Amarillo Biosciences, Inc. – Clinical Study Protocol #03HUHI19

EVALUATION OF NATURAL HUMAN INTERFERON ALPHA ADMINISTERED OROMUCOSALLY IN THE TREATMENT OF ORAL WARTS IN HIV- SEROPOSITIVE SUBJECTS RECEIVING COMBINATION ANTI-RETROVIRAL THERAPY:  A PHASE 2 CLINICAL TRIAL

 

SYNOPSIS

Title: Evaluation of Natural Human Interferon Alpha Administered Oromucosally in the Treatment of Oral Warts in HIV-Seropositive Subjects Receiving Combination Anti-Retroviral Therapy: A Phase 2 Clinical Trial. 

Study Design: Phase 2, Blinded, Randomized, Parallel study

Objective:  To determine the effect and safety of 1,500 international units (IU) of natural human interferon alpha (IFNa) administered by the oral mucosal route in the treatment of oral warts in HIV-seropositive subjects receiving combination anti-retroviral therapy.

Subject Population: A total of 80 HIV-infected subjects who have been diagnosed with multiple oral warts will be enrolled in this study.  All subjects will receive combination anti-retroviral therapy consisting of at least 2 nucleoside and/or non-nucleoside reverse transcriptase inhibitors (RTI) with or without 1 or more protease inhibitors (PI).

Dosage and Duration of Treatment:  The subjects will be randomly assigned in a ratio of 3:1 to active treatment or placebo.  Subjects in the active treatment arm (n=60) will receive lozenges containing 500 IU IFNa and will dissolve one such lozenge in the oral cavity 3 times per day (morning, afternoon, evening) to achieve a total daily dose of 1,500 IU IFNa.  Placebo subjects (n=20) will take a matching placebo lozenge three times per day. 

A 6-week supply of blinded lozenges will be given to enrolled subjects at study weeks 0, 6, 12 and 18 according to the randomization scheme.  Subjects will self-administer study drug daily for a maximum duration of 24 consecutive weeks in this study.

Evaluations:  The safety and effect of IFNa lozenge treatment will be assessed by oral examination of lesions, subject questionnaire, investigator global assessment, laboratory evaluations, and monitoring of adverse events and vital signs.  Oral examinations will be performed at screening (study weeks -4 to -1), week 0 (baseline), and every 6 weeks during treatment up to and including week 24.  The subject questionnaire and investigator global assessment regarding changes from baseline will be performed at weeks 6, 12, 18, and 24.  Hematology and serum chemistry will be assessed at screening and study week 24.  As a safety evaluation, quantitative HCV RNA testing will be performed at screening and week 24 in subjects known to be HCV positive.  A schematic outline of study procedures is provided in Appendix A.

Primary Endpoint:  The primary endpoint will be change in total oral mucosal area covered by warts.  Based on changes in wart area, subjects will be categorized as:

Responder:  Decrease in the oral mucosal surface area covered by ≥ 75%.
Non- Responder: Decrease in the oral mucosal surface area covered by < 75%.

Secondary Endpoints:  Total surface area of the lips covered by warts will be a secondary study endpoint. Based on changes in wart area from baseline, subjects will be categorized as responders or non-responders, using the same 75% reduction criterion applied to the primary endpoint. The other secondary endpoints will be a subject questionnaire and an investigator’s assessment regarding global oral changes.  At each evaluation, subjects will be asked to rate change in the condition of their oral warts and mouth as "better", "worse", or "unchanged" from baseline.  Investigators will be asked to rate their subjects as “improved”, “worsened”, or “unchanged” from baseline.

4.2.1   Inclusion Criteria

Each subject enrolled in the study must meet the following entry criteria:

1)         Is a male or a non-pregnant, non-lactating female. (Note: pre-menopausal females will be tested for pregnancy.)
2)         Is ³18 years of age.
3)         Is documented as HIV-seropositive.
4)         Must be receiving anti-retroviral therapy that includes at least two nucleoside or non-nucleoside reverse transcriptase inhibitors with or without protease inhibitors.
5)         Must be receiving a consistent dose and schedule of anti-retroviral therapy within the 30 days prior to the anticipated baseline (week 0) visit.  The goal is to enroll subjects whose anti-retroviral therapy schedule is likely to remain unchanged during the 24 weeks of the study, so any planned changes should be made and stabilized prior to study entry. Note: The effect of “drug holidays” (interruption of antiretroviral therapy due to adverse reactions and/or lack of efficacy) on a subject’s continuing study eligibility will be assessed on a case-by-case basis by the Sponsor in consultation with the investigator.
6)         Has biopsy-proven, HPV-induced oral warts.
7)         Meets all of the following criteria:

• hemoglobin > 8 g/dl
• absolute neutrophil count > 750 cells/ml
• platelet count > 75,000/ml
• AST < 5 times the upper limit of normal (ULN)
• bilirubin £ 2.5 times ULN
• alkaline phosphatase < 5 times ULN
• creatinine < 2.5 mg/ml

8)         Is currently exhibiting multiple oral warts, involving at least 20mm2 of the oral mucosa. Note: This criterion must be met post-biopsy, if performed.
 9)        Has signed an IRB‑approved subject consent form.
10)      Is willing and able to comply with the protocol.
11)      Has completed all Screening procedures satisfactorily, is deemed to be an acceptable subject and is otherwise eligible for entry into the study.

4.2.2   Exclusion Criteria

Any subject who meets any of the following criteria will be excluded from the study:

1)         Is exhibiting any of the following AIDS-related opportunistic infection such as: Kaposi's sarcoma, Pneumocystis carinii pneumonia, tuberculosis, cryptococcal meningitis, CMV retinitis, lymphoma, and Mycobacterium avium complex.
2)         Has used any agent or other therapies for the treatment of oral warts within 30 days prior to the start of study treatment, or is expected to use such therapy during the course of the study. Cimetidine use is allowed, even if prescribed as a treatment for oral warts, provided the subject has been on a stable dose/schedule for 30 days prior to screening.
3)         Has hypersensitivity to interferon.
4)         Has used an investigational agent within 30 days prior to the start of study treatment, or is expected to use an investigational agent other than IFNa during the study.
5)         Is a pregnant or lactating female, or is of childbearing potential and is unwilling to use a medically acceptable contraceptive method throughout the study.
6)         Has had exposure to any oral IFNa therapy within 30 days of initiation of study treatment.
7)         Has had exposure to any parenteral IFNa therapy within 1 year prior to initiation of study treatment.
8)         Has had exposure to systemic steroids within 30 days of initiation of study treatment. Note: If a subject has used steroids for any period of time prior to initiation of study treatment (week 0) then a 30-day washout is required. After initiation of study treatment, if a subject uses steroids <7 consecutive days, this will be considered intermittent use and will be allowed. If the subject requires >7 days of consecutive steroid treatment after initiation of study treatment, the subject’s continuing study eligibility will be evaluated on a case-by-case basis by the Sponsor in consultation with the investigator.
9)         Has a history of, or is currently exhibiting any disease or condition which, in the opinion of the Principal Investigator, would place the subject at increased risk during study therapy.
10)      Has any abnormality in a hematologic or biochemical variable which, in the opinion of the Principal Investigator, would place the subject at increased risk during study therapy.

APPENDIX A – SCHEMATIC OUTLINE OF STUDY PROCEDURES

 

	S	W0	W6	W12	W18	W24
Informed Consent	X
Medical History	X
Eligibility Criteria	X
Vital Signs1	X	X	X	X	X	X
Oral Examination of Warts	X	X	X	X	X	X
Subject Questionnaire			X	X	X	X
Investigator Global Assessment			X	X	X	X
Concomitant Medications	X	X	X	X	X	X
Lab Evaluations2	X					X
Wart Biopsy3	X
Adverse Events			X	X	X	X
Compliance Audit			X	X	X	X

• Vital signs include the measurement of heart rate, blood pressure and temperature.
• Lab evaluations include hematology and serum chemistry for all subjects. Hematology evaluations include Hb, Hct, RBC, WBC (total and differential) and platelet count. Serum chemistry evaluations include total bilirubin, uric acid, creatinine, total protein, albumin, AST, ALT, alkaline phosphatase, GGT, glucose, cholesterol, triglycerides, sodium, potassium, calcium and CO2. For subjects known to be co-infected with hepatitis C virus at the time of the screening visit, lab evaluations will also include quantitative HCV RNA assessment.
• If documentation of a positive biopsy performed within the last 12 months is available for review, a current biopsy is not required.