Effect of LY450139, a ?-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo

• Register: EUCTR
• Last refreshed on: 22 April 2013
• Main ID: EUCTR2008-002758-39-DE
• Date of registration: 28/07/2008
• Prospective Registration: Yes
• Primary sponsor: Eli Lilly and Company
• Public title: Effect of LY450139, a ?-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo
• Scientific title: Effect of LY450139, a ?-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo
• Date of first enrolment: 03/03/2009
• Target sample size: 1500
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-002758-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: yes Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Bulgaria, France, Germany, Hungary, Italy, Portugal

Key inclusion & exclusion criteria

Inclusion criteria:
A patient included in the study must meet all of the following inclusion criteria:
[1] Meets National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable AD
[2] Has a Modified Hachinski Ischemia Scale score of =4
[3] Has an MMSE score of 16 through 26 at Visit 1
[4] Has a Geriatric Depression Scale (GDS) score of =6 (on the staff-administered short form)
[5] Has a magnetic resonance imaging (MRI) or computerized tomography (CT) scan performed within the past 2 years that has confirmed no findings inconsistent with a diagnosis of AD.
[6] Is at least 55 years old. If female, must be postmenopausal (as evidenced by a lack of menstruation for at least 12 consecutive months or by having had a bilateral oophorectomy).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
A patient will be excluded from the study if he or she meets any of the following exclusion criteria:
[1] Meets National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN) criteria for vascular dementia
[2] Does not have a reliable caregiver who is in frequent contact with the patient (defined as at least 10 hours per week), will accompany the patient to the office and/or be available by telephone at designated times, and will monitor administration of prescribed medications. Note: The caregiver must be able to communicate with site personnel and be willing to comply with protocol requirements, and in the investigator’s opinion must have adequate literacy to complete the protocol-specified questionnaires. Participants living in an assisted-living facility may be included if study medication intake is supervised and if regular contact with a caregiver who accompanies the patient is maintained.
[3] Is not capable of swallowing whole oral medications
[4] Has serious or unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease or other conditions that, in the investigator’s opinion, could interfere with the analyses of safety and efficacy in this study; or has a life expectancy of <2 more years
[5] Has a history within the past 5 years of a serious infectious disease affecting the brain, including neurosyphilis, meningitis, or encephalitis
[6] Has a history within the past 5 years of a primary or recurrent malignant disease, with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen post resection
[7] Has compromised renal function at Visit 1, as determined by creatinine clearance <30 mL/min based on Cockcroft-Gault calculation of creatinine clearance
[8] Has a history of chronic alcohol or drug abuse or dependence within the past 5 years
[9] Requires the use of concomitant medications that prolong the QT/QTc interval or has a known history of Long QT Syndrome or Brugada Syndrome. Has ECG abnormalities obtained at Visit 1 or at predose Visit 2 (baseline value) that, in the opinion of the investigator, are clinically significant with regard to the patient’s participation in the study; or has a QTc abnormality at Visit 1 or predose Visit 2 (baseline value) as indicated by a mean QTc interval >458 ms if male or >474 ms if female. (See Protocol Section 6.3.2.2 for details on use of QTc for exclusion.)
[10] Has evidence of significant active cardiac disease, uncontrolled hypertension, uncompensated congestive heart failure, or endocarditis
[11] Has potassium <3.2 mEq/L at Visit 1
[12] Has absolute lymphocyte count <0.5 GI/L at Visit 1
[13] Has platelets <75 GI/L at Visit 1
[14] Has a known history of HIV
[15] Has a history of clinically significant multiple or severe drug allergies
[16] At Visit 1, has alanine transaminase (ALT/SGPT) values =2 times the upper limit of normal (ULN) of the performing laboratory, aspartate transaminase (AST/SGOT) values =3 times the ULN, or total bilirubin values =2 times the ULN
[17] Requires or is expected to require use of excluded drugs, in particular, specific calcium-channel blockers, immune modulators, or immunosuppressants

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Alzheimers Disease
MedDRA version: 9.1 Level: LLT Classification code 10001896 Term: Alzheimer's disease

Intervention(s)

Product Name: LY450139
Product Code: LY450139
Pharmaceutical Form: Tablet
INN or Proposed INN: LY450139
Current Sponsor code: LY450139
Other descriptive name: LY450139
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: LY450139
Product Code: LY450139
Pharmaceutical Form: Tablet
INN or Proposed INN: LY450139
Current Sponsor code: LY450139
Other descriptive name: LY450139
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: LY450139
Product Code: LY450139
Pharmaceutical Form: Tablet
INN or Proposed INN: LY450139
Current Sponsor code: LY450139
Other descriptive name: LY450139
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 140-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: Secondary objectives of this study are as follows:
•To test the hypothesis that LY450139 is a disease-modifying medication independent of acute symptomatic effects
•To provide supporting evidence that LY450139 is a disease-modifying compound, multiple biomarkers will be assessed
•LY450139 will acutely reduce A-Beta in plasma within 6 hours of administration
•LY450139 will attenuate the accelerated rate of decline in brain glucose metabolism
•LY450139 will reduce brain amyloid burden as compared to placebo
•LY450139 will reduce the elevated concentrations of CSF tau proteins
•To compare the safety of LY450139 and placebo
•To characterize population pharmacokinetics (PK) of LY450139.
In addition,a number of exploratory hypotheses related to biomarkers will be tested.
For a complete list of secondary objectives please refer to the study protocol.

Primary end point(s): In Europe, for the CHMP, the primary objective will be assessed by a stratified analysis of baseline-to-endpoint change using 2 coprimary outcomes: the ADAS-Cog11 and the ADCS-ADL. The specific hypothesis is that the change from baseline to endpoint for the study drug will be significantly less than that for placebo. Specifically, a summary score approach based on a stratification method (Dawson 1994;Thomas et al. 2000) will be applied to analyze the data. The analysis will be stratified according to patterns of missing data and then the strata-specific test statistics will be combined into an overall test of group equality.

Main Objective: The primary objective of this study is to test the hypothesis that LY450139 given orally will slow the decline associated with AD as compared to placebo. Because of differences in regulatory requirements across regions, this objective will be assessed using different statistical methods. In one region, one method will be considered primary and the other secondary, and this relationship will be reversed for the second region. This is discussed more fully in Section 8. Both methods will use a study endpoint sometime between 64 and 88 weeks after initiation of treatment; the precise timing for this endpoint is specified in an ethical review board (ERB) supplement to this protocol.
For a complete list of primary objectives please refer to the study protocol.

Secondary ID(s)

H6L-MC-LFBC (c)