A Study to Assess Dolutegravir in HIV-infected Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen.

Study Overview
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Brief Summary
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The purpose of this trial is to assess the antiviral activity and safety of a dolutegravir (DTG) containing regimen in HIV-1 infected, antiretroviral therapy (ART)-experienced adults with current or historical failure on an integrase inhibitor (INI) containing regimen. The study will assess DTG 50mg twice daily administered initially with the current failing ART regimen but then with an optimised background ART regimen (OBR) after Day 7. The first analyses will be conducted after the last subject enrolled has completed 24 weeks. Subjects may remain on study after Week 24.

Detailed Description
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ING112574 is a Phase 3, multicentre, open-label, single arm study to assess the antiviral activity and safety of DTG containing regimen in HIV-1 infected ART-experienced adults with historical or current evidence of resistance to RAL or ELV. Initially, a minimum of 100 subjects will be enrolled to receive DTG 50mg twice daily with the current failing regimen for 7 days but with OBR from Day 8. Subjects must also have documented genotypic and/or phenotypic resistance to at least one compound in two or more of the other approved classes of ART but must also be able to include at least one fully active drug in the OBR to be started Day 8. The first data cut will take place after the (approximate) 100th subject enrolled completes the Week 24 visit. Enrollment will continue until a further 50 to 100 subjects have been recruited. All subjects who successfully complete 24 weeks of treatment will continue to have access to DTG until it is locally available as long as they continue to derive clinical benefit. ViiV Healthcare is the sponsor of this study.

Official Title
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A Phase III Study to Demonstrate the Antiviral Activity and Safety of Dolutegravir in HIV-1 Infected Adult Subjects With Treatment Failure on an Integrase Inhibitor Containing Regimen.

Conditions
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Infection, Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: dolutegravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening plasma HIV-1 RNA ≥500 copies/mL ART-experienced, INI-experienced, DTG naïve Experienced virological failure on raltegravir (RAL) or elvitegravir (ELV) regimen The subject's HIV-1 shows resistance to RAL or ELV at Screening or at prior time point of virological failure on RAL or ELV Documented resistance to at least one drug from each of three or more of all approved classes of ART Be able to receive at least one fully active drug as part of the OBR from Day 8 Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol) Willing and able to understand and provide signed and dated written informed consent prior to Screening. Exclusion Criteria: Women who are pregnant or breast feeding An active AIDS-defining condition at Screening (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3) Moderate to severe hepatic impairment as defined by Child-Pugh classification Anticipated need for HCV therapy during the first 24 weeks of the study Recent history of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding Allergy or intolerance to the study drugs or their components or drugs of their class Malignancy within the past 6 months Treatment with an HIV-1 therapeutic vaccine within 90 days of Screening Treatment with radiation therapy, cytotoxic chemotherapeutic agents or any immunomodulator within 28 days of Screening Treatment with any agent, other than licensed ART, with documented activity against HIV-1 in vitro within 28 days of first dose of investigational product Treatment with etravirine, efavirenz, or nevirapine within 14 days of Day 1(etravirine may be used if coadministered with lopinivir/ritonavir or darunavir/ritonavir) Treatment with tipranivir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir within 28 days prior to Screening Verified Grade 4 laboratory abnormality at Screening ALT> 5 times the upper limit of normal (ULN) at Screening ALT ≥ 3X ULN and bilirubin > 1.5 X ULN (with 35% direct bilirubin) at Screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dolutegravir<br>dolutegravir plus background antiretroviral therapy optimised at Day 8 | Drug: dolutegravir<br>* 50 mg twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 | Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8. | Baseline and Day 8 | 
| Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 24 | The number of participants who had viral load <50 copies/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window. | Week 24 | 
| Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48 | The number of participants who had viral load <50 copies/mL at Week 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window. | Week 48 | 
| Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. | From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days) | 
| Number of Participants With Adverse Events of the Indicated Severity, Per the Division of Acquired Immune Deficiency Syndrome (DAIDS) Grading Scale | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening. | From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days) | 
| Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade | The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity. | From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days) | 
| Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade | The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity. | From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 | The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40 and 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI [due to missing data/discontinuation of investigational product prior to the visit window]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window | Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 | 
| Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL From Week 48 Every 12 Weeks up to Study Completion | The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Weeks 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 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. | 
| Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study Completion | Mean change from Baseline in plasma HIV-1 RNA was assesseed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48 , 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study completion (Up to Week 180) | 
| Absolute Values for CD4+ Cell Counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ Cell Counts at Baseline and Weeks 4, 12, 24, and 48 | Absolute values for CD4+ cell counts were assessed at Baseline, Day 8 and Weeks 4, 8, 12, 16, and 24, and absolute values for CD8+ cell counts were assessed at Baseline and Weeks 4, 12, 24, and 48. | Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 | 
| Median Change From Baseline in CD4+ Cell Counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks Until Study Completion | Median change from Baseline in CD4+ cell counts was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180. v | 
| Ratio of CD4+/CD8+ Cell Count at Baseline and Weeks 4, 12, 24, and 48 | The ratio of CD4+/CD8+ cell count (measured in cells/mm^3) was assessed at Baseline and at Weeks 4, 12, 24, and 48. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count. | Baseline; Weeks 4, 12, 24, and 48 | 
| Number of Participants With HIV-1 Disease Progression (Acquired Immune Deficiency Syndrome [AIDS] or Death) | The number of participants with HIV-1 disease progression (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 end of treatment visit for each participant, up to Week 180 (median of 758 days) | 
| Cmax and Ctau of DTG | The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24. | Day 8, Week 4, and Week 24 | 
| AUC(0-tau) and AUC(0-24) of DTG | The area under the time concentration curve over the dosing interval (AUC[0-tau]) and from 0 to 24 hours (AUC[0-24]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24. | Day 8, Week 4, and Week 24 | 
| C0 Assessment of DTG | The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hours post-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population. | Day 8, Week 4, and Week 24 | 
| 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 a <0.5 log10 copies(c)/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 c/mL. PDVF after Day 8 is defined as virological non-respones (decrease in plasma HIV-1 RNA of <1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 c/mL and confirmed plasma HIV-1 RNA levels >=400 c/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 c/mL after prior confirmed suppression to <400 c/mL and confirmed plasma HIV-1 RNA levels >1 log10 c/mL above the nadir value [nadir: >=400 c/mL]). | From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days) | 
| 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 as a <0.5 log10 copies/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is <400 copies/mL. PDVF after Day 8 was defined for virological non-response (decrease in plasma HIV-1 RNA of less than 1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA <400 copies/mL and confirmed plasma HIV-1 RNA levels >=400 copies/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to >=400 copies/mL after prior confirmed suppression to <400 copies/mL and confirmed plasma HIV-1 RNA levels >1 log10 copies/mL above the nadir value, where nadir is >=400 copies/mL). | From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK1349572, resistance to raltegravir or elvitegravir, Integrase inhibitor, ART-experienced, dolutegravir