The Safety and Effectiveness of Hydroxyurea and ddI Used Individually or Together in HIV-Infected Patients

A Phase I/II Dosing Study of the Safety and Antiretroviral Activity of Hydroxyurea Alone and in Combination With ddI Compared With ddI Alone in Subjects With HIV Infection

To determine the safety and tolerability of hydroxyurea at two doses alone and in combination with didanosine (ddI). To compare the short term antiviral effect of ddI monotherapy versus hydroxyurea plus ddI, as measured by plasma RNA levels at 8 weeks of therapy. [AS PER AMENDMENT 10/1/97: Accrual to arms involving hydroxyurea alone has been closed.] Current antiviral therapies for HIV-1 are limited by a few choices, and the lack of sustained clinical benefit from the drugs. The mechanisms that account for the lack of prolonged inhibition of viral replication by these agents are not fully understood. The activity of RT inhibitors might be potentiated by inhibiting host cellular enzymes essential for efficient HIV reverse transcription. Based on this information, comparisons of the antiviral effects of ddI monotherapy and hydroxyurea plus ddI, with the cellular enzyme ribonucleotide reductase as a potential target, should be done.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Didanosine; Drug: Hydroxyurea

Detailed Description

Current antiviral therapies for HIV-1 are limited by a few choices, and the lack of sustained clinical benefit from the drugs. The mechanisms that account for the lack of prolonged inhibition of viral replication by these agents are not fully understood. The activity of RT inhibitors might be potentiated by inhibiting host cellular enzymes essential for efficient HIV reverse transcription. Based on this information, comparisons of the antiviral effects of ddI monotherapy and hydroxyurea plus ddI, with the cellular enzyme ribonucleotide reductase as a potential target, should be done.

This is a 24-week study, with two 12-week treatment periods. Patients are randomized to one of five treatment arms based upon a patient's history of antiretroviral therapy (naive vs. experienced). The five treatment arms are:

1. ddI plus hydroxyurea placebo.
2. hydroxyurea (lower dose) plus ddI placebo for 4 weeks; then hydroxyurea (higher dose) plus ddI.
3. hydroxyurea (higher dose) plus ddI placebo for 4 weeks; then hydroxyurea (higher dose) plus ddI.
4. hydroxyurea (lower dose) plus ddI.
5. hydroxyurea (higher dose) plus ddI. After the completion of week 12, patients on combination therapy remain on their current therapy and patients on ddI plus placebo have hydroxyurea replace the placebo at 1 of 2 assigned doses (1:1 randomization). AS PER AMENDMENT 5/5/97: If after the 24-week treatment period, a patient has an RNA level less than or equal to 5,000 copies/ml or less than 20,000 copies/ml with a greater than 1 log10 decline from baseline, she has the option to continue therapy open-label ddI plus hydroxyurea for an additional 24 weeks.

AS PER AMENDMENT 10/1/97: Accrual to the arms involving hydroxyurea alone has been closed. Patients are randomized to one of the three treatment arms, as follows:

1. hydroxyurea placebo plus ddI.
2. hydroxyurea (lower dose) plus ddI.
3. hydroxyurea (higher dose) plus ddI.

• Study Type: Interventional
• Enrollment: 140
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 921036325
      • Univ of California / San Diego Treatment Ctr
    • San Francisco, California, United States, 94115
      • Stanford at Kaiser / Kaiser Permanente Med Ctr
    • Stanford, California, United States, 943055107
      • Stanford Univ Med Ctr
    • Torrance, California, United States, 90502
      • Harbor UCLA Med Ctr
  • Colorado
    • Denver, Colorado, United States, 80262
      • Univ of Colorado Health Sciences Ctr
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hosp
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Med Ctr
    • New York, New York, United States, 10016
      • Bellevue Hosp / New York Univ Med Ctr
    • New York, New York, United States, 10029
      • Mount Sinai Med Ctr
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Univ of North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Univ Med Ctr
  • Ohio
    • Cincinnati, Ohio, United States, 452670405
      • Univ of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve Univ
    • Cleveland, Ohio, United States, 441091998
      • MetroHealth Med Ctr
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univ of Pennsylvania at Philadelphia
    • Philadelphia, Pennsylvania, United States, 191075098
      • Thomas Jefferson Univ Hosp
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Julio Arroyo
  • Washington
    • Seattle, Washington, United States, 981224304
      • Univ of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

AS PER AMENDMENT 5/5/97:

• PCP prophylaxis with trimethoprim/sulfamethoxazole or Dapsone.

Patients must have:

• HIV-1 infection.
• AS PER AMENDMENT 5/5/97:
• CD4 count of 200 - 700 cells/mm3 within 60 days prior to study entry.
• AS PER AMENDMENT 10/1/97:
• HIV RNA plasma level < 20,000 copies/ml within 60 days of enrollment (obtained at a laboratory certified to perform the Roche Monitor assay).

Exclusion Criteria

Co-existing Condition:

Patients with any of the following symptoms or conditions are excluded:

• CMV, MAC, toxoplasmosis, or disseminated fungal infection requiring acute or chronic therapy.
• Significant medical illness as determined by investigator.
• Active diagnosis of any malignancy, including visceral Kaposi's sarcoma or extensive cutaneous Kaposi's sarcoma for which systemic chemotherapy is anticipated within the next 24 weeks.
• Current Grade 2 or greater peripheral neuropathy.

Concurrent Medication:

Excluded:

• Acute or chronic therapy for CMV, MAC, toxoplasmosis, or disseminated fungal infection.

AS PER AMENDMENT 5/5/97:

• All antiretroviral medications other than those provided on study.
• Systemic chemotherapy for active malignancies, including systemic treatment for KS.
• Agents with myelosuppressive potential, including tegretol, carboplatin, carmustine, cyclophosphamide and fluorouracil.
• Granulocyte colony stimulating factor (G-CSF) except while hydroxyurea or matching placebo is held.

Drugs associated with peripheral neuropathy, including:

• hydralazine, disulfiram, nitrofurantoin, cisplatinum, diethyldithiocarbamate, gold, rifampin, chloramphenicol, clioquinol, ethambutol, ethionamide, glutethimide, sodium cyanate, and thalidomide.

Patients with any of the prior conditions are excluded:

• History of transfusion dependent anemia, defined as any history of repeated transfusion with two or more units of red blood cells.
• At the discretion of the investigator, history of pancreatitis.

Prior Medication:

Excluded:

• More than 2 weeks prior treatment with ddI.

AS PER AMENDMENT 5/5/97:

• Other antiretrovirals must be discontinued at least 14 days prior to randomization.
• Prior hydroxyurea.
• Any candidate HIV vaccine or agent with potential immune modulating effects within the past 30 days.
• Any colony stimulating factor or erythropoietin within the past 60 days.

Prior Treatment:

Excluded:

• Transfusion with red blood cells within the past 60 days.

Risk Behavior:

Excluded:

• At the investigator's discretion, any active substance abuse, including alcohol abuse interfering with compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Ian Frank, MD, Division of Infectious Diseases, University of Pennsylvania; Study Chair: Joseph Eron, MD, University of North Carolina

Publications and helpful links

General Publications

• Frank I, Boucher H, Fiscus S, Flexner C, Valentine F, Gulick R, Fox L, Eron J. Phase I/II dosing study of once-daily hydroxyurea (HU) alone vs didanosine (ddI) alone vs ddI + HU. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:143 (abstract no 402)
• Frank I, Bosch RJ, Fiscus S, Valentine F, Flexner C, Segal Y, Ruan P, Gulick R, Wood K, Estep S, Fox L, Nevin T, Stevens M, Eron JJ Jr; ACTG 307 Protocol Team. Activity, safety, and immunological effects of hydroxyurea added to didanosine in antiretroviral-naive and experienced HIV type 1-infected subjects: a randomized, placebo-controlled trial, ACTG 307. AIDS Res Hum Retroviruses. 2004 Sep;20(9):916-26. doi: 10.1089/aid.2004.20.916.

Study record dates

Study Major Dates

• Study Completion (Actual): January 1, 2000

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Antiviral Agents; Hydroxyurea; Didanosine
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Infections; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Antineoplastic Agents; Antisickling Agents; Hydroxyurea; Didanosine
• Other Study ID Numbers: ACTG 307; 11282 (Registry Identifier: DAIDS ES)