| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to Moderate Alzheimer's Disease |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| 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 |
•To investigate the effects of daily dosing for 24 weeks with RSG XR versus placebo on cognitive function in subjects with mild to moderate Alzheimer’s disease as a function of APOE ε4 status.
•To investigate the effects of daily dosing for 24 weeks with RSG XR versus placebo on overall clinical response in subjects with mild to moderate Alzheimer’s disease as a function of APOE ε4.
•To estimate the effects of donepezil on cognitive function and overall clinical response in the total population
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| E.2.2 | Secondary objectives of the trial |
1.To assess the safety and tolerability of RSG XR versus placebo in subjects with mild to moderate AD and to monitor the safety and tolerability of donepezil.
2.To examine the time course of any cognitive effects of RSG XR.
3.To investigate the effects of RSG XR on measures of behavior and activities of daily living.
4.To investigate the effects of RSG XR on subject- and caregiver-reported health outcomes measures, including resource utilization, subject quality of life, and caregiver quality of life.
5.To investigate the effects of RSG XR on short term memory.
6.To evaluate RSG XR for cognitive efficacy in relation to potential disease modification effects.
7.To evaluate the pharmacokinetics of RSG XR in mild to moderate Alzheimer’s disease subject.
8.To explore the relationship between systemic RSG XR exposure and clinical efficacy.
*Please refer to protocol for additional secondary objectives |
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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 |
| An optional sub-study will be conducted at some sites, investigating the effects of RSG XR on bone health status |
|
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1.Male or female subject with a clinical diagnosis of probable Alzheimer's disease in accordance with NINCDS-ADRDA criteria for at least 3 months (Appendix 3)
(Note: National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and Alzheimer's Disease and Related Disorders Association (ADRDA).)
2.Subject has mild to moderate Alzheimer's disease as defined by a MMSE score 10 to 23 inclusive at Screening.
3.Hachinski Ischemia Score ≤ 4 at Screening (See Appendix 4).
4.Age ≥50 and ≤90 years.
5.Subject has not taken an approved Alzheimer’s therapy in the last 30 days.
6.Subject has not had a previous history of hypersensitivity or intolerance to AChEIs.
7.Current use of medication is in accordance with the criteria listed in Table 2 (Permitted Medications, Section 8.1).
8.Female subjects must be post-menopausal (i.e. > 1 year without menstrual period), surgically sterile, or agree to use adequate method of contraception (Appendix 5) for the duration of the study. Female subjects who are pre-menopausal or who have been post-menopausal for < 1 year must undertake pregnancy testing (urine test) at Visit 1, which must be negative.
9.Brain CT or MRI scan performed within the past 12 months or at Screening, showing no evidence of any other potential cause of dementia other than Alzheimer's disease.
(Note: Questionable CT or MRI scans should be discussed with the medical monitor, using central imaging guidelines.)
10.Neurological exam without focal changes (excluding changes attributable to AD or peripheral trauma).
11.Subject has the ability to comply with procedures for cognitive and other testing
Please refer to the protocol for full ist of inclusion criteria |
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| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1.Diagnosis of possible, probable, or definite vascular dementia in accordance with NINDS-AIREN criteria (Appendix 6).
(Note: National Institute of Neurological Disorders and Stroke (NINDS) and Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN).)
2.History or evidence of any other CNS disorder that could be interpreted as a cause of dementia: e.g. cerebrovascular disease (stroke, hemorrhage), structural abnormality, epilepsy, infectious or inflammatory/demyelinating CNS conditions, Parkinson's disease.
3.Evidence of the following disorders: current vitamin B12 deficiency, positive syphilis serology or active thyroid dysfunction (particularly that suggestive of hypothyroidism), including abnormally high or low serum levels of thyroid stimulating hormone (TSH) that are clinically significant in the opinion of the investigator.
(Note: Testing is required for each parameter only when no result is available from previous 12 months.)
4.History of Type 1 diabetes mellitus or secondary diabetes mellitus.
5.Type 2 diabetes mellitus where the subject is being treated with insulin, a PPARγ agonist, or an insulin secretagogue (e.g. a sulfonylurea or glitinide).
6.Any patient with an HbA1c ≥8.5% (See Section 6.3.8.4 for Safety Measures for Enrolled Subjects with Type 2 Diabetes Mellitus).
7.History or clinical/laboratory evidence congestive heart failure defined by the New York Heart Association criteria (Class I to IV cardiac status; Appendix7).
8.History of cardiovascular event within the last 6 months (i.e. intervention, percutaneous coronary intervention, vascular surgery, acute coronary syndrome [non Q-wave myocardial infarction, Q-wave myocardial infarction, unstable angina] or significant arrhythmia; or major intervention (e.g. cardiac surgery or angiography plus stenting) scheduled).
9.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, or current active depression requiring initiation of treatment.
(Note: If not currently treated, but active depression is suspected, the Cornell Scale for Depression in Dementia (CSDD, Appendix 8) can be used by the Investigator as a guide for deciding whether a prospective subject requires treatment. If the subject has a CSDD score >7, the Investigator should decide if the subject has depression in need of prescribed medication, and a CSDD >12 is considered a strong indicator that treatment is needed. Subjects will be allowed to re-screen after their depression has been adequately managed for >3 months.)
10.History or presence of gastro-intestinal, hepatic, or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs, or any other clinically relevant abnormality, medical or psychiatric condition, which, in the opinion of the Investigator, makes the subject unsuitable for inclusion in the study.
11.Clinically significant peripheral edema at the time of screening.
12.Current or recent drug or alcohol abuse or dependence (defined by DSM-IV criteria for substance-related disorders), or recent or remote history of the same if that could be a contributing factor to the dementia.
13.Systolic blood pressure >165 or <90 mmHg or diastolic blood pressure >95 or <60 mmHg at the time of screening.
14.Clinically significant anemia (i.e. hemoglobin <11 g/dL for males or <10 g/dL for females) or presence of hemoglobinopathies which would prevent accurate assessment of HbA1c.
15.Abnormal kidney function tests (more than 1.5 ULN).
16.ALT, AST, or alkaline phosphatase values >2.5 times the upper limit of normal, total bilirubin values >1.5 times the upper limit of normal, or history of severe hepatobiliary disease (e.g. hepatitis B or C, or cirrhosis, Child-Pugh Class B/C).
(Note: For subjects with a diagnosis of Gilberts Syndrome and an isolated increase in total bilirubin >1.5 ULN, fractionation should be performed. If all of the following conditions are met, the patient may enter or remain in the study, even if total bilirubin >1.5 ULN:
• an elevated unconjugated (indirect) bilirubin;
• the percentage of direct bilirubin <35%;
• ALT, AST, and alkaline phosphatase <2.5 ULN if subject is in screening, or ≤3 ULN if subject is already randomized into the study)
17.History of a bone marrow transplant.
18.Subject is unable (with assistance, if appropriate) to take study medication as prescribed throughout the study or is at risk of non-compliance with study medication or procedures.
Please refer to the protocol for complete list of exclusion criteria
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline in Alzheimer's Disease Assessment Scale – cognitive subscale (ADAS-Cog; [Rosen, 1984]) total score at Week 24, as a function of APOE ε4 status.
Change from baseline in Clinician’s Interview-Based Impression of Change – plus (CIBIC+) [Schneider, 1997]) score at Week 24, as a function of APOE ε4 status.
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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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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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| Last subject Last Visit, see protocol |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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