Valganciclovir (Page 7 of 8)

14 CLINICAL STUDIES

14.1 Adult Patients

Induction Therapy of CMV Retinitis: In one randomized open-label controlled study, 160 patients with AIDS and newly diagnosed CMV retinitis were randomized to receive treatment with either valganciclovir tablets (900 mg twice daily for 21 days, then 900 mg once daily for 7 days) or with intravenous ganciclovir solution (5 mg per kg twice daily for 21 days, then 5 mg per kg once daily for 7 days). Study participants were: male (91%), White (53%), Hispanic (31%), and Black (11%). The median age was 39 years, the median baseline HIV-1 RNA was 4.9 log10, and the median CD4 cell count was 23 cells/mm3. A determination of CMV retinitis progression by the masked review of retinal photographs taken at baseline and Week 4 was the primary outcome measurement of the 3-week induction therapy. Table 19 provides the outcomes at 4 weeks.

Table 19 Week 4 Masked Review of Retinal Photographs in CMV Retinitis Study
Intravenous Ganciclovir Valganciclovir Tablets
Determination of CMV retinitis progression at Week 4 N=80 N=80
ProgressorNon-progressor 763 764
Death Discontinuations due to Adverse Events Failed to return 211 121
CMV not confirmed at baseline or no interpretable baseline photos 6 5

Maintenance Therapy of CMV Retinitis: No comparative clinical data are available on the efficacy of valganciclovir tablets for the maintenance therapy of CMV retinitis because all patients in the CMV retinitis study received open-label valganciclovir tablets after Week 4. However, the AUC for ganciclovir is similar following administration of 900 mg valganciclovir tablets once daily and 5 mg per kg intravenous ganciclovir once daily. Although the ganciclovir Cmax is lower following valganciclovir tablets administration compared to intravenous ganciclovir, it is higher than the Cmax obtained following oral ganciclovir administration. Therefore, use of valganciclovir tablets as maintenance therapy is supported by a plasma concentration-time profile similar to that of two approved products for maintenance therapy of CMV retinitis.

Prevention of CMV Disease in Heart, Kidney, Kidney-Pancreas, or Liver Transplantation: A double blind, double-dummy active comparator study was conducted in 372 heart, liver, kidney, or kidney-pancreas transplant patients at high risk for CMV disease (D+/R-). Patients were randomized (2 valganciclovir : 1 oral ganciclovir) to receive either valganciclovir tablets (900 mg once daily) or oral ganciclovir (1000 mg three times a day) starting within 10 days of transplantation until Day 100 post-transplant. The proportion of patients who developed CMV disease, including CMV syndrome and/or tissue-invasive disease during the first 6 months post-transplant was similar between the valganciclovir tablets arm (12.1%, N=239) and the oral ganciclovir arm (15.2%, N=125). However, in liver transplant patients, the incidence of tissue-invasive CMV disease was significantly higher in the valganciclovir group compared with the ganciclovir group. These results are summarized in Table 20.

Mortality at six months was 3.7% (9/244) in the valganciclovir group and 1.6% (2/126) in the oral ganciclovir group.

Table 20 Percentage of Patients with CMV Disease, Tissue-Invasive CMV Disease or CMV Syndrome by Organ Type: Endpoint Committee, 6 Month ITT Population
GCV = oral ganciclovir; VGCV = valganciclovir
*
Number of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome
CMV syndrome was defined as evidence of CMV viremia accompanied with fever greater than or equal to 38°C on two or more occasions separated by at least 24 hours within a 7-day period and one or more of the following: malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
CMV Disease * Tissue-Invasive CMV Disease CMV Syndrome
Organ VGCV(N=239) GCV(N=125) VGCV(N=239) GCV(N=125) VGCV(N=239) GCV(N=125)
Liver 19% 12% 14% 3% 5% 9%
(n=177) (22 / 118) (7 / 59) (16 / 118) (2 / 59) (6 / 118) (5 / 59)
Kidney 6% 23% 1% 5% 5% 18%
(n=120) (5 / 81) (9 / 39) (1 / 81) (2 / 39) (4 / 81) (7 / 39)
Heart 6% 10% 0% 5% 6% 5%
(n=56) (2 / 35) (2 / 21) (0 / 35) (1 / 21) (2 / 35) (1 / 21)
Kidney / Pancreas 0% 17% 0% 17% 0% 0%
(n=11) (0 / 5) (1 / 6) (0 / 5) (1 / 6) (0 / 5) (0 / 6)

Prevention of CMV Disease in Kidney Transplantation: A double-blind, placebo-controlled study was conducted in 326 kidney transplant patients at high risk for CMV disease (D+/R-) to assess the efficacy and safety of extending valganciclovir CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive valganciclovir tablets (900 mg once daily) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo. Extending CMV prophylaxis with valganciclovir until Day 200 post-transplant demonstrated superiority in preventing CMV disease within the first 12 months post-transplant in high risk kidney transplant patients compared to the 100 day dosing regimen (primary endpoint). These results are summarized in Table 21.

Table 21 Percentage of Kidney Transplant Patients with CMV Disease, Tissue-Invasive CMV Disease or CMV Syndrome, 12 Month ITT Population
VGCV = valganciclovir.
*
Number of patients with CMV disease = Number of patients with tissue-invasive CMV disease or CMV syndrome
CMV syndrome was defined as evidence of CMV viremia accompanied with at least one of the following: fever (greater than or equal to 38°C), severe malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, and elevation of hepatic transaminases
Two patients in the 100 day group had both tissue-invasive CMV disease and CMV syndrome; however, these patients are counted as having only tissue-invasive CMV disease.
CMV Disease * Tissue-Invasive CMV Disease CMV Syndrome
100 Days VGCV (N=163) 200 Days VGCV (N=155) 100 Days VGCV (N=163) 200 Days VGCV (N=155) 100 Days VGCV (N=163) 200 DaysVGCV (N=155)
Cases 36.8% (60/163) 16.8% (26/155) 1.8% (3/163) 0.6% (1/155) 35.0% (57/163) 16.1% (25/155)

The percentage of kidney transplant patients with CMV disease at 24 months post-transplant was 38.7% (63/163) for the 100 day dosing regimen and 21.3% (33/155) for the 200 day dosing regimen.

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