E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
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 |
To evaluate the safety and tolerability of two doses of ORY-2001 in patients with mild-moderate Alzheimer's Disease |
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E.2.2 | Secondary objectives of the trial |
To investigate the effect of two doses of ORY-2001 on the clinical domains of Alzheimer´s Disease |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men and women 50-85 years of age 2. Body mass index (BMI) of at least 18.5 kg/m2 3. Probable AD diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria 4. MMSE score at Screening and Baseline Visits of at least 16 and not greater than 26 5. Evidence of the AD pathophysiological process indicated by decreased levels of amyloid AB and increased levels of total Tau protein or phospho-Tau protein in CSF 6. Ambulatory or ambulatory aided patient (i.e. walker or cane) 7. Outpatient consulting a general practitioner, or a phsychiatrist/neurologist/geriatrician 8. Formal education for more than 6 years 9. Knowledgeable and reliable close relative/caregiver who will accompany the patient to all clinic visits during the study 10. Prior treatment: a. Daily treatment with the same acetylcholinesterase inhibitor (oral donepezil, oral or transdermal patch rivastigmine, or oral galantamine) for at least 6 months prior the Screening Visit and on a stable dose (i.e. the patient’s individual maintenance dose) for at least 4 months prior to the Screening Visit and throughout the Screening Period (applicable for centres located in Spain, France and UK) or b. Patients with no previous AD treatment (i.e.: AChEI or memantine) before the Screening Visit. These AD treatment-naïve patients should not receive AD treatment other than ORY-2001 at any moment from Screening Visit and throughout the study (only applicable for centres located in France and UK) 11. Stable pharmacological treatment of any other chronic condition for at least one month prior to screening – including anti-inflammatories 12. Fertile male and female must use highly effective contraception, from the Screening Visit until 90 days after last dose of the IMP, defined as: a. A method with less than 1% failure rate (e.g. permanent sterilisation, hormone implants, hormone injections, intrauterine devices, or vasectomised partner) OR b. The use of two methods of contraception (e.g. one barrier method [condom, diaphragm or cervical/vault caps] with spermicide and one hormonal contraceptive [e.g. combined oral contraceptives, patch, vaginal ring, injectable and implants]) *Following menarche and until becoming post-menopausal unless permanently sterile. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause 13. Signed informed consent by patient (or legal representative, if applicable) and a close relative/caregiver prior to the initiation of any study specific procedure |
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E.4 | Principal exclusion criteria |
1. Failure to perform screening or baseline examinations 2. Hospitalisation or change of concomitant medication 1 month prior to Screening visit or during Screening Period 3. Member or immediate family of the study personnel or subordinate (or immediate family of a subordinate) to any of the study personnel 4. Patient under forced treatment 5. Clinical, laboratory or neuroimaging findings consistent with: a. Other primary degenerative dementia; for instance, dementia with Lewy bodies, frontotemporal dementia, Huntington’s disease, Jakob-Creutzfeld Disease, Down’s syndrome b. Other neurodegenerative condition; for instance, Parkinson’s disease, amyotrophic lateral sclerosis c. Cerebrovascular disease: major infarct, one strategic or more than 2 lacunar infarcts or extensive white matter lesions as described by local radiologist d. Other central nervous system diseases; for instance, severe head trauma, tumours, subdural hematoma or other space occupying processes 6. A current DSM-5 diagnosis of major depression, schizophrenia or bipolar disorder 7. Positive results for tuberculosis (the status must be determined as usual clinical practice, i.e. by medical history, signs and symptoms), human immunodeficiency virus (HIV), hepatitis C or hepatitis B (hepatitis B surface antigen [HbsAg]) serology at the Screening Visit 8. Clinically significant, advanced or unstable disease that may interfere with evaluation: a. Seizures disorders b. Respiratory insufficiency (partial pressure of oxygen <60 mm Hg and partial pressure of carbon dioxide >50 mmHg) c. Hepatic impairment (serum total bilirubin value, serum alanine aminotransferase [ALT], serum aspartate aminotransferase [AST] and gamma-glutamyltransferase [GGT] 1.5 x upper limit of normal [ULN]) d. Renal insufficiency (serum creatinine >2mg/dl) e. Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within 6 months before Screening Visit) f. Hypertension treatment with more than 2 drugs g. Atrioventricular block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males >450 msec and females >470 msec) h. Uncontrolled diabetes (Hb1Ac >7.5) i. Haematological disorders, especially thrombocytopenia (platelets <75 000/mm3) and neutropenia (neutrophils <1 500/mm3) j. Malignant tumours within the last 5 years other than basal cell or Stage 1 squamous cell carcinoma of the skin 9. Disability that may prevent the patients from completing all study requirements; for instance, blindness, deafness, severe language difficulty 10. Chronic drug intake of: a. Acenocoumarol, warfarin or digitoxin b. Antidepressants (other than selective serotonin reuptake inhibitors [SSRIs] or selective serotonin–norepinephrine reuptake inhibitors [SSNRIs]), neuroleptics or sedatives. Note 2: Short and medium half-life oral benzodiazepines (alprazolam, lorazepam, midazolam, oxazepam, temazepam) and Z-drugs (zaleplon, zolpidem, zoplicone) are allowed in occasional short term prescription. Patients should not take these medications within 24 hours before any study visit.) c. Memantine d. Systemic anticholinergics e. Nootropics; for instance, racetams, anphetamines, metylphenidate, levodopa, atomoxetina, preparations containing Gingko biloba or St John′s Wort f. Centrally active anti-hypertensive drugs (such as clonidine, a-methyldopa, guanidine, guanfacine) g. Corticosteroids or immunosuppressant h. Antipsychotics i. MAO inhibitors j. No regular intake of medications acting directly on central nervous system that investigator consider relevant to the study 11. Treatment with anti-amyloid beta or anti-Tau protein monoclonal antibodies or other disease modifying strategies within three months or five half-lives, whichever is longer, prior to the Screening Visit 12. Treatment with an active vaccine targeting amyloid beta or Tau protein 13. Suspected or known drug or alcohol abuse 14. Metallic implants or any other cause precluding the performance of brain MRI 15. Enrolment in another investigational study within the previous 3 months 16. Suicide attempt within the last year or significant risk of suicide (in the opinion of the investigator, defined as a “yes” to suicidal ideation questions 4 or 5, or answering “yes” to suicidal behaviour on the Columbia-Suicide Severity Rating Scale within the past 12 months) 17. Any condition that in the opinion of the investigator makes the patient unsuitable for inclusion in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety • Number, frequency and severity of Treatment Emergent Adverse Events (TEAEs) up to Week 24 and Week 48 • Number, frequency and severity of Serious TEAEs up to Week 24 and Week 48 • Number and percentage of withdrawn patients due to TEAEs up to Week 24 and Week 48 • Change from baseline to Week 24 and Week 48 in physical examination, vital signs and ECG parameters • Frequency of physical examination parameters, vital signs and ECG parameters of potential clinical concern throughout the study period • Change from baseline to Week 24 and Week 48 in clinical laboratory parameters (haematology, including platelets) and clinical chemistry • Frequency of clinical laboratory parameters (haematology, including platelets, and clinical chemistry) of potential clinical concern throughout the study period • Use of concomitant medication throughout the study period |
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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) |
Efficacy • Change from Baseline to Week 24 and Week 48 compared to placebo in the Cohen-Mansfield Agitation Inventory (CMAI) • Change over time compared to placebo in the CMAI • Change from Baseline to Week 24 and Week 48 compared to placebo in the Clinician version of the Apathy Evaluation Scale (AES-C) • Change over time compared to placebo in the AES-C • Change from Baseline to Week 12, Week 24 and Week 48 compared to placebo in the 14-item Alzheimer's Disease Assessment Scale-Cognitive • Change from Baseline to Week 12, Week 24 and Week 48 compared to placebo in the Computerised Cognitive Test battery • Change from Baseline to Week 24 and Week 48 compared to placebo in the MMSE • Change from Baseline to Week 24 and Week 48 compared to placebo in the Clinical Dementia Rating Scale Sum of Boxes • Change from Baseline to Week 24 and Week 48 compared to placebo in the Cornell Scale for Depression in Dementia (CSDD) • Change over time compared to placebo the CSDD |
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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 | 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 | No |
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) | 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 | 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 | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 17 |
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 | 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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |