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

NCT ID: NCT00001038

Last Updated: 2011-03-01

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

1200 participants

Study Classification

INTERVENTIONAL

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Cytomegalovirus Infections HIV Infections

Study Design

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Primary Study Purpose

TREATMENT

Interventions

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Valacyclovir hydrochloride

Intervention Type DRUG

Acyclovir

Intervention Type DRUG

Eligibility Criteria

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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.
Minimum Eligible Age

13 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Glaxo Wellcome

INDUSTRY

Sponsor Role collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role lead

Principal Investigators

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Feinberg J

Role: STUDY_CHAIR

Locations

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Birmingham Veterans Administration Med Ctr

Birmingham, Alabama, United States

Site Status

Los Angeles County - USC Med Ctr

Los Angeles, California, United States

Site Status

CARE Ctr / UCLA Med Ctr

Los Angeles, California, United States

Site Status

Highland Gen Hosp / San Francisco Gen Hosp

Oakland, California, United States

Site Status

Univ of California / San Diego Treatment Ctr

San Diego, California, United States

Site Status

Kaiser Permanente Med Ctr

San Francisco, California, United States

Site Status

Univ of Colorado Health Sciences Ctr

Denver, Colorado, United States

Site Status

Yale Univ

New Haven, Connecticut, United States

Site Status

Northwestern Univ Med School

Chicago, Illinois, United States

Site Status

Indiana Univ Hosp

Indianapolis, Indiana, United States

Site Status

Johns Hopkins Hosp

Baltimore, Maryland, United States

Site Status

Harvard (Massachusetts Gen Hosp)

Boston, Massachusetts, United States

Site Status

Boston Med Ctr

Boston, Massachusetts, United States

Site Status

Washington Univ

St Louis, Missouri, United States

Site Status

Mount Sinai Med Ctr

New York, New York, United States

Site Status

North Central Bronx Hosp / Bronx Municipal Hosp

The Bronx, New York, United States

Site Status

Univ of North Carolina School of Medicine

Chapel Hill, North Carolina, United States

Site Status

Ohio State Univ Hosp Clinic

Columbus, Ohio, United States

Site Status

Girard Med Ctr

Philadelphia, Pennsylvania, United States

Site Status

Univ TX Galveston Med Branch

Galveston, Texas, United States

Site Status

Univ of Washington / Madison Clinic

Seattle, Washington, United States

Site Status

Saint Vincent's Hosp Med Centre

Sydney, , Australia

Site Status

Southern Alberta HIV Clinic / Foothills Hosp

Calgary, Alberta, Canada

Site Status

Sunnybrook Health Science Ctr

Toronto, Ontario, Canada

Site Status

Toronto Hosp

Toronto, Ontario, Canada

Site Status

Montreal Chest Institute

Montreal, Quebec, Canada

Site Status

Montreal Gen Hosp

Montreal, Quebec, Canada

Site Status

Hvidovre Univ Hosp

Hvidore, , Denmark

Site Status

Services des Maladies Infectieuses

Paris, , France

Site Status

Universitatsklinikum Rudolf Virchow

Berlin, , Germany

Site Status

Universita Cattolica del Sacro Cuore

Rome, , Italy

Site Status

South Hosp

Stockholm, , Sweden

Site Status

Medizinische Universibatspoliklinik Infekbiologie

Bern, , Switzerland

Site Status

Royal Free Hosp

London, , United Kingdom

Site Status

Westminster Hosp

London, , United Kingdom

Site Status

Countries

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United States Australia Canada Denmark France Germany Italy Sweden Switzerland United Kingdom

References

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Feinberg JE, Hurwitz S, Cooper D, Sattler FR, MacGregor RR, Powderly W, Holland GN, Griffiths PD, Pollard RB, Youle M, Gill MJ, Holland FJ, Power ME, Owens S, Coakley D, Fry J, Jacobson MA. A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group. J Infect Dis. 1998 Jan;177(1):48-56. doi: 10.1086/513804.

Reference Type BACKGROUND
PMID: 9419169 (View on PubMed)

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)

Reference Type BACKGROUND

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

Reference Type BACKGROUND

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)

Reference Type BACKGROUND

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)

Reference Type BACKGROUND

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)

Reference Type BACKGROUND

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)

Reference Type BACKGROUND

Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore). 1997 Sep;76(5):369-80. doi: 10.1097/00005792-199709000-00004. No abstract available.

Reference Type BACKGROUND
PMID: 9352739 (View on PubMed)

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)

Reference Type BACKGROUND

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)

Reference Type BACKGROUND

Nokta MA, Holland F, De Gruttola V, Emery VC, Jacobson MA, Griffiths P, Pollard RB, Feinberg JE; AIDS Clinical Trials Group, Protocol 204/GlaxoWellcome 123-014, International CMV Prophylaxis Study Group. Cytomegalovirus (CMV) polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to CMV disease. J Infect Dis. 2002 Jun 15;185(12):1717-22. doi: 10.1086/340651. Epub 2002 May 31.

Reference Type BACKGROUND
PMID: 12085316 (View on PubMed)

Other Identifiers

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FDA 104C

Identifier Type: -

Identifier Source: secondary_id

ACTG 204

Identifier Type: -

Identifier Source: org_study_id

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