Clinical Trial Result Information

Protocol number
WV16789

Title of Study
Investigation of the gastrointestinal tolerability of a new Roche 625 mg formulation of Viracept (nelfinavir) in subjects with HIV-1 infection.

Sponsor
Hoffman-La Roche Inc

Company division
Pharmaceutical

Product name
Viracept

Generic name
nelfinavir

Therapeutic area
HIV infection

Clinical study summary
This was an open-label, 2 arm study to assess the gastrointestinal tolerability and safety of a new formulation of Viracept. Patients with HIV-1 infection naïve or experienced to Viracept were eligible to enter the study.

Study center(s)
21 centers in France, Germany, Italy, Mexico, Poland, Spain, Switzerland and UK.

Phase of development
III

Objectives
To describe the gastrointestinal tolerability and acceptability of the Viracept 625 mg film-coated tablet formulation. In the patients switching from the currently marketed 250 mg formulation of Viracept, a comparison was to be made between the tolerability of the two formulations.

Methodology
Patients entering the study who were stable and tolerating an antiretroviral (ART) regimen which included the marketed formulation of Viracept 250 mg for a minimum of 8 weeks (at least 4 weeks on a BID regimen) were asked to complete a standard stool diary for 14 days. At the end of this 14 day ‘run-in’ period, all patients switched their nelfinavir component to the Roche Viracept 625 mg formulation (1250 mg BID) for 28 days and were asked to continue the stool diary until the end of the main study period. A second group of patients (ART naïve or ART-experienced) initiating Viracept treatment as part of their ART regimen were asked to complete a standard stool diary for 14 days while remaining on their current regimen. These patients then received the 625 mg Viracept formulation (1250 mg BID) for 28 days as part of their new ART regimen and were also asked to complete the stool diary for the duration of the study.

At the end of the 28 days of study drug, all patients were offered the choice to receive the current marketed formulation of Viracept (5 x 250 mg BID) or continue taking the Roche 625 mg formulation (2 x 625 mg BID) until such time as Viracept 625 mg tablets would become available through a Special License Program or as a marketed formulation. All adverse events occurring during the main study period with the Viracept 625 mg formulation (i.e. day 15-day 42) are presented here.

Number of patients (planned/analyzed)
189 patients enrolled.

Diagnosis and main criteria for inclusion
Patients with HIV-1 infection on a stable antiretroviral treatment (ART) regimen which included Viracept (nelfinavir ‘switch’ patients). Patients were to have a viral load of ≤ 2000 copies per mL and CD4 cell count of ≥ 200 per μL. Patients with HIV-1 infection initiating nelfinavir (either ART-naïve or ART-experienced). No restriction on viral load or CD4 cell count (‘new nelfinavir’ patients).

Test product, dose and mode of administration or test procedure
Viracept 625 mg film coated tablets.

Duration of treatment
28 days.

Reference therapy, dose and mode of administration or reference procedure
Marketed formulation of Viracept 250 mg film coated tablets.

Criteria for evaluation (efficacy, safety)
Tolerability and safety: The primary parameters were in order of priority, the patient preference scores for either Viracept formulation (recorded on Day 42 of the study), the incidence and duration of GI upset (loose stools, fecal urgency) and the incidence and duration of moderate/severe diarrhea. Gastrointestinal tolerability and bowel function (diarrhea) were assessed prior to initiation of study drug (Day 1-14) and for the first 4 weeks on study medication (Day 15-42) by means of standard stool diaries to measure frequency and looseness of stools. Pathogen staining was performed in patients reporting diarrhea of moderate or greater severity according to ACTG classification. Adverse events and laboratory values (serum chemistry, including liver function tests and hematology values) were recorded during the Viracept 625 mg treatment period. ECG recording was performed on Day 14 and Day 42. Efficacy: HIV-1 RNA levels and CD4 counts were measured at screening, Day 14 and Day 42. Pharmacokinetics: ‘Switch’ patients: Trough levels of nelfinavir and M8 (metabolite) were measured at steady-state on each formulation of Viracept, for therapeutic drug monitoring purposes. ‘New nelfinavir’ patients: Trough levels of nelfinavir and M8 were measured at steady-state only on Day 28, for therapeutic drug monitoring purposes. Quality of life was assessed using FAHI (Functional Assessment of HIV Infection) scores.

Statistical methods
Descriptive analyses of the primary study parameters and secondary efficacy endpoints were presented. All safety data were listed and summarized.

Summary (efficacy, safety, other results)
Tolerability and safety: Patient preference scores recorded at the end of the Viracept 625 mg treatment period (Day 42) indicated that more than 90% (112/122 ‘switch’ patients; p<0.0001) expressed a preference for the Viracept 625 mg tablet formulation. This preference was based primarily on the reduced tablet count associated with the new formulation (2 x 625 mg BID versus 5 x 250 mg BID), although a number of the patients who expressed a preference indicated that the tablet was easier to swallow (58/112 patients), was associated with better bowel function (64/112 patients) or had better overall tolerability (46/112 patients).
Of those patients who completed the 28 day treatment period with the Viracept 625 mg formulation, when given the option to continue into the follow-up study, only 2 patients decided to receive the Viracept 250 mg formulation.
The incidence of gastrointestinal (GI) upset in ‘switch’ patients was lower during the Viracept 625 mg treatment period compared with the Viracept 250 mg run-in period. This was a consistent trend and was seen in the additional analyses addressing the primary objective such as the duration of GI upset and incidence and duration of diarrhea. The incidence of moderate/severe diarrhea during the study was low. Nonetheless, a reduction in the percentage of patients experiencing this event was observed between the Viracept 250 mg treatment run-in period (11.1%) and the Viracept 625 mg treatment period (6.5%).
The mean quality of life scores were similar in patients taking either formulation of Viracept, but marginal improvement was observed in patients taking the Roche Viracept 625mg tablet formulation.
During the study, limited ECG assessments were performed. In Viracept treatment-experienced 'switch' patients, analysis of the QT/QTc values was inconclusive due to the absence of baseline (ie. pre-nelfinavir) ECGs. However, baseline values were available for the 'new' nelfinavir patients, enabling more detailed analysis of any effects on QT interval prolongation that may be attributable to Viracept 625 mg. No adverse events indicative of a QT-interval prolongation were identified in the nelfinavir naïve patients from this analysis.
The majority of adverse events reported during the study were mild in intensity and most were reported by no more than one patient each. No deaths were reported and only one patient withdrew prematurely as a result of adverse events (taste alteration and nausea). Both events were considered by the investigator probably related to trial treatment. Two serious adverse events were recorded during the study. These events (‘dyspepsia’ and ‘difficulty in walking’), were recorded by patients in the ‘switch’ treatment group, and were considered by the investigator unrelated to trial treatment. Although a number of marked laboratory test parameter abnormalities were identified during the study, the majority of these were single events and none was considered clinically significant in this patient population.
TDM pharmacokinetics: there was significant interpatient variability in the trough levels of nelfinavir. However, the majority of patients had nelfinavir trough levels greater than 1000ng/mL.
Efficacy: While accepting the limitations of the available data (due to the short study duration and limited sample size), it can be stated that similar numbers of patients switching from the Viracept 250 mg formulation remained suppressed for HIV viral load during treatment with the Roche Viracept 625 mg treatment regimen. In addition, over the course of the study the CD4 lymphocyte count was maintained. Furthermore, ‘new nelfinavir’ patients, particularly those who had not received prior ART experienced a marked reduction in viral load and increase in CD4 count after treatment with the Viracept 625 mg-containing ART regimen.

Conclusions
The Roche Viracept 625 mg film-coated tablet was well tolerated with no new safety concerns when administered as part of an antiretroviral combination therapy regimen to patients with HIV-1 infection. Results indicated a highly statistically significant patient preference for the Roche Viracept 625 mg formulation and a consistent trend for improvement in a number of parameters assessing GI tolerability compared to the currently marketed Viracept 250 mg film-coated tablet formulation. The Roche Viracept 625mg tablet evaluated in this study is not available, and is distinct from the Pfizer Viracept 625mg tablet formulation that is available in North America.

Publications (references, if available)
Nieto-Cisneros L, Johnson M, Horban A et al. Investigation of the gastrointestinal tolerability and pharmacokinetics of the Roche nelfinavir 625 mg film-coated tablets in comparison with nelfinavir 250 mg film-coated tablets (Viracept®) in HIV patients.
(4th International Workshop on Clinical Pharmacology of HIV Therapy: 27-29 March 2003; Cannes, France).
Nieto-Cisneros L, Johnson M, Horban A et al. Roche Viracept (Nelfinavir) 625 mg film-coated tablets: Investigation of safety and gastrointestinal tolerability of this new formulation in comparison with 250 mg film-coated tablets (Viracept®) in HIV patients.
(2nd IAS Conference on HIV Pathogenesis and Treatment: 13 16 July 2003; Paris, France).

Date of report
7/1/2003

Click here for the protocol registry listing of this trial.