Phase I Study of INO-1800 With or Without INO-9112 + EP in Chronic Hepatitis B Subjects

Phase I, Randomized, Open-Label, Active-Controlled, Dose Escalation Study to Evaluate the Safety, Tolerability & Immunogenicity of INO-1800 Alone or in Combination With INO-9112 Delivered IM Followed by EP in Select Nucleos(t)Ide Analogue-Treated, Chronic Hepatitis B Patients

This was an open-label study that evaluated the safety, tolerability, and immunogenicity of dose combinations of INO-1800 (DNA plasmids encoding Hepatitis B surface antigen [HBsAg] and Hepatitis B core antigen [HBcAg]) and INO-9112 (DNA plasmid encoding human interleukin 12) delivered by electroporation (EP) in 90 (ninety) nucleos(t)ide analogue treated participants.

Study Overview

• Status: Completed
• Conditions: Hepatitis B
• Intervention / Treatment: Biological: INO-1800; Drug: Nucleos(t)ide Analogue Treatment; Biological: INO-9112

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Mater Adult Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
• Hong Kong
  • Hong Kong, Hong Kong, 00000
    • The University of Hong Kong
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital
• Philippines
  • Pasig City, Philippines, 1605
    • The Medical City
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taoyuan County
    • Linkou, Taoyuan County, Taiwan, 333
      • Chang Gung Memorial Hospital
• Thailand
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Siriraj Hospital, Mahidol University
  • Chiang Mai
    • Tha Muang, Chiang Mai, Thailand, 50200
      • Maharaj Nakorn Chiang Mai Hospital
  • Muang District
    • Khon Kaen, Muang District, Thailand, 40002
      • Srinagarind Hospital
• United States
  • California
    • San Diego, California, United States, 92105
      • Research and Education, Inc.
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Schiff Center for Liver Disease
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health
    • New York, New York, United States, 10029
      • Mount Sinai - PRIME
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • UC Physicians Company, LLC/Division of Digestive Diseases
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Philadelphia VA Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harbourview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA:

• Chronic Hepatitis B virus infection
• Negative for Hepatitis A IgM, C, D and HIV
• Liver biopsy, Fibroscan® or equivalent elastography-based test obtained within the past 6 months demonstrating liver disease without evidence of bridging fibrosis or cirrhosis supported by platelet count greater than the central laboratory LLN at screening
• Positive for Hepatitis B surface antigen (≥250 IU/mL at screening)
• Nucleos(t)ide treatment for at least 1 year with ongoing nucleos(t)ide analogue treatment at randomization
• HBV DNA <90 IU/mL for ≥6 months prior to randomization
• Screening laboratory values within normal range
• ALT ≤1.5x upper limit of normal (ULN) from 2 measurements separated by at least 14 days during the 6 months prior to randomization and ALT at screening ≤1.5x ULN
• AST, TBili, DBili, GGT, Alk Phos and albumin within normal range or judged to be not clinically significant by PI and medical monitor at screening
• For men and women who are not postmenopausal [i.e. ≥ 12 months of non-therapy-induced amenorrhea, confirmed by follicle stimulating hormone (FSH), if not on hormone replacement] or surgically sterile (vasectomy in males or absence of ovaries and/or uterus in females) agreement to remain abstinent or use 1 highly effective or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and at least through week 12 after last dose

EXCLUSION CRITERIA:

• Pregnant or breastfeeding females
• Positive serum pregnancy test at screening or positive urine pregnancy test at randomization
• Use of topical corticosteroids at or near the intended administration site
• Autoimmune disorders, transplant recipients, other immunosuppression including any concurrent condition requiring the use of immunosuppressive/immunomodulating agents (eye drop-containing and infrequent inhaled corticosteroids are permissible)
• Need for systemic antiviral treatment (other than for chronic hepatitis B infection)
• Documented history or other evidence of decompensated liver disease (e.g., ascites, bleeding from esophageal varices, Child-Pugh clinical classification B or C)
• History of liver cirrhosis demonstrated by biopsy, Fibroscan® or equivalent elastography-based test
• History of other evidence of a medical condition associated with chronic liver disease [e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), toxin exposure, thalassemia, etc.]
• Documented history or other evidence of metabolic liver disease within 1yr of randomization
• Abnormal renal function including serum creatinine >ULN or calculated creatinine clearance <70 mL/min (using the Cockcroft Gault formula)
• History of or suspicion of HCC
• Screening alpha fetoprotein ≥13 ng/mL
• Prior history or current malignancy other than adequately treated BCC, unless history of BCC is near intended administration site
• History of significant medical conditions [e.g., cardiac (including ventricular or supraventricular arrhythmias), renal disease, pulmonary, gastrointestinal, neurological]
• Significant acute infection (e.g., influenza, local infection) or any other clinically significant illness within 2 weeks of randomization
• Administration of any blood product within 3 mon of randomization
• History of seizures (unless seizure free for 5yrs)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: low dose, standard regimen; Participants received 3 or 4 doses of 0.3 mg INO-1800 delivered by EP in a standard regimen while continuing treatment with nucleos(t)ide analogue treatment.	Biological: INO-1800; INO-1800 delivered by EP; Drug: Nucleos(t)ide Analogue Treatment; Continued treatment with nucleos(t)ide analogue
Experimental: Group A: mid dose, standard regimen; Participants received 3 or 4 doses of 2 mg INO-1800 delivered by EP in a standard regimen while continuing treatment with nucleos(t)ide analogue treatment.	Biological: INO-1800; INO-1800 delivered by EP; Drug: Nucleos(t)ide Analogue Treatment; Continued treatment with nucleos(t)ide analogue
Experimental: Group A: high dose, standard regimen; Participants received 3 or 4 doses of 9 mg INO-1800 delivered by EP in a standard regimen while continuing treatment with nucleos(t)ide analogue treatment.	Biological: INO-1800; INO-1800 delivered by EP; Drug: Nucleos(t)ide Analogue Treatment; Continued treatment with nucleos(t)ide analogue
Experimental: Group B: mid dose, standard regimen; Participants received 3 or 4 doses of 2 mg INO-1800 + 0.25 mg INO-9112 delivered by EP in a standard regimen while continuing treatment with nucleos(t)ide analogue treatment.	Biological: INO-1800; INO-1800 delivered by EP; Drug: Nucleos(t)ide Analogue Treatment; Continued treatment with nucleos(t)ide analogue; Biological: INO-9112; INO-9112 delivered by EP
Experimental: Group B: high dose, standard regimen; Participants received 3 or 4 doses of 9 mg INO-1800 + 0.25 mg INO-9112 delivered by EP in a standard regimen while continuing treatment with nucleos(t)ide analogue treatment.	Biological: INO-1800; INO-1800 delivered by EP; Drug: Nucleos(t)ide Analogue Treatment; Continued treatment with nucleos(t)ide analogue; Biological: INO-9112; INO-9112 delivered by EP
Active Comparator: Active Control: nucleos(t)ide analogue treatment; Participants continued treatment with nucleos(t)ide analogue treatment.	Drug: Nucleos(t)ide Analogue Treatment; Continued treatment with nucleos(t)ide analogue

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Assessment (Composite of multiple measures: pain (VAS), adverse events, lab abnormalities, changes in vital signs)	Composite outcome measure consisting of multiple measures, including: Local pain immediately after Study Treatment/EP and at select times using a visual analog scale (VAS) from 0 to 10, with 0 representing "No Pain" and 10 representing "Worst Pain"; Frequency and severity of local and systemic events for at least 7 days after Study Treatment/EP; Frequency and severity of laboratory abnormalities; Frequency and severity of all adverse events; Changes in vital signs	Signing of ICF through up to 76 weeks following the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunogenicity Assessment	Composite outcome measure consisting of multiple measures, including; Breadth and Magnitude of antigen specific cellular immune responsesInterferon-ɣ ELISpotFlow Cytometry for T-cell activation, cytolytic phenotype, memory phenotype; Breadth and Magnitude of antigen specific ELISA	Baseline (screening and first dose) and select points up to 76 weeks after the first dose
Viral/Antiviral Assessment	Composite outcome measure consisting of multiple measures, including: Evaluate effect on HBsAg kinetics as measured in the quantitative HBsAg assay; Evaluate effect on maintenance of HBV DNA suppression (< 90 IU/ml) as measured in the quantitative viral load assay	Screening and/or first dose and select points up to 76 weeks after the first dose

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Assessment	Composite outcome measure consisting of multiple measures, including: Relationship between immunogenicity and antiviral response; Expression of individual markers potentially predictive of immunogenic and antiviral responses	Screening and/or first dose and select points up to 76 weeks after the first dose

Collaborators and Investigators

• Sponsor: Inovio Pharmaceuticals
• Investigators: Study Director: ShuPing Yang, MD, PhD, Inovio Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2015
• Primary Completion (Actual): May 22, 2018
• Study Completion (Actual): May 22, 2018

Study Registration Dates

• First Submitted: April 21, 2015
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimate): May 1, 2015

Study Record Updates

• Last Update Posted (Actual): October 15, 2019
• Last Update Submitted That Met QC Criteria: October 11, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: immunotherapy; electroporation; Chronic HBV; DNA vaccine
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic
• Other Study ID Numbers: HBV-001