| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
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. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum H6L-MC-LFBC(1) ([18F]-FDG-PET)
Effect of LY450139, a gamma-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo
Protocol Addendum (1) Approved by Lilly: 28 March 2008
Objectives:
Measurement of local cerebral glucose metabolism by positron emission tomography (PET) using the radioactive tracer fluorine-18 (F-18) fluorodeoxyglucose ([18F]-FDG)
One of the secondary objectives of this study will be to test the hypothesis that LY450139 will attenuate the accelerated rate of decline in brain glucose metabolism, as compared to placebo. To this end, [18F]-FDG-PET measurements will be conducted in up to 225 patients. The measure is included as an addendum primarily because not all sites have the capability to perform the test.
Protocol Addendum H6L-MC-LFBC(2) (vMRI)
Effect of LY450139, a gamma-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo
Protocol Addendum (2) Approved by Lilly: 28 March 2008
Objectives:
One of the secondary objectives of this study will be to test the hypothesis that LY450139 will attenuate the accelerated rate of decline in brain volume as compared to placebo. To this end, vMRI measurements will be conducted in up to 225 patients.
Objectives:
Use a radioactive tracer has been developed for PET that is a ligand for amyloid to meet 2 secondary study objectives: first, to test the hypothesis that amyloid burden will be reduced in patients treated with LY450139 (versus placebo) and second, that only patients demonstrating sufficient amyloid burden at baseline will respond to treatment as determined by clinical measures
Protocol Addendum H6L-MC-LFBC(8.1) (Lumbar Punctures)
Effect of LY450139, a gamma-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo
Protocol Addendum (8.1) Approved by Lilly: 13 August 2008
Objectives:
First, CSF tau and phosphorylated forms of tau (p-tau) are known to be elevated in patients with Alzheimer’s disease . One secondary objective of the study is to show that CSF tau/p-tau will be less elevated in patients receiving LY450139 than in patients receiving placebo.
Second, CSF AB1-42 concentrations are known to be reduced in patients with AD. An exploratory objective of the study is to show that CSF AB1-42 concentrations may be normalized (increased) in patients treated with LY450139. Because treatment with LY450139 would be expected to acutely decrease CSF AB1-42 concentrations, at the end of the randomized treatment period, CSF will be obtained for AB1-42 measurements approximately 24 hours after dosing. Given that the effect of daily dosing may be longer than 24 hours after chronic LY450139 administration, CSF AB1-42 concentrations might be decreased rather than increased at this endpoint measurement; thus, this will be considered an exploratory analysis
Protocol Sample Banking Addendum H6L-MC-LFBC(5)
Effect of LY450139, a gamma-Secretase Inhibitor, on the Progression of Alzheimer’s Disease as Compared with Placebo
Protocol Addendum (5) Approved by Lilly: 28 March 2008
Objectives:
The Banked Samples are collected and banked for research to identify the (1) genes, (2) gene products, (3) biochemical markers, or (4) any combination thereof associated with diseases, response to clinical trial medication, or both or other medication taken during the trial. For example, in Study H6L-MC-LFBC (LFBC), genes and proteins related to Alzheimer’s disease may be assessed.
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| E.3 | Principal 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).
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| E.4 | Principal 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 (see Protocol Section 5.7.2 for more details)
[18] Has received AChEIs or memantine for less than 4 months or has less than 2 months of stable therapy on these treatments by Visit 2 (Note: If a patient has recently stopped AChEIs or memantine, he or she must have discontinued treatment at least 2 months before Visit 2.) See Protocol Section 5.7.1 for details regarding patients on donepezil.
[19] Has received medications that affect the central nervous system (CNS; except treatments for AD) for less than 4 weeks (That is, doses of chronic medications that affect CNS should be stable for at least 4 weeks before Visit 2.)
[20] Has previously completed or withdrawn from this study
[21] Has received treatment within the past 90 days with a drug that has not received regulatory approval for any indication at the time of study entry
[22] Has received treatment within the 18 months previous to Visit 1 with an investigational treatment that is a monoclonal antibody intended to treat AD
[23] Has ever received active vaccination therapy for AD
[24] Is a member of the investigator site personnel directly affiliated with this study and/or his or her immediate family (Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.)
[25] Is a Lilly employee
[26] Lacks, in the investigator’s opinion, adequate premorbid literacy to complete the required psychometric tests.
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| E.5 End points |
| E.5.1 | 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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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