Clinical Trial Result Information

Protocol number
WV15376

Title of Study
A Randomized Controlled Comparison of the Safety and Efficacy of Ro107-9070 (Valganciclovir) vs Intravenous Ganciclovir as Induction Therapy for the Treatment of Newly Diagnosed Cytomegalovirus Retinitis

Sponsor
Roche Products Ltd.

Company division
Pharmaceutical

Product name
Valcyte

Generic name
valganciclovir

Therapeutic area
Cytomegalovirus infections

Clinical study summary
This was an open-label, controlled, parallel-design study with patients randomized to receive induction therapy comprising either 5 mg/kg intravenous (iv) ganciclovir bid for 3 weeks followed by 5 mg/kg iv ganciclovir qd for 1 week, or 900 mg Valcyte (valganciclovir) po bid for 3 weeks followed by 900 mg Valcyte po qd for 1 week. After this 4-week randomized phase, all patients received maintenance therapy comprising 900 mg Valcyte po qd, with multiple cycles of re-induction therapy with 900 mg Valcyte po bid permitted upon cytomegalovirus retinitis (CMVR) progression.

Study center(s)
42 centers in Australia, Brazil, Canada, Europe, Mexico, and the United States.

Phase of development
III

Objectives
(1) To investigate the efficacy of Valcyte when used as induction therapy in patients with newly diagnosed retinitis; (2) To investigate the safety profile of Valcyte in this indication; (3) To assess the effects of induction and maintenance-level dosing of Valcyte on CMV viral load, estimated by plasma CMV polymerase chain reaction; (4) To assess the pharmacokinetics (PK) of ganciclovir following administration of Valcyte.

Methodology
Ophthalmological assessments were performed in an unblinded fashion at screening, baseline (Day 0), and every 2 weeks through Week 16, then monthly until termination and at the follow-up visit (2 weeks after the last dose of study drug). Retinal photographs were taken for masked assessment of CMVR disease status at baseline, then every 2 weeks through first progression of CMVR or at Week 16 (whichever occurred first), then at intervals until second progression or termination. Serial blood and urine PK samples were collected at the end of Weeks 1 and 4 for quantification of Valcyte and ganciclovir. Safety and laboratory assessments were performed at screening; and at intervals until termination. Adverse events were monitored throughout the study. Following a protocol amendment, retinal photographs were discontinued.

Number of patients (planned/analyzed)
160

Diagnosis and main criteria for inclusion
Patients >13 years of age with newly diagnosed CMVR; absolute neutrophil count (ANC) >=750 cells/µL, platelet count >=75,000/µL, and creatinine clearance rate >70 mL/min.

Test product, dose and mode of administration or test procedure
Valcyte, 900 mg/po/bid/until termination.

Duration of treatment
4 weeks of treatment with ganciclovir or Valcyte, followed by extension treatment with Valcyte (mean of 555 days in randomized ganciclovir group, and mean of 537 days in randomized Valcyte group).

Reference therapy, dose and mode of administration or reference procedure
Ganciclovir sodium,5 mg/kg/iv/bid/4 weeks.

Criteria for evaluation (efficacy, safety)
Efficacy parameters: Induction phase: Primary: proportion of patients in each group with CMV retinitis progression between baseline and week 4, as determined by the marked assessment of retinal photographs, and with progression defined as 1) movement of lesion border>=750μm over a front >=750μm, 2) presence of new area of retinitis >=1/4 disc area in size. Secondary: comparison of the proportion of patients in each greatment group achieving satisfactory induction by week 4 and by week 6. Maintenance phase: (1) Time to first progression of CMVR (movement of retinitis lesion borders >=750 µm, or appearance of a new area of retinitis >=1/4 disc area in size), based on photographic and ophthalmologic data; (2) Time to second progression of retinitis, based on photographic and ophthalmologic data; (3) Incidence and time to development of contralateral CMVR; (4) Incidence of extraocular CMV disease; (5) Incidence and time to deterioration in visual acuity.

Pharmacodynamic parameters: reduction of CMV viral load, as detected by CMV PCR.

Pharmacokinetec parameters: Primary: AUC and Cmax

Safety parameters: (1) Adverse events; (2) Laboratory tests; (3) Vital signs.

Statistical methods
Valcyte was to be deemed to provide an acceptable therapeutic effect relative to iv ganciclovir if the lower end of the 90.4% confidence interval (CI) for the between-group difference in CMVR progression proportions by Week 4 (iv ganciclovir minus Valcyte) is greater than -d (d = 0.25).
Ho: Lower confidence bound (iv ganciclovir minus Valcyte) greater than or equal to -d.
H1: Lower confidence bound (iv ganciclovir minus Valcyte) greater than -d.

Due to the noncomparative nature of the extension (maintenance) phase of the study, no statistical tests were conducted on the extension data. 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 dosing with IV ganciclovir or oral Valcyte (according to randomization).

Summary (efficacy, safety, other results)
Efficacy: Based on the masked assessment of fundus photographs, the efficacy of Valcyte was comparable to that of iv ganciclovir as induction therapy for newly diagnosed CMVR. An equal proportion of patients in the two treatment groups (10%) were graded as having progression of CMVR by week 4, and the lower boundary of the 90.4% confidence interval of the between-group difference in progression proportions (-0.082) was well above the pre-specified equivalence value of -0.25. In addition, a similar proportion of patients in each treatment group were graded by photographic assessment as having achieved a satisfactory response to induction therapy by week 4 (77% ganciclovir; 72% Valcyte) and by week 6 (63% ganciclovir; 70% Valcyte). Only 3 patients (all on the ganciclovir arm) developed contralateral CMVR between baseline and week 6, and overall, no marked between-group treatment differences were noted in the proportion of patients with deterioration in visual acuity at weeks 2, 4 and 6, or with deterioration in vision assessment at weeks 2 and 4. By week 4, only 4 patients in each treatment group were culture positive for CMV in either blood, urine or semen.

The masked photographic assessment of retinitis progression demonstrated that a comparable proportion of patients on IV ganciclovir (55%) and on Valcyte (54%) experienced progression when death prior to progression was censored at the date of last photographic assessment. The proportion of patients remained comparable when death was regarded as progression (69% ganciclovir; 65% Valcyte). The mean ( median) time to first photographic progression was 212 (126) days for the ganciclovir arm and 224 (180 )days for the Valcyte arm. Using a more conservative linear interpolation analysis, median time to first photographic progression was 125 days for the ganciclovir arm, and 160 days for the Valcyte arm.

A comparable proportion of patients on both arms with unilateral CMVR at baseline developed contralateral CMVR based on photographic data (18% ganciclovir, 21% Valcyte), and the incidence of deterioration in visual acuity was also similar in the 2 treatment groups (31% ganciclovir, 36% Valcyte). Three patients (2 originally randomized to IV ganciclovir and 1 to Valcyte) developed extraocular CMV disease during the study (CMV esophagitis, CMV viremia, and CMV encephalitis).

Pharmacokinetics: The pharmacokinetic data derived from this study were consistent with those quoted in the product labeling for ganciclovir and Valcyte.

Safety: At both induction and maintenance-level dosing, the safety profile of Valcyte appeared consistent with the known safety profile of ganciclovir. The overall pattern of adverse events was broadly comparable in both treatment groups, with the most common adverse events being diarrhea, pyrexia, anemia, neutropenia, nausea, and oral candidiasis. During the induction phase of the study, diarrhea was more frequent in the Valcyte arm than in the ganciclovir arm ( 19% versus 10% patients, respectively), as was oral candidiasis (14% versus 6% patients, respectively). In both treatment groups, the majority of adverse events were considered either mild or moderate in intensity and unrelated to trial treatment. Neutropenia and anemia were the most common severe or potentially life-threatening related adverse events.

There were 47 (30%) patient deaths during the study, of which 3 were considered related to trial treatment (hypovolemic shock, probably related; hepatic failure and upper gastrointestinal hemorrhage, remotely related). The most frequently reported serious adverse events were pyrexia, Pneumocystis carinii pneumonia, and neutropenia.

The overall pattern of laboratory shifts was similar for both treatment groups, with the most common marked laboratory shifts being reductions in ANC, hemoglobin level, or platelet count. Most patients who experienced clinically significant neutropenia, anemia, or thrombocytopenia had recovery of cell counts following treatment or interruption of the study drug.

Conclusions
The results of this study demonstrate the comparable efficacy of oral Valcyte and iv ganciclovir as induction therapy for newly diagnosed CMVR, and 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 to that of ganciclovir.

Publications (references, if available)
Martin D, Sierra-Madero J, Walmsley S et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N.Engl.J.Med.346:1119-1126 (2002)

Date of report
3/1/2004