Clinical trial NCT00549198: KIVEXA Vs TRUVADA, Both Administered With Efavirenz, In ART-Naive Subjects
Official title: Study of Once-Daily Abacavir/Lamivudine Versus Tenofovir/Emtricitabine, Administered With Efavirenz in Antiretroviral-Naive, HIV-1 Infected Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Infection, Human Immunodeficiency Virus I
HIV Infection
Keywords: tenofovir
HIV
efavirenz
naive
lamivudine
abacavir
emtricitabine
renal
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-10-25
Enrollment: 392
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: Recently, the fixed-dose combinations (FDC) KIVEXA™ (abacavir/lamivudine) and TRUVADA (tenofovir disoproxil fumarate/emtricitabine) have facilitated the usage of once-daily regimens. However data from head-to-head randomized trials comparing these two FDCs as part of an initial regimen are not available at present. The long-term toxicity profiles of these regimens are of particular importance, as treatment of HIV is currently life-long and therefore, minimizing long-term toxicity and maximizing adherence and duration of regimen maintenance are critical therapy objectives.

The primary endpoint is estimated glomerular filtration rate (GFR), as measured by the modified diet in renal disease (MDRD) equation, a validated estimate of renal function.

Detailed description: ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship.

Eligibility criteria: Inclusion Criteria:

* Subject is at least 18 years of age.
* Subject is antiretroviral-naïve (defined as having no previous therapy with any NNRTI and 14 days of prior therapy with any other antiretroviral).
* Subject has plasma HIV-1 RNA 1,000 copies/mL at screening. This test may be repeated once within the 45-day screening window.
* 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 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 considered adequate for inclusion into 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).

* Prior to randomization, subjects 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.
* 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 a serious medical condition, which in the opinion of the Investigator would compromise the safety of the subject.
* Subject has a history of inflammatory bowel disease or other gastrointestinal dysfunction.
* Subject has any acute laboratory abnormality at screening.
* Subject has an estimated creatinine clearance within the screening period \<50mL/min via the Cockcroft-Gault method.
* Alanine aminotransferase (ALT) \>5 times the upper limit of normal.
* Subjects with a history of thyroid disease, hyperparathyroid disease, chronic hyper or hypocalcemia, vitamin D deficiency, or receiving thyroid hormone or parathyroid hormone replacement within 28 days prior to screening.
* Subjects with a history of systemic inflammatory arthritis.
* Subjects who are hepatitis B positive at screening.
* Subject requires treatment with radiation therapy or cytotoxic chemotherapeutic agents.
* 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 to 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:
* Medications with significant drug-drug interactions with efavirenz:voriconazole, terfenadine, astemizole, cisapride, ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine), midazolam, triazolam, St. John's wort, carbamazepine, phenytoin, phenobarbital, rifampin, pimozide, bepridil
* Medications which may impact on bone mineral density: oral or systemic corticosteroids, anticonvulsants, heparin, warfarin, cyclosporine, bisphosphonates, calcitonin, parathyroid hormone, Vitamin D supplements and analogues, Calcium supplements, oestrogen or progesterone replacement (oral hormonal contraception permitted), raloxifene, tamoxifen, testosterone or anabolic steroid replacement/supplements.
* Systemic interleukins or interferons
* Subject has a history of allergy to any of the protocol-specified medications or any excipients therein.
* Subject has evidence of genotypic resistance at screening (according to central lab interpretation) or prior documented evidence of genotypic and/or phenotypic (above threshold for reduced susceptibility) resistance to any of the following drugs: efavirenz, abacavir, lamivudine, tenofovir, emtricitabine.
* Subjects who are unsuitable for DEXA scanning should be excluded, including 1) Less than three vertebra in the range of L1 to L4 that are suitable for BMD measurement by DEXA, or 2) Bilateral hip replacement.
* 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.

Primary outcomes:
measure: Mean Change From Baseline in Estimated Glomerular Filtration Rate (GFR), Calculated by Modification of Diet in Renal Disease (MDRD) Equation, at Week 48
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Mean Change From Baseline in Estimated Glomerular Filtration Rate (GFR), Calculated by Modification of Diet in Renal Disease (MDRD) Equation, at Week 24
timeFrame: Baseline, Week 24
measure: Mean Change From Baseline in Estimated Glomerular Filtration Rate (GFR), Calculated by Modification of Diet in Renal Disease (MDRD) Equation, at Week 96
timeFrame: Baseline, Week 96
measure: Mean Change From Baseline in Estimated GFR, Calculated by Cockcroft-Gault Equation, at Week 24
timeFrame: Baseline, Week 24
measure: Mean Change From Baseline in Estimated GFR, Calculated by Cockcroft-Gault Equation, at Week 48
timeFrame: Baseline, Week 48
measure: Mean Change From Baseline in Estimated GFR, Calculated by Cockcroft-Gault Equation, at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With Decline From Baseline in Estimated GFR, Calculated by MDRD and Cockcroft-Gault Equations, of >=10 mL/Min/1.73 m^2 (mL/Min for Cockcroft-Gault), >=20 mL/Min/1.72 m^2, >=10%, and >=20% at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With Decline From Baseline in Estimated GFR, Calculated by MDRD and Cockcroft-Gault Equations, of >=10 mL/Min/1.73m^2 (mL/Min for Cockcroft-Gault), >=20 mL/Min/1.72m^2, >=10%, and >=20% at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With Decline From Baseline in Estimated GFR, Calculated by MDRD and Cockcroft-Gault Equations, of >=10 mL/Min/1.73m^2 (mL/Min for Cockcroft-Gault), >=20 mL/Min/1.72m^2, >=10%, and >=20% at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With National Kidney Foundation Chronic Kidney Disease Stage 1, 2, 3, 4, or 5 Categories of Renal Function at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With National Kidney Foundation Chronic Kidney Disease Stage 1, 2, 3, 4, or 5 Categories of Renal Function at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With National Kidney Foundation Chronic Kidney Disease Stage 1, 2, 3, 4, or 5 Categories of Renal Function at Week 96
timeFrame: Baseline, Week 96
measure: Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD), Measured by Dual-energy X-ray Absorptiometry (DXA), at Week 24
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline in Hip Bone Mineral Density (BMD), Measured by Dual-energy X-ray Absorptiometry (DXA), at Week 24
timeFrame: Baseline, Week 24
measure: Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD), Measured by Dual-energy X-ray Absorptiometry (DXA), at Week 48
timeFrame: Baseline, Week 48
measure: Percent Change From Baseline in Hip Bone Mineral Density (BMD), Measured by Dual-energy X-ray Absorptiometry (DXA), at Week 48
timeFrame: Baseline, Week 48
measure: Percent Change From Baseline in Lumbar Spine Bone Mineral Density (BMD), Measured by Dual-energy X-ray Absorptiometry (DXA), at Week 96
timeFrame: Baseline, Week 96
measure: Percent Change From Baseline in Hip Bone Mineral Density (BMD), Measured by Dual-energy X-ray Absorptiometry (DXA), at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With a Decline From Baseline in Lumbar Spine and Hip Bone Mineral Density (BMD) >=2.0% and >=6.0% at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With a Decline From Baseline in Lumbar Spine and Hip Bone Mineral Density (BMD) >=2.0% and >=6.0% at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With a Decline From Baseline in Lumbar Spine and Hip Bone Mineral Density (BMD) >=2.0% and >=6.0% at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants Meeting World Health Organization (WHO) Criteria for Osteopenia (T-score of -2.5 to -1.0) and Osteoporosis (T-score of <-2.5) at Week 24
timeFrame: Week 24
measure: Number of Participants Meeting World Health Organization (WHO) Criteria for Osteopenia (T-score of -2.5 to -1.0) and Osteoporosis (T-score of <-2.5) at Week 48
timeFrame: Week 48
measure: Number of Participants Meeting World Health Organization (WHO) Criteria for Osteopenia (T-score of -2.5 to -1.0) and Osteoporosis (T-score of <-2.5) at Week 96
timeFrame: Week 96
measure: Number of Participants Experiencing an Adverse Event (AE) Leading to Discontinuation by Week 24
timeFrame: Baseline to Week 24
measure: Number of Participants Experiencing an Adverse Event (AE) Leading to Discontinuation by Week 48
timeFrame: Baseline to Week 48
measure: Number of Participants Experiencing an Adverse Event (AE) Leading to Discontinuation by Week 96
timeFrame: Baseline to Week 96
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting Total Cholesterol at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting Total Cholesterol at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting Total Cholesterol at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Low-density Lipoprotein (LDL) at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Low-density Lipoprotein (LDL) at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Low-density Lipoprotein (LDL) at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting High-density Lipoprotein (HDL) at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting High-density Lipoprotein (HDL) at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting High-density Lipoprotein (HDL) at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting Triglycerides at Week 24
timeFrame: Baseline, Week 24
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting Triglycerides at Week 48
timeFrame: Baseline, Week 48
measure: Number of Participants With the Indicated Change From Baseline in National Cholesterol Education Program (NCEP) Thresholds for Fasting Triglycerides at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants With the Indicated Treatment-emergent Division of AIDS (DAIDS) Toxicities at Week 24
timeFrame: Week 24
measure: Number of Participants With the Indicated Treatment-emergent Division of AIDS (DAIDS) Toxicities at Week 48
timeFrame: Week 48
measure: Number of Participants With the Indicated Treatment-emergent Division of AIDS (DAIDS) Toxicities at Week 96
timeFrame: Week 96
measure: Number of Participants With HIV-1 RNA <50 Copies/Milliliter (c/mL) and 400 c/mL at Week 24
timeFrame: Week 24
measure: Number of Participants With HIV-1 RNA <50 Copies/Milliliter (c/mL) and 400 c/mL at Week 48
timeFrame: Week 48
measure: Number of Participants With HIV-1 RNA <50 Copies/Milliliter (c/mL) and 400 c/mL at Week 96
timeFrame: Week 96
measure: Change From Baseline in Cluster Difference 4 (CD4+) Cell Count at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Cluster Difference 4 (CD4+) Cell Count at Week 48
timeFrame: Baseline, Week 48
measure: Change From Baseline in Cluster Difference 4 (CD4+) Cell Count at Week 96
timeFrame: Baseline, Week 96
measure: Number of Participants Classified as Protocol-defined Failures With Treatment-emergent Resistance to Study Drug in the Indicated Viruses at Week 96
timeFrame: Week 96
measure: Number of Participants Who Indicated "Yes" or "No" to the Question of Whether Unplanned Healthcare Resources Were Utilized
timeFrame: Baseline to Week 96
Other outcomes:
measure: Exploratory Analysis of Change From Baseline in Albumin as a Ratio to Urine Creatinine at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in Beta 2 Microglobulin (B2M) as a Ratio to Urine Creatinine at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in N-acetyl-B-glucosaminidase (NAG) as a Ratio to Urine Creatinine at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in Retinol Binding Protein (RBP) as a Ratio to Urine Creatinine at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in Procollagen Type 1 Amino-terminal Propeptide (P1NP) at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in Type 1 Collagen Cross-linked C-telopeptide at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in Osteocalcin at Week 96
timeFrame: Baseline, Week 96
measure: Exploratory Analysis of Change From Baseline in Bone Specific Alkaline Phosphatase (BSAP) at Week 96
timeFrame: Baseline, Week 96
Locations:
city: Innsbruck
country: Austria
facility: GSK Investigational Site
city: Salzburg
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
facility: GSK Investigational Site
city: Brugge
country: Belgium
facility: GSK Investigational Site
city: Bruxelles
country: Belgium
facility: GSK Investigational Site
city: Charleroi
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Aalborg
country: Denmark
facility: GSK Investigational Site
city: Aarhus N
country: Denmark
facility: GSK Investigational Site
city: Hvidovre
country: Denmark
facility: GSK Investigational Site
city: Koebenhavn
country: Denmark
facility: GSK Investigational Site
city: Odense C
country: Denmark
facility: GSK Investigational Site
city: Garches
country: France
facility: GSK Investigational Site
city: Levallois-Perret
country: France
facility: GSK Investigational Site
city: Saint Denis Cedex 01
country: France
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Duesseldorf
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Dublin
country: Ireland
facility: GSK Investigational Site
city: Dublin
country: Ireland
facility: GSK Investigational Site
city: Ferrara
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Modena
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Rimini
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Legnano (MI
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: Torino
country: Italy
facility: GSK Investigational Site
state: Piemonte
city: Riga
country: Latvia
facility: GSK Investigational Site
city: Alkmaar
country: Netherlands
facility: GSK Investigational Site
city: Den Haag
country: Netherlands
facility: GSK Investigational Site
city: Groningen
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
city: Amadora
country: Portugal
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Basel
country: Switzerland
facility: GSK Investigational Site
city: Bern
country: Switzerland
facility: GSK Investigational Site
city: Lausanne
country: Switzerland
facility: GSK Investigational Site
city: St Gallen
country: Switzerland
facility: GSK Investigational Site
city: Zuerich
country: Switzerland
facility: GSK Investigational Site
city: Zurich
country: Switzerland
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
state: Lancashire
city: Woolwich, London
country: United Kingdom
facility: GSK Investigational Site
state: London
city: Edinburgh
country: United Kingdom
facility: GSK Investigational Site
state: Midlothian
city: Brighton
country: United Kingdom
facility: GSK Investigational Site
state: Sussex East
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Birmingham
country: United Kingdom
facility: GSK Investigational Site
city: Farnworth, Bolton
country: United Kingdom
facility: GSK Investigational Site
city: Gloucester
country: United Kingdom
facility: GSK Investigational Site
city: Leicester
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
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
city: Middlesborough
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Post FA, Moyle GJ, Stellbrink HJ, Domingo P, Podzamczer D, Fisher M, Norden AG, Cavassini M, Rieger A, Khuong-Josses MA, Branco T, Pearce HC, Givens N, Vavro C, Lim ML. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 2010 Sep;55(1):49-57. doi: 10.1097/QAI.0b013e3181dd911e.