HIV-1 Infection Study of Once a Day Versus Twice a Day Protease Inhibitor in Antiretroviral Treatment Naive Adults

HIV-1 Infection Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00450580
• Other study ID #: APV109141
• Status: Completed
• Phase: Phase 3
• First received: March 21, 2007
• Last updated: May 31, 2012
• Start date: March 2007
• Est. completion date: August 2008

Study information

• Verified date: April 2012
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory AgencyBelgium: Federal Agency for Medicinal Products and Health ProductsSpain: Ministry of Health and ConsumptionFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesRomania: National Medicines AgencyItaly: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 212
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Communicable Diseases
• HIV Infections
• HIV-1 Infection
• Immunologic Deficiency Syndromes
• Infection
• Infection, Human Immunodeficiency Virus I

Intervention

Drug:
• fosamprenavir/ritonavir
Fosamprenavir (FPV, TELZIR) is currently licensed in Europe for twice daily (BID) dosing in combination with ritonavir (RTV, Norvir) as a boosting agent

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Antwerpen
Belgium	GSK Investigational Site	Brussel
Belgium	GSK Investigational Site	Gent
France	GSK Investigational Site	Besançon
France	GSK Investigational Site	Bordeaux
France	GSK Investigational Site	Clamart
France	GSK Investigational Site	La Roche Sur Yon cedex 9
France	GSK Investigational Site	Levallois-Perret
France	GSK Investigational Site	Lyon Cedex 03
France	GSK Investigational Site	Nantes
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Orléans
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris
France	GSK Investigational Site	Paris Cedex 10
France	GSK Investigational Site	Paris Cedex 13
France	GSK Investigational Site	Saint Denis Cedex 01
France	GSK Investigational Site	Strasbourg
France	GSK Investigational Site	Suresnes Cedex
France	GSK Investigational Site	Tourcoing
Germany	GSK Investigational Site	Dortmund	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Fuerth	Bayern
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Hannover	Niedersachsen
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Osnabrueck	Niedersachsen
Germany	GSK Investigational Site	Stuttgart	Baden-Wuerttemberg
Italy	GSK Investigational Site	Brescia	Lombardia
Italy	GSK Investigational Site	Busto Arsizio (VA)	Lombardia
Italy	GSK Investigational Site	Catanzaro	Calabria
Italy	GSK Investigational Site	Grosseto	Toscana
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Bucharest
Romania	GSK Investigational Site	Constanta
Romania	GSK Investigational Site	Iasi
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	Volgograd
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Elche (Alicante)
Spain	GSK Investigational Site	La Coruña
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Malaga
Spain	GSK Investigational Site	Marid
Spain	GSK Investigational Site	Mataro
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Sevilla
Spain	GSK Investigational Site	Valencia
Switzerland	GSK Investigational Site	St Gallen
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	London

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Romania,  Russian Federation,  Spain,  Switzerland,  United Kingdom, 

References & Publications (2)

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.

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):

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With HIV-1 RNA <400 and >=400 Copies/mL Over 48 Weeks	A blood sample was drawn to determine the amount of HIV-1 RNA virus in copies/mL at week 48. The percentage of participants with HIV-1 RNA <400 copies/mL at Week 48 was determined by the Time to Loss Of Virologic Response (TLOVR) algorithm.	Week 48	No
Secondary	Percentage of Participants With HIV-1 RNA <50 and >=50 Copies/mL by Visit Over 48 Weeks	A blood sample was drawn to determine the amount of HIV-1 RNA virus in copies/mL at week 48. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 48 was determined by the TLOVR algorithm	Week 48	No
Secondary	Number of Participants With HIV-1 RNA <400 Copies/mL (Primary Endpoint) at Week 48 Categorised by Baseline Viral Load, TLOVR Analysis	The number of participants with HIV-1 RNA <400 copies/mL at Week 48 was determined (by analysis of blood draw) and categorised by baseline viral load (BVL).	Week 48	No
Secondary	Number of Participants With HIV-1 RNA <400 Copies/mL (Primary Endpoint) at Week 48 Categorised by Baseline CD4+ Count, TLOVR Analysis	The number of participants with HIV-1 RNA <400 copies/mL at week 48 was determined (by analysis of blood draw) and categorised by baseline CD4+ count.	Week 48	No
Secondary	Change From Baseline in Non-HDL Cholesterol at Week 48	Blood samples were drawn to determine the non-HDL cholesterol levels at Week 48. The mean absolute change in non-HDL cholesterol was defined as the Week 48 levels minus levels at baseline.	Week 48	Yes
Secondary	Number of Protocol-defined Virological Failures With Genotypic and Phenotypic Resistance Changes	A blood sample was drawn at the time of confirmation of virological failure, and mutations present in the virus were identified and compared to those found in the blood sample at baseline. New mutations were tabulated by drug class. RT, reverse transcriptase. Virological failure could occur anytime from Week 4 to Week 48.	Time to virologic failure; Week 4 up to Week 48	No
Secondary	Steady-state Levels of Amprenavir (APV) and Ritonavir (RTV) Ctau at Weeks 4, 12, and 24	Blood samples were drawn at Weeks 4, 12, and 24 to determine plasma concentrations (Ctau) of APV and RTV	Weeks 4, 12, and 24	No
Secondary	Study Endpoints for a Subset of Subjects Receiving Study Drug Beyond 48 Weeks	Adaptive two-stage design study up to 48 weeks. N=200, expanding to 728 if continuation criteria were achieved based on a 24-week interim analysis. The initial 200 participants would continue until the last subject of the expanded cohort reached 48 weeks and would constitute the subset. As continuation criteria were not achieved, the study did not proceed to the second stage, and full analysis was performed on the initial 200 participants only.	Up to 60 weeks	No