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A Phase 2a Study to Evaluate the Effect of Rilapladib (SB-659032) in Alzheimer's Disease

2018年8月7日 更新者：GlaxoSmithKline

A Phase 2a Study to Evaluate the Effect of Rilapladib (SB-659032) on Biomarkers Related to the Pathogenesis and Progression of Alzheimer's Disease

The study is designed to investigate the effects of rilapladib on biomarkers related to the Alzheimer's disease, and cognitive function.

調査の概要

状態

完了

条件

介入・治療

詳細な説明

The study is in subjects with Alzheimer's disease and evidence of cerebrovascular disease (CVD) who are currently treated with an acetylcholinesterase inhibitor (AChEI) and/or memantine. The study is a randomized, double-blind, placebo controlled, parallel group, repeat dose design, in which subjects (up to 60 randomized subjects per arm) will receive oral placebo or rilapladib (250 mg), once daily for 24 weeks in addition to their stable background AD therapy consisting of an acetylcholinesterase inhibitor (AChEI) and/or memantine. Subjects will take 250mg of rilapladib or placebo once daily for a period of 24 weeks. The total duration of participation for each subject will be approximately 30 weeks comprising approximately 4 weeks screening, 24 weeks treatment and 2 weeks follow-up. From the time of randomization and throughout the treatment period subjects will attend visits after 1 week, 4 weeks and thereafter every 4 weeks until Week 24. A follow-up visit will occur approximately 2 weeks after the final dose of study medication. Cognitive assessments will be performed at the screening visit, at the randomization (baseline) visit and at weeks 12 and 24 of the treatment period. Cerebrospinal fluid (CSF) samples will be taken via lumbar puncture at baseline and Week 24 for biomarker analyses related to Alzheimer's disease. Blood samples will be collected throughout the study for pharmacokinetics and a range of biomarker analyses. A range of safety and tolerability assessments will also be performed (including vital signs, laboratory tests, eye examinations and ECGs).

研究の種類

介入

入学 (実際)

124

段階

  • フェーズ2

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

  • イタリア
    • Lazio
      • Roma、Lazio、イタリア、00185
        • GSK Investigational Site
    • Liguria
      • Genova、Liguria、イタリア、16132
        • GSK Investigational Site
    • Lombardia
      • Brescia、Lombardia、イタリア、25125
        • GSK Investigational Site
      • Milano、Lombardia、イタリア、20122
        • GSK Investigational Site
    • Veneto
      • Verona、Veneto、イタリア、37134
        • GSK Investigational Site
  • カナダ
    • Ontario
      • Toronto、Ontario、カナダ、M3B 2S7
        • GSK Investigational Site
    • Quebec
      • Gatineau、Quebec、カナダ、J9A 1K7
        • GSK Investigational Site
      • Sherbrooke、Quebec、カナダ、J1H 1Z1
        • GSK Investigational Site
  • スウェーデン
      • Stockholm、スウェーデン、SE-141 86
        • GSK Investigational Site
  • スペイン
      • Baracaldo/Vizcaya、スペイン、48903
        • GSK Investigational Site
      • Barcelona、スペイン、08014
        • GSK Investigational Site
      • Castellón de La Plana、スペイン、12004
        • GSK Investigational Site
      • Getafe/Madrid、スペイン、28905
        • GSK Investigational Site
      • L'Hospitalet de Llobregat、スペイン、08907
        • GSK Investigational Site
      • Madrid、スペイン、28006
        • GSK Investigational Site
  • ドイツ
    • Baden-Wuerttemberg
      • Ellwangen、Baden-Wuerttemberg、ドイツ、73479
        • GSK Investigational Site
      • Tuebingen、Baden-Wuerttemberg、ドイツ、72076
        • GSK Investigational Site
      • Ulm、Baden-Wuerttemberg、ドイツ、89081
        • GSK Investigational Site
    • Bayern
      • Alzenau、Bayern、ドイツ、63755
        • GSK Investigational Site
    • Hessen
      • Bad Homburg、Hessen、ドイツ、61348
        • GSK Investigational Site
    • Niedersachsen
      • Achim、Niedersachsen、ドイツ、28832
        • GSK Investigational Site
      • Hannover、Niedersachsen、ドイツ、30559
        • GSK Investigational Site
    • Nordrhein-Westfalen
      • Bochum、Nordrhein-Westfalen、ドイツ、44787
        • GSK Investigational Site
      • Bochum、Nordrhein-Westfalen、ドイツ、44791
        • GSK Investigational Site
      • Bochum、Nordrhein-Westfalen、ドイツ、44892
        • GSK Investigational Site
      • Koeln、Nordrhein-Westfalen、ドイツ、50935
        • GSK Investigational Site
    • Schleswig-Holstein
      • Oldenburg、Schleswig-Holstein、ドイツ、26122
        • GSK Investigational Site
  • ノルウェー
      • Lørenskog、ノルウェー、1478
        • GSK Investigational Site
  • ブルガリア
      • Sofia、ブルガリア、1431
        • GSK Investigational Site
      • Sofia、ブルガリア、1113
        • 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

50年～80年 (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:

  1. A clinical diagnosis of possible Alzheimer's disease in accordance with the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, with radiological (Magnetic Resonance Imaging [MRI] or Computed Tomography [CT]) evidence of significant cerebrovascular disease (CVD), assessed within the last 12 months
  2. Male or female between 50 and 80 years of age inclusive, at the time of signing the informed consent.
  3. Subject has a documented history of at least 6 months of ongoing Alzheimer's disease therapy (AChEIs and/or memantine) with stable dosing for at least the last 2 months (and with no intent to change for the duration of the study).
  4. Mini-Mental Status Examination (MMSE) score between 20 and 26 at Screening.
  5. Clinical Dementia Rating Scale (CDR) score of 0.5 or 1.0 at Screening.
  6. A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea; or of child-bearing potential and agrees to use acceptable contraception methods
  7. Subject has provided full written informed consent prior to the performance of any protocol-specified procedure; or if the subject is unable to provide informed consent due to cognitive status, the subject will provide assent and full written informed consent will be provided by a legally acceptable representative
  8. The subject has a dedicated caregiver who is willing to supervise participation in the study
  9. In the opinion of the investigator, the subject has the ability to comply with study procedures (cognitive and other testing) and is fluent in the language used for the administration of the cognitive tests.

Exclusion Criteria:

  1. History and/or evidence of any other CNS disorder that could be interpreted as a cause of dementia: e.g. structural or developmental abnormality, epilepsy, infectious, degenerative or inflammatory/demyelinating CNS conditions such as, Parkinson's disease and frontotemporal dementia
  2. History of significant psychiatric illness such as schizophrenia or bipolar affective disorder that in the opinion of the Investigator would interfere with participation in the study; major depressive disorder (according to DSM-IV) in the past year; current active depression requiring initiation of treatment (or is believed to account for substantial degree of cognitive impairment)
  3. Evidence of the following disorders: current vitamin B12 deficiency, positive syphilis serology (unless neurosyphilis was ruled out) or active thyroid dysfunction (particularly suggestive of hypothyroidism), including abnormally high or low serum levels of thyroid stimulating hormone (TSH), where this is thought to be the cause of, or to contribute to the severity of the subject's dementia.
  4. History of alcohol or other substance abuse, according to the DSM-IV criteria, or recent or remote history of the same if that could be a contributing factor to dementia.
  5. History of intra cerebral haemorrhage due to any of the following causes: cerebral amyloid angiopathy, uncontrolled hypertension, cerebral arteriovenous malformation, coagulopathy, CNS vasculitis or any other condition that the investigator and/or medical monitor considers as a relevant risk factor for intracerebral haemorrhage

  6. Recent (i.e.,<6 months from Screening Visit) cardiovascular event defined as:

    1. ST-elevation MI or non-ST-elevation MI, confirmed by cardiac enzyme elevation and ECG changes
    2. coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft )
    3. stroke of any etiology
    4. resuscitated sudden death
    5. prior carotid surgery or stenting procedure
  7. Poorly controlled hypertension despite lifestyle modifications and pharmacotherapy (either systolic blood pressure >160mmHg or diastolic blood pressure >110mmHg)
  8. QTcB interval >450 msec; or QTcB > 480 msec in subjects with bundle branch block based on ECG assessment at the Screening visit.
  9. HbA1c >12.0 at Screening, or uncontrolled diabetes in the opinion of the investigator.
  10. History of glaucoma or any other findings in the baseline eye exam that, in the opinion of the investigator, would exclude the subject from participation in the study.
  11. History of adult asthma (or reactive airway disease) manifested by bronchospasm in the past 6 months, or currently taking regular anti-asthmatic medication(s).
  12. Previous history of anaphylaxis, severe allergic reaction or history of hypersensitivity to any of the components of the formulation.
  13. Significant abnormalities on clinical chemistry, haematology or urinalysis at Screening, including clinically significant anaemia.
  14. History of chronic viral hepatitis (including presence of B surface antigen or hepatitis C antibody), or other chronic hepatic disorders.

  15. Abnormal Screening blood tests exceeding any of the limits defined below:

    1. Alanine transaminase (ALT) or aspartate transaminase (AST) >1.5 x the upper limit of normal (ULN)
    2. Alkaline phosphatase (AP) and bilirubin >1.5X ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
    3. Calculated creatinine clearance < 30 ml/min (per Cockcroft & Gault) at Screening
  16. Other clinically significant abnormality on physical (including neurological), laboratory or ECG examination that could be detrimental to the subject in the opinion of the Investigator or could compromise the integrity of the study.
  17. Planned major surgery within the study period.
  18. Use of systemic steroids or other immunosuppressants within the last 30 days prior to screening.
  19. Current treatment with barbiturates, MAO inhibitors, butyrophenones, phenothiazines and other "conventional" antipsychotic within 30 days or 5 half-lives prior to Screening, whichever is longer.
  20. Treatment with antidepressants, (other than MAO inhibitors), thyroid hormones, atypical antipsychotics (e.g. risperidone), benzodiazepines and other sedatives / hypnotics unless prescribed at a stable dose for at least 2 months prior to Screening. Note: Benzodiazepines or other sedatives/hypnotics (including antihistamines) with half-life less than 6 hours can be taken on a prn (as needed) basis but must not be taken within 5 half lives prior to cognitive testing.
  21. Current treatment with known potent inhibitors of CYP3A4 (e.g. ketoconazole, rifampin, modafinil).
  22. Current treatment with known potent Pgp inhibitors (itraconazole, ketoconazole, cyclosporin, loperamide, diltiazem, verapamil, spironolactone, quinidine, bepridil, quinine, carvedilol)
  23. Cognitive tasks prescribed for cognitive rehabilitation and performed under medical supervision in the 6 months prior to screening and/or during study
  24. Investigational medications or devices including symptomatic AD treatment during the 60 days prior to the Screening visit, or within 5 half-lives of use of the investigational drug prior to the Screening Visit, whichever is longer.

  25. Participation in another investigational drug (with the exception of anti-amyloid monoclonal antibodies [mAbs]) or device study where subject was treated chronically (i.e. > 1 single dose) with a study agent intended to impact AD progression during the 12 months prior to the Screening visit.

    1. Subjects who participated in an investigational drug study that involved chronic dosing with a monoclonal antibody at any time in the past are excluded from this study, unless it is known that they received placebo during the previous study.
    2. Subjects who participated in previous single-dose studies of anti-amyloid mAbs will be permitted provided the subject's dose of the mAb is at least 5 half-lives removed; the subjects did not experience any moderate adverse events classified as possibly drug-related or any serious adverse event during that study; the subject did not drop out of the previous study (i.e. completed all safety assessments)
  26. Subjects, who in the investigator's judgement, pose a significant suicide risk (e.g. history of suicidal behaviour in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months).
  27. Subject or caregiver is an immediate family member or employee of the participating Investigator, any of the participating site staff or GSK staff.

  28. Any contraindication to lumbar puncture or insertion of CSF catheter, including but not limited to

    1. Thrombocytopenia or other coagulation disorders (including subjects receiving coumarin-derived anti-coagulants or low-molecular-weight heparin).
    2. The presence of cutaneous or soft tissue infection overlying or adjacent to the site of lumbar puncture.
    3. Previous spinal surgery that could complicate access to the subarachnoid space.
    4. Suspicion of increased intracranial pressure due to a cerebral mass.

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：ランダム化
  • 介入モデル：並列代入
  • マスキング：トリプル

武器と介入

参加者グループ / アーム
介入・治療
実験的：250mg rilapladib
Experimental drug
薬：250mg rilapladib
Experimental Drug
プラセボコンパレーター：プラセボ
プラセボ比較器
薬：プラセボ
プラセボ コンパレータ

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
Change From Baseline (Day 0) in Cerebral Spinal Fluid (CSF) Amyloid Beta Peptide (Abeta) 42 and Abeta40 at Week 24
時間枠：Baseline (Day 0) and Week 24
CSF Abeta biomarkers (Abeta42, Abeta40) were assessed at Baseline visit (Day 0) and Week 24 (Day 168). Change from Baseline in CSF Abeta42 and Abeta40 are summarized. Baseline and Week 24 study visits were taken place at approximately the same time of day in the morning (preferably between 08:00 and 12:00) to improve the reliability of CSF. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value. The data is presented in for adjusted mean and standard error of adjusted mean.
Baseline (Day 0) and Week 24
Change From Baseline (Day 0) in CSF Abeta42/ Abeta40 Ratio at Week 24
時間枠：Baseline (Day 0) and Week 24
CSF Abeta biomarkers (Abeta42, Abeta40) were assessed at Baseline visit (Day 0) and Week 24 (Day 168). Change from Baseline in CSF Abeta42/Abeta40 ratio is summarized. Baseline and Week 24 study visits were taken place at approximately the same time of day in the morning (preferably between 08:00 and 12:00) to improve the reliability of CSF. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value. The data is presented in for adjusted mean and standard error of adjusted mean.
Baseline (Day 0) and Week 24
Change From Baseline (Day 0) in CSF Tau and Phosphorylated Tau (P-tau) Measures at Week 24
時間枠：Baseline (Day 0) and Week 24
CSF tau and P-tau were assessed at Baseline visit (Day 0) and Week 24 (Day 168). Change from Baseline in CSF tau and P-tau was summarized. Baseline and Week 24 study visits were taken place at approximately the same time of day in the morning (preferably between 08:00 and 12:00) to improve the reliability of CSF. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value. The data is presented in for adjusted mean and standard error of adjusted mean.
Baseline (Day 0) and Week 24
Change From Baseline (Day 0) in the Computerized Test Battery for Cognition (CogState) Battery Working Memory/Executive Function (WM/EF) Composite Score at Week 24
時間枠：Baseline (Day 0) and Week 24
The WM/EF composite score was comprised of 5 functional tests including 1) Controlled oral word association which measured language fluency, planning and working memory, 2) Category naming: It measures semantic fluency, planning and working memory, 3) One-back: This is a measure of working memory. 4) Trail B: This is a measure of motor speed, visual scanning, and visual-motor integration. This test required attention and cognitive flexibility. 5) Go No-Go task: This test evaluate accuracy and reaction time for each response. The composite score calculated by standardizing the total score: sum of all responses obtained from these 5 functional test by using the formula (Total score of ITT population at baseline - Total score at Week 24) /standard deviation of mean total mean score at baseline. The observed composite score ranged from minimum -1.474 and maximum 1.596. Lower score means better cognitive status. Change from Baseline was calculated as post-dose visit minus Baseline value.
Baseline (Day 0) and Week 24

二次結果の測定

結果測定
メジャーの説明
時間枠
Change From Baseline (Day 0) in CSF Albumin Quotients at Week 24
時間枠：Baseline (Day 0) and Week 24
CSF albumin quotient was assessed at Baseline visit (Day 0) and Week 24 (Day 168). Change from Baseline in albumin quotient is summarized. Baseline and Week 24 study visits were taken place at approximately the same time of day in the morning (preferably between 08:00 and 12:00) to improve the reliability of CSF. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value. The data is presented in for adjusted mean and standard error of adjusted mean.
Baseline (Day 0) and Week 24
Change From Baseline (Day 0) in Plasma Levels of Abeta42 and Abeta40 at Week 24
時間枠：Baseline (Day 0) and Week 24
Plasma Abeta biomarkers (Abeta42, Abeta40) were assessed at Baseline visit (Day 0) and Week 24 (Day 168). Change from Baseline in plasma Abeta42 and Abeta40 are summarized. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value. The data is presented in for adjusted mean and standard error of adjusted mean.
Baseline (Day 0) and Week 24
Change From Baseline (Day 0) in Plasma Levels of Abeta42/Abeta40 Ratio at Week 24
時間枠：Baseline (Day 0) and Week 24
Plasma Abeta biomarkers (Abeta42, Abeta40) were assessed at Baseline visit (Day 0) and Week 24 (Day 168). Change from Baseline in plasma Abeta42/Abeta40 ratio is summarized. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value. The data is presented in for adjusted mean and standard error of adjusted mean.
Baseline (Day 0) and Week 24
Percentage Inhibition in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity at Week 24
時間枠：Baseline (Day 0) and Week 24
Plasma Lp-PLA2 was assessed at Baseline visit (Day 0) and Week 24 (Day 168). Percentage inhibition in plasma Lp-PLA2 activity ratio is summarized. Percentage inhibition was calculated by dividing change from Baseline in plasma LpPLA2 by Baseline LpPLA2 multiplied by -100. Baseline value was defined as the latest Day 0 value. Change from Baseline was calculated as post-dose (Week 24) visit value minus Baseline value.
Baseline (Day 0) and Week 24
Change From Baseline (Day 0) in CogState Battery Overall Composite Score
時間枠：Baseline (Day 0) and Week 12 (Day 84), Week 24 (Day 168)
CogState battery overall composite score comprised of 8 functional tests 1) Controlled oral word association test measured language fluency, planning and working memory. 2) Category naming test measured semantic fluency, planning and working memory. 3) One-back test measured working memory. 4) Trail B test measured motor speed, visual scanning and visual-motor integration, required attention and cognitive flexibility. 5) Go No-Go task evaluated accuracy and reaction time for each response. 6) International shopping list immediate and delayed recall tests measured episodic memory. 7) Identification task test assessed visual attention. 8) Trail A test measured psychomotor speed and attention. Composite score= total score (sum of all responses from 8 functional test) by formula (Total score at baseline - Week 24) / SD of total score at baseline. Score ranged: -1.070 to 0.907. Lower score indicated the better cognitive status. Change from Baseline= post-dose visit minus Baseline value
Baseline (Day 0) and Week 12 (Day 84), Week 24 (Day 168)
Change From Baseline (Day 0) in CogState Battery Attention Composite Score
時間枠：Baseline (Day 0) and Week 12 (Day 84), Week 24 (Day 168)
CogState battery attention composite score comprised of 2 functional tests including 1) Identification task test assessed visual attention and 2) Trail A test measured psychomotor speed and attention. Composite score calculated by standardizing the total score (sum of all responses from 2 functional test) by formula (Total score at baseline - Week 24) / SD of total score at baseline. The observed composite score ranged from minimum -1.756 and maximum 1.330. Higher score indicated the better attention. Baseline value was defined as the latest Day 0 value and Change from Baseline was calculated as post-dose visit minus Baseline value
Baseline (Day 0) and Week 12 (Day 84), Week 24 (Day 168)

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

GlaxoSmithKline

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

便利なリンク

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

2011年10月1日

一次修了 (実際)

2013年2月4日

研究の完了 (実際)

2013年2月18日

試験登録日

最初に提出

2011年9月1日

QC基準を満たした最初の提出物

2011年9月1日

最初の投稿 (見積もり)

2011年9月5日

学習記録の更新

投稿された最後の更新 (実際)

2018年9月24日

QC基準を満たした最後の更新が送信されました

2018年8月7日

最終確認日

2017年7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

  • 114458

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

はい

IPD プランの説明

Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

試験データ・資料

  1. データセット仕様
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register
  2. 個人参加者データセット
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register
  3. インフォームド コンセント フォーム
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register
  4. 統計分析計画
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register
  5. 研究プロトコル
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register
  6. 注釈付き症例報告書
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register
  7. 臨床研究報告書
    情報識別子：114458
    情報コメント：For additional information about this study please refer to the GSK Clinical Study Register

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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