A Phase I Study of the Safety and Pharmacokinetics of Recombinant Human CD4-Immunoglobulin G (rCD4-IgG) Administered by Intravenous Bolus Injection in Combination With Oral Zidovudine in Patients With AIDS and AIDS-Related Complex

To determine the safety profile of recombinant human CD4-immunoglobulin G (CD4-IgG) and zidovudine (AZT) combination therapy in patients with AIDS or AIDS-related complex (ARC); to assess pharmacokinetic (blood level) properties of CD4-IgG in combination with AZT; and to obtain preliminary indication of the antiviral and immunologic effects of CD4-IgG in combination with AZT in patients with AIDS and ARC.

Treatment of AIDS has been directed toward the underlying retroviral infection as well as toward specific opportunistic infections and malignancies that are associated with the syndrome. The most extensively studied drugs are reverse transcriptase inhibitors such as AZT and other nucleoside analogs, including didanosine (ddI) and dideoxycytidine (ddC). The most extensive clinical experience has been achieved with AZT. These clinical trials indicated a decreased incidence of opportunistic infection and increased survival in patients with AIDS. However, AZT treatment is associated with dose-limiting toxicities. Additionally, identification of resistance to AZT has increased the need to test the effectiveness of AZT in combination with other drugs. CD4-IgG is capable of binding to HIV envelope protein (gp120) and inhibiting HIV infectivity in test tube studies. Potential therapeutic benefit in patients with HIV infection may be derived from CD4-IgG.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Zidovudine; Drug: CD4-IgG

Detailed Description

Treatment of AIDS has been directed toward the underlying retroviral infection as well as toward specific opportunistic infections and malignancies that are associated with the syndrome. The most extensively studied drugs are reverse transcriptase inhibitors such as AZT and other nucleoside analogs, including didanosine (ddI) and dideoxycytidine (ddC). The most extensive clinical experience has been achieved with AZT. These clinical trials indicated a decreased incidence of opportunistic infection and increased survival in patients with AIDS. However, AZT treatment is associated with dose-limiting toxicities. Additionally, identification of resistance to AZT has increased the need to test the effectiveness of AZT in combination with other drugs. CD4-IgG is capable of binding to HIV envelope protein (gp120) and inhibiting HIV infectivity in test tube studies. Potential therapeutic benefit in patients with HIV infection may be derived from CD4-IgG.

AMENDED: Previously, rCD4-IgG had been administered on a mcg/kg basis. Subjects now receive rCD4-IgG as a fixed dose. Changes to the maintenance schedule were made to accommodate the new dosages. Original design: This study is divided into two parts: A pharmacokinetic evaluation, and a safety evaluation. The pharmacokinetic evaluation is done in selected patients. For the safety evaluation patients will receive rCD4-IgG at a fixed dose level twice weekly by intravenous bolus injection (over 1 minute) for 12 weeks. Zidovudine (AZT) is administered orally 3 times daily at one of two dose levels. Eight subjects, at least 4 of whom with p24 levels greater than 75 pg/m, are entered at each dose level of CD4-IgG beginning with dose level 1. If 3 or more patients at a dose level experience grade 3 or 4 toxicity then no further patients will be added to that or higher dose levels. Pharmacokinetics of CD4-IgG alone and in combination with AZT is evaluated in patients at dose level 2 only. Patients receive one IV bolus of CD4-IgG on day 1 and samples are drawn beginning 15-30 minutes prior to the CD4-IgG injection. There is an 8 day washout period. Beginning on day 9 and continuing through day 24, patients receive AZT daily. CD4-IgG is administered by IV bolus on day 16. Samples are drawn beginning 15-30 minutes prior to the injection of CD4-IgG. The pharmacokinetic evaluation terminates 8 days after the second CD4-IgG injection (day 24). Extended treatment will be made available to patients at the discretion of the Principal Investigator.

• Study Type: Interventional
• Enrollment: 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 921036325
      • Univ of California / San Diego Treatment Ctr
  • Florida
    • Miami, Florida, United States, 331361013
      • Univ of Miami School of Medicine
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Univ of Massachusetts

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:

• Topical acyclovir.

Patients must have the following:

• HIV seropositivity.
• Life expectancy of at least 3 months.
• No white or red blood cell casts in urine.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

• Serious active opportunistic infection or malignancies other than Kaposi's sarcoma.
• Kaposi's sarcoma requiring therapy, tumor-associated edema, or visceral disease.

Concurrent Medication:

Excluded:

• Intravenous acyclovir for Herpes.
• Interferon.
• Systemic corticosteroids.
• Nonsteroidal anti-inflammatory agents.
• Intravenous acyclovir.
• Other known immunomodulatory agents.
• Dideoxycytosine (ddC), didanosine (ddI).
• Other nucleoside analogs not specifically allowed.
• Other experimental therapy.

Patients with the following are excluded:

• Serious active opportunistic infection or malignancies other than Kaposi's sarcoma.
• More than 120 days (total) of prior zidovudine (AZT) therapy.
• Currently receiving intravenous acyclovir for Herpes.

Prior Medication:

Excluded:

• > 120 days total of prior zidovudine (AZT) therapy.
• Excluded within 3 weeks of study entry:
• Immunomodulatory agents.
• Other experimental therapy.

Prior Treatment:

Excluded within the past 3 months:

• Transfusion.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Genentech, Inc.

Publications and helpful links

General Publications

• Meng TC, Fischl MA, Cheeseman SH, Spector SA, Resnick L, Boota A, Petrakis T, Wright B, Richman DD. Combination therapy with recombinant human soluble CD4-immunoglobulin G and zidovudine in patients with HIV infection: a phase I study. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Feb 1;8(2):152-60.

Study record dates

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 (Estimate): August 6, 2008
• Last Update Submitted That Met QC Criteria: August 5, 2008
• Last Verified: December 1, 1994

More Information

Terms related to this study

• Keywords: Acquired Immunodeficiency Syndrome; Drug Evaluation; Zidovudine; Recombinant Proteins; IgG; Administration, Oral; Injections, Intravenous; Antigens, CD4; Carrier Proteins
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; 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; AIDS-Related Complex; Physiological Effects of Drugs; 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; Immunologic Factors; Zidovudine; CD4 Immunoadhesins
• Other Study ID Numbers: ACTG 134; D0156g