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

• Status: Completed
• Trial end date: 1969-12-31
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Boehringer Ingelheim
• Treatments: Nevirapine

Criteria

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.