Dose-finding Study of GSK2248761 in Antiretroviral Therapy-Naive Subjects (SIGNET)

NCT01231555 | Terminated Phase 2 Results DMC

• 1 other identifier: 113404
• Study Type: interventional
• Target: 23
• Locations: 3 countries
• Sites: 12

Brief Summary

This 96 week, Phase 2b study in 150 HIV-1 infected antiretroviral (ART) naive 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 efavirenz (EFV) 600 mg once daily. The background ART for all 3 arms will be chosen by the Investigators and will be either abacavir/lamivudine \[ABC/3TC\] or tenofovir/emtricitabine \[TDF/FTC\] fixed dose combination (FDC) tablets. Antiviral activity, safety, PK, and development of viral resistance will be evaluated.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

antiretroviral; HAART; NNRTI; emtricitabine; Sexually Transmitted Disease; antiretroviral therapy (ART)-naive adults; Immunologic Deficiency Syndrome; tenofovir; abacavir; Retroviridae Infections; GSK2248761; lamivudine; Acquired ImmunoDeficiency Syndrome (AIDS); HIV infection; efavirenz

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Plasma HIV-1 RNA Below 50 Copies/mL as a Function of Viral Load

  This analysis was based on the Missing, Switch or Discontinuation equals Failure (MSDF) algorithm (as codified by the FDA's "snapshot" algorithm) and was adjusted for stratification factors and stage of recruitment. Dose selection was based primarily on antiviral activity and tolerability in conjunction with immunologic, safety, virologic resistance and pharmacokinetic (PK) measures. The efficacy decision criteria was based on an observed difference of \>=8% between the two GSK2248761 dosage arms.

  Up to Week 16

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

  Adverse event (AE) is an unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain time period after the study has ended. This change may or may not be caused by the intervention being studied. Serious adverse event (SAE) is an adverse event that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above.

  Up to 20 Weeks

Secondary Outcomes (6)

• Change From Baseline (Day 1) in Plasma HIV-1 RNA Over Period

  Baseline (Day 1) up to Week 16

• Number of Participants With HIV Associated Conditions

  Up to 20 Weeks

• Number of Participants With HIV Disease Progression

  Up to 20 Weeks

• Number of Participants Discontinuing the Study Drugs Due to AEs

  Up to 20 weeks

• Number of Participants With Changes in Electrocardiogram (ECG) From Baseline (Day 1) Over 16 Weeks

  Baseline (Day 1) to 16 weeks

Study Arms (3)

GSK2248761 100 mg once daily

EXPERIMENTAL

In combination with either abacavir/lamivudine FDC qd or tenofovir/emtricitabine FDC qd

Drug: GSK2248761 100 mg once daily

GSK2248761 200 mg once daily

EXPERIMENTAL

In combination with either abacavir/lamivudine FDC qd or tenofovir/emtricitabine FDC qd

Drug: GSK2248761 200 mg once daily

Efavirenz 600 mg once daily

ACTIVE COMPARATOR

In combination with either abacavir/lamivudine FDC qd or tenofovir/emtricitabine FDC qd

Drug: Efavirenz 600 mg once daily

Interventions

GSK2248761 100 mg once daily DRUG

1x100 mg capsule plus matching placebo

GSK2248761 100 mg once daily

GSK2248761 200 mg once daily DRUG

2x100 mg capsules

GSK2248761 200 mg once daily

Efavirenz 600 mg once daily DRUG

1x600mg tablet

Efavirenz 600 mg once daily

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. A female is eligible to enter and participate in the study if she is (1) Non-childbearing potential, (2) Child-bearing potential, with a negative pregnancy test at screen 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 1000 copies/mL
• CD4+ cell count greater than or equal to 200 cells/mm3
• Antiretroviral-naive

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
• Evidence of viral resistance to any antiviral drug indicative of primary transmitted resistance in a screening or historical resistance test result
• 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 upper limits of normal (ULN). Subjects with ALT \> 2x ULN 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 ECG, specifically (a single repeat is allowed to determine eligibility): (1) Heart rate \<45 and \>100 beats per minute (bpm) (males); \<50 and \>100 bpm (females). Note: A heart rate from 100 to 110 bpm can be rechecked within 30 minutes to verify eligibility, (2) QRS duration \> 120 msec, (3) QTc interval \> 450 msec (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 \> 40 msec 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

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (12)

GSK Investigational Site

Levallois-Perret, 92300, France

Location

GSK Investigational Site

Montpellier, 34295, France

Location

GSK Investigational Site

Nice, 06202, France

Location

GSK Investigational Site

Paris, 75018, France

Location

GSK Investigational Site

Frankfurt am Main, Hesse, 60311, Germany

Location

GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

Location

GSK Investigational Site

Berlin, 12157, Germany

Location

GSK Investigational Site

Hamburg, 20146, Germany

Location

GSK Investigational Site

Hamburg, 20246, Germany

Location

GSK Investigational Site

Badalona, 08916, Spain

Location

GSK Investigational Site

Barcelona, 08036, Spain

Location

GSK Investigational Site

Marid, 28040, Spain

Location

Related Publications (1)

• 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992 Dec 18;41(RR-17):1-19.

  PMID: 1361652 BACKGROUND

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Retroviridae Infections; HIV Infections

Interventions

IDX 899; efavirenz

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Lentivirus Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

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: October 14, 2010
• First Posted: November 1, 2010
• Study Start: November 18, 2010
• Primary Completion: July 4, 2011
• Study Completion: July 4, 2011
• Last Updated: November 17, 2017
• Results First Posted: November 17, 2017

Record last verified: 2017-08

Locations

FR (4); DE (5); ES (3)