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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hepatitis B

Intervention / Treatment
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* Biological: INO-1800
* Biological: INO-9112
* Drug: Nucleos(t)ide Analogue Treatment


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: low dose, standard regimen<br>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<br>* INO-1800 delivered by EP<br>Drug: Nucleos(t)ide Analogue Treatment<br>* Continued treatment with nucleos(t)ide analogue<br>|
| Experimental: Group A: mid dose, standard regimen<br>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<br>* INO-1800 delivered by EP<br>Drug: Nucleos(t)ide Analogue Treatment<br>* Continued treatment with nucleos(t)ide analogue<br>|
| Experimental: Group A: high dose, standard regimen<br>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<br>* INO-1800 delivered by EP<br>Drug: Nucleos(t)ide Analogue Treatment<br>* Continued treatment with nucleos(t)ide analogue<br>|
| Experimental: Group B: mid dose, standard regimen<br>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<br>* INO-1800 delivered by EP<br>Biological: INO-9112<br>* INO-9112 delivered by EP<br>Drug: Nucleos(t)ide Analogue Treatment<br>* Continued treatment with nucleos(t)ide analogue<br>|
| Experimental: Group B: high dose, standard regimen<br>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<br>* INO-1800 delivered by EP<br>Biological: INO-9112<br>* INO-9112 delivered by EP<br>Drug: Nucleos(t)ide Analogue Treatment<br>* Continued treatment with nucleos(t)ide analogue<br>|
| Active Comparator: Active Control: nucleos(t)ide analogue treatment<br>Participants continued treatment with nucleos(t)ide analogue treatment. | Drug: Nucleos(t)ide Analogue Treatment<br>* Continued treatment with nucleos(t)ide analogue<br>|

What is the study measuring?
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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 responses Interferon-ɣ ELISpot Flow 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic HBV, immunotherapy, DNA vaccine, electroporation