Clinical trial NCT00450580: HIV-1 Infection Study of Once a Day Versus Twice a Day Protease Inhibitor in Antiretroviral Treatment Naive Adults
Official title: Study of Once-Daily Versus Twice-Daily Fosamprenavir Plus Ritonavir, Administered With Abacavir/Lamivudine Once-Daily in Antiretroviral-Naive HIV-1 Infected Adult Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus I
HIV-1 Infection
Keywords: protease inhibitor,
HIV-1,
Fosamprenavir,
non-HDL cholesterol
ritonavir,
naive,
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2007-03-22
Enrollment: 212
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Percentage of Participants With HIV-1 RNA <400 and >=400 Copies/mL Over 48 Weeks
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With HIV-1 RNA <50 and >=50 Copies/mL by Visit Over 48 Weeks
timeFrame: Week 48
measure: Number of Participants With HIV-1 RNA <400 Copies/mL (Primary Endpoint) at Week 48 Categorised by Baseline Viral Load, TLOVR Analysis
timeFrame: Week 48
measure: Number of Participants With HIV-1 RNA <400 Copies/mL (Primary Endpoint) at Week 48 Categorised by Baseline CD4+ Count, TLOVR Analysis
timeFrame: Week 48
measure: Change From Baseline in Non-HDL Cholesterol at Week 48
timeFrame: Week 48
measure: Number of Protocol-defined Virological Failures With Genotypic and Phenotypic Resistance Changes
timeFrame: Time to virologic failure; Week 4 up to Week 48
measure: Steady-state Levels of Amprenavir (APV) and Ritonavir (RTV) Ctau at Weeks 4, 12, and 24
timeFrame: Weeks 4, 12, and 24
measure: Study Endpoints for a Subset of Subjects Receiving Study Drug Beyond 48 Weeks
timeFrame: Up to 60 weeks
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: GSK Investigational Site
city: Brussel
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Besançon
country: France
facility: GSK Investigational Site
city: Bordeaux
country: France
facility: GSK Investigational Site
city: Clamart
country: France
facility: GSK Investigational Site
city: La Roche Sur Yon cedex 9
country: France
facility: GSK Investigational Site
city: Levallois-Perret
country: France
facility: GSK Investigational Site
city: Lyon Cedex 03
country: France
facility: GSK Investigational Site
city: Nantes
country: France
facility: GSK Investigational Site
city: Nice
country: France
facility: GSK Investigational Site
city: Orléans
country: France
facility: GSK Investigational Site
city: Paris Cedex 10
country: France
facility: GSK Investigational Site
city: Paris Cedex 13
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Saint Denis Cedex 01
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Suresnes Cedex
country: France
facility: GSK Investigational Site
city: Tourcoing
country: France
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Stuttgart
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Fuerth
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Osnabrueck
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Dortmund
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Catanzaro
country: Italy
facility: GSK Investigational Site
state: Calabria
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Brescia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Busto Arsizio (VA)
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Grosseto
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Constanta
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Volgograd
country: Russian Federation
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Elche (Alicante)
country: Spain
facility: GSK Investigational Site
city: La Coruña
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Malaga
country: Spain
facility: GSK Investigational Site
city: Marid
country: Spain
facility: GSK Investigational Site
city: Mataro
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: St Gallen
country: Switzerland
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Ross LL, Robinson MD, Carosi G, et al. Impact of HIV subtype on response and resistance in antiretroviral-naïve adults comparing treatment with once daily versus twice daily Ritonavir boosted Fosamprenavir in combination with Abacavir/Lamivudine. [Drugs Ther Stud]. 2012;2(e1):
citation: Carosi G, Lazzarin A, Stellbrink H, et al. Efficacy and Safety of Fosamprenavir + Ritonavir (FPV/RTV) 700mg/100mg Twice Daily (BID) Versus FPV/RTV 1400mg/100mg Once Daily (QD) with ABC/3TC QD over 24 Weeks. Abstract H-1244, 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2008.
citation: Carosi, Lazzarin, Stellbrink, Moyle, Rugina, Staszewski, Givens, Ross, Granier, Ait-Khaled, Leather, Nichols. Study of once-daily versus twice-daily fosamprenavir plus ritonavir administered with abacavir/lamivudine once daily in antiretroviral-naive HIV-1-infected adult subjects. HIV Clin Trials. 2009 Nov-Dec;10(6):356-67. doi: 10.1310/hct1006-356.
citation: Hughes S, Cuffe RL, Lieftucht A, Garrett Nichols W. Informing the selection of futility stopping thresholds: case study from a late-phase clinical trial. Pharm Stat. 2009 Jan-Mar;8(1):25-37. doi: 10.1002/pst.323.