HIV-1 Infection Study of Once a Day Versus Twice a Day Protease Inhibitor in Antiretroviral Treatment Naive Adults
Condition: Infection, Human Immunodeficiency Virus I; HIV-1 Infection
MeSH terms: Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: fosamprenavir/ritonavir
Intervention description: Fosamprenavir (FPV, TELZIR) is currently licensed in Europe for twice daily (BID) dosing in combination with ritonavir (RTV, Norvir) as a boosting agent
Intervention MeSH terms: Ritonavir; Fosamprenavir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 212.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: protease inhibitor,; HIV-1,; Fosamprenavir,; non-HDL cholesterol; ritonavir,; naive,

Summary:

      This is a Phase IIIB, 48 Week, multicentre, randomized, open-label, parallel group study
      comparing the safety and efficacy of fosamprenavir plus ritonavir 1400mg/100mg once-daily to
      fosamprenavir plus ritonavir 700mg/100mg twice-daily, both administered with
      abacavir/lamivudine 600mg/300mg once-daily in antiretroviral-naive HIV-1 infected adults.
      This study utilizes a group-sequential design with two stages: 1) an interim 24 week cohort
      analysis of approximately 200 subjects and 2) if study continuation criteria are met at this
      interim analysis, further enrolment of an additional 528 subjects, followed over a minimum of
      48 weeks. The objectives of the study are to demonstrate 1) non-inferior antiviral activity
      of fosamprenavir/ritonavir 1400mg/100mg QD compared to fosamprenavir/ritonavir 700mg/100mg
      BID and 2) a superior fasting non-HDL lipid profile in subjects receiving
      fosamprenavir/ritonavir 1400mg/100mg QD.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject is ≥18 years of age.

          -  Subject is antiretroviral-naïve (defined as having ≤14 days of prior therapy with any
             antiretroviral agent).

          -  Subject has plasma HIV-1 RNA ≥1,000 copies/mL at screening.

          -  Subject is willing and able to understand and provide written informed consent prior
             to participation in this study.

          -  A female is eligible to enter and participate in the study if she is of:

               1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant,
                  including any female who is post-menopausal); or,

               2. Child-bearing potential, has a negative pregnancy test (serum b-HCG) at screen
                  and agrees to one of the following methods of contraception (any contraception
                  method must be used consistently and correctly, i.e., in accordance with both the
                  approved product label and the instructions of a physician):

                    -  Complete abstinence from intercourse from 2 weeks prior to administration of
                       the investigational products, throughout the study, and for at least 2 weeks
                       after discontinuation of all study medications

                    -  Double barrier method (male condom/spermicide, male condom/diaphragm,
                       diaphragm/spermicide). Hormonal contraception will not be permitted in this
                       study

                    -  Any intrauterine device (IUD) with published data showing that the expected
                       failure rate is <1% per year.

                    -  Sterilization (female subject or male partner of female subject). All
                       subjects participating in the study should be counselled on the practice of
                       safer sex.

          -  Prior to randomization, subjects entering Stage 2 must have been screened and be
             negative for the HLA-B*5701 allele. Test may be performed by local laboratory and
             results must be available for source document verification according to local
             practices.

        Exclusion Criteria:

          -  Subject is in the initial acute phase of a CDC Clinical Category C infection at
             Baseline. Subjects may be enrolled provided they are receiving treatment for such
             infections and are clinically improving at the Baseline visit.

          -  Subject is enrolled in one or more investigational drug protocols, which may impact
             HIV RNA suppression.

          -  Subject is, in the opinion of the Investigator, unable to complete the study dosing
             period and protocol evaluations and assessments.

          -  Subject is either pregnant or breastfeeding.

          -  Subject suffers from any serious medical condition (such as pancreatitis, diabetes,
             congestive heart failure, cardiomyopathy or other cardiac dysfunction) which in the
             opinion of the Investigator would compromise the safety of the subject.

          -  Subject has a pre-existing mental, physical, or substance abuse disorder which, in the
             opinion of the Investigator, may interfere with the subject's ability to comply with
             the dosing schedule and protocol evaluations and assessments.

          -  Subject has a history of inflammatory bowel disease or intestinal malignancy,
             intestinal ischemia, malabsorption, or other gastrointestinal dysfunction, which, in
             the opinion of the Investigator, may interfere with drug absorption or render the
             subject unable to take oral medication.

          -  Subject has any acute laboratory abnormality at screening, which, in the opinion of
             the Investigator, would preclude the subject's participation in the study of an
             investigational compound. If subjects are found to have an acute Grade 4 laboratory
             abnormality at screening, this test may be repeated once within the 45-day screening
             window. Any verified Grade 4 laboratory abnormality would exclude a subject from study
             participation.

          -  Subject has an estimated creatinine clearance < 50 mL/min via the Cockcroft-Gault
             method [Cockcroft, 1976]. This test may be repeated once within the 45-day screening
             window.

        NOTE: Creatinine clearance should be estimated using the following formula:

        For serum creatinine concentration in mg/dL:

        For serum creatinine concentration in µmol/L:

          -  Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or hepatic
             impairment as determined by Child-Pugh Score ≥ 5.

          -  Subject is receiving, or has received within 90 days prior to screen, any lipid
             lowering agent, including drugs from the following classes: HMG-CoA reductase
             inhibitors (statins), niacin, fibrates, bile acid sequestrants, and/or fish oil
             supplements. Subjects anticipated to require initiation of therapy with these agents
             within 12 weeks of Baseline are not eligible to participate.

          -  Subject has received treatment with radiation therapy or cytotoxic chemotherapeutic
             agents within 28 days prior to Screening, or has an anticipated need for these agents
             within the study period.

          -  Subject has received treatment with an HIV-1 immunotherapeutic vaccine or any agents
             with documented activity against HIV-1 in vitro within 28 days prior Screening, or an
             anticipated need during the study.

          -  Subjects who require treatment with any of the following medications within 28 days of
             commencement of investigational product, or an anticipated need during the study:

               -  Amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergonovine,
                  ergotamine, flecainide, halofantrine, lidocaine, lovastatin, methylergonovine,
                  midazolam, pimozide, propafenone, quinidine, simvastatin, terfenadine, triazolam.

               -  Carbamazepine, dexamethasone, phenobarbital, phenytoin, primidone, rifampin, St
                  Johns Wort (Hypericum perforatum), troglitazone.

               -  Systemic interleukins or interferons.

          -  Subject has a history of allergy to any of the investigational products or any
             excipients therein.

          -  Subject has evidence of genotypic (as defined by the current ANRS AC-11 algorithm)
             resistance at screening or prior documented evidence of genotypic and/or phenotypic
             (above threshold for reduced susceptibility) resistance to amprenavir/ritonavir,
             abacavir or lamivudine.

          -  Subjects recruited at sites in France will be excluded if:

               -  The subject is not affiliated with or a beneficiary of a social security.

               -  The subject has previously participated in an experimental drug and/or vaccine
                  trial(s) within 60 days or 5 half-lives, or twice the duration of the biological
                  effect of the experimental drug or vaccine - whichever is longer, prior to
                  screening for the study.

               -  The subject will participate simultaneously in another clinical study.
                  Notwithstanding these minimum inclusion and exclusion criteria, investigators are
                  urged to follow country specific guidelines where they exist when making
                  decisions about subjects who are eligible for study participation.