Clinical Trial Result Information

Title of Study:
An Open-Label Study of the Safety and Tolerability of Valganciclovir, an Oral Prodrug of Ganciclovir, for the Treatment of Cytomegalovirus Retinitis in Subjects with AIDS

Fast Facts:

Protocol number:	WV15705
Sponsor:	Roche Products Ltd
Company division:	Pharmaceutical
Product name:	Valcyte
Generic name:	valganciclovir
Phase of development:	III
Therapeutic area, approved indication:	Cytomegalovirus infections
Date of report:	3/1/2004

Clinical study summary:
This was an open-label, single-arm study, with all patients (HIV-positive, with CMV retinitis) receiving Valcyte (valganciclovir) 900 mg po bid for 21 days (induction therapy) followed by Valcyte 900 mg po qd as maintenance therapy for the treatment of cytomegalovirus retinitis (CMVR).

Study center(s) :
43 centers in Australia, Brazil, Canada, Mexico, France, Germany, Italy, Spain, the United Kingdom, and the United States.

Objectives:
To evaluate the safety and tolerability of Valcyte when given as treatment for CMVR.

Methodology:
Patients with active CMVR received an induction dose of Valcyte 900 mg po bid for 21 days, followed by a maintenance dose of 900 mg po qd. For patients with quiescent CMVR, treatment was initiated and continued with the maintenance dose of 900 mg po qd. Patients who had progression of CMVR could receive multiple cycles of induction and maintenance therapy and could continue until common study closure or until commercial supplies of the drug became available. Safety and efficacy assessments occurred at screening, Week 2, and monthly thereafter, and following a protocol amendment reduced to once every 2 months.

Number of patients (planned/analyzed):
212

Diagnosis and main criteria for inclusion:
HIV-positive patients >=13 years of age with CMVR; receipt of >=4 weeks of anti-CMV treatment.

Test product, dose and mode of administration or test procedure:
Valcyte, 900 mg/po/bid/21 days; 900 mg/po/qd/until common study closure or until Valcyte becomes commercially available

Duration of treatment:
The mean duration of treatment was 779 days

Reference therapy, dose and mode of administration or reference procedure:
Not applicable

Criteria for evaluation (efficacy, safety):
Safety parameters: (1) Adverse events; (2) Laboratory tests; (3) Vital signs; (4) Concomitant medications.

Efficacy parameters: Ophthalmology (based on dilated, indirect ophthalmoscopy): (1) Incidence of/time to progression of CMVR; (2) Incidence of/time to contralateral disease (in those patients presenting with disease in 1 eye); (3) Incidence of changes in visual acuity; (4) Incidence of/time to extraocular CMV events.

Statistical methods:
Due to the exploratory, noncomparative nature of this study, no statistical tests were conducted. Descriptive analyses of the primary (safety) study parameters are presented. Secondary (efficacy) endpoints and selected adverse event data are expressed as incidence rates and time-to-event data, the time to event being calculated from the day of first dose of Valcyte.

Summary (efficacy, safety, other results):
Safety: The most commonly reported adverse events (frequency >30%) were diarrhea, nausea, and fever. Other frequently reported adverse events (>20% incidence) were candidiasis, headache, dermatitis, neutropenia, anemia, insomnia, cough, vomiting, and fatigue. The majority of adverse events were considered to be of mild or moderate intensity (86%) and unrelated to study treatment (88%). Severe and life-threatening drug-related adverse events were most often disorders of the blood and lymphatic system (neutropenia, anemia, thrombocytopenia, and pancytopenia) and gastrointestinal disorders (diarrhea, nausea, and vomiting).

A total of 44 patients (21%) died during the study; 5 of these deaths (due to secondary sepsis, multi-organ failure, renal failure, Pneumocystis carinii pneumonia, and brain neoplasm) were considered to be related to study treatment. The most common serious adverse events were anemia and neutropenia, which were experienced by 8% and 7% of patients, respectively. Fever and pneumonia were each reported by 6% of patients.

Thirtyseven patients (17%) withdrew from the study due to clinical adverse events, mainly infections (7%) and disorders of the blood and lymphatic system (7%).

The most common laboratory abnormalities were neutropenia, anemia, and thrombocytopenia. Severe neutropenia (ANC <500 cells/µL) was observed in 28 patients (31%), severe anemia (hemoglobin <8.0 g/dL) in 32 patients (15%), and severe thrombocytopenia (platelet count <25,000 cells/µL) in 8 patients (4%). Elevations in liver function enzymes were also observed, with marked increases in GGT and ALT occurring in 22 (11%) and 13 patients (6%), respectively.

No new toxicities appeared during treatment with oral Valcyte that have not been observed during treatment with ganciclovir.

Efficacy: Based on funduscopy by the evaluating ophthalmologist, 41 of 212 patients (19%) experienced progression of CMVR during the study. The median time to CMVR could not be calculated due to the low number of progression events; however, the mean time to progression was 538 days. Of the 41 patients with a first progression, 18 patients went on to experience a second progression of CMV retinitis in the same eye following re-induction therapy. Of the 113 patients who entered the study with unilateral retinitis, 10 (8.8%) developed CMVR in the previously unaffected eye. Five patients (2%) developed extraocular CMV disease of whom 2 had a history of extraocular disease that was inactive at screening. Fifteen patients (7%) required a ganciclovir intraocular implant as a result of CMVR progression, with 10 of these requiring multiple implants. A total of 23 patients (11%) experienced a retinal detachment during the study.

Conclusions:
The results of this study demonstrate the tolerability and safety of Valcyte for the long-term maintenance treatment of CMVR. The adverse event profile of Valcyte was shown to be comparable with that of ganciclovir. Descriptive efficacy data from this study support the use of Valcyte for the maintenance treatment of CMV retinitis in patients with AIDS.

Publications (references, if available):
Lalezari J, Lindley J, Walmsley S et al A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. JAIDS 30: 392-400 (2002)