A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in the Central Nervous System in HIV-1 Infected ART-naive Subjects

NCT01499199 | Completed Phase 3 Results

• 1 other identifier: 116070
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 3

Brief Summary

ING116070 is a Phase IIIb single-arm, open-label, multicenter study. The study will be conducted in approximately 14 HIV-1 infected antiretroviral therapy (ART)-naïve subjects. Subjects who fulfill eligibility requirements will receive dolutegravir (DTG) 50 mg once daily in combination with the fixed dose dual nucleoside reverse transcripatase inhibitor(NRTI) abacavir/lamivudine (ABC/3TC) for 96 weeks. One pair of pharmacokinetic (PK) samples in plasma and cerebral spinal fluid (CSF) (matching time) for determination of DTG concentration will be collected at Week 2 and Week 16. Samples for plasma HIV-1 RNA will be collected at Baseline and various time points throughout the study and samples for HIV-1 RNA levels in the CSF will be collected at Baseline, Week 2 and Week 16. Safety, additional measures of antiviral activity and development of viral resistance will also be evlauated. The primary analysis will take place after the last subject completes 16 weeks on therapy; additional analyses will be conducted after the last subject completes Weeks 2 and 96 (end of study).

Conditions

Infection, Human Immunodeficiency Virus

Keywords

cerebrospinal fluid (CSF); ART-naive; integrase inhibitor; dolutegravir; antiretroviral therapy naive

Outcome Measures

Primary Outcomes (5)

• The Ratio of Total and Unbound DTG Concentrations Between Cerebrospinal Fluid (CSF) and Plasma at Week 2 and Week 16

  Cerebrospinal fluid (CSF) is a clear, colorless bodily fluid produced in the choroid plexus of the brain. The CFS samples were collected at the Week 2 and Week 16 visits, within 1 hour of plasma pharmacokinetic (PK) sampling. The ratio (presented as a percentage) of CSF DTG concentration over paired plasma total DTG concentration (RCSF\_plasma) was calculated at the Week 2 and Week 16 visits.

  Week 2 and Week 16

• Total DTG Plasma Concentrations at Week 2 and Week 16

  Total plasma DTG concentrations were calculated at the Week 2 and Week 16 visits.

  Week 2 and Week 16

• Unbound DTG Plasma Concentrations at Week 2 and Week 16

  Unbound (free, not bound to cellular proteins) plasma DTG concentrations were calculated at the Week 2 and Week 16 visits.

  Week 2 and Week 16

• Plasma DTG Unbound Fraction at Week 2 and Week 16

  The unbound fraction of DTG in plasma (presented as a percentage of unbound \[i.e., free DTG not bound to cellular proteins\] DTG plasma concentration over paired plasma total DTG concentration) was calculated at the Week 2 and Week 16 visits.

  Week 2 and Week 16

• DTG Concentrations in CSF at Weeks 2 and Week 16

  CSF is a clear, colorless bodily fluid produced in the choroid plexus of the brain. The CFS samples were collected at the Week 2 and Week 16 visits, within 1 hour of plasma PK sampling. DTG concentration in CSF were calculated at the Week 2 and Week 16 visits.

  Week 2 and Week 16

Secondary Outcomes (11)

• Number of Participants With Plasma HIV-1 RNA <50 Copies Per Milliliter (c/mL) at Baseline and Weeks 2, 4, 8, 12, and 16

  Baseline; Weeks 2, 4, 8, 12, and 16

• Absolute Values and Change From Baseline in Plasma Human Immunodeficiency Virus (HIV-1) Ribonucleic Acid (RNA) Levels at Weeks 2, 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96

  Baseline; Weeks 2, 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96

• Number of Participants With CSF HIV-1 RNA <50 Copies/Milliliter (c/mL) at Baseline, Week 2, and Week 16

  Baseline, Week 2, and Week 16

• Absolute Values and Change From Baseline in CSF HIV-1 RNA Levels at Week 2 and Week 16

  Baseline, Week 2, and Week 16

• Number of Participants With the Indicated Number of Copies of HIV-1 RNA in Both the CSF and Plasma at Baseline, Week 2, and Week 16

  Baseline, Week 2, and Week 16

Study Arms (1)

Dolutegravir 50mg Once Daily

EXPERIMENTAL

All subjects will receive 50mg dolutegravir once daily in combination with background antiretroviral therapy consisting of one abacavir/lamivudine fixed dose combination tablet once daily

Drug: Dolutegravir

Interventions

Dolutegravir DRUG

50mg Once Daily

Dolutegravir 50mg 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 at least 18 years of age. Females are eligible to enter and participate in the study if she is (1) of non-childbearing potential or (2) of childbearing potential with a negative pregnancy test at Screening and Day 1 and agrees to use protocol-defined methods of birthcontrol while on the study.
• HIV-1 infection as documented by Screening plasma HIV-1 RNA greater than or equal to 5000 copies/mL
• CD4+ cell count greater than or equal to 200 cells/mm3
• Antiretroviral-naive (less than or equal to 10 days of prior therapy with any antiretroviral agent following diagnosis of HIV-1 infection)
• Signed and dated written informed consent is obtained from the subject or the subject's legal representative prior to screening
• Documentation that the subject has been screened for, and is negative for the HLA-B\*5701 allele
• Is willing to undergo serial lumbar punctures

You may not qualify if:

• Relative or absolute contraindication to lumbar puncture, such as current coagulopathy, thrombocytopenia (platelets less than 50,000/microliter), hemophilia, or use of anticoagulant medication
• Moderate or severe cognitive impairment
• Women who are pregnant or breastfeeding
• Any evidence of an active Center for Disease Control and Prevention (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy or historic CD4+ cell levels less than 200cells/mm3
• Subjects with any degree of hepatic impairment
• Positive for Hepatitis B at screening (+HbsAg), or an anticipated need for Hepatitis C virus (HCV) therapy during the study
• History or presence of allergy or intolerance to the study drugs or their components or drugs of their class
• Recent history (less than or equal to 3 months) of any upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
• Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any immunomodulators that alter immune responses
• Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 in vitro within 28 days of first dose of IP
• Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP
• Any evidence of primary viral resistance based on the presence of any major resistance-associated mutation in the Screening result or, if known, any historical resistance test result. Note: retests of Screening genotypes are not allowed
• Alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN)
• ALT greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with greater than 35% direct bilirubin)

Sponsors & Collaborators

• ViiV Healthcare: lead
• Shionogi: collaborator
• GlaxoSmithKline: collaborator

Study Sites (3)

GSK Investigational Site

Los Angeles, California, 90069, United States

Location

GSK Investigational Site

San Diego, California, 92103, United States

Location

GSK Investigational Site

Providence, Rhode Island, 02906, United States

Location

Related Publications (3)

• Letendre S, Mills A, Tashima K, et al. Distribution and antiviral activity in cerebrospinal fluid (CSF) of the integrase inhibitor, dolutegravir (DTG): ING116070 week 16 results. Published at: Conference on Retroviruses and Opportunistic Infections - 20th Annual; March 3-6, 2013; Atlanta, GA.

  BACKGROUND

• Letendre S, Mills A, Tashima K, et al. CSF penetration and antiviral activity of the integrase inhibitor, dolutegravir (DTG, GSK1349572): ING116070 week 16 results. Published at: International Symposium on Neuropsychiatry & HIV - 6th; May 9-10, 2013; Barcelona, Spain

  BACKGROUND

• Letendre SL, Mills AM, Tashima KT, Thomas DA, Min SS, Chen S, Song IH, Piscitelli SC; extended ING116070 study team. ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. Clin Infect Dis. 2014 Oct;59(7):1032-7. doi: 10.1093/cid/ciu477. Epub 2014 Jun 18.

  PMID: 24944232 DERIVED

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

Interventions

dolutegravir

Condition Hierarchy (Ancestors)

HIV Infections; 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

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

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 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2011
• First Posted: December 26, 2011
• Study Start: January 1, 2012
• Primary Completion: October 1, 2012
• Study Completion: May 1, 2014
• Last Updated: February 25, 2015
• Results First Posted: November 25, 2013

Record last verified: 2015-01

Locations

US (3)