Clinical Trial Result Information

Title of Study:
Open, multicenter, randomized, treatment simplification study to evaluate the pharmacological efficacy and safety of a nelfinavir-ritonavir combination one/day (OD) in comparison to nelfinavir twice/day (BID), using the new formulation of nelfinavir 625 mg in HIV-1 patients pretreated with nelfinavir 250 mg.

Fast Facts:

Protocol number:	ML17025
Sponsor:	Roche SAS
Company division:	Pharmaceutical
Product name:	Viracept
Generic name:	nelfinavir
Phase of development:	II
Therapeutic area, approved indication:	HIV Infections
Date of report:	10/27/2005

Clinical study summary:
This open-label, multicenter, randomized, parallel-group, treatment simplification study evaluated the efficacy and safety of a nelfinavir/ritonavir combination given once a day compared with nelfinavir (Viracept) given twice a day in HIV-1 patients pretreated with Viracept 250 mg. Patients received either Viracept 1875 mg combined with ritonavir 200 mg once a day and reverse transcriptase inhibitors (prior treatment maintained), or Viracept 1250 mg twice a day and reverse transcriptase inhibitors (prior treatment maintained) for 6 months.

Study center(s) :
21 centers, in France.

Objectives:
Primary: At Month 3, demonstrate the pharmacologic noninferiority of Viracept 625 mg once a day versus Viracept 625 mg BID.

Secondary: (1) Pharmacologic evaluation between Viracept 250 mg and Viracept 625 mg; (2) Evaluation of safety (in particular gastrointestinal) between the 2 treatment arms and the 2 Viracept dosages; (3) Evaluation of antiviral immunovirologic efficacy between the 2 treatment arms; (4) Evaluation of adherence between the 2 treatment arms.

Methodology:
In this phase II, comparative, multicenter, randomized, open-label study, 2 parallel groups of patients infected with HIV-1 and currently taking nelfinavir 1250mg bid received for 6 months either Viracept 1875 mg once a day (3 tablets) combined with ritonavir 200 mg once a day (OD; 2 capsules) in the morning and reverse transcriptase inhibitors (prior treatment maintained), or Viracept 1250 mg (2 tablets) BID, morning and evening, and reverse transcriptase inhibitors (prior treatment maintained). The study involved 7 visits: a selection visit, an inclusion visit, and monthly visits following treatment.

Number of patients (planned/analyzed):
97 randomized, 93 evaluated for intent-to-treat (ITT) efficacy, 86 evaluated for per protocol (PP) efficacy, 94 evaluated for safety.

Diagnosis and main criteria for inclusion:
Outpatients ≥18 years of age infected with HIV-1; treatment with Viracept 250 mg BID for >3 months; treatment with antiretroviral tritherapy or quadritherapy including, in addition to Viracept, 2 or 3 nucleoside and/or nucleotide analogues; plasma viral RNA <200 copies/mL; plasma nelfinavir concentration ≥800 ng/mL; no advancing opportunistic infection.

Test product, dose and mode of administration or test procedure:
Viracept 1875 mg (625 mg/tablet) po, ritonavir 200 mg (100 mg/capsules) po, Viracept 1250 mg (625 mg/tablet) po.

Duration of treatment:
6 months.

Reference therapy, dose and mode of administration or reference procedure:
None.

Criteria for evaluation (efficacy, safety):
Primary: Efficacy: At Month 3, the percentage of patients whose allocated treatment was maintained and whose adjusted nelfinavir C_min value was ≥800 ng/mL at 12 hours or 24 hours, depending on the Viracept administration regimen.

Secondary: Kinetics: (1) Percentage of patients whose assigned treatment was maintained, with adjusted nelfinavir + M8 (nelfinavir active metabolite) C_min ≥800 ng/mL or ≥1000 ng/mL at Months 1, 3, and 6; (2) Percentage of patients whose assigned treatment was maintained, with adjusted nelfinavir C_min ≥800 ng/mL at Months 1 and 6; (3) Adjusted raw nelfinavir CC_min values and adjusted raw nelfinavir + M8 CC_min values at Months 1, 3, and 6; (4) Adjusted M8/nelfinavir ratio at Months 1, 3, and 6; (5) intracellular plasma concentrations and plasma/intracellular CC_min ratio (Day 30, Months 1, 3, and 6).

Immunovirologic and genotypic: (1) Viral RNA as raw value and log10 at months 1, 2, 3, 4, and 6; (2) Virologic responders at months 1- 6; (3) Virologic failures; (4) CD4/CD8 levels at Day 30, Months 1, 2, 3, 4, and 6.

Safety: (1) Adverse events; (2) Clinical chemistry parameters; (3) Vital signs; (4) Echocardiographic parameters; (5) Auto-questionnaire on safety.

Statistical methods:
The principal analysis was carried out in the PP population. Noninferiority was demonstrated if the 95% confidence interval (CI) of the difference concerning the principal criterion between the 2 arms was included within the noninferiority interval [-∞; 20%], with a risk of 5%. The analysis was repeated for the ITT population in order to confirm noninferiority. Patients having switched the treatment arm were considered to be failures in the ITT population at the moment of the switch.

Summary (efficacy, safety, other results):
Efficacy: All patient characteristics were comparable in the 2 treatment groups at inclusion. Treatment adherence was statistically higher in the BID group than in the once-a-day (OD) group: 95.4 ± 8.1% vs 85.4 ± 24.2%; (P = 0.011), explained by the fact that all treatment arm switches occurred in the OD group.

The principal objective, to verify the pharmacologic noninferiority of the Viracept 625 mg formulation combined with ritonavir taken as a single daily administration versus Viracept taken twice a day, was not reached. The difference in percentages of patients with a nelfinavir C_min at Month 3 ≥800 ng/mL at 12 or 24 hours (depending on the administration regimen) was 35.1% in the PP population (43.6% in the OD group and 78.7% in the BID group), and 36.6% in the ITT population (40.9% in the OD group and 77.6% in the BID group). The hypothesis of noninferiority, ie, a difference between the 2 treatment groups ≤20%, could thus not be accepted at the alpha risk of 5% in both the PP and ITT populations. Moreover the superiority of the BID treatment group was demonstrated; the comparison between the 2 treatment groups was statistically significant in both populations: P = 0.002 in PP and P = 0.001 in ITT.

At M6, the nelfinavir C_min values were significantly higher in the BID group than in the OD group (P < 0.001). The nelfinavir + M8 C_min values were also significantly higher in the BID group, at both Month 3 and Month 6 than in the OD group (P < 0.001 at Months 3 and 6). The M8 metabolite was statistically higher in the OD treatment group at both Month 3 and Month 6: than in the BID group (M3: P < 0.001; M6: P = 0.036).

At M3, the mean viral RNA values were 225.0 ± 1063.5 copies/mL in the OD group and 75.0 ± 104.8 copies/mL in the BID group; at Month 6, they were 587.1 ± 3169.1 copies/mL and 54.6 ± 18.6 copies/mL, respectively.

The percentage of patients with a viral RNA less than 50 copies/mL at Month 3 was 79.5% in the OD group and 85.7% in the BID group; at Month 6, these percentages were 72.7% and 89.8%, respectively. CD4 and CD8 did not differ between the 2 treatment groups at Month 3 or Month 6. The mean CD4 values were respectively 424.2 ± 207.9 cells/mm3 and 476.6 ± 236.8 cells/mm3 in the OD group, and 400.4 ± 195.8 cells/mm3 and 434.9 ± 193.4 cells/mm3 in the BID group (P = 0.733 at Month 3 and P = 0.450 at Month 6).  The mean CD8 values were respectively 700.4 ± 281.7 cells/mm3 and 762.7 ± 394.0 cells/mm3 in the OD group, 674.5 ± 249.4 cells/mm3 and 747.6 ± 291.1 cells/mm3 in the BID group (P = 0.946 at Month 3 and P = 0.609 at Month 6).

Safety: The frequency of patients with an adverse event was comparable between the 2 treatment groups: 60% of patients in the OD group versus 63.3% of those in the BID group (P = 0.745), with a respective mean number of events of 2.13 and 1.49 per patient. These events were primarily gastrointestinal disorders, infections, and cutaneous pathologies. Although the frequency of patients presenting at least 1 treatment-related adverse event did not differ statistically, it was higher in the OD group: 22.2% of patients versus 10.2% in the BID group (P = 0.112), with a higher number of reported events judged to be related to the treatment: 33 events versus 6. They were primarily gastrointestinal disorders (29 events) and less commonly nervous system disorders (5 events). Four serious adverse events were reported in the OD group and 2 in the BID group. None of these events was judged to be attributable to the study treatment and none led to dropout from the study. Finally, 3 patients in the OD group dropped out of the study because of adverse events: two of these patients discontinued due to adverse events considered related to Viracept treatment (diarrhea, ballooning, nausea, headaches, vertigo, lipodystrophy and hot flushes). In addition, all hematologic parameters and vital signs remained stable throughout the study in both treatment groups. In contrast, alkaline phosphatases and triglycerides were elevated in the OD group, increasing from 77.0 ± 23.4 UI/L and 1.9 ± 1.4 mmol/L at the time of selection to 92.6 ± 33.6 UI/L and 2.5 ± 1.9 mmol/L (P≤0.05 in both cases).

Conclusions:
The non-inferiority of a once-daily administration of 1875 mg of Viracept combined with 200 mg of ritonavir, compared to the administration of 1250 mg of Viracept BID, could not be demonstrated. The nelfinavir Cmin levels were lower in the Viracept OD group compared to the BID group. No significant adverse events attributable to Viracept were detected in the OD treatment group. Nevertheless, digestive events including diarrhea and and hypertriglyceridemia appeared less frequently in the BID group.