Clinical trial NCT00950859: A Pilot Study Assessing the Integrase Inhibitor GSK1349572 in HIV-infected Persons With Virus Resistant to Raltegravir
Official title: A Pilot Study to Assess the Antiviral Activity of GSK1349572 Containing Regimen in Antiretroviral Therapy (ART)-Experienced, HIV-1-infected Adult Subjects With Raltegravir Resistance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Infection, Human Immunodeficiency Virus
Keywords: treatment experienced
HIV Infection
raltegravir resistance
GSK1349572
optimized background regimen
integrase inhibitor
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2009-08-03
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Integrase is an enzyme produced by HIV so that the virus can multiply in the human body. GSK1349572 is a new drug in the integrase inhibitor class that prevents the enzyme from working properly and therefore prevents the virus from multiplying.

GSK1349572 has shown to be effective against viruses in a short-term monotherapy study in adults with no previous exposure to integrase inhibitors. The purpose of this study is to determine whether GSK1349572 is effective in the treatment of HIV-infected patients who no longer respond to treatment with the approved integrase inhibitor raltegravir and carry viruses with resistance to this drug. The safety and efficacy of GSK1349572 50mg once daily in combination with the background HIV drugs previously administered (unless discontinuation of a particular drug is required) will be assessed over 10 days (functional monotherapy phase), followed by the evaluation of the safety and efficacy of GSK1349572 given with a new optimised background regimen from Day 11 through at least Week 24.

Detailed description: Study (ING112961) is a Phase IIb, multicentre, open-label, single arm, two cohorts, pilot study to assess the antiviral activity of GSK1349572 containing regimen in HIV-1 infected ART-experienced adults with raltegravir (RAL) resistance. The study will include approximately 50 ART-experienced subjects with either current or past virologic failure to RAL. All subjects must harbour isolates with RAL resistance mutations at Screening. Subjects should also have documented genotypic and/or phenotypic resistance to at least one compound from each of three or more of the approved classes of ART (including integrase inhibitors \[INIs\]). Subjects with current RAL virologic failure will substitute RAL with GSK1349572 50mg once daily and continue the remaining components of their failing regimen through Day 10. Subjects with historical RAL virologic failure will add GSK1349572 50mg once daily to their failing regimen through Day 10. On Day 11 all subjects will continue GSK1349572 and optimize their background therapy. Antiviral activity, safety and tolerability of GSK1349572 will be evaluated at Day 11 and over time through at least Week 24.

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 with a plasma HIV-1 RNA \> 1,000 copies/mL at study entry. Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol)
* ART-experienced (defined as on stable ART for at least the last 2 months) and is either currently experiencing virologic failure to RAL or experienced virologic failure to RAL \> 8 weeks prior to Screening
* Must have documented RAL genotypic resistance on study entry genotype
* Must have documented genotypic or phenotypic resistance to at least one drug from each of three or more of all approved classes of ART
* For Cohort II, Subjects MUST be able to receive at least one fully active drug as part of the Day 11 optimised background regimen
* Willing and able to understand and provide signed and dated written informed consent prior to screening

Exclusion Criteria:

* Any pre-existing mental, physical, or substance abuse disorder which, 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
* Currently take and/or anticipated need for EFV, NVP, FPV/RTV or TPV/RTV during the study
* Treatment with any of the following medications within 15 days of starting study drug, or anticipated to need, during the course of the study: Etravirine (unless co-administered with LPV/RTV or DRV/RTV), rifampin, rifabutin, phenytoin, phenobarbital, barbiturates, glucocorticoids, modafinil, oxcarbazepine, pioglitazone, troglitazone, carbamazepine, St. Johns wort
* Previous participation in an experimental drug and/or vaccine trial(s) within 30 days or 5 half-lives
* History of ongoing or clinically relevant pancreatitis or hepatitis within the previous 6 months
* Expected to require treatment for HCV infection during the first 24 weeks of the study
* Evidence of cirrhosis with or without hepatitis viral co-infection
* History of upper gastrointestinal bleed and/or active peptic ulcer disease
* Screening haemoglobin \<10g/dL (100g/L)
* Subject suffers from a serious medical condition which could compromise the safety of the subject.
* Any condition that could interfere with the absorption, distribution, metabolism or excretion of the drug or render the subject unable to take oral medication
* Screening lipase 3 times the upper limit of normal (ULN)
* Any acute or Grade 4 laboratory abnormality at screening
* Screening alanine aminotransferase (ALT) \>5xULN
* Screening ALT 3xULN and bilirubin 1.5xULN (with 35% direct bilirubin)
* Personal or family history of prolonged QT syndrome.
* Any clinically significant finding, as specified in the protocol, on screening or baseline electrocardiograph (ECG)
* History of allergy to the study drugs or their components or drugs of their class
* Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days prior to screening, or future need of treatment with these agents during the study
* Treatment with immunomodulators within 28 days prior to screening or subject has received an HIV-1 vaccine within 90 days prior to screening

Primary outcomes:
measure: Number of Participants Who Achieved HIV-1 RNA <400 Copies (c)/Milliliter (mL) or at Least 0.7 log10 c/mL Below Their Baseline Value at Day 11
timeFrame: Baseline (Day 1) and Day 11
Secondary outcomes:
measure: Mean Change From Baseline in Plasma HIV-1 RNA at Day 6 to 8, Day 11, Weeks 4, 12, 24, 48, 72, 96, From Week 108 Every 12 Weeks up to Study Completion
timeFrame: Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, 96, from 108 every 12 weeks up to study completion
measure: Number of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL at Baseline and Weeks 4, 12, 24, 48, 72, and 96: TLOVR Analysis.
timeFrame: Baseline; Weeks 4, 12, 24, 48, 72, and 96
measure: Proportion of Participants Who Achieved Plasma HIV-1 RNA <400 c/mL and <50 c/mL From Week 48 Every 12 Weeks up to Study Completion
timeFrame: From Week 48 every 12 weeks up to study completion
measure: Change From Baseline in CD4+ Cell Count at Day 11 and Weeks 4, 12, 24, 48, 72, 96, Week 108 Every 12 Weeks up to Study Completion
timeFrame: Baseline; Day 11; Weeks 4, 12, 24, 48, 72, 96, from Week 108 every 12 weeks up to study completion
measure: Cmax, Cmin, and Ctau of DTG
timeFrame: Day 10
measure: C0 Assessment of DTG
timeFrame: Day 10; Weeks 4 and 24
measure: Tmax of DTG
timeFrame: Day 10
measure: AUC0-24 Assessment of DTG
timeFrame: Day 10
measure: Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences
timeFrame: From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
measure: Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death
timeFrame: From the day of the first dose of study drug until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
measure: Number of Participants (Cumulative) With Protocol-defined Virological Failure (PDVF) at Day 11 and Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, 96, Week 108 Every 12 Weeks up to Study Completion
timeFrame: Day 11; Weeks 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84, 96, from Week 108 every 12 weeks up to study completion
measure: Number of Participants With the Indicated Genotypic Resistance at Baseline
timeFrame: Baseline
measure: Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group
timeFrame: Baseline (Day 1)
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 (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
measure: Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance
timeFrame: From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)
measure: Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities
timeFrame: From start of study treatment until the end of treatment visit for each participant, up to Week 264 for Cohort I and up to Week 228 for Cohort II
measure: Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities
timeFrame: From start of study treatment until the end of treatment visit for each participant, up to Week 264 for Cohort I and up to Week 228 for Cohort II
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
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: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Santa Fe
country: United States
facility: GSK Investigational Site
state: New Mexico
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Bordeaux
country: France
facility: GSK Investigational Site
city: Le Kremlin-Bicêtre Cedex
country: France
facility: GSK Investigational Site
city: Lyon Cedex 03
country: France
facility: GSK Investigational Site
city: Marseille
country: France
facility: GSK Investigational Site
city: Montpellier Cedex 5
country: France
facility: GSK Investigational Site
city: Nice
country: France
facility: GSK Investigational Site
city: Paris Cedex 13
country: France
facility: GSK Investigational Site
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
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: Sevilla
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, Poizot-Martin I, Richmond G, Soriano V, Ait-Khaled M, Fujiwara T, Huang J, Min S, Vavro C, Yeo J; VIKING Study Group. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2013 Mar 1;207(5):740-8. doi: 10.1093/infdis/jis750. Epub 2012 Dec 7.