Clinical trial NCT00000970: A Study of Foscarnet Plus Ganciclovir in the Treatment of Cytomegalovirus of the Eye in Patients With AIDS Who Have Already Been Treated With Ganciclovir
Official title: A Phase I Open-Labeled Study of Long Term Combined or Alternating Foscarnet/Ganciclovir Maintenance Therapy for AIDS Patients With CMV Retinitis After Ganciclovir Induction Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cytomegalovirus Retinitis
HIV Infections
Keywords: Retinitis
AIDS-Related Opportunistic Infections
Ganciclovir
Drug Evaluation
Drug Therapy, Combination
Foscarnet
Cytomegalovirus Infections
Acquired Immunodeficiency Syndrome
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Astra USA
name: Hoffmann-La Roche
First posted: 2001-08-31
Enrollment: 30
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To examine the safety and tolerance of the administration of ganciclovir and foscarnet given together or alternately; to determine the interactive pharmacokinetics (blood level) profile of long-term combined and alternating therapy with these two drugs. Additional objectives are to examine the effect of these treatments in controlling time to cytomegalovirus (CMV) retinitis progression and to examine the antiviral activity of combined and alternating ganciclovir/foscarnet treatment and development of antiviral resistance. Sight-threatening CMV retinitis occurs in at least 6 percent of AIDS patients. By 1991 (US), there may be 6000 to 10000 patients with CMV retinitis. Many clinical reports suggest that both ganciclovir (DHPG) and foscarnet have an antiviral effect against CMV that is often associated with clinical stabilization. Effectiveness of ganciclovir and foscarnet is correlated with weekly maintenance and since toxicity is dose-limiting in up to 20 percent of patients receiving either drug for long periods, it may be beneficial in long-term maintenance treatment to combine or alternate these two drugs at a lower total weekly dose of each drug.

This strategy may result in a greater net antiviral effect with less toxicity than is seen with either drug alone, because the toxicities of each drug are quite different.

Detailed description: Sight-threatening CMV retinitis occurs in at least 6 percent of AIDS patients. By 1991 (US), there may be 6000 to 10000 patients with CMV retinitis. Many clinical reports suggest that both ganciclovir (DHPG) and foscarnet have an antiviral effect against CMV that is often associated with clinical stabilization. Effectiveness of ganciclovir and foscarnet is correlated with weekly maintenance and since toxicity is dose-limiting in up to 20 percent of patients receiving either drug for long periods, it may be beneficial in long-term maintenance treatment to combine or alternate these two drugs at a lower total weekly dose of each drug.

This strategy may result in a greater net antiviral effect with less toxicity than is seen with either drug alone, because the toxicities of each drug are quite different.

All patients have newly diagnosed CMV retinitis and have completed a 14-day course of intravenous ganciclovir or foscarnet induction therapy within 1 week prior to study entry. The maintenance period consists of a 12-week study period followed by a 40 week follow-up period. Treatment consists of either combined sequential daily maintenance therapy of both foscarnet and ganciclovir or alternating daily treatment with ganciclovir one day and foscarnet the following day.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Allowed:

* Chemotherapy for Kaposi's sarcoma (excluding interferon) if patient is hematologically stable for at least 30 days prior to entry.
* Zidovudine (AZT), dideoxyinosine (ddI), dideoxycytidine (ddC) after first two weeks of study period if absolute neutrophil count is \> 1000 cells/mm3 and hemoglobin = or \> 8 g/dl.
* Vancomycin.
* Fluconazole or investigational triazoles (e.g., itraconazole, SCH 39304) for disseminated fungal infection.
* Pneumocystis carinii pneumonia prophylaxis (except parenteral pentamidine).
* Acyclovir or other appropriate medication may be instituted in the event of the appearance of Herpes simplex virus
* (HSV) or Varicella zoster virus (VZV) infections.
* G-CSF or GM-CSF for grade 4 neutropenia.

Concurrent Treatment:

Allowed:

* Recombinant human erythropoietin.

Prior Medication: Required:

* Completion of 14-day course of intravenous ganciclovir induction therapy (2.5 mg/kg IV q8h or 5 mg/kg q12h for 14 days) or foscarnet induction therapy (60 mg/kg q8h adjusted for renal function for 14 days) within 1 week prior to study entry. Patients who do not initiate the study immediately upon completing ganciclovir induction therapy should receive a maintenance ganciclovir regimen of 5 mg/kg/day or 6 mg/kg/day 5 x week or a foscarnet regimen of 90-120 mg/kg/day until initiating study drug.

Patients must:

* Have a diagnosis of cytomegalovirus retinitis and HIV infection.
* Be capable of giving informed consent. Patients \< 18 years of age may participate with the consent of parent, guardian, or person with power of attorney.

Allowed:

* History of seizure disorder or a central nervous system (CNS) mass lesion.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

* Evidence of tuberculous, diabetic or hypertensive retinopathy.
* Osteomalacia, neoplasm metastatic to bone or other bone disease.
* Any clinically significant pulmonary or neurologic impairment (for example, patients who are intubated or comatose).
* Retinal detachment.
* Corneal, lens, or vitreous opacification precluding funduscopic exam.

Concurrent Medication:

Excluded:

* Immunomodulators, biologic response modifiers or investigational agents not specifically allowed.
* Aminoglycosides, amphotericin B, probenecid, parenteral pentamidine.
* Zidovudine (AZT), dideoxyinosine (ddI), dideoxycytidine (ddC) until completion of second week of maintenance therapy. ddC use is discouraged but not prohibited because of paucity of experience of this drug with ganciclovir and foscarnet.

Anti-cytomegalovirus (CMV) therapy:

* Ganciclovir, CMV hyperimmune serum/globulin, interferons, immunomodulators.
* Prophylactic antiviral therapy with acyclovir.

Patients with the following are excluded:

* Active AIDS-defining opportunistic infection requiring therapy that is currently causing nephrotoxicity or myelosuppression.
* Known hypersensitivity to either of the study therapies.

Prior Medication:

Excluded:

* Foscarnet or ganciclovir for CMV retinitis (excluding the 14-day induction period).

Prior Treatment:

Excluded:

* Cytomegalovirus (CMV) hyperimmune globulin within 14 days prior to study entry.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Ctr.
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
name: Jacobson MA
role: STUDY_CHAIR
References:
citation: Jacobson MA, Kramer F, Bassiakos Y, Hooton T, Polsky B, Geheb H, O'Donnell JJ, Walker JD, Korvick JA, van der Horst C. Randomized phase I trial of two different combination foscarnet and ganciclovir chronic maintenance therapy regimens for AIDS patients with cytomegalovirus retinitis: AIDS clinical Trials Group Protocol 151. J Infect Dis. 1994 Jul;170(1):189-93. doi: 10.1093/infdis/170.1.189.
citation: Aweeka FT, Gambertoglio JG, Kramer F, van der Horst C, Polsky B, Jayewardene A, Lizak P, Emrick L, Tong W, Jacobson MA. Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis. Clin Pharmacol Ther. 1995 Apr;57(4):403-12. doi: 10.1016/0009-9236(95)90209-0.