Study Of Chemokine Coreceptor 5 (CCR5) Antagonist GW873140 In R5-Tropic Treatment-Experienced HIV-Infected Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of the CCR5 antagonist GW873140 or placebo in combination with an optimized background regimen in treatment-experienced HIV-infected subjects with R5-tropic virus

Official Title
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A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel Group Study to Compare the Efficacy and Safety of GW873140 400mg BID in Combination With a Ritonavir-containing Optimized Background Therapy (OBT) Regimen Versus Placebo Plus OBT Over 48 Weeks.

Conditions
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Infection, Human Immunodeficiency Virus I

Intervention / Treatment
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* Drug: GW873140


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-infected. Screening viral load at least 5000copies/mL. R5-tropic only virus at screening. Total prior antiretroviral experience of at least 3 months and documented resistance to at least one drug in each of the following classes: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI). Stable antiretroviral regimen (or no antiretroviral treatment) for at least 4 weeks before screening. Able to receive a ritonavir-boosted protease inhibitor during treatment studies. Women of childbearing potential must use specific forms of contraception. Exclusion criteria: Acute laboratory abnormalities. History of pancreatitis or hepatitis, hepatitis B or hepatitis C coinfection, or any chronic liver disease. Screening liver function tests will be used to determine eligibility. R5/X4-tropic, X4-tropic only, or non-phenotypeable virus at screening. Changes to antiretroviral therapy from 4 weeks prior to screening until Day 1 of treatment study. Pregnancy or breastfeeding women. Recent participation in an experimental drug trial. Prior use of a CCR5 or CXCR4 antagonist. Significant ECG abnormalities or significant history of active pancreatitis, hepatitis, opportunistic infections, malabsorption disorders, cancer, or severe illness. Current use of certain medications may exclude participation in this study. Additional qualifying criteria and laboratory test requirements to be assessed by study physician.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GW873140<br> | Drug: GW873140<br>* 400 mg twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Plasma HIV-1 RNA <400 Copies Per Milliliter (Copies /mL) at Week 24 and 48 | Assessment for plasma HIV-1 RNA was done at Week 24 and also planned at Week 48 by polymerase chain reaction (PCR) analysis. Data is reported for number of participants with plasma HIV-1 RNA <400 copies/mL at Week 24. Data was not collected for Week 48 due to early termination of the study. | Week 24 | 
| Average Area Under the Curve Minus Baseline (AAUCMB) of Plasma HIV-1 RNA Through the Entire Study Period | The area under the plasma HIV-1 RNA curve (AUC) was computed using the trapezoidal rule for all assessments (scheduled and unscheduled) at their actual time points. Baseline was defined as the mean of the Baseline (Day 1) and pre-treatment visit values. Participants without a Baseline assessment was removed from the analysis. The AAUCMB was computed by the AUC divided by the duration of the profile (i.e., the number of days on randomized therapy) minus the Baseline measurement. Data is reported up to Week 40 only due to early termination of the study. | Up to Week 40 | 
| Number of Participants With >= 1.0 log10 Copies/mL Decrease in Plasma HIV-1 RNA From Baseline Over Time | The plasma HIV-1 RNA polymerase chain reaction (PCR) assessments were planned at pre-Baseline (between 1 and 14 days prior to Day 1), up to Week 12 Follow- up of the Randomized Phase, up to Week 12 Follow-up of the Open Labeled Non-Randomized phase and every 6 months Follow-up of off study drug/on study phase, however the study was early terminated at Week 40. Baseline was defined as the mean of the Baseline (Day 1) and pre-treatment visit values. | Day 1 up to Week 12 Follow-up of the Randomized Treatment phase, up to Week 12 Follow-up of the Open Labeled Non-Randomized phase and every 6 months Follow-up of off study drug/on study phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Plasma HIV-1 RNA <50 Copies/mL at Week 24 and 48 | Assessment for plasma HIV-1 RNA was done at Week 24 and also planned at Week 48 by PCR analysis. Data is reported for number of participants with plasma HIV-1 RNA <50 copies/mL at Week 24. Data was not collected for Week 48 due to early termination of the study. | Week 24 | 
| Number of Participants With Any Adverse Event (AE), Serious Adverse Event (SAE), Death, Drug-related AE and AE Leading to Treatment Discontinuation | 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 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, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, hypersensitivity reaction to abacavir. AEs were classified as potentially drug-related, based on the investigator's judgment. | Up to Follow-up (Week 52) | 
| Number of Participants With Treatment Emergent Laboratory Abnormalities for Chemistry Data at Any Visit Post-Baseline | The participants with treatment emergent toxicities of laboratory abnormalities for chemistry data is reported . Participants with toxicities were categorized according to the division of AIDS (DAIDS) toxicity grading scale. Scale ranges from grade 1(mild)=symptoms causing no or minimal interference with usual social & functional activities, grade 2 (moderate)=symptoms causing greater than minimal interference with usual social & functional activities, grade 3 (severe)=symptoms causing inability to perform usual social & functional activities and grade 4 (potentially life threatening)=symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. Scale ranges from 1-4, where higher grade reflects greater severity of symptoms. Baseline was defined as assessments done at Day 1. Only those parameters for which at least one value of toxicity grade was reported are summarized. | Up to Week 40 | 
| Change From Baseline in Chemistry Parameters of ALT, ALP, AST and CK During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Chemistry Parameters of CO2 Content/Bicarbonate, Chloride, Cholesterol, Glucose, High DL Cholesterol, LDL Cholesterol, Triglycerides, Potassium, Urea and Sodium During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Chemistry Parameter of Creatinine and Total Bilirubin During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Chemistry Parameter of Albumin During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Chemistry Parameter of Lipase During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Haematology Parameters of Basophils, Eosinophils, Lymphocytes, Monocytes, Platelet Count, Total Neutrophils, White Blood Cell (WBC) Count During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Haematology Parameter of Mean Corpuscle Volume (MCV) During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Haematology Parameter of Hematocrit During the Randomized Treatment Phase. | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Haematology Parameter of Hemoglobin During the Randomized Treatment Phase | Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values. | Baseline (Day 1), Week 12 and Week 24 | 
| Change From Baseline in Electrocardiograph (ECG) Parameter of Heart Rate (HR) During the Randomized Treatment Phase | 12-lead ECG assessments were obtained at Day 1 (triplicate measurements), Week 4 and Week 24. The assessments were done using an ECG machine that automatically calculated the heart rate. Baseline was defined as the mean of the triplicate assessment done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 4 and 24) values. | Baseline (Day 1), Week 4 and Week 24 | 
| Change From Baseline in ECG Parameter of RR Interval, Uncorrected QT Interval, QTc Interval (Fridericia), QTc Interval (Bazette), PR Interval and QRS Duration During the Randomized Treatment Phase | 12-lead ECG assessments were obtained at Day 1 (triplicate measurements), Week 4 and Week 24. The assessments were done using an ECG machine that automatically measured RR, PR, QRS, uncorrected QT, QTc (Bazette) and QTc (Fridericia) intervals. Baseline was defined as the mean of the triplicate assessment done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 4 and Week 24) values. | Baseline (Day 1), Week 4 and Week 24 | 
| Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Counts During the Randomized Treatment Phase | The CD4 cell count is an indication of the strength of the immune system. The assessment of CD4 cell count was done by flow cytometry. Baseline was defined as the mean of the Baseline (Day 1) and pre-treatment visit values. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12, 24 and 40) values. | Baseline (Day 1), Week 12, Week 24 and Week 40 | 
| Time to Centres for Disease Control and Prevention (CDC) Class C Acquired Immune Deficiency Syndrome (AIDS)-Defining Event or Death | The time to CDC class C AIDS-defining event or death was planned to be assessed as 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). | Up to Week 12 Follow-up of the Randomized phase, up to Week 12 Follow-up of the Open Labeled Non-Randomized phase and every 6 months Follow-up of off study drug/on study phase | 
| Number of Participants With Development of Antiretroviral Resistance to GW873140 400 mg BID and Other Antiretroviral Drugs | Assessment for the development of antiretroviral resistance was performed at each visit up to Follow-up. The genotypic analysis of viral resistance associated mutations was done using protease and reverse transcriptase enzymes. The number of participants with treatment emergent changes in reverse transcriptase and protease genotypic mutations were reported. | Up to Follow-up (Week 52) | 
| Number of Participants With 50% Inhibitory Concentration (IC50) Fold Resistance at Baseline | The IC50 is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. IC50 was collected for abacavir (ABC), atazanavir (ATV), delavirdine (DLV), didanosine (DDI), efavirenz (EFV), emtricitabine, enfuvirtide , fosamprenavir (AMP), GW873140 (APL), indinavir (IDV), indinavir rooted with ritonavir (IDV/r), lamivudine, lopinavir rooted with ritonavir (LPV/r), nelfinavir (NFV), nevirapine (NVP), ritonavir (RTV), saquinavir (SQV), stavudine, tenofovir (TFV), tipranavir rooted with ritonavir (TPV/r), zidovudine (ZDV). Data is categorized for number of participants with each IC50 concentration of the individual drugs at Baseline (Day 1). | Baseline (Day 1) | 
| Plasma GW873140 400 mg BID Pharmacokinetic (PK) Parameter of Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length (Tau) (AUC [0-tau]) During the Randomized Treatment Phase | AUC (0- tau) GW873140 was defined as the area under the plasma concentration-time curve from time 0 to tau. Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24. It was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. | Week 4 (pre-dose [0 hour], 1, 2, 3, 4, 6, 8, 10 hour post-evening dose), Week 12 (pre-dose [0 hour] and 2-4 hour post-morning dose) and Week 24 (pre-dose and 2-4 hour post-morning dose) | 
| Plasma GW873140 400 mg BID PK Parameter of Maximum Observed Plasma Concentration (Cmax) During the Randomized Treatment Phase | Cmax is defined as the first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24. | Week 4 (pre-dose [0 hour], 1, 2, 3, 4, 6, 8, 10 hour post-evening dose), Week 12 (pre-dose [0 hour] and 2-4 hour post-morning dose) and Week 24 (pre-dose and 2-4 hour post-morning dose) | 
| Plasma GW873140 400 mg BID PK Parameter of Time of Maximum Observed Plasma Concentration (Tmax) During the Randomized Treatment Phase | Tmax is defined as the time at which Cmax is observed, determined directly from the raw concentration-time data. Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24. | Week 4 (pre-dose [0 hour], 1, 2, 3, 4, 6, 8, 10 hour post-evening dose), Week 12 (pre-dose [0 hour] and 2-4 hour post-morning dose) and Week 24 (pre-dose and 2-4 hour post-morning dose) | 
| Plasma GW873140 400 mg BID PK Parameter of Concentration at End of Dosing Interval (Trough Concentration [Cτ]) During the Randomized Treatment Phase | Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24. | Week 4 (pre-dose [0 hour], 1, 2, 3, 4, 6, 8, 10 hour post-evening dose), Week 12 (pre-dose [0 hour] and 2-4 hour post-morning dose) and Week 24 (pre-dose and 2-4 hour post-morning dose) | 
| Investigational Product Adherence Measured by Pill Counts | Adherence to investigational product was planned to be evaluated using pill counts of unused investigational product (blinded GW873140 or placebo, open-label GW873140 for open label phase). This assessment was planned to be conducted at each time the participant received a new (refill) supply of study medication. | Up to Week 48 of Randomized Treatment phase and up to Switch + 24 Weeks of the Open Labeled phase | 
| Number of Participants Who Were Bothered by Each of Several Specific Symptoms Evaluated Using the HIV Symptom Index Questionnaire During the Randomized Treatment Phase | The HIV Symptom Index Questionnaire was planned to be used to evaluate how bothersome certain symptoms were during the conduct of this clinical study. The participant self-report instrument had 20 items, each of which asked about a specific symptom or group of related symptoms that participants might have had during the past 4 weeks and the degree to which the participant is bothered by the symptom. The symptom index comprised 32 common and HIV-specific symptoms scored in terms of presence/absence (1, 0) and severity on a 4-point scale (0 = not at all to 3 =quite a bit). Higher score represented greater severity of symptoms. | Upto Week 48 | 
| Number of Participants With the Impact on Health Related Quality of Life Measured by Euro Quality of Life (Qol) Questionnaire During the Randomized Treatment Phase | The EuroQol is a standardized instrument for use as a measure of health related quality of life. It consists of two pages comprising the EuroQoL 5 Dimension 5 level (EQ-5D5) descriptive system and the EQ visual analogue scale (VAS). The EQ-5D5 comprises of five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety). Each dimension comprises five levels of response (no problems, mild problems, moderate problems, moderate to extreme problems, and extreme problems). The EQ VAS records the respondents self-rated health status on a vertical graduated (0 to 100) VAS. Higher score represented greater severity of diseases. | Up to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1 GW873140 CCR5 antagonist experienced