Full Text View  
  Tabular View  
  Contacts and Locations  
  No Study Results Posted  
  Related Studies  
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)
This study has been completed.
Sponsors and Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
Upjohn
Glaxo Wellcome
Information provided by: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00000742
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: Atevirdine mesylate
Drug: Zidovudine
Drug: Didanosine
Phase I

MedlinePlus related topics: AIDS
Drug Information available for: Zidovudine Didanosine Atevirdine Atevirdine mesylate
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Safety Study
Official Title: 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)

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Estimated Enrollment: 15
Detailed Description:

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.

Part I: Five male patients enter a pharmacokinetic concentration-controlled trial of U-87201E plus zidovudine at the University of Rochester site only. A target plasma concentration range at trough for U-87201E will be determined. Pharmacokinetic monitoring continues for 7 days or until the desired dose regimen has been determined. The five patients may be eligible to continue in Part II of the study to complete a total of 12 weeks of therapy.

Part II: At least 10 male patients (all sites eligible) in addition to the five patients from Part I receive doses of U-87201E as determined by Part I and AZT at the same dose as in Part I. Therapy is administered for 12 weeks. Patients with no decreased viral susceptibility to U-87201E after 6 weeks may be offered an extension to 24 or more weeks of therapy. Patients are followed weekly for 8 weeks and every other week thereafter until the end of the study.

Part III: At least eight patients who have received 24 weeks of U-87201E/AZT have ddI added to the regimen for 12 additional weeks.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

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).

Exclusion Criteria

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:

  • History of inability to tolerate zidovudine (200 mg q 8 hours).

Part III patients only:

  • History of pancreatitis or > grade 2 peripheral neuropathy.

Prior Medication:

Excluded:

  • Cytotoxic chemotherapy within 1 month prior to study entry.

Part II only:

  • prior therapy with antiretroviral or immunomodulatory agents (including but not limited to AZT, ddI, ddC, and interferon).

Current use of alcohol or illicit drugs.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00000742

Locations
United States, California
Univ of Southern California / LA County USC Med Ctr
Los Angeles, California, United States, 900331079
United States, New York
Univ of Rochester Medical Center
Rochester, New York, United States, 14642
United States, South Carolina
Julio Arroyo
West Columbia, South Carolina, United States, 29169
Sponsors and Collaborators
Upjohn
Glaxo Wellcome
Investigators
Study Chair: Reichman R
  More Information

Click here for more information about Zidovudine  This link exits the ClinicalTrials.gov site
Click here for more information about Didanosine  This link exits the ClinicalTrials.gov site

Publications:
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.
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)
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.
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)
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)

Study ID Numbers: ACTG 199
Study First Received: November 2, 1999
Last Updated: July 29, 2008
ClinicalTrials.gov Identifier: NCT00000742  
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Didanosine
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Antiviral Agents
Zidovudine

Study placed in the following topic categories:
Virus Diseases
Sexually Transmitted Diseases, Viral
Didanosine
Disease Susceptibility
HIV Infections
Sexually Transmitted Diseases
Acquired Immunodeficiency Syndrome
Zidovudine
AIDS-Related Complex
Genetic Predisposition to Disease
Retroviridae Infections
Immunologic Deficiency Syndromes

Additional relevant MeSH terms:
Antimetabolites
Anti-Infective Agents
RNA Virus Infections
Disease Attributes
Anti-HIV Agents
Slow Virus Diseases
Immune System Diseases
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Infection
Antiviral Agents
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Pathologic Processes
Anti-Retroviral Agents
Therapeutic Uses
Lentivirus Infections
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on January 15, 2009