A Pilot Study Assessing the Integrase Inhibitor GSK1349572 in HIV-infected Persons With Virus Resistant to Raltegravir

Infection, Human Immunodeficiency Virus Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00950859
• Other study ID #: 112961
• Status: Completed
• Phase: Phase 2
• First received: July 23, 2009
• Last updated: November 5, 2015
• Start date: August 2009
• Est. completion date: January 2015

Study information

• Verified date: September 2015
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: January 2015
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Immunologic Deficiency Syndromes
• Infection, Human Immunodeficiency Virus

Intervention

Drug:
• GSK1349572 (Cohort I)
50 mg once daily
• GSK1349572 (Cohort II)
50 mg twice daily

Locations

Country	Name	City	State
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
France	GSK Investigational Site	Bordeaux
France	GSK Investigational Site	Le Kremlin-Bicêtre Cedex
France	GSK Investigational Site	Lyon Cedex 03
France	GSK Investigational Site	Marseille
France	GSK Investigational Site	Montpellier Cedex 5
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Paris Cedex 13
Italy	GSK Investigational Site	Milano	Lombardia
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Sevilla
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Fort Lauderdale	Florida
United States	GSK Investigational Site	Fort Lauderdale	Florida
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Santa Fe	New Mexico
United States	GSK Investigational Site	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Canada,  France,  Italy,  Spain, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	The number of participants who acheived Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) <400 c/mL or at least 0.7 log10 c/mL below their Baseline value at Day 11 was assessed. The last observation was carried forward if a participant had missed the Day 11 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 11. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 11.	Baseline (Day 1) and Day 11	No
Secondary	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	Mean change from Baseline in Plasma HIV-1 RNA was assessed on Day 6 to 8, Day 11, and Weeks 4, 12, 24, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 using data of the observed cases. Study Day 1 was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline; Day 6 to 8; Day 11; Weeks 4, 12, 24, 48, 72, 96, from 108 every 12 weeks up to study completion	No
Secondary	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.	The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 4, 12, 24, 48, 72, and 96 per the Food and Drug Administration's Time to Loss of Virological Response (TLOVR) algorithm. Using the TLOVR algorithm, participants are considered to have failed on therapy if they never achieved confirmed RNA levels below the threshold, if they had confirmed rebound of RNA above the threshold, if they made a non-permitted change in background regimen, or if they permanently discontinued investigational product for any reason.	Baseline; Weeks 4, 12, 24, 48, 72, and 96	No
Secondary	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	The number of participants with plasma HIV-1 RNA <400 c/mL or <50 c/mL was assessed at Weeks 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).	From Week 48 every 12 weeks up to study completion	No
Secondary	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	Change from Baseline in CD4+ cell count was assessed at Day 11 and at Weeks 4, 12, 24, 48, 72, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, and 264 . Study Day 1 was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.	Baseline; Day 11; Weeks 4, 12, 24, 48, 72, 96, from Week 108 every 12 weeks up to study completion	No
Secondary	Cmax, Cmin, and Ctau of DTG	The maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), and concentration at the end of a dosing interval (Ctau) of DTG were assessed at Day 10. Blood samples for pharmacokinetic (PK) assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.	Day 10	No
Secondary	C0 Assessment of DTG	The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 10, and Weeks 4 and 24. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose).	Day 10; Weeks 4 and 24	No
Secondary	Tmax of DTG	The tmax is defined as the time of occurrence of the maximum plasma concentration (Cmax). The tmax was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.	Day 10	No
Secondary	AUC0-24 Assessment of DTG	AUC is defined as the area under the DTG concentration-time curve as a measure of drug exposure. AUC(0-24) is defined as the area under the concentration-time curve from time zero (pre-dose) to 24 hours. AUC0-24 of DTG was assessed at Day 10. Blood samples for pharmacokinetic assessments were collected at pre-dose (within 15 minutes prior to dose) and 2, 3, 4, 8, and 24 hours post-dose on Day 10 for DTG 50 mg OD and pre-dose (within 15 minutes prior to dose) and 2, 3, 4 and 8 hours post morning dose and 12 hours post evening dose for DTG 50 mg BID.	Day 10	No
Secondary	Number of Participants With the Indicated HIV-1 Associated Conditions, Excluding Recurrences	The number of participants with post-Baseline emergent HIV-1 disease progression (Acquired immunodeficiency syndrome (AIDS) or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).	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)	No
Secondary	Number of Participants With HIV-1 Associated Disease Progression With the Indicated Shifts to CDC Class C or Death	The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the CDC 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).	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)	No
Secondary	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	PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, =400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.	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	No
Secondary	Number of Participants With the Indicated Genotypic Resistance at Baseline	At Baseline, the integrase genotypic results were used to document resistance to raltegravir (RAL) and for the allocation of participants to one of two genotypic groups according to their RAL signature mutations to ensure a broad range of sensitivity to DTG. These results were not used to pre-define subgroup for analysis.	Baseline	No
Secondary	Median Fold Change in Sensitivity to DTG by the Baseline (Day 1) IN Mutational Group	Summary of median fold change in sensitivity to DTG by Integrase (IN) mutational group was assessed. The IN mutational group comprises of the following mutations: Q148 +2, Q148 +1, mixture (participants with virus containing more than one Y143, Q148 or N155 mutation at Day 1), Y143, N155, other (participants with virus having no mutations at codons 143, 148, or 155 at Day 1). Fold change (FC) is the fold change in 50% Inhibitory Concentration (IC50) relative to the wild-type control virus.	Baseline (Day 1)	No
Secondary	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	An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log10 c/mL unless <400 c/mL or an increase of >= 1.0 log10 c/mL from nadir; and at or after Week 16, =400 c/mL. PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of the original sample.	From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)	No
Secondary	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	The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF.The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined in relation to Baseline plasma HIV-1 RNA levels: at Day 11, a decrease of <0.7 log 10 c/mL unless <400 c/mL; at Weeks 8 to <16, a decrease of <1.0 log 10 c/mL unless <400 c/mL or an increase of >=1.0 log 10 c/mL from nadir; and at or after Week 16, =400 c/mL . PDVF at Day 11 was based on a single plasma HIV-1 RNA evaluation and did not require confirmation. Confirmation testing was required for visits at or after Week 8. For the combination treatment phase, all HIV-1 RNA samples that meet a criterion for suspected PDVF must be confirmed by a second measurement performed at least 1 week but not more than 4 weeks apart from the date of original sample.	From Baseline (Day 1) until study completion (median 605 days for Cohort I, median 1181 days for Cohort II)	No
Secondary	Number of Participants With the Indicated Grade 3 and Grade 4 Clinical Chemistry Toxicities	Hematology and clinical chemistry data were summarized according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Potentially life-threatening. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. The Grade 3 and Grade 4 clinical chemistry toxicities included: Albumin, Alkaline Phosphatase, Amylase, Aspartate Amino Transferase, Carbon dioxide content/Bicarbonate, Creatinine, Creatinine Clearance, Hypercalcemia, Hyperglycaemia, Hyperkalemia, Hypernatremia, Hypocalcemia, Hypoglycaemia, Hypokalemia, Hyponatremia, LDL Cholesterol, Magnesium, Phosphorus inorganic, and Total Bilirubin, Alanine Amino Transferase, Calcium, Chloride, Cholesterol, Creatine Kinase, Direct Bilirubin, Glucose, High Density Lipid (HDL), Cholesterol direct, Lipase, Potassium, Sodium, Total Cholesterol, Triglycerides, Urea/Blood Urine Nitrogen.	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	No
Secondary	Number of Participants With the Indicated Grade 3 and Grade 4 Hematological Toxicities	Hematology and clinical chemistry data were summarized according to Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, dated December 2004. Grade 1, Mild; Grade 2, Moderate; Grade 3, Severe; Grade 4, Potentially life-threatening. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred. The Grade 3 and Grade 4 hematological toxicities included: Hemoglobin, Platelet Count, Total Neutrophils, and White Blood Cell count.	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	No