Testing the AVI-7100 Flu Drug in Healthy Volunteers

Despite currently available antivirals, influenza causes significant morbidity and mortality (estimated 36,000 deaths each year in the United States alone). More agents are needed in the armamentarium of anti-influenza medications including novel mechanisms of action and parenteral agents.

This study will evaluate the safety of a novel RNA based therapeutic AVI-7100. Beginning with a low single-dose, subjects are randomized to receive either AVI-7100 or placebo and evaluated on Study Days 0, 1, 2, 4, 10, 28. The safety and tolerability is evaluated using symptoms, clinical laboratory tests, ECG, and pharmacokinetics. Utilizing a series of stopping rules and a medical monitor, the dose will be escalated as safety and tolerability are established. Once the maximum tolerated dose (MTD) is established in the first part of this study (either limited by adverse effects or up to maximum anticipated dose), the safety and tolerability of multi-dose administration will begin (replicating anticipated clinical use). Subjects again are randomized to either AVI-7100 or placebo daily for 5 days, and evaluated on Study Days 0, 1, 2, 3, 4, 5, 6, 8, 14, and 32. The dose used in the multi-dose cohorts will also be escalated as safety and tolerability are established.

• INCLUSION CRITERIA:

• Age greater than or equal to 18 years and less than or equal to 60 years
• Body mass index (BMI) of 19-32 kg/m(2)
• Estimated glomerular filtration rate greater than or equal to 90 mL/min at screening, calculated using the MDRD formula
• Subjects must agree to:
• Not take any prescription or OTC medications with the exception of Tylenol, vitamins, seasonal allergy medications, and/or contraceptive medications for a period 7 days prior and during study drug administration.
• Not consume any alcohol for a period 2 days prior to and during study drug administration.

• One of the following in order to avoid pregnancy:
• Females who are able to become pregnant (i.e., are not postmenopausal)
• have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception.
• From the date of the subject s signing of the informed consent form through 28 days after the last dose of study drug. At least one of the methods of contraception should be a barrier method.
• Males who have not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of the subject s signing of the informed consent form through 28 days after the last dose of study drug.

Exclusion criteria

• Any chronic medical problem that requires daily oral medications (except Tylenol, oral contraceptives, vitamins, and seasonal allergy medications), or other medical history that in the opinion of the investigator significantly increases the risk associated with a phase I drug.
• History of cardiovascular disease or unexplained syncope
• Women who are breast-feeding.
• Positive urine or serum pregnancy test.
• Abnormal ECG

-defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table.

--evaluating PR interval, QTc interval and rhythm.

• Abnormal chemistry panel

-defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table

--evaluating only sodium [Na], potassium [K], serum bicarbonate [total CO2], creatinine, glucose,albumin, ALT, AST, ALKP, GGT, total bilirubin, LDH, and estimated GFR by the MDRD equation.

• Abnormal complete blood count (CBC)

-defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table

-- evaluating only the WBC (to include absolute neutrophil and lymphocyte counts), hemoglobin, hematocrit, and platelets.

• Abnormal urinalysis

-defined as any clinically significant baseline Grade 1 or greater toxicity

--evaluating only protein, and RBCs.

• Urine-albumin-to-creatinine ratio (UACR) >30 mg/g.
• Positive serology for Hepatitis B surface antigen.
• Positive serology for Hepatitis C.
• Positive serology for HIV-1.
• Positive urine drug screen.
• Participation in a study with receipt of any investigational drug within 5 half-lives or 30 days, whichever is longer, prior to study drug administration (i.e., Day 0)
• Donation of blood or blood products within 30 days or plasma within 2 weeks prior to study drug administration (i.e., Day 0)
• Receipt of blood products within 2 months prior to study drug administration (i.e., Day 0)
• Receipt of any vaccination within 30 days prior to study drug administration (i.e., Day 0)
• Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject s ability to complete and/or participate in this clinical study.