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

NCT ID: NCT00001074

Last Updated: 2021-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Completion Date: 2000-01-31

Brief Summary

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.

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.

Conditions

HIV Infections

Keywords

Didanosine; Drug Therapy, Combination; Antiviral Agents; Hydroxyurea

Study Design

• Primary Study Purpose: TREATMENT

Interventions

Hydroxyurea

Intervention Type: DRUG

Didanosine

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ian Frank, MD

Role: STUDY_CHAIR

Division of Infectious Diseases, University of Pennsylvania

Joseph Eron, MD

Role: STUDY_CHAIR

University of North Carolina

Locations

Univ of California / San Diego Treatment Ctr

San Diego, California, United States

Stanford at Kaiser / Kaiser Permanente Med Ctr

San Francisco, California, United States

Stanford Univ Med Ctr

Stanford, California, United States

Harbor UCLA Med Ctr

Torrance, California, United States

Univ of Colorado Health Sciences Ctr

Denver, Colorado, United States

Johns Hopkins Hosp

Baltimore, Maryland, United States

Beth Israel Med Ctr

New York, New York, United States

Bellevue Hosp / New York Univ Med Ctr

New York, New York, United States

Mount Sinai Med Ctr

New York, New York, United States

Univ of North Carolina

Chapel Hill, North Carolina, United States

Duke Univ Med Ctr

Durham, North Carolina, United States

Univ of Cincinnati

Cincinnati, Ohio, United States

Case Western Reserve Univ

Cleveland, Ohio, United States

MetroHealth Med Ctr

Cleveland, Ohio, United States

Univ of Pennsylvania at Philadelphia

Philadelphia, Pennsylvania, United States

Thomas Jefferson Univ Hosp

Philadelphia, Pennsylvania, United States

Julio Arroyo

West Columbia, South Carolina, United States

Univ of Washington

Seattle, Washington, United States

Countries

United States

References

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)

Reference Type: RESULT

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.

Reference Type: RESULT

PMID: 15597521 (View on PubMed)

Other Identifiers

11282

Identifier Type: REGISTRY

Identifier Source: secondary_id

ACTG 307

Identifier Type: -

Identifier Source: org_study_id