Dose-finding Study of GSK2248761 in Antiretroviral Therapy-experienced Subjects With NNRTI-resistant HIV Infection

Study Overview
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Brief Summary
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This 48 week, phase 2b study in 150 HIV-1 infected antiretroviral therapy experienced adult subjects consists of a dose-ranging evaluation of GSK2248761 at blinded doses of 100 mg and 200 mg once daily with a control arm of open-label etravirine (ETV) 200 mg twice daily. The background ART for all three arms will be darunavir/ritonavir (DRV/r) 600 mg/100 mg twice daily plus raltegravir (RAL) 400 mg twice daily. Antiviral activity, safety, PK, and development of viral resistance will be evaluated.

Detailed Description
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Study SGN113399 is a Phase 2b randomized, partially-blinded, multicenter, parallel-group, dose-ranging study to be conducted in HIV-1 infected ART-experienced adults with documented NNRTI resistance. A minimum of 150 subjects will be randomized 1:1:1 to one of two GSK2248761 doses or a control regimen containing ETV (50 subjects per group); all subjects will also receive darunavir/ritonavir and raltegravir. The trial will be partially blinded, i.e. subjects receiving GSK2248761 and the investigators will be blinded to the dose they receive. Subjects will not be blinded to whether they receive GSK2248761 or ETV. Randomization will be stratified by: HIV-1 VL at screening, <50,000 copies/mL or >/50,000 copies/mL, and Darunavir susceptibility (screening phenotype fold change <7 or >/7 to 20) Background ART will be administered open-label. The primary endpoint analysis will take place after all subjects have completed Week 16. An optimal dose of GSK2248761 will be determined by the Week 16 analysis; this dose selection will be confirmed using an analysis from all subjects following completion of Week 24. If there is a clear efficacy, safety or tolerability advantage driving dose selection for GSK2248761, then all subjects receiving the non-selected dose of GSK2248761 will be switched to the selected dose following dose confirmation, after all subjects have completed Week 24. If no differentiation of dose can be made based on objective measures of efficacy, safety or tolerability, then both doses will be continued through Week 48. After Week 48, all subjects will be expected to obtain local access to all commercially available ART. No regimen switches of either background ART (DRV/r and RAL) or test agent or control (GSK2248761 and ETV) are allowed during the 48 week period of the study. Study Endpoints/Assessments Subjects will have assessments performed which will include baseline demographics, disease characteristics, pharmacogenetics (PGx) and safety (laboratory and clinical evaluations). On study safety, efficacy, virologic, immunologic, and PK evaluations will also be conducted. The primary endpoint will be the proportion of subjects with HIV-1 RNA <50copies/mL at Week 16. Dose selection will be based primarily on antiviral activity and tolerability in conjunction with immunologic, safety, virologic resistance and PK measures. Data from the Week 24 analysis will be used to confirm dose selection. ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship

Official Title
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A Phase 2b Study to Select a Once Daily Oral Dose of GSK2248761 in HIV-1 Infected Antiretroviral Therapy Experienced Adults With Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) Resistance

Conditions
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Infection, Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: GSK2248761 100 mg once daily
* Drug: GSK2248761 200 mg once daily
* Drug: Etravirine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected adults greater than or equal to 18 years of age. Females are eligible to enter and participate in the study if she is (1) non-childbearing potential, (2) child bearing potential with negative pregnancy test at screening and Day 1 and agrees to use protocol-specified methods of birth control while on study. HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to 400copies/mL Previously received or current treatment with antiretroviral therapy (HAART) for HIV-1 infection (patient may be off ART at time of screening) HIV-1 harboring NNRTI resistance by screening genotype (defined as the presence of at least 1 NNRTI resistance-associated mutations) Exclusion Criteria: Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the subject's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the subject Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the subject unable to take oral medication Women who are currently breastfeeding Any evidence of an active Centers for Disease and Prevention Control (CDC) Category C disease [CDC, 1993], except cutaneous Kaposi's sarcoma not requiring systemic therapy History of ongoing or clinically relevant hepatitis within the previous 6 months, including chronic hepatitis B virus (HBV) infection (HBsAg positive). Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; subjects who are anticipated to require such therapy during the randomized portion of the study must be excluded History of liver cirrhosis with or without hepatitis viral co-infection Ongoing or clinically relevant pancreatitis History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia Personal or known family history of prolonged QT syndrome History or presence of allergy or intolerance to the study drugs or their components, or a history of drug or other allergy that, in the opinion of the Principal Investigator, contraindicates their participation. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled HIV-1 genotype results with any of the following will be excluded: (1)Any screening genotype with virus showing a Y181 mutation in combination with any other NNRTI resistance-associated mutations, (2) Any screening genotype with virus showing a Y181I or Y188L alone or in combination with any other NNRTI resistance-associated mutations HIV-1 phenotype results with any of the following will be excluded: (1) Any screening phenotype with virus showing etravirine fold change >10, (2) Any screening phenotype with virus showing darunavir fold change > 20, (3) Any screening phenotype with virus showing raltegravir fold change >1.5 Any acute laboratory abnormality at screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound. Any verified Grade 4 laboratory abnormality at screening would exclude a subject from study participation unless the Investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the medical monitor Any of the following laboratory values at screening: (1) Creatinine clearance <50 mL/min via Cockroft-Gault method, (2) Alanine aminotransferase (ALT) greater than or equal to 5 times ULN. Subjects with ALT >2xULN but <5xULN may participate in the study, if in the opinion of the Investigator and GSK medical monitor the lab abnormality will not interfere with the study procedures or compromise subject safety, (3) Alanine aminotransferase (ALT) greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin Any clinically significant finding on screening electrocardiograph (ECG), specifically (a single repeat is allowed to determine eligibility): (1) Heart rate <45 and >100bpm (males), <50 and >100bpm (females); Note: A heart rate from 100 to 110 BPM can be rechecked within 30 minutes to verify eligibility, (2) QRS duration >120msec, (3) QTc interval >450msec, (4) Non-sustained (greater than or equal to 3 consecutive beats) or sustained ventricular tachycardia, (5) Sinus pauses >2.5 seconds, (6) 2nd degree (Type II) or higher AV (Atrioventricular) block, (7) Evidence of WPW (Wolff-Parkinson-White) syndrome (ventricular preexcitation), (8) Pathologic Q waves (defined as Q wave >40msec OR depth >0.4 mV, (9) Any other abnormality which in the opinion of the investigator would interfere with the safety of the subject Treatment with any of the following agents within 28 days prior to screening, or has an anticipated need for these agents during the study: (1) radiation therapy or cytotoxic chemotherapeutic agents, (2) immunomodulators (such as systemic corticosteroids, interleukins, or interferons); Note: Subjects using short-term (<7 day) steroid tapers and inhaled corticosteroids are eligible for enrollment, (3) Any non-protocol-specified agent with documented activity against HIV-1 in vitro Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to screening Receipt of an experimental drug and/or vaccine within 28 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 Immunization within 28 days prior to first dose of IP

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2248761 100mg OAD<br>In combination with darunavir/ritonavir BID and raltegravir BID | Drug: GSK2248761 100 mg once daily<br>* 1 100mg capsule OAD plus matching placebo<br>|
| Experimental: GSK2248761 200mg OAD<br>In combination with darunavir/ritonavir BID and raltegravir BID | Drug: GSK2248761 200 mg once daily<br>* 2 100mg capsules OAD<br>|
| Active Comparator: Etravirine<br>In combination with darunavir/ritonavir BID and raltegravir BID | Drug: Etravirine<br>* 2 100mg tablets twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies Per Milliliter (/mL) at Week 16 | Plasma for quantitative HIV-1 RNA was collected. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 16 has been presented. A 2 ml plasma was assayed with the real-time NucliSens EasyQ HIV-1 assay (bioMerieux) capable of quantifying as low as 2.5 c/mL by using three modifications to the standard assay: 15 microliters (µl) of extracted eluate, 20 µl of primer, and 5 µl of 2X enzyme in place of standard kit volumes. The validated assay incorporated molecular beacons for detection. | At Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011) | 
| Number of Participants With Abnormal Clinical Chemistry Laboratory Data With Grade 3 or 4 Treatment-Emergent (TE) Toxicities | A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of IP). Division of acquired immunodeficiency syndrome (AIDS) toxicity scale for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 was used for grading i.e. Grade 3=severe and Grade 4=potentially life threatening. Categories with values have been presented. No toxicity-related dose reductions of IP was allowed. IP and background antiretroviral therapy (ART) was restarted as soon as medically appropriate; in general, this was no longer than 14] days after discontinuation (unless Grade 3 or 4 toxicities persisted). | Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011) | 
| Number of Participants With Abnormal Hematology Laboratory Data With Grade 3 or 4 TE Toxicities | A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of IP). The hematology parameters included hemoglobin, total neutrophils, and white blood cells (WBC) count. Categories with values has been presented. Grade 3=severe and Grade 4=potentially life threatening. No toxicity-related dose reductions of IP was allowed. IP and background ART was restarted as soon as medically appropriate; in general, this was no longer than 14] days after discontinuation (unless Grade 3 or 4 toxicities persisted). | Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011) | 
| Change From Baseline in Plasma HIV-1 RNA Prior to Switch of GSK2248761 | A switch was defined as any ART substitution or addition in the participant's ART regimen. Any ART switch permitted per protocol that was determined necessary and documented prior to the first on-treatment visit where HIV-1 RNA was assessed could occur without penalty. However, any participants with an ART switch not permitted per protocol or ART switch permitted per protocol with a viral load >=50 copies/mL at the time of the decision to switch was made was counted as a non-responder from that point onward for all assessment windows without a viral load measurement collected prior to the switch. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1. The unit is log10 copies per milliliter (log10 copies/mL). | Baseline (Day 1) and Week 2, 4, 8, 12 and 16 | 
| Change From Baseline in Plasma HIV-1 RNA After Switch of GSK2248761 | A switch was defined as any ART substitution or addition in the participant's ART regimen. Any ART switch permitted per protocol that was determined necessary and documented prior to the first on-treatment visit where HIV-1 RNA was assessed could occur without penalty. However, any participants with an ART switch not permitted per protocol or ART switch permitted per protocol with a viral load >=50 copies/mL at the time of the decision to switch was made was counted as a non-responder from that point onward for all assessment windows without a viral load measurement collected prior to the switch. Change from Baseline was calculated as (observed value - Baseline value ). Baseline was Day 1. | Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and follow-up Week 4, 8, 12 | 
| Number of Participants Who Experienced Disease Progression (HIV-associated Conditions, AIDS and Death) | Clinical DP was defined as progression from Baseline HIV disease status:Category A at Baseline to Centers for Disease Control and Prevention(CDC) category B event, category A at Baseline to CDC category C event, category B at Baseline to CDC category C event, category C at Baseline to new CDC category C event or category A, B or C at Baseline to death. Category A consisted of one or more of the conditions like asymptomatic HIV infection, persistent generalized lymphadenopathy and acute (primary) HIV infection with accompanying illness in an adolescent or adult(>13 years) with documented HIV infection. Category B consisted like Bacillary angiomatosis, Candidiasis, oropharyngeal (thrush), Candidiasis, vulvovaginal; persistent, frequent, oral, Herpes zoster etc. Category C included clinical conditions listed like Candidiasis of bronchi, trachea, or lungs, Candidiasis, esophageal, Cervical cancer, Coccidioidomycosis, disseminated or extrapulmonary etc in AIDS surveillance case definition. | Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011) | 
| Absolute Values of CD4+ Cell Counts After Switch of GSK2248761 | CD4 is a receptor for the HIV virus. Most of the damage to an AIDS participant's immune system was done by the virus' destruction of CD4+ lymphocytes. Absolute values of CD4+ cell counts after Switch of GSK2248761 has been presented. | Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and Follow-up Week 4, 8, 12 | 
| Change From Baseline in CD4+ Cell Counts Prior to Switch of GSK2248761 | CD4 is a receptor for the HIV virus. Most of the damage to an AIDS patient's immune system is done by the virus' destruction of CD4+ lymphocytes. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1 value. | Baseline (Day 1) and Week 2, 4, 8, 12 and 16 | 
| Change From Baseline in CD4+ Cell Counts After Switch of GSK2248761 | CD4 is a receptor for the HIV virus. Most of the damage to an AIDS patient's immune system is done by the virus' destruction of CD4+ lymphocytes. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1 value. | Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and Follow-up Week 4, 8, 12 | 
| Number of Participants Who Discontinued Treatment Due to AEs | An AE is defined as any untoward medical occurrence in a 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. | Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011) | 
| Number of Participants With Electrocardiograph (ECG) With Values of Potential Critical Concern (PCI) | Number of participants with ECG of PCI above 480 has been presented. ECG was be performed twice on Day 1 at least 5 minutes apart and following 5 minutes of rest in a semi supine position at ∼1 hour prior to first dose. ECG evaluations at other visits was obtained after dosing, preferably at 2 hours post dosing. An ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals was used. | Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NNRTI, raltegravir, ritonavir, darunavir, HIV, GSK2248761, antiretroviral, HIV Infection, HAART