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

NCT01199731 | Terminated Phase 2 Results

• 1 other identifier: 113399
• Study Type: interventional
• Target: 30
• Locations: 5 countries
• Sites: 41

Brief Summary

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.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

raltegravir; NNRTI; ritonavir; darunavir; HIV; GSK2248761; antiretroviral; HIV Infection; HAART

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

  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

  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

  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

  Baseline (Day 1) and Week 2, 4, 8, 12 and 16

• Change From Baseline in Plasma HIV-1 RNA After Switch of GSK2248761

  Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and follow-up Week 4, 8, 12

Study Arms (3)

GSK2248761 100mg OAD

EXPERIMENTAL

In combination with darunavir/ritonavir BID and raltegravir BID

Drug: GSK2248761 100 mg once daily

GSK2248761 200mg OAD

EXPERIMENTAL

In combination with darunavir/ritonavir BID and raltegravir BID

Drug: GSK2248761 200 mg once daily

Etravirine

ACTIVE COMPARATOR

In combination with darunavir/ritonavir BID and raltegravir BID

Drug: Etravirine

Interventions

GSK2248761 100 mg once daily DRUG

1 100mg capsule OAD plus matching placebo

GSK2248761 100mg OAD

GSK2248761 200 mg once daily DRUG

2 100mg capsules OAD

GSK2248761 200mg OAD

Etravirine DRUG

2 100mg tablets twice daily

Etravirine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (41)

GSK Investigational Site

Birmingham, Alabama, 35294, United States

Location

GSK Investigational Site

Phoenix, Arizona, 85012, United States

Location

GSK Investigational Site

Bakersfield, California, 93301, United States

Location

GSK Investigational Site

Beverly Hills, California, 90211, United States

Location

GSK Investigational Site

Fresno, California, 93721, United States

Location

GSK Investigational Site

Long Beach, California, 90813, United States

Location

GSK Investigational Site

Los Angeles, California, 90069, United States

Location

GSK Investigational Site

San Francisco, California, 94115, United States

Location

GSK Investigational Site

Washington D.C., District of Columbia, 20007, United States

Location

GSK Investigational Site

Washington D.C., District of Columbia, 20009, United States

Location

GSK Investigational Site

Fort Lauderdale, Florida, 33308, United States

Location

GSK Investigational Site

Fort Lauderdale, Florida, 33316, United States

Location

GSK Investigational Site

Ft. Pierce, Florida, 34982, United States

Location

GSK Investigational Site

Orlando, Florida, 32804, United States

Location

GSK Investigational Site

Springfield, Massachusetts, 01107, United States

Location

GSK Investigational Site

Kansas City, Missouri, 64106, United States

Location

GSK Investigational Site

Hillsborough, New Jersey, 08844, United States

Location

GSK Investigational Site

Newark, New Jersey, 07102, United States

Location

GSK Investigational Site

Santa Fe, New Mexico, 87505, United States

Location

GSK Investigational Site

New York, New York, 10003, United States

Location

GSK Investigational Site

Stony Brook, New York, 11794, United States

Location

GSK Investigational Site

The Bronx, New York, 10467, United States

Location

GSK Investigational Site

Valhalla, New York, 10595, United States

Location

GSK Investigational Site

Chapel Hill, North Carolina, 27514, United States

Location

GSK Investigational Site

Charlotte, North Carolina, 28209, United States

Location

GSK Investigational Site

Portland, Oregon, 97210, United States

Location

GSK Investigational Site

Austin, Texas, 78705, United States

Location

GSK Investigational Site

Dallas, Texas, 75246, United States

Location

GSK Investigational Site

Fort Worth, Texas, 76104, United States

Location

GSK Investigational Site

Longview, Texas, 75605, United States

Location

GSK Investigational Site

Brussels, 1000, Belgium

Location

GSK Investigational Site

Liège, 4000, Belgium

Location

GSK Investigational Site

Toronto, Ontario, M5B 1L6, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2L 4P9, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2X 2P4, Canada

Location

GSK Investigational Site

Montreal, Quebec, H3G 1A4, Canada

Location

GSK Investigational Site

Milan, Lombardy, 20127, Italy

Location

GSK Investigational Site

Monza, Lombardy, 20052, Italy

Location

GSK Investigational Site

Bucharest, 021105, Romania

Location

GSK Investigational Site

Bucharest, 030303, Romania

Location

GSK Investigational Site

Constanța, 900709, Romania

Location

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; HIV Infections

Interventions

IDX 899; etravirine

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Limitations and Caveats

Enrollment in this study was terminated prematurely on 01 April 2011 due to a safety finding (convulsion) in 5/20 participants receiving GSK2248761.

Results Point of Contact

• Title: GSK Response Center
• Organization: ViiV Healthcare

866-435-7343

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 9, 2010
• First Posted: September 13, 2010
• Study Start: October 5, 2010
• Primary Completion: July 19, 2011
• Study Completion: July 19, 2011
• Last Updated: November 17, 2017
• Results First Posted: October 12, 2017

Record last verified: 2017-10

Locations

US (30); CA (4); BE (2); RO (3); IT (2)