A Phase I Concentration-Controlled Trial to Assess the Safety, Tolerance, Pharmacokinetics and Development of Decreased HIV-1 Susceptibility to the Combination of Atevirdine Mesylate (U-87201E), Zidovudine (AZT), and Didanosine (ddI)

NCT00000742 | Completed Phase 1

• 2 other identifiers: ACTG 19911175
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 5

Brief Summary

Part I: To determine the pharmacokinetic dose for atevirdine mesylate ( U-87201E ) when used in combination with zidovudine ( AZT ). To determine the pharmacokinetic profiles of U-87201E and AZT over a 12-week period. Part II: To determine whether or not decreased viral susceptibility to U-87201E develops when the drug is administered concomitantly with AZT for 12 weeks. Part III: To evaluate the pharmacokinetic effects of ddI/AZT/U-87201E therapy and to assess changes in viral susceptibility to U-87201E. Interest exists in the development of antiretroviral agents that possess different mechanisms of action from nucleoside analogs such as AZT. U-87201E is a non-nucleoside reverse transcriptase (RT) inhibitor that has demonstrated activity against HIV-1; however, an emerging characteristic of non-nucleoside RT inhibitors is the development of rapid resistance to HIV isolates. Whether this resistance can be prevented in the presence of nucleoside analogs such as AZT and ddI has yet to be determined.

Conditions

HIV Infections

Keywords

Didanosine; Drug Therapy, Combination; Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Antiviral Agents; Zidovudine

Interventions

Atevirdine mesylate DRUG

Zidovudine DRUG

Didanosine DRUG

Eligibility Criteria

• Age: 13 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Concurrent Medication:
• Allowed:
• PCP prophylaxis with aerosolized pentamidine, trimethoprim / sulfamethoxazole or dapsone.
• Clotrimazole troches or nystatin oral suspension for oral candidiasis.
• Acyclovir (up to 1000 mg/day) for herpes lesions.
• Patients must have:
• HIV infection documented by serologic tests or HIV culture OR prior diagnosis of AIDS by established CDC criteria.
• CD4 counts = or \< 500 cells/mm3 on two evaluations.
• Part II only:
• No prior therapy with antiretroviral or immunomodulating agents (e.g., AZT, ddI, ddC, interferon).

You may not qualify if:

• Co-existing Condition:
• Patients with the following symptoms and conditions are excluded:
• Acute medical problems at time of study entry (including active opportunistic infections such as active cryptococcosis, Pneumocystis carinii, herpes zoster, histoplasmosis, or CMV, or nonopportunistic diseases including liver disease, renal disease, orthostatic hypotension, hypertension, lymphoma).
• Current diagnosis of malignancy for which systemic therapy would be required during the study.
• Concurrent Medication:
• Excluded:
• Any other investigational drugs.
• Phenobarbital, phenytoin, ketoconazole, rifampin, cimetidine, beta blockers, chronic anti-acid therapy, antiarrhythmic agents or other medications known to affect cardiac conduction or seizure threshold.
• Cytotoxic chemotherapy.
• Patients with the following prior conditions are excluded:
• History of cardiovascular disease including conduction disturbances, arrhythmias, atherosclerotic heart disease, or valvular heart disease.
• History of CNS disease such as seizure disorder, AIDS Dementia Complex, Progressive Multifocal Leukoencephalopathy, or any other active neurological disorder.
• History of active or chronic gastrointestinal disorders such as chronic diarrhea (\> 4 weeks duration), constipation, unexplained abdominal pain (such as irritable bowel syndrome), or other GI motility disorders.
• History of hypercholesterolemia requiring medication or serum cholesterol = or \> 300.
• Part I patients only:

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Upjohn: collaborator
• Glaxo Wellcome: collaborator

Study Sites (5)

USC CRS

Los Angeles, California, 90033, United States

Location

Univ. of Miami AIDS CRS

Miami, Florida, United States

Location

Washington U CRS

St Louis, Missouri, United States

Location

Univ. of Rochester ACTG CRS

Rochester, New York, 14642, United States

Location

The Ohio State Univ. AIDS CRS

Columbus, Ohio, United States

Location

Related Publications (5)

• Reichman RC, Morse GD, Demeter LM, Resnick L, Bassiakos Y, Fischl M, Para M, Powderly W, Leedom J, Greisberger C, et al. Phase I study of atevirdine, a nonnucleoside reverse transcriptase inhibitor, in combination with zidovudine for human immunodeficiency virus type 1 infection. ACTG 199 Study Team. J Infect Dis. 1995 Feb;171(2):297-304. doi: 10.1093/infdis/171.2.297.

  PMID: 7531207 BACKGROUND

• Morse G, Fischl M, Leedom J, Batts D, Cox S, Reichman R. Atevirdine (ATV) pharmacokinetics (PK) and dosage requirements during a concentration-targeted (CT) phase I study (ACTG 199). Int Conf AIDS. 1993 Jun 6-11;9(1):477 (abstract no PO-B26-2050)

  BACKGROUND

• Morse GD, Reichman RC, Fischl MA, Para M, Leedom J, Powderly W, Demeter LM, Resnick L, Bassiakos Y, Timpone J, Cox S, Batts D. Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies. The ACTG 187 and 199 study teams. Antiviral Res. 2000 Jan;45(1):47-58. doi: 10.1016/s0166-3542(99)00073-x.

  PMID: 10774589 BACKGROUND

• Reichman R, Fischl M, Para M, Powderly W, Timpone J, Bassiakos Y. Phase I study of atevirdine (ATV), a non-nucleoside reverse transcriptase inhibitor, given in combination with zidovudine (ZDV). The ACTG 199 Team. Int Conf AIDS. 1993 Jun 6-11;9(1):478 (abstract no PO-B26-2055)

  BACKGROUND

• Demeter LM, Resnick L, Tarpley WG, Fischl M, Para M, Reichman RC. Prolonged sensitivity of HIV-1 isolates to atevirdine (ATV) in a phase 1 clinical trial of ATV and zidovudine (ZDV) (ACTG 199). The ACTG 199 Study Team. Int Conf AIDS. 1993 Jun 6-11;9(1):242 (abstract no PO-A26-0643)

  BACKGROUND

MeSH Terms

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome; AIDS-Related Complex

Interventions

atevirdine; Zidovudine; Didanosine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Inosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Ribonucleosides

Study Officials

• Reichman R

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 1999
• First Posted: August 31, 2001
• Study Completion: October 1, 1993
• Last Updated: November 4, 2021

Record last verified: 2021-10

Locations

US (5)