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

2015年1月15日 更新者：ViiV Healthcare

A Single-arm Study of the Safety, Efficacy and Central Nervous System and Plasma PK of GSK1349572 (Dolutegravir, DTG) 50 mg Once Daily in Combination With the Abacavir/Lamivudine Fixed Dose Combination Tablet Over 96 Weeks in HIV-1 Infected Antiretroviral Naive Adult Subjects

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).

調査の概要

状態

完了

条件

介入・治療

詳細な説明

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 meet all screening requirements may enter the study and initiate treatment as soon as all screening procedures have been completed and results are available and on file. The 14-day screening period may be extended to 28 days to allow receipt of all Screening assessment results and to accommodate scheduling.

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 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).

Subjects are considered to have completed the study if they remain on therapy (i.e., have not permanently discontinued investigational product [IP]) and complete the Treatment Phase, including the Week 96 visit.

研究の種類

介入

入学 (実際)

13

段階

  • フェーズ 3

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

  • アメリカ
    • California
      • Los Angeles、California、アメリカ、90069
        • GSK Investigational Site
      • San Diego、California、アメリカ、92103
        • GSK Investigational Site
    • Rhode Island
      • Providence、Rhode Island、アメリカ、02906
        • GSK Investigational Site

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年歳以上 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject
  • 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
  • Any verified Grade 4 laboratory abnormality (a single repeat test is allowed during the Screening period to verify a 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 is exclusionary
  • 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)
  • Subject has creatinine clearance of less than 50 mL/min via Cockroft-Gault method

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：なし
  • 介入モデル：単一グループの割り当て
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：Dolutegravir 50mg Once Daily
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
薬：Dolutegravir
50mg Once Daily

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
The Ratio of Total and Unbound DTG Concentrations Between Cerebrospinal Fluid (CSF) and Plasma at Week 2 and Week 16
時間枠：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
時間枠：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
時間枠：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
時間枠：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
時間枠：Week 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

二次結果の測定

結果測定
メジャーの説明
時間枠
Number of Participants With Plasma HIV-1 RNA <50 Copies Per Milliliter (c/mL) at Baseline and Weeks 2, 4, 8, 12, and 16
時間枠：Baseline; Weeks 2, 4, 8, 12, and 16
HIV-1 RNA response in plasma was measured as the number of participants with HIV-1 RNA less than 50 c/mL at Baseline, Week 2, Week 4, Week 8, Week 12, and Week 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
時間枠：Baseline; Weeks 2, 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96
The plasma samples were collected at the Week 2, Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, and Week 96 visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
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
時間枠：Baseline, Week 2, and Week 16
The antiviral activity of dolutegravir in CSF over time was measured as the number of participants with HIV-1 RNA <50 copies/milliliter (c/mL).
Baseline, Week 2, and Week 16
Absolute Values and Change From Baseline in CSF HIV-1 RNA Levels at Week 2 and Week 16
時間枠：Baseline, Week 2, and Week 16
The antiviral activity of dolutegravir in CSF over time was measured as absolute values and change from Baseline in HIV-1 RNA levels in CSF at Week 2 and Week 16. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
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
時間枠：Baseline, Week 2, and Week 16
The relationship between HIV-1 RNA suppression in plasma and the CSF was measured as a comparison and as a change in the number of participants in the cross tabulation of <50 copies/mL in plasma, <50 copies/mL in CSF, >=50 copies/mL in plasma, and >=50 copies/mL in CSF at Baseline, Week 2, and Week 16.
Baseline, Week 2, and Week 16
Pearson Correlation Between CSF DTG Concentration and Absolute Values and Change From Baseline (CFB) in CSF HIV-1 RNA at Week 2, Week 16, and Overall
時間枠：From Baseline to Week 16
The Pearson Correlation Coefficient is a measure of the correlation between CSF DTG concentrations and absolute values/changes from Baseline in CSF HIV-1 RNA at Week 2 and Week 16. CSF HIV-1 RNA is measured as log10 copies per milliliter (copies/mL).
From Baseline to Week 16
Absolute Values and Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Counts at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96
時間枠：Baseline; Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96
The absolute value for CD4+ cell count (cells per millimeters cubed [mm^3]) was assessed at Baseline, Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, Week 48, Week 60, Week 72, Week 84, and Week 96. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Baseline; Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, and 96
Absolute Values and Change From Baseline in Cluster of Differentiation 8+ (CD8+) Cell Counts at Weeks 4, 12, 16, 24, 48, and 96
時間枠：Baseline; Weeks 4, 12, 16, 24, 48, and 96
The absolute value for CD48+ cell count (cells per millimeters cubed [mm^3]) was assessed at Baseline, Week 4, Week 12, Week 16, Week 24, Week 48, and Week 96. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Baseline; Weeks 4, 12, 16, 24, 48, and 96
Number of Participants With Post-Baseline HIV-1-associated Conditions, Including Recurrences
時間枠：Baseline through the date the last participant completed Week 96 + follow-up visit (if applicable)
The number of participants who reported a new or recurrent Centers for Disease Control and Prevention (CDC) Class B or Class C condition was assessed from Baseline though the date the last participant completed Week 96 + the follow-up visit (if applicable). Category (CAT) A: one or more of the following conditions (CON), without any CON listed in Categories B and C: asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying illness or history of acute HIV infection. CAT B: symptomatic CON that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or that are considered by physicians to have a clinical course or to require management that is complicated by HIV infection; and not included among CON listed in clinical CAT C. CAT C: the clinical CON listed in the AIDS surveillance case definition.
Baseline through the date the last participant completed Week 96 + follow-up visit (if applicable)
The Numbers of Participants (Par.) With Clinical Adverse Events or Laboratory Abnormalities
時間枠：Baseline (BL) through the date the last participant completed Week (W) 96 + the follow-up visit (if applicable)
An AE is 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. An SAE is 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, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Refer to the general Adverse AE/SAE module for a complete list of AEs/SAEs. Any abnormal laboratory test result (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., electrocardiograms [ECGs], radiological scans, vital sign measurements), including those that worsen from Baseline, and were felt to be clinically significant in the medical and scientific judgment of the investigator, were recorded as AEs or SAEs. Clinically suspected cases of hypersensitivity to ABC were also SAEs.
Baseline (BL) through the date the last participant completed Week (W) 96 + the follow-up visit (if applicable)
Number of Participants With Treatment-emergent Genotypic and Phenotypic Resistance to DTG and Other Antiretroviral Therapy (ART)
時間枠：Baseline through the date the last participant completed Week 96
The number of participants with treatment-emergent genotypic and phenotypic resistance to integrase inhibitors (INIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transctiptase inhibitors (NNRTIs), and protease inhibitors (PIs) was assessed.
Baseline through the date the last participant completed Week 96

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

ViiV Healthcare

協力者

GlaxoSmithKline
Shionogi

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始

2012年1月1日

一次修了 (実際)

2012年10月1日

研究の完了 (実際)

2014年5月1日

試験登録日

最初に提出

2011年12月15日

QC基準を満たした最初の提出物

2011年12月21日

最初の投稿 (見積もり)

2011年12月26日

学習記録の更新

投稿された最後の更新 (見積もり)

2015年2月25日

QC基準を満たした最後の更新が送信されました

2015年1月15日

最終確認日

2015年1月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • 116070

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