Clinical trial NCT00001074: The Safety and Effectiveness of Hydroxyurea and ddI Used Individually or Together in HIV-Infected Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infections
Keywords: Didanosine
Drug Therapy, Combination
Antiviral Agents
Hydroxyurea
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: Stanford
country: United States
facility: Stanford Univ Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Med Ctr
state: Ohio
city: Philadelphia
country: United States
facility: Univ of Pennsylvania at Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ Hosp
state: Pennsylvania
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
Study officials:
affiliation: Division of Infectious Diseases, University of Pennsylvania
name: Ian Frank, MD
role: STUDY_CHAIR
affiliation: University of North Carolina
name: Joseph Eron, MD
role: STUDY_CHAIR
References:
citation: 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)
citation: 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.