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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00001074
First received: November 2, 1999
Last updated: July 26, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
HIV Infections
Drug: Hydroxyurea
Drug: Didanosine
Phase 1

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


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

Estimated Enrollment: 140
Study Completion Date: January 2000
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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001074

Locations
United States, California
Univ of California / San Diego Treatment Ctr
San Diego, California, United States, 921036325
Stanford at Kaiser / Kaiser Permanente Med Ctr
San Francisco, California, United States, 94115
Stanford Univ Med Ctr
Stanford, California, United States, 943055107
Harbor UCLA Med Ctr
Torrance, California, United States, 90502
United States, Colorado
Univ of Colorado Health Sciences Ctr
Denver, Colorado, United States, 80262
United States, Maryland
Johns Hopkins Hosp
Baltimore, Maryland, United States, 21287
United States, New York
Bellevue Hosp / New York Univ Med Ctr
New York, New York, United States, 10016
Mount Sinai Med Ctr
New York, New York, United States, 10029
Beth Israel Med Ctr
New York, New York, United States, 10003
United States, North Carolina
Univ of North Carolina
Chapel Hill, North Carolina, United States, 275997215
Duke Univ Med Ctr
Durham, North Carolina, United States, 27710
United States, Ohio
Univ of Cincinnati
Cincinnati, Ohio, United States, 452670405
Case Western Reserve Univ
Cleveland, Ohio, United States, 44106
MetroHealth Med Ctr
Cleveland, Ohio, United States, 441091998
United States, Pennsylvania
Univ of Pennsylvania at Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Thomas Jefferson Univ Hosp
Philadelphia, Pennsylvania, United States, 191075098
United States, South Carolina
Julio Arroyo
West Columbia, South Carolina, United States, 29169
United States, Washington
Univ of Washington
Seattle, Washington, United States, 981224304
Sponsors and Collaborators
Investigators
Study Chair: Ian Frank, MD Division of Infectious Diseases, University of Pennsylvania
Study Chair: Joseph Eron, MD University of North Carolina
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00001074     History of Changes
Other Study ID Numbers: ACTG 307, 11282
Study First Received: November 2, 1999
Last Updated: July 26, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Didanosine
Drug Therapy, Combination
Antiviral Agents
Hydroxyurea

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Didanosine
Hydroxyurea
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents
Antineoplastic Agents
Antisickling Agents
Hematologic Agents

ClinicalTrials.gov processed this record on August 19, 2014