Clinical trial NCT00000742: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Didanosine
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Antiviral Agents
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Upjohn
name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 15
Sex: MALE
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
Study officials:
name: Reichman R
role: STUDY_CHAIR
References:
citation: 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.
citation: 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)
citation: 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.
citation: 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)
citation: 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)