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A Phase I Concentration-Targeted Multidose Study of Atevirdine Mesylate ( U-87201E ), AZT, and ddI or ddC

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Atevirdine mesylate
Zidovudine
Zalcitabine
Didanosine
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring Zalcitabine, Didanosine, Drug Therapy, Combination, Acquired Immunodeficiency Syndrome, AIDS-Related Complex, Antiviral Agents, Zidovudine

Eligibility Criteria

13 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Concurrent Medication: Allowed: PCP prophylaxis with pentamidine, TMP/SMX, or dapsone (if appropriate). Clotrimazole troches or nystatin oral suspension for oral candidiasis. Acyclovir (up to 1000 mg/day) for herpes lesions. Supportive care as deemed necessary for toxicities . Patients must have: HIV infection. CD4 count <= 500 cells/mm3. No active opportunistic infections. Consent of parent, guardian, or person with power of attorney, if less than 18 years of age. NOTE: Participation of women in the study is encouraged. Exclusion Criteria Co-existing Condition: Patients with the following symptoms and conditions are excluded: Acute medical problems, including opportunistic infections (e.g., active cryptococcosis, Pneumocystis carinii, herpes zoster, histoplasmosis, and CMV) or nonopportunistic diseases (e.g., liver or renal disease or lymphoma). Current diagnosis of malignancy for which systemic therapy would be required during the study. Active gastrointestinal disorders. Concurrent Medication: Excluded: Investigational drugs. Systemic therapy for malignancy. Phenobarbital, phenytoin, ketoconazole, rifampin, rifabutin, cimetidine, beta blockers, chronic antacids, antiarrhythmic agents, or other medications known to affect cardiac conduction or seizure threshold. Patients with the following prior conditions are excluded: History of any cardiovascular disease, including conduction disturbances, arrhythmias or atherosclerotic heart disease. History of CNS disease such as seizure disorder, AIDS Dementia Complex, progressive multifocal leukoencephalopathy, or any other active neurological disorder. History of chronic gastrointestinal disorders such as chronic diarrhea (> 4 weeks duration). Prior Medication: Excluded: Antiretroviral or immunomodulator agents (such as AZT, ddI, ddC, interferon, etc.) within 15 days prior to study entry. Cytotoxic chemotherapy within 1 month prior to study entry. Prior U-87201E or other non-nucleoside reverse transcriptase inhibitors (i.e., nevirapine, TIBO, L697,661). Present use of alcohol or illicit drugs.

Sites / Locations

  • USC CRS
  • Univ. of Miami AIDS CRS
  • St. Louis ConnectCare, Infectious Diseases Clinic
  • Washington U CRS
  • Univ. of Rochester ACTG CRS
  • The Ohio State Univ. AIDS CRS

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
October 27, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Upjohn, Glaxo Wellcome
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1. Study Identification

Unique Protocol Identification Number
NCT00000753
Brief Title
A Phase I Concentration-Targeted Multidose Study of Atevirdine Mesylate ( U-87201E ), AZT, and ddI or ddC
Official Title
A Phase I Concentration-Targeted Multidose Study of Atevirdine Mesylate ( U-87201E ), AZT, and ddI or ddC
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
February 1995 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Upjohn, Glaxo Wellcome

4. Oversight

5. Study Description

Brief Summary
To determine the safety, toxicity, pharmacokinetic profile, and antiretroviral activity of atevirdine mesylate ( U-87201E ) in HIV-infected patients. Per 06/04/93 amendment, to also evaluate the interactive effects of didanosine ( ddI ) or zalcitabine ( dideoxycytidine; ddC ) with zidovudine ( AZT ) on the pharmacokinetics of U-87201E and to assess the effects of the triple combination therapies on immunologic and virologic parameters. Since the use of non-nucleoside reverse transcriptase inhibitors such as U-87201E has been associated with the rapid development of resistant HIV isolates, an initial evaluation of this drug in patients was made in combination with AZT. Because of the inability to detect resistance after 6 weeks of combined AZT/U-87201E therapy, this protocol will initially investigate U-87201E administered alone and then investigate the effect of this drug with AZT and ddI or ddC.
Detailed Description
Since the use of non-nucleoside reverse transcriptase inhibitors such as U-87201E has been associated with the rapid development of resistant HIV isolates, an initial evaluation of this drug in patients was made in combination with AZT. Because of the inability to detect resistance after 6 weeks of combined AZT/U-87201E therapy, this protocol will initially investigate U-87201E administered alone and then investigate the effect of this drug with AZT and ddI or ddC. Ten patients are treated at each of three targeted concentration ranges of U-87201E. Patients in the second cohort are enrolled immediately after patients in the first cohort are accrued; patients in the third cohort are enrolled when 5 of 10 patients in the second cohort have tolerated that dose for at least 4 weeks. The MTD will be the dose below that which produces dose-limiting grade 3 or 4 toxicity in five out of 10 patients. At least two women and five antiretroviral naive patients must be enrolled in each dose concentration range. Patients receive at least 8 weeks of monotherapy with U-87201E, with possible extension to at least 24 weeks with the same dose of U-87201E alone or in combination with zidovudine plus either ddI or ddC. Patients are followed weekly for at least 8 weeks and, if applicable, at weeks 10, 12, 16, 20, and 24 and monthly thereafter, up to 1 month following the last dose. Patients on combination therapy will have an indwelling venous catheter inserted for the first 2 days of combination therapy. Per 10/15/93 amendment, if no MTD is established with the first three cohorts, then 10 additional patients will be enrolled at a fourth concentration.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
Zalcitabine, Didanosine, Drug Therapy, Combination, Acquired Immunodeficiency Syndrome, AIDS-Related Complex, Antiviral Agents, Zidovudine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Masking
None (Open Label)
Enrollment
30 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Atevirdine mesylate
Intervention Type
Drug
Intervention Name(s)
Zidovudine
Intervention Type
Drug
Intervention Name(s)
Zalcitabine
Intervention Type
Drug
Intervention Name(s)
Didanosine

10. Eligibility

Sex
All
Minimum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Concurrent Medication: Allowed: PCP prophylaxis with pentamidine, TMP/SMX, or dapsone (if appropriate). Clotrimazole troches or nystatin oral suspension for oral candidiasis. Acyclovir (up to 1000 mg/day) for herpes lesions. Supportive care as deemed necessary for toxicities . Patients must have: HIV infection. CD4 count <= 500 cells/mm3. No active opportunistic infections. Consent of parent, guardian, or person with power of attorney, if less than 18 years of age. NOTE: Participation of women in the study is encouraged. Exclusion Criteria Co-existing Condition: Patients with the following symptoms and conditions are excluded: Acute medical problems, including opportunistic infections (e.g., active cryptococcosis, Pneumocystis carinii, herpes zoster, histoplasmosis, and CMV) or nonopportunistic diseases (e.g., liver or renal disease or lymphoma). Current diagnosis of malignancy for which systemic therapy would be required during the study. Active gastrointestinal disorders. Concurrent Medication: Excluded: Investigational drugs. Systemic therapy for malignancy. Phenobarbital, phenytoin, ketoconazole, rifampin, rifabutin, cimetidine, beta blockers, chronic antacids, antiarrhythmic agents, or other medications known to affect cardiac conduction or seizure threshold. Patients with the following prior conditions are excluded: History of any cardiovascular disease, including conduction disturbances, arrhythmias or atherosclerotic heart disease. History of CNS disease such as seizure disorder, AIDS Dementia Complex, progressive multifocal leukoencephalopathy, or any other active neurological disorder. History of chronic gastrointestinal disorders such as chronic diarrhea (> 4 weeks duration). Prior Medication: Excluded: Antiretroviral or immunomodulator agents (such as AZT, ddI, ddC, interferon, etc.) within 15 days prior to study entry. Cytotoxic chemotherapy within 1 month prior to study entry. Prior U-87201E or other non-nucleoside reverse transcriptase inhibitors (i.e., nevirapine, TIBO, L697,661). Present use of alcohol or illicit drugs.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Reichman R
Official's Role
Study Chair
Facility Information:
Facility Name
USC CRS
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Univ. of Miami AIDS CRS
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
St. Louis ConnectCare, Infectious Diseases Clinic
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63112
Country
United States
Facility Name
Washington U CRS
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Univ. of Rochester ACTG CRS
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
The Ohio State Univ. AIDS CRS
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
9768622
Citation
Demeter LM, Meehan PM, Morse G, Fischl MA, Para M, Powderly W, Leedom J, Holden-Wiltse J, Greisberger C, Wood K, Timpone J Jr, Wathen LK, Nevin T, Resnick L, Batts DH, Reichman RC. Phase I study of atevirdine mesylate (U-87201E) monotherapy in HIV-1-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Oct 1;19(2):135-44. doi: 10.1097/00042560-199810010-00006.
Results Reference
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PubMed Identifier
10774589
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.
Results Reference
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A Phase I Concentration-Targeted Multidose Study of Atevirdine Mesylate ( U-87201E ), AZT, and ddI or ddC

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