E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alzheimer's disease and healthy controls (2 groups: 1 group with young healthy volunteers, 1 group with elderly healthy volunteers) |
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E.1.1.1 | Medical condition in easily understood language |
Patients with dementia and healthy control group (2 groups: 1 group with young healthy volunteers, 1 group with elderly healthy volunteers) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001896 |
E.1.2 | Term | Alzheimer's disease |
E.1.2 | System Organ Class | 100000004852 |
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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 objective of this study is to examine differences in Pgp function at the BBB between AD patients and age-matched control subjects by performing (R)-11C-verapamil PET scans before, during and after Pgp modulation with tariquidar. Tariquidar will be administered at a dose of 3 mg/kg which corresponds to the half-maximum effect dose for inhibition of Pgp at the BBB. We hypothesize that AD patients will show higher increases in (R)-11C-verapamil brain distribution following tariquidar administration than control subjects due to reduced cerebral Pgp function in AD patients. Furthermore the influence of ABCB1 single nucleotide polymorphisms (SNPs, 3435C>T, 2677G>T, 1236C>T) on (R)-11C-verapamil distribution to the brain before, during and after tariquidar infusion will be assessed.
To compare rate constants of (R)-11C-verapamil transport across the BBB before, during and after tariquidar infusion between AD patients and age-matched control subjects. Secondary objectives:
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E.2.2 | Secondary objectives of the trial |
To assess the influence of ABCB1 SNPs on (R)-11C-verapamil brain distribution before, during and after tariquidar infusion in AD patients and age-matched control subjects. To assess regional differences in (R)-11C-verapamil brain distribution before, during and after tariquidar infusion in AD patients and age-matched control subjects. To compare tariquidar plasma pharmacokinetics in AD patients and age-matched control subjects. To assess age dependency of cerebral Pgp function before and after pharmacological modulation. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• signed informed consent • age: ≥18 years old • physical examination and laboratory analysis: no presence of clinically relevant abnormal findings or values which the investigator considers may interfere with the objectives of the present study • no diseases, which the investigator considers may affect the outcome of the study • ability to comprehend the full nature and purpose of the study, including possible risks and side effects
Patient group (additionally): • Diagnosis of probable Alzheimer’s disease based on the NINCDS/ADRDA criteria . The severity of AD in a range from mild to moderate, which is in accordance with a MMSE score ≤12 and ≥26. The Hachinski score must be <4 • A person who takes care of the patient must agree to accompany the subject to all study procedures • MRI must support AD diagnosis • Preferably 11C-PIB® positive scan
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E.4 | Principal exclusion criteria |
• Unwillingness to sign the informed consent • age:<18 years old • any abnormality found as part of the pre-treatment screening or in any of the laboratory tests performed that the investigators considers to interfere with the objectives of the present study or • any medication during two weeks before the start of the study, which the investigator considers may affect the validity of the study, due to interference with CYP3A4, Pgp or BCRP (Pgp inductors such as St. John’s wort, rifampicin or inhibitors such as esomeprazole, omeprazole, pantoprazole, lansoprazole, atrovastatin, itraconazole) or may cause potential harm to the subject (e.g. drug-drug interaction between tariquidar and loperamide or quinidine) • any disease which the investigator considers may affect the outcome of the study • participation in the evaluation of any drug within four weeks before the start of the study or participation in studies with radiation within 1 year before the start of the study • inability to comprehend the full nature and purpose of the study • contraindication for MRI imaging e.g. claustrophobia, metallic endoprosthesis, stent implantation in the last months • actual vitamin B12 and folic acid deficiency or history of craniocerebral injury • history of drug or alcohol abuse • Participation in clinical studies with exposure to radiation exceeding the allowed maximum foreseen by the current guidelines (http://ec.europa.eu/energy/nuclear/radioprotection/publication/doc/136_en.pdf
Patient group (additionally): AD patients with concomitant delirium • patients with Hachinski score >4, MMSE score out of the range of ≥12 and ≤26 • patients and/or caregiver with probable compliance problems |
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E.5 End points |
E.5.1 | Primary end point(s) |
Transfer rate constants of 11C-verapamil before and after tariquidar infusion as calculated by pharmacokonetic modeling |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Modeling the slope of 11C-verapamil brain uptake increase as response to tariquidar infusion; Genetic analysis |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
other condition (healthy volunteers) |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |