A Controlled, Randomized Phase II Study of the Safety and Efficacy of Combined Therapy With Ganciclovir and Granulocyte-Macrophage Colony Stimulating Factor Versus Ganciclovir Alone for the Treatment of Sight-Threatening Cytomegalovirus Retinitis in AIDS Patients

Trial Information

A Controlled, Randomized Phase II Study of the Safety and Efficacy of Combined Therapy With Ganciclovir and Granulocyte-Macrophage Colony Stimulating Factor Versus Ganciclovir Alone for the Treatment of Sight-Threatening Cytomegalovirus Retinitis in AIDS Patients

AMENDED: In ACTG 004, among 11 AIDS patients with CMV infection receiving DHPG maintenance
therapy (5 mg/kg, 5x/week) with stable white blood cells (WBC)/absolute neutrophil counts
(ANC) 7 (64 percent) required dose reduction or discontinuation of both antiviral
medications due to granulocytopenia when AZT (600 mg/day) was added. A mean nadir ANC of 717
cells/ml was reached at a mean of 5 weeks of concomitant DHPG/AZT therapy in these patients.
While recovery of depressed ANC occurred following discontinuation of study medications,
progressive CMV infection (most commonly retinitis) occurred in 19 of 40 patients and seemed
to be associated with DHPG therapy interruption. Only 3 of 40 patients were able to tolerate
the complete 16 week study duration of DHPG/AZT. Pharmacokinetic studies of
co-administration of DHPG and AZT revealed no significant drug-drug interactions. The study
investigators concluded that the main, treatment limiting toxicity of combination DHPG/AZT
therapy is granulocytopenia and that many patients treated on this study developed
intercurrent OIs or staphylococcal septicemia. In order to determine whether patients
receiving maintenance DHPG therapy with or without GM-CSF can tolerate concomitant AZT
therapy, extended maintenance therapy with the assigned study regimen in combination with
AZT will be incorporated into this protocol. Original design: CMV infection causes
inflammation of the retina and can lead to permanent blindness. Treatment for CMV retinitis
with DHPG has been shown to be effective in halting the progression of retinal disease.
During DHPG treatment, however, about 30 to 55 percent of patients develop decreased white
blood cell counts. GM-CSF, a naturally occurring human hormone, stimulates the body's bone
marrow to produce more white blood cells. Studies with GM-CSF in AIDS patients have shown
that it can significantly increase depressed white blood cell counts in these patients.

AMENDED: Following completion of Phase A, study participants may elect to extend their
assigned maintenance therapy (DHPG alone or DHPG/GM-CSF) in combination with AZT therapy
(Phase B). GM-CSF dosing will be titrated as above to maintain a target ANC of 2500-5000
cells/mm3. Those patients receiving DHPG/AZT who develop neutropenia (ANC less than 750/ml)
on two occasions will begin GM-CSF to maintain a target ANC of 2500-5000 cells/mm3. A
similar schedule of clinical, ophthalmologic and laboratory evaluations will be followed in
order to determine the efficacy and safety of extended maintenance therapy combined with
AZT. Close monitoring of antiviral (CMV, HIV) and immunomodulatory activity will be
assessed. This second phase of the study will last for an additional 52 weeks. AMENDED:
Extended to 68 weeks. Original design: Patients are hospitalized for a minimum of 7 days to
begin treatment for CMV retinitis. They are randomly assigned to one of two groups to
receive DHPG either with or without GM-CSF. DHPG is given by intravenous infusion every 12
hours for the first 14 days. DHPG maintenance therapy is then given once a day, 7 days/week
for the remaining 14 weeks of the study. For patients in the DHPG with GM-CSF group, the
GM-CSF is given by subcutaneous injection for the 16 weeks of the study.