A study to assess the effect of rilapladib (SB 659032) on Alzheimer’s disease.

Phase 1

Conditions: Alzheimer's Disease
MedDRA version: 14.1Level: LLTClassification code 10001896Term: Alzheimer's diseaseSystem Organ Class: 10029205 - Nervous system disorders
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: EUCTR2010-020993-41-SE

Lead Sponsor: GlaxoSmithKline Research and Development Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 120

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, including at least one of the following:
a. CT: Extensive periventricular and deep white matter lesions: patchy or diffuse symmetrical areas of low attenuation (intermediate density between normal white matter and cerebrospinal fluid), with ill-defined margins extending to the centrum semiovale, and at least one lacunar infarct.
And/Or
b. MRI: White matter lesions: extending caps or irregular halo or diffusely confluent hyperintensities or extensive white matter changes
And/Or
c. Lacunar cases: Multiple lacunes (e.g. > 5) in the deep grey matter.
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:
a. Non-childbearing potential defined as pre-menopausal females with a
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory].
NB: Females on hormone replacement therapy (HRT) and whose
menopausal status is in doubt will be required to use one of the
contraception methods described in the protocol.
b. Child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until completion of the follow-up visit.
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 (i.e. clinic visits, medication). A non-cohabiting caregiver must spend sufficient time with the subject so that, in the opinion of the Investigator, the caregiver can reliably assess cognitive function, activities and behaviour for the purpose of the baseline CDR assessment, and to oversee the subject’s compliance and to report on their health throughout the study. This would normally be possible
when the caregiver spends a few hours each day with the subject.
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 tes

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 (in accordance with the Work Group on Frontotemporal Dementia and Pick’s Disease criteria)
2. History of significant psychiatric illness such as schizophrenia or bipolar affective disorder that would interfere with participation in the study; major depressive disorder in the past year; current active depression requiring initiation of treatment
3. Evidence of: current vitamin B12 deficiency, positive syphilis serology or active thyroid dysfunction.
4. History of alcohol or other substance abuse.
5. History of intra cerebral haemorrhage due to: CAA, 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 CV event defined as:
a. ST-elevation MI or non-ST-elevation MI,
b. coronary revascularization (PCI or CABG)
c. stroke
d. resuscitated sudden death
e. 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.
9. HbA1c >12.0 at Screening, or uncontrolled diabetes.
10. History of glaucoma or any other findings in the baseline eye exam.
11. History of adult asthma (or reactive airway disease).
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.
14. History of chronic viral hepatitis or other chronic hepatic disorders.
15. Abnormal Screening blood tests regarding: ALT or AST, alkaline phosphatase and bilirubin, creatinine clearance
16. Other clinically significant abnormality on physical (including neurological), laboratory or ECG examination that could be detrimental to the subject.
17. Planned major surgery within the study period.
18. Use of systemic steroids or other immunosuppressants within the last 30 days.
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.
21. Current treatment with known potent inhibitors of CYP3A4.
22. Current treatment with known potent Pgp inhibitors.
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 e

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To examine in an exploratory manner whether rilapladib produces changes in CSF biomarkers that are consistent with effects on increased CNS Aß clearance in AD patients and whether these findings are associated with changes in CSF neurodegenerative markers and selected cognitive endpoints.;Secondary Objective: - To examine the effects of rilapladib on BBB permeability (CSF albumin<br>quotient), peripheral Aß levels (Aß42 and Aß40) and plasma Lp-PLA2 activity.<br>- To further evaluate the effects of rilapladib on cognition.<br>- To assess the safety and tolerability of rilapladib over a 24 week treatment period.;Primary end point(s): • Change from baseline in CSF Aß42, Aß40 and Aß42/ Aß40 ratios at Week 24.<br>• Change from baseline in CSF tau and P-tau measures at Week 24.<br>• Change from baseline in the CogState battery working memory/executive function composite score at Week 24.;Timepoint(s) of evaluation of this end point: Week 24

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): • Change from baseline in CSF albumin quotients at Week 24.<br>• Change from baseline in plasma levels of Aß42, Aß40 and ratio Aß42/Aß40 at Week 24.<br>• Change from baseline in plasma Lp-PLA2 activity at Week 24.<br>• Change from baseline in CogState battery overall composite score.<br>• Change from baseline in CogState battery attention composite score.<br><br>Safety Endpoints<br>• Assessment of safety and tolerability by analysis of AE data and changes from<br>baseline in vital signs, clinical laboratory values, neurological examination, EM<br>of peripheral blood mononuclear cells and electrocardiograms (ECGs).<br>;Timepoint(s) of evaluation of this end point: Week 24

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