000IU/mL for HBeAg-positive subject ii. ≥2000IU/mL for HBeAg-negative subjects
b. Part 2: HBV DNA must be adequately suppressed, defined as plasma or serum HBV DNA <LLOQ.
8. Plasma or serum HBsAg concentration >50IU/mL.
9. Alanine aminotransferase (ALT) concentration:
a. Part 1: ALT < 5 X ULN
b. Part 2: ALT £ULN
A subject will not be eligible for inclusion in this studyif any of the following criteria apply:
1. Medical history
a. Historyof or active diagnosis of liver disease other than CHB, such as autoimmune hepatitis, non-alcoholic fattyliver disease/non-alcoholic steatohepatitis, hemochromatosis, or liver failure.
b. Historyor other clinical evidence of hypertension, significant or unstable cardiacdisease (e.g., prolonged QT syndrome [torsade de pointes], angina, congestive heart failure, myocardial infarction, diastolic dysfunction, significant arrhythmia,coronaryheart disease and/or clinicallysignificant ECG abnormalities).
c. Uncontrolled or historyof difficult to control hypertension.
d. Historyof, or active diagnosis of, primaryorsecondaryrenal disease (e.g., renal disease secondarytodiabetes,hypertension, vascular disease, etc.).
e. Historyof extrahepatic disorders possiblyrelated to HBV immune complexes (e.g., glomerulonephritis and polyarteritis nodosa).
f. Historyof bleeding diathesis or coagulopathy. g. Historyof or suspected presence of vasculitis. h. Historyof Gilbert’s Syndrome.
i. Historyofmalignancywithin the past 5years with the exception of specific cancers that are cured by surgical resection (e.g., skin cancer), subjects under evaluation for possible malignancyare not eligible.
2. Historyof/sensitivityto GSK3389404 or components thereof or a historyof drug
or other allergythat,in the opinion of the investigator or medical monitor, contraindicates their participation.
3. Confirmed or suspected HCC as evidenced by:
a. Alpha-fetoprotein concentration ≥200 ng/mL. If the screening alpha- fetoprotein concentration is ≥50 ng/mLand <200ng/mL, the absence of liver mass must be documented byimaging within 6 months before randomization.
4. Liver cirrhosis or evidence of cirrhosis as determined byanyof the following:
a. Positive liver biopsy(i.e., Metavir Score F4) within 12 months of screening
b. Fibroscan >12 kPa within 12 months of screening
c. Aspartate aminotransferase (AST)-PlateletIndex(APRI) >2 and
FibroSure result >0.7 within 12 months of screening
For subjects without a test for cirrhosis in the above timeframes, APRI and
FibroSure should be performed during the screening period to rule out cirrhosis.
5. A positive hepatitis C virus (HCV) antibodytest
6. A positive human immunodeficiencyvirus(HIV)antibodytest
7. Positive hepatitis D virus (HDV) antibodytest
8. Laboratoryresults as follows:
a. Total bilirubin concentration >1.25 XULN
b. Serum albumin concentration <3.5 g/dL
c. International normalized ratio (INR) >1.25 d. Platelet count X109/L
e. Serum creatinine concentration greater than the ULN
f. Glomerular filtration rate (GFR) <90mL/minascalculatedbythe Chronic
KidneyDisease Epidemiologic Collaboration (CKD-EPI) formula.
Subjects with GFR L/min but ³ 80 mL/min maybe considered after consultation with the GSK medical monitor.
g. Urine albumin to creatinine ratio (ACR)≥0.03 mg/mg. In the event of an ACR above this threshold, eligibilitymaybe confirmed bya second measurement
9. Positive test for blood in urine. In the event of a positive test, the test maybe repeated once, and ifrepeat is negative or if urine microscopyreveals h-power field (HPF), the subject is considered eligible.
10. Fridericia’s QT correction formula (QTcF) ≥450 msec (mean of triplicate measurements).
11. Currentlytaking, or took within 3 months of screening, any immunosuppressing drugs (e.g., prednisone), other than a short course of therapy(≤2weeks).
12. Current alcohol use as judged by investigator to potentiallyinterfere with participant compliance.
13. A positive pre-studytreatment screen or an unwillingness to refrain from use of the illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
14. Where participation in the studywould result in donation of blood or blood products in excess of 500mLwithin a 56-dayperiod.
15. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing dayin the current study: 5 half-lives (if known) or twice the duration (if known) of the biological effect of the studytreatment (whichever is longer) or 90days(ifhalf- life or duration is unknown).
16. Prior treatment with anyoligonucleotide or small interfering RNA (siRNA)
within 12 months prior to the first dosing day.
GSK3389404 is being developed for the treatment of chronic hepatitis B (CHB) virus infection. The development goal for GSK3389404 is the establishment of a finite duration treatment that results in sustained suppression of hepatitis B virus (HBV) replication and viral antigen production after cessation of all treatments for CHB due to the restoration of a functional immune response in the absence of high antigen levels.
ISIS 505358, known as the parent molecule of GSK3389404, is a 2′-O-(2′-methoxyethyl) (2′-MOE) chimeric second-generation antisense oligonucleotide (ASO) drug targeted to HBV ribonucleic acid (RNA). GSK3389404, the prodrug, was derived from ISIS 505358. GSK3389404 is a 2′-MOE chimeric second-generation ASO drug targeted to HBV RNA that is covalentlybonded to triantennaryN-acetyl galactosamine (GalNAc), a
high-affinityligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR) to form an ASO GalNAc conjugate to enhance deliveryof GSK3389404 to hepatocytes.
Following entryinto target cells the GalNAc conjugate prodrug GSK3389404 is metabolized within hepatocytes to release ISIS 505358. ISIS 505358 is complementaryto sequences present in all HBV-derived RNA transcripts and its hybridization (binding) to the cognate RNA results in ribonuclease H-mediated degradation. It is highlyspecific for HBV RNA transcripts and is not homologous to anyregions of the human transcriptome, including either a single nucleotide mismatch or with 17 or more consecutive nucleotide matches.
ISIS 505358 has been studied in healthyvolunteers at various dose levels and for durations up to 1 month. GSK3389404 has been administered to healthyvolunteers in Study202007, an on-going study to assess the safety, tolerability and pharmacokinetics (PK) of single and multiple ascending doses of GSK3389404. Results from the
completed studyofISIS 505358 and from the single ascending dose (SAD) portion of the ongoing Study202007 have not identified anysafetyfindings to date that would preclude further clinical development. A comprehensive summaryof the preclinical findings for GSK3389404 including pharmacology, drug metabolism and pharmacokinetics (DMPK) and toxicologyare available in the Investigator’s Brochure (IB). The clinical safety findings for both GSK3389404 and ISIS 505358 are also summarized in the IB [GlaxoSmithKline Document Number2015N236049_02].
To assess the safety, tolerability, and PK profile of GSK3389404 in single (Part1) and multiple (Part 2) administration in subjects with CHB.
To identify one or more efficacious dose(s) and dosing regimen(s) of GSK3389404 over a planned duration of 3 months(Part 2).
To assess the PD effect of GSK3389404 in subjects with CHB (Part 1 and Part 2).
To investigate the PK of the metabolite of GSK3389404,alsoknownasISIS 505358, <!--[if gte mso 9]>
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