Clinical trial NCT00951015: A Dose Ranging Trial of GSK1349572 and 2 NRTI in HIV-1 Infected, Therapy Naive Subjects
Official title: A Phase IIb Study to Select a Once Daily Dose of GSK1349572 Administered With Either Abacavir/Lamivudine or Tenofovir/Emtricitabine in HIV-1 Infected Antiretroviral Therapy Naive Adult Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus
Keywords: GSK1349572
emtricitabine
tenofovir
efavirenz
abacavir
antiretroviral therapy naive
dose selection
HIV-1 Infection
integrase inhibitor
HIV infection
once daily
lamivudine
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Shionogi
name: GlaxoSmithKline
First posted: 2009-08-03
Enrollment: 208
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 Phase IIb study in HIV-infected antiretroviral naive subjects will select an optimal once daily dose of GSK1349572 from a range of doses for future evaluation.

Detailed description: This Phase IIb study in HIV-infected antiretroviral naive adult subjects will include a dose-ranging evaluation of GSK1349572 10mg, 25mg and 50mg once daily blinded doses and a control arm of open label efavirenz 600mg once daily. Background ART for all study subjects will be chosen by the investigators and will be either Truvada or Epzicom/Kivexa. Data from the three doses of GSK1349572 will be compared on the basis of antiviral activity, safety/tolerability and pharmacokinetics over 16-24 weeks.

Several planned interim analyses will evaluate data in real time; any doses considered inferior will be dropped and subjects on those doses of GSK1349572 will have the option to switch to either the highest dose still under investigation or the selected dose. Subjects will be able to remain in the study, unless they reach a stopping criterion, for at least 96 weeks.

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:

* HIV-1 infected male or female adults at least 18 years of age. Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol);
* HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to 1000copies/mL;
* CD4+ cell count greater than or equal to 200cells/mm3 (or higher as local guidelines dictate);
* ART-naive (less than or equal to 10 days of prior therapy with any antiretroviral agent). Any previous exposure to an HIV integrase inhibitor other than GSK1349572 will be exclusionary.
* No evidence of viral resistance to any antiretroviral drug indicative of primary transmitted resistance at screening;
* Able to understand and comply with protocol requirements;
* Able to provide written informed consent prior to screening;
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Note: Subjects starting abacavir as part of the NRTI backbone must have been screened and be negative for the HLA-B\*5701 allele.

Exclusion Criteria:

* Any pre-existing or serious mental or physical disorder which could compromise ability to comply with the protocol or compromise subject safety;
* Women who are pregnant or breastfeeding;
* An active AIDS-defining condition at the screening visit;
* Previous participation in an experimental drug and/or vaccine trial(s) within 30 days or 5 half-lives;
* History of clinically relevant pancreatitis or hepatitis within the previous 6 months, including HBsAg positive result. Asymptomatic HCV infection will not be exclusionary, however subject who will require HCV therapy during the trial should be excluded. Any subject with a history of liver cirrhosis with or without hepatitis viral co-infection will be excluded.
* Any condition which could interfere with the absorption, distribution, metabolism or excretion of the drug;
* Any acute or Grade 4 laboratory abnormality at screening;
* History of upper gastrointestinal bleed and/or subjects with active peptic ulcer disease;
* Estimated creatinine clearance \<50 mL/min;
* Alanine aminotransferase (ALT) greater than or equal to 5 times ULN;
* Alanine aminotransferase (ALT) greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with \>35% direct bilirubin);
* Lipase greater than or equal to 3xULN;
* Hemoglobin \< 100 g/L(10 g/dL);
* History of allergy to the study drugs or their components or drugs of their class;
* Treatment with radiation therapy, cytotoxic chemotherapeutic agents, any agents with activity against HIV-1 or immunomodulators within 28 days prior to screening;
* Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to screening;
* History of protocol-defined cardiac diseases;
* Personal or family history of prolonged QT syndrome;
* Any clinically significant finding, as specified in the protocol, on electrocardiograph (ECG);
* Significant blood loss in excess of 500 mL within a 56 day period prior to screening visit;
* Immunization within 30 days prior to first dose of investigational product;
* French subjects: The subject has participated in any study using an investigational drug during the previous 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 or the subject will participate simultaneously in another clinical study.

Primary outcomes:
measure: Number of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 16
timeFrame: Week 16
Secondary outcomes:
measure: Viral Change Over the Initial 2 Weeks of Treatment
timeFrame: Baseline and Week 2
measure: Change From Baseline in HIV-1 RNA at the Indicated Time Points
timeFrame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96
measure: Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Counts at the Indicated Time Points
timeFrame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96
measure: Number of Participants With New HIV-associated Conditions of the Indicated Class
timeFrame: From Baseline up to Week 96
measure: Number of Participants With the Indicated Type of HIV-1 Disease Progression (AIDS or Death)
timeFrame: From Baseline up to Week 96
measure: Number of Participants With Plasma HIV-1 RNA <50 c/mL
timeFrame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96
measure: Number of Participants With Plasma HIV-1 RNA <400 c/mL
timeFrame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96
measure: Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Events (SAE)
timeFrame: From Baseline up to Week 96/Early Withdrawal
measure: Number of Participants With the Indicated Grade 1 to Grade 4 Treatment-emergent Clinical Chemistry and Hematology Toxicities
timeFrame: From Baseline up to Week 96/Early Withdrawal
measure: Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance
timeFrame: From Baseline up to Week 96/Early Withdrawal
measure: Number of Participants With the Indicated Treatment-emergent Major Mutations of Other Classes Detected at the Time of Protocol-defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance
timeFrame: From Baseline up to Week 96/Early Withdrawal
measure: Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) at the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance
timeFrame: From Baseline up to Week 96/Early Withdrawal
measure: Plasma DTG Concentration
timeFrame: Week 2, Week 12, and Week 24
measure: AUC(0-tau) of DTG
timeFrame: Pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2
measure: Maximal Concentration (Cmax), Minimal Concentration (Cmin), and Concentration at the End of Dosing Interval (Ctau) of DTG
timeFrame: Pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2
measure: Pre-dose Concentration (C0) and C0 Avg of DTG
timeFrame: Week 2, Week 12, and Week 24
measure: Time to Maximal Drug Concentration (Tmax) of DTG
timeFrame: Pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2
measure: Relationship Between the Change From Baseline in Plasma HIV-1 RNA at Week 2 and the Indicated Plasma DTG PK Parameters
timeFrame: Week 2
measure: Relationship Between the Change From Baseline in CD4+ Cell Counts at Week 96 and the Indicated Plasma DTG PK Parameters
timeFrame: Week 96
measure: Relationship Between the Indicated Safety Parameters at Week 96 and the Indicated Plasma DTG PK Parameters
timeFrame: Week 96
measure: Relationship Between Gastrointestinal System Organ Class AEs of Special Interest at Week 96 and the Indicated Plasma DTG PK Parameters
timeFrame: Week 96
Other outcomes:
measure: Change From Baseline in Cluster of Differentiation 8+ (CD8+) Cell Counts at the Indicated Time Points
timeFrame: Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Bakersfield
country: United States
facility: GSK Investigational Site
state: California
city: Long Beach
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Santa Fe
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Lyon cedex 04
country: France
facility: GSK Investigational Site
city: Montpellier Cedex 5
country: France
facility: GSK Investigational Site
city: Nantes
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: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Bergamo
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Brescia
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: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Barcelona
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
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, Rockstroh JK, Almond S, Song I, Brothers C, Min S. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012 Feb;12(2):111-8. doi: 10.1016/S1473-3099(11)70290-0. Epub 2011 Oct 20.