| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with mild or moderate Alzheimer disease. |
|
| 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 |
|
| 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 decline of AD as compared to placebo |
|
| E.2.2 | Secondary objectives of the trial |
| 1) to test the hypothesis that LY450139 is a disease-modifying medication independent of acute symptomatic effects; 2) to provide supporting evidence that LY450139 is a disease-modifying compound; 3) to compare the safety of LY450139 and placebo; 4) to characterize population pharmacokinetics (PK) of LY450139, explore potential factors that may influence variability of PK, and explore the association of PK variables with efficacy, biomarkers, and safety parameters; 5) to test the hypothesis that LY450139 will slow the rate of decline of AD, compared to placebo; and, 6) to assess global clinical benefit of treatment with LY450139. |
|
| 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 |
ALTRI SOTTOSTUDI: -Misurazione del volume del cervello tramite risonanza magnetica. - Misurazione del glucosio nel cervello tramite PET - Puntura lombare per l'analisi del liquido cerobrospinale.
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| E.3 | Principal 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 staffadministered short form) [5] A magnetic resonance imaging (MRI) or computerized tomography (CT) scan performed within the past 2 years has confirmed no findings inconsistent with a diagnosis of AD. Results of this MRI or CT are to be on file at the site. If a patient has not had a prestudy MRI/CT scan in the past 2 years or attempts to obtain offsite imaging results are unsuccessful, then a screening non-contrast head CT is to be performed; due diligence to obtain offsite results should be documented in the patient's file prior to obtaining a screening noncontrast head CT scan. [6] Is at least 55 years old. If female, must be post-menopausal (as evidenced by a lack of menstruation for at least 12 consecutive months or by having had a bilateral oophorectomy). |
|
| E.4 | Principal exclusion criteria |
| [7] Meets National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN) criteria for vascular dementia [8] 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 assistedliving facility may be included if study medication intake is supervised and if regular contact with a caregiver who accompanies the patient is maintained. [9] Is not capable of swallowing whole oral medications [10] 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 years [11] Has a history within the past 5 years of a serious infectious disease affecting the brain, including neurosyphilis, meningitis, or encephalitis [12] 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 (PSA) post resection [13] Has compromised renal function at Visit 1, as determined by creatinine clearance <30 mL/min based on Cockcroft-Gault calculation of creatinine clearance: Men: (140 - age) x (weight in kg) -or- (140 - age) x (weight in kg) 72 x (serum creatinine in mg/100 mL) 0.81 x (serum creatinine in μmol/L) Women: (either of above formulas) x 0.85 [14] Has a history of chronic alcohol or drug abuse within the past 5 years [15] 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 Section 6.3.2.2 for details on use of QTc for exclusion.) [16] Has evidence of significant active cardiac disease, uncontrolled hypertension, uncompensated congestive heart failure, or endocarditis [17] Has potassium <3.2 mEq/L at Visit 1 [18] Has absolute lymphocyte count <0.5 GI/L at Visit 1 [19] Has platelets <75 GI/L at Visit 1 [20] Has a known history of HIV see Protocol p. 22-25. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of this study is to test the hypothesis that LY450139 given orally will slow decline of AD as compared to placebo. For the FDA, this will be assessed using a slope analysis of 2 coprimary outcomes (ADAS-Cog11 and ADCS-ADL), in which the specific hypothesis is that the rate of change over time (slope) for LY450139 will be significantly less than that for placebo, as assessed using a repeated measures model. Specifically, each of the two primary endpoints, ADAS-Cog11 and the ADCS-ADL, will be analyzed separately using a repeated-measures mixed model analysis. For the CHMP, the primary objective will be assessed by change from baseline to endpoint using 2 coprimary outcomes: the ADAS-Cog11 and the ADCS-ADL. The specific hypothesis is that the change from baseline to endpoint will be significantly less than that for placebo, as assessed by a stratified analysis of baseline to endpoint change. Change from baseline difference in the MMSE scores will also be analyzed using a repeated measures mixed model analysis. |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| - same IMP used at different dosage |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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