The following datasets contain the data available for EPPT MAY2013-02-01. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 36 datasets contain the raw form data received, excluding PII.

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Trial Summary

The primary objective is to determine the safety profile of the HCV DNA vaccine, consisting of INO-8000 (HCV antigen DNA) alone or co-administered with INO-9012 (IL-12 adjuvant DNA); and to identify a dose of INO-9012 (IL-12 adjuvant DNA) for co-administration with INO-8000 (HCV antigen DNA) based on induction of HCV-specific IFN-γ production by peripheral blood mononuclear cells at 26 weeks compared to baseline in HCV-infected participants.

Scheduled dose levels:

Vaccine administration at Day 0, Week 4 (+/-3 days), Week 12 (+/-3 days), and Week 24(+/-7 days)

• Dose Level 0: INO-8000 (6 mg) alone (starting dose)
• Dose Level 1: INO-8000 (6 mg) with INO-9012 (0.3 mg)
• Dose Level 2: INO-8000 (6 mg) with INO-9012 (1.0 mg)
• Dose Level 3: INO-8000 (6 mg) with INO-9012 (3.0 mg)

Target Enrollment: 32

Actual Enrollment: 33

Enrollment Statistics

Actual Registration: 23

• 33 were evaluated for eligibility
• 10 were excluded for not meeting inclusion/exclusion criteria
• 23 were registered for intervention (22 received at least 1 dose of the vaccine)
• 20 completed study
• 1 lost to Follow-up
• 1 lost to intercurrent illness
• 1 withdrew

Participant Statistics:

Eligibility Criteria

Inclusion Criteria

Pre-Registration Inclusion:

• Presence of active, chronic HCV infection confirmed by positive HCV RNA
• Willingness to use adequate contraception to avoid pregnancy or impregnation for the duration of study participation; Note:
• The effects of INO-8000 with or without INO-9012 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
• 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 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
• Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Examples of contraceptive methods with an expected failure rate of < 1% per year include male sterilization and hormonal implants; alternatively, proper use of combined oral or injected hormonal contraceptives and certain intrauterine devices or two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year (barrier methods must always be supplemented with the use of a spermicide)
• Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• Should a female partner of a male study participant become pregnant while the male participant is on study, the male participant should inform his study physician immediately
• Willingness to avoid excessive use of alcohol during the study; note: excessive use is defined as drinking >= 8 alcoholic drinks per week on average
• Willingness to provide blood samples for research tests specified in the protocol
• Ability to understand and willingness to sign a written informed consent document

Registration Inclusion:

• Serum or plasma HCV RNA level >= 10,000 IU/mL
• Screening HCV genotype, demonstrating genotype 1
• Alpha feto protein (AFP) levels within normal institutional limits or judged to be not clinically significant by the investigator; Exception: If deemed clinically significant, then liver imaging must be available within previous 6 months (e.g., ultrasound, computed tomography [CT] scan, magnetic resonance imaging [MRI]) showing no evidence of hepatocellular carcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Screening laboratory values (serum chemistry, hematology, prothrombin time [PT](international normalized ratio [INR])/activated partial thromboplastin time [APTT], and creatine phosphokinase [CPK]) obtained up to 45 days prior to administration of first vaccine injection on day 0 within institutional normal range or judged to be not clinically significant by principal investigator (PI) and medical monitor
• 12-lead electrocardiogram (ECG) showing normal heart rhythm; note: if there are abnormalities, then the abnormalities must be deemed of no clinical significance

Exclusion Criteria

Pre-Registration Exclusion:

• Failure of previous HCV therapies
• Human immunodeficiency virus (HIV) infection
• Any previous treatment for HCV =< 6 months prior to registration
• Other uncontrolled immune-compromising illness
• Autoimmune disorders, transplant recipients, other immunosuppression including any concurrent condition requiring the use of immunosuppressive/ immunomodulating agents; Exception: eye drop-containing and infrequent inhaled corticosteroids are permissible; topical corticosteroids are permissible at locations other than the administration site (upper arm); Note: All systemic corticosteroids must be discontinued at least 4 weeks prior to randomization; inhaled corticosteroids must be discontinued >= 48 hours prior to randomization and courses of more than 2 weeks are not permissible within 4 weeks of randomization
• Ongoing hepatitis B virus (HBV) infection
• Documented evidence of fibrosis or cirrhosis (Metavir 2, 3, and 4) and subjects with significant extrahepatic manifestations of hepatitis C (such as cryoglobulinemia with symptoms or evidence of end-organ manifestations, renal disease, type 2 diabetes, or porphyria cutanea tarda
• Other known causes of significant liver disease including chronic or acute hepatitis B, acute hepatitis A, hemochromatosis, or homozygote alpha-1 antitrypsin deficiency
• Active malignancy; exception: non-melanoma skin cancers cancer(s) for which diagnosis and treatment was completed >= 3 years prior to pre-registration
• History of major organ transplantation with an existing functional graft
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• History of cardiac arrhythmia, controlled or uncontrolled, including ventricular and supraventricular arrhythmia
• Pregnant or nursing women; Note: Pregnant women are excluded from this study because INO-8000 has an unknown potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with this DNA vaccine, breastfeeding should be discontinued if the mother is treated with INO-8000
• Current diagnosis or history of cardiac pre-excitation syndromes (e.g. Wolff-Parkinson-White)
• Metal implants on same limb as intended administration site
• Tattoos, scars, active lesions, or rashes =< 2 cm of the intended site of study treatment
• Documentation of history of seizure within previous 5 years
• Pacemaker or other implanted device
• Any condition that, in the clinical judgement of the investigator, would place a participant at unreasonably increased risk

Registration Exclusion:

• Receiving any other investigational agents =< 6 months prior to Registration
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to INO-8000 and INO-9012

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Results/Findings:

Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. We studied the safety and immunogenicity of a novel therapeutic hepatitis C virus (HCV) genotype 1a/1b consensus DNA vaccine, INO-8000, encoding HCV NS3, NS4A, NS4B and NS5A proteins alone or co-administered with DNA encoding interleukin-12 (IL-12) (INO-9012), a human cytokine that stimulates cellular immune function, in individuals with chronic hepatitis C. This was a phase I, multi-site dose-escalation trial with an expansion cohort evaluating doses of 0, 0.3, 1.0, and 3.0 mg of INO-9012 (IL-12 DNA) as an addition to 6.0 mg of (INO-8000) (HCV DNA vaccine). Vaccines were administered by intramuscular injection followed by electroporation at study entry and at weeks 4, 12, and 24. HCV-specific CD4+ and CD8+ T cell immune responses were measured by IFN-γ ELISpot and flow cytometry-based assays. Transient, mild-to-moderate injection site reactions unrelated to interleukin-12 DNA dose were common. Increases in HCV-specific IFN-γ production occurred in 15/20 (75%) participants. Increases in the frequency of HCV-specific CD4+ and CD8+ T cells occurred at all dose-levels, with the greatest increases seen at 1.0 mg of INO-9012. HCV-specific CD8+ and CD4+ T cell activities increased in 16/18 (89%) and 14/17 (82%) participants with available data, respectively. The vaccine regimen was safe and induced HCV-specific CD4+ and CD8+ cellular immune responses of modest magnitude in most HCV-infected participants. The addition of 1.0 mg of IL-12 DNA provided the best enhancement of immune responses. The vaccine regimen had little effect on controlling HCV viremia.

Source:

• Phase I Trial of a Therapeutic DNA Vaccine for Preventing Hepatocellular Carcinoma from Chronic Hepatitis C Virus (HCV) Infection.
  Jacobson JM, Zahrieh D, Strand CA, Cruz-Correa M, Pungpapong S, Roberts LR, Mandrekar SJ, Rodriguez LM, Boyer J, Marrero I, Kraynyak KA, Morrow MP, Sylvester AJ, Pawlicki JM, Gillespie E, Barranco E, Richmond E, Umar A, Weiner DB, Limburg PJ, ...show more Cancer Prevention Network
  Cancer Prev Res (Phila). 2023 Mar 1; Volume 16 (Issue 3): Pages 163-173 PUBMED