The Safety and Effectiveness of BI-RG-587 in HIV-Infected Patients

An Open Label, Staggered Rising Dose Cohort Study Assessing Safety, Tolerance, and Activity of BI-RG-587 in Patients With HIV Infection (CD4+ Cell Count < 400 Cells/mm3)

To assess the safety and tolerance of multiple oral doses of Nevirapine (BI-RG-587). To generate data on the pharmacokinetics and dose proportionality of Nevirapine with multiple dosing. To characterize the pattern of virological activity in vivo. Improvement in virological end points will be examined for association with dose and absorption. To determine whether development of resistance is reflected in return of virological activity and, if so, when markers reflect this resistance. To determine if improvements of immunological endpoints are detectable in the number of patients studied. A compound free of the toxic effects of nucleoside chain terminators such as zidovudine (AZT) may have an advantage over currently available treatments for HIV infection. Such a compound has further advantages if it is active against AZT-resistant isolates. Nevirapine (BI-RG-587) has shown in vitro inhibitory activity against HIV-1 reverse transcriptase (RT). The molecular mechanism of the RT inhibitory effect is hypothesized to be non-competitive inhibition due to its binding to an RT site distinct from those for the RNA template primer, the deoxynucleotide triphosphate or the RNase H catalytic site.

A compound free of the toxic effects of nucleoside chain terminators such as zidovudine (AZT) may have an advantage over currently available treatments for HIV infection. Such a compound has further advantages if it is active against AZT-resistant isolates. Nevirapine (BI-RG-587) has shown in vitro inhibitory activity against HIV-1 reverse transcriptase (RT). The molecular mechanism of the RT inhibitory effect is hypothesized to be non-competitive inhibition due to its binding to an RT site distinct from those for the RNA template primer, the deoxynucleotide triphosphate or the RNase H catalytic site.

This is a staggered dose escalation cohort trial which examines the safety, tolerance, pharmacokinetics and activity of Nevirapine (BI-RG-587) in patients with HIV infection. Groups of 10 patients must have completed 4 weeks of therapy without requiring dose interruption before the next dosage level can be initiated. All 10 patients must be enrolled at a lower dosage level before the next dosage level can be initiated. Patients discontinue antiretroviral therapy, after signing informed consent, 28 days prior to receipt of a first dose of Nevirapine. Screening lab tests, including p24 antigen and plasma viremia, and CD4+ cell count determination are performed 21 days prior to drug dosing in Part I. Patients are notified of screening laboratory measures that exclude them from study participation. Upon such notification patients have the option to resume prior antiretroviral therapy or to repeat those values in one week. Part II consists of two 8-hour intensive blood sampling periods plus frequent trough value blood samplings. Safety, trough value blood sampling, and activity assessments are performed in Part III. An assessment of dose-tolerance and of activity is made in Study Week 12 in order that patients may continue Nevirapine chronic therapy for an additional 12 weeks. The Final Visit in Part IV takes place on Study Week 24 to complete the trial. Patients who complete 24 weeks are offered the option to continue on Nevirapine chronic therapy at the initial or an altered dose on a separate open-label protocol.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Pentamidine or dapsone prophylaxis for Pneumocystis carinii pneumonia (PCP) in patients with a CD4+ cell count = or < 200 cells/mm3.
• Antifungal prophylaxis with oral fluconazole or ketoconazole.
• Antiviral prophylaxis with a maximum of 1 gram of oral acyclovir per day.
• Acute therapy for intercurrent infections so long as that therapy is not an excluded medication of an excluded opportunistic infection.

Patients must have:

• Positive HIV antibody test results by ELISA.
• Average of CD4+ cell count at 60 and at 21 days prior to study beginning = or < 400 cells/mm3.
• Seven of 10 patients in each treatment arm must have p24 antigen levels = or > 70 pg/ml (> 50 pg/ml at U. of Mass. site only) or be plasma viremic.
• Preserved hematologic, hepatic, and renal function as defined by required lab values.
• Ambulatory performance score of = or > 70 Karnofsky.
• Ability to voluntarily provide written informed consent prior to treatment.
• Willingness and ability to follow protocol requirements.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Active cytomegalovirus disease.
• Toxoplasmic encephalitis requiring suppressive therapy.
• Mycobacteriosis requiring maintenance chemotherapy.
• Visceral Kaposi's sarcoma requiring chemotherapy and/or irradiation.
• Malignancy other than Kaposi's sarcoma or limited cutaneous basal cell carcinoma.
• More than mild diarrhea (defined as more than transient or > 4 loose stools per day).

Concurrent Medication:

The following medications / substances may NOT be ingested up to one hour before or 4 hours after a Nevirapine dose:

• Antacids (particularly those containing calcium carbonate).
• Cimetidine.
• Carafate.
• Cholestyramine resin.
• Alcohol and alcohol-containing substances.
• Benzodiazepines (diazepam, triazolam).

Excluded:

• Any approved or investigational antiretroviral, immunosuppressive, or cytotoxic drugs.
• Glucocorticoids and steroid hormones (including oral contraceptives).
• Dicumarol, warfarin, and other anticoagulant medications.
• Nitroglycerin.
• Digitoxin.
• Valproic acid.
• Tolbutamide.
• Doxycycline.
• Chloramphenicol.
• Isoniazid.
• Any sulfonamide medications.

Patients with the following are excluded:

• History of clinically important disease other than HIV infection defined by the investigator as possibly putting the patient at risk during study participation.
• Conditions listed in Exclusion Co-Existing Conditions and symptoms.
• Having received any approved or investigational antiretroviral, immunosuppressive, or cytotoxic drugs or any other experimental drug with 4 weeks of study entry.
• A positive zidovudine (AZT) detection assay performed 7 days prior to drug dosing will exclude patients from study participation.

Prior Medication:

Excluded within 4 weeks of study entry:

• Any approved or investigational antiretroviral, immunosuppressive or cytotoxic drugs.
• Glucocorticoids and steroid hormones (including oral contraceptives).
• Dicumarol, warfarin, and other anticoagulant drugs.
• Nitroglycerin. Digitoxin.
• Valproic acid.
• Tolbutamide.
• Doxycycline.
• Chloramphenicol.
• Isoniazid.
• Antiepileptics (phenobarbital and other barbiturates).
• Trimethoprim / sulfamethoxazole (Bactrim).

Risk Behavior:

Excluded:

• Patients whose use of alcohol or drugs is sufficient to impair compliance with protocol requirements.