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A Study of Valacyclovir Hydrochloride in the Prevention of Life-Threatening Cytomegalovirus Disease in HIV-Infected Patients

This study has been completed.
Sponsor:
Collaborator:
Glaxo Wellcome
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00001038
First received: November 2, 1999
Last updated: February 28, 2011
Last verified: February 2011
  Purpose

PRIMARY: To evaluate the efficacy of valacyclovir hydrochloride (BW 256U87) in the prevention of cytomegalovirus (CMV) end-organ disease in HIV/CMV co-infected patients with CD4+ lymphocytes < 100 cells/mm3. To assess the impact of BW 256U87, high-dose oral acyclovir and low-dose oral acyclovir on survival.

SECONDARY: To evaluate the effect of BW 256U87 on quality of life, the safety of the drug administered concurrently with standard antiretroviral agents and other essential therapies for the treatment and prevention of opportunistic diseases, and the efficacy of BW 256U87 in suppressing activation of other herpesviruses. To evaluate serologic and virologic risk factors for the development of CMV disease, including assessment of HIV activation, and the risk of developing drug-resistant CMV, HSV, and VZV.

Gastrointestinal absorption of acyclovir is not high enough to prevent CMV disease in patients with advanced HIV disease, although there is evidence that high doses of the drug may extend survival. Valacyclovir, a prodrug that is rapidly converted to acyclovir after oral administration, has a higher absorption rate and may therefore provide inhibitory activity against CMV.


Condition Intervention Phase
Cytomegalovirus Infections
HIV Infections
Drug: Valacyclovir hydrochloride
Drug: Acyclovir
Phase 3

Study Type: Interventional
Study Design: Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind Trial of Valacyclovir Hydrochloride (BW 256U87) Prophylaxis for Opportunistic Cytomegalovirus End-Organ Disease in Patients With Advanced HIV Infection (< 100 CD4+ Lymphocytes)

Resource links provided by NLM:


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

Estimated Enrollment: 1200
Primary Completion Date: May 1996 (Final data collection date for primary outcome measure)
Detailed Description:

Gastrointestinal absorption of acyclovir is not high enough to prevent CMV disease in patients with advanced HIV disease, although there is evidence that high doses of the drug may extend survival. Valacyclovir, a prodrug that is rapidly converted to acyclovir after oral administration, has a higher absorption rate and may therefore provide inhibitory activity against CMV.

Patients are randomized to receive BW 256U87 alone or acyclovir alone as control at either high-dose or low-dose. The acyclovir controls will provide suppressive therapy for herpes simplex infections and may affect survival.

  Eligibility

Ages Eligible for Study:   13 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Concurrent Medication:

Recommended:

  • PCP prophylaxis.

Allowed:

  • Any antiretroviral therapies available by prescription or through expanded access or Treatment IND programs, including combination or sequential use.
  • Chemotherapy for Kaposi's sarcoma, lymphoma, or other malignancies IF patient is hematologically stable for at least 30 days prior to study entry.
  • Discrete courses of oral or parenteral acyclovir for VZV or HSV infection, not to exceed 21 days per episode (may co-enroll on ACTG 169). For recurrent episodes, open-label acyclovir for a total of 60 days over a 12-month period is allowed. Study drug is interrupted.
  • Supportive therapies available by prescription, expanded access, or Treatment IND programs, such as G-CSF, GM-CSF, and erythropoietin.
  • Other medications necessary for the patient's welfare, at the discretion of the investigator.

Patients must have:

  • HIV infection or AIDS-defining conditions.
  • CD4+ count < 100 cells/mm3.
  • IgG antibodies to CMV.
  • No active CMV disease or history of CMV end-organ disease.
  • Consent of parent or guardian if less than 18 years of age.
  • Ability to comply with protocol.

NOTE:

  • Patients may be co-enrolled in ACTG primary infection Phase II/III studies, ACTG opportunistic infection protocols, or treatment protocols or similar studies sponsored by other research networks as long as those studies do not violate the restrictions placed on concomitant therapies and toxicity management.

Prior Medication:

Allowed:

  • PCP prophylaxis.
  • Any antiretroviral therapies available by prescription or through expanded access or Treatment IND programs, including combination or sequential use.
  • Chemotherapy for Kaposi's sarcoma, lymphoma, or other malignancies.
  • Acyclovir.
  • Supportive therapies available by prescription, expanded access, or Treatment IND programs, such as G-CSF, GM-CSF, and erythropoietin.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

  • Nausea or vomiting that precludes oral dosing.
  • Ocular media opacities that preclude adequate visualization of fundi.
  • Pregnancy.
  • Known hypersensitivity to acyclovir.
  • Known lactose intolerance.

Concurrent Medication:

Excluded:

  • Systemic interferons and immunomodulators (including CMV hyperimmune serum/globulin and chronic corticosteroids at doses in excess of physiologic replacement).
  • Probenecid.
  • Investigational or marketed agents with potential activity against CMV, herpes simplex, and/or Varicella zoster, EXCEPT as specifically allowed.

Patients with the following prior condition are excluded:

  • Pre-existing necrotizing retinopathy that may interfere with a subsequent diagnosis of CMV retinitis.

Prior Medication:

Excluded:

  • Prior ganciclovir, foscarnet, or any investigational anti-CMV agent including use of foscarnet for acyclovir-resistant herpes.
  • Interferons, immunomodulators (other than colony stimulating factors), or CMV hyperimmune globulin within 30 days prior to study entry.
  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: NCT00001038

  Show 35 Study Locations
Sponsors and Collaborators
Glaxo Wellcome
Investigators
Study Chair: Feinberg J
  More Information

Publications:
Fry J, Coakley D, Power M, Feinberg J. International collaborative clinical trials: the ACTG 204 experience. Int Conf AIDS. 1996 Jul 7-12;11(2):276 (abstract no ThB4146)
Griffiths PD, Feinberg J. Detection of cytomegalovirus in samples from patients enrolled in ACTG 204 / Glaxo Wellcome 123-014. Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:54
Brosgart C, Fisher E, Pulling C, Chaloner K, Cohn D, Elsadr W, Verheggen R, Schmetter B, Alston B. Prevalence of asymptomatic CMV retinitis (CMVR) in AIDS patients. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:152 (abstract no 453)
Fisher E, Brosgart C, Cohn D, Chaloner K, Pulling C, Alston B, Schmetter B, El-Sadr W. Placebo (PLC)-controlled, multicenter trial of adefovir dipivoxil (ADV) in patients (pt) with HIV disease. . Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:160 (abstract no 491)
Feinberg JE, Bell WR, Chulay JD. A thrombotic microangiopathy (TMA)-like syndrome in patients with advanced HIV disease in a cytomegalovirus (CMV) prophylaxis trial (ACTG 204). Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:196 (abstract no 715)
Sprenger HG, Law G, Pastoor G, Postma S, Schirm J, Weits J, The TH. Cytomegalovirus antigenemia (CMVAg) compared with other CMV tests during phase III study of valaciclovir (VACV) for CMV prophylaxis in advanced HIV disease (ACTG 204 study). Int Conf AIDS. 1996 Jul 7-12;11(2):285 (abstract no ThB4200)
Emery V, Sabin C, Feinberg J, Grywacz M, Knight S, Griffiths P. Quantitative effects of valaciclovir on the replication of cytomegalovirus in patients with advanced HIV disease. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:153 (abstract no 459)
Weinberg A, Schneider SA, Clark JC. Acyclovir (ACV) and valacyclovir (VAL) prophylaxis of AIDS patients does not alter cytomegalovirus (CMV) susceptibility to ganciclovir (GCV) or foscarnet (FOS). Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18:202 (abstract no I87)

ClinicalTrials.gov Identifier: NCT00001038     History of Changes
Other Study ID Numbers: ACTG 204, FDA 104C
Study First Received: November 2, 1999
Last Updated: February 28, 2011
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Cytomegalovirus Infections
Acquired Immunodeficiency Syndrome
Antiviral Agents

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
Communicable Diseases
Cytomegalovirus Infections
HIV Infections
Infection
DNA Virus Infections
Herpesviridae Infections
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
RNA Virus Infections
Retroviridae Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Virus Diseases
Acyclovir
Valacyclovir
Anti-Infective Agents
Antiviral Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014