| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The agitation/aggression symptoms in patients with Alzheimer’s disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| The agitation/aggression symptoms in patients with Alzheimer’s disease |
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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 | 19.1 |
| 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 |
|
| 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 the study is to evaluate efficacy of ORM-12741 on agitation/aggression symptoms in patients with mild to moderate Alzheimer’s disease. The efficacy of ORM-12741 administered both as immediate release (IR) and modified release (MR) formulations will be evaluated and compared to placebo. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to evaluate the efficacy of ORM-12741 on cognition and psychotic and depressive symptoms, as well as to evaluate the safety of ORM-12741. |
|
| 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 |
All subjects participating in this study will provide a blood sample for extraction of DNA to determine the carrier status for the following genes (markers): apolipoprotein E and alpha-2C AR. These markers have been associated with cognitive or neuropsychiatric symptoms in AD, or affect the target receptor, and may predict the subject’s response to the study treatment. In addition, other markers relevant to the absorption, distribution, metabolism, excretion, efficacy, and safety of ORM-12741 or its metabolites, may be studied.
This sub-study is in accordance with Protocol V1.0 dated 19Dec2014 |
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| E.3 | Principal inclusion criteria |
1. Written informed consent (IC) for participation in the study (co-signed by the subject’s next of kin or caregiver, or other legally acceptable representative, if required by the local regulations/guidelines/ethics committee [EC]) obtained from the subject.
2. Written IC obtained from a consistently available caregiver informant who is knowledgeable of the subject’s condition and its progression and is willing to accompany the subject to all visits and supervise the administration of the study medication. The caregiver should be in contact with the subject on most days, as the contact is necessary to ensure accurate reporting of the subject’s behaviour on rating scales.
3. Age of 55-90 years (inclusive). Inclusion of subjects above the age of 80 years will need the medical monitor’s approval before enrolment.
4. Male or female subjects with diagnosis of probable AD according to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease
5. History of progressive cognitive deterioration prior to baseline (via caregiver or medical record review).
6. Brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) consistent with a diagnosis of AD (within 18 months or at screening). In case the medical history suggests a neurological event between the previous scan and the screening, the scan should be repeated.
7. Mini-mental state examination (MMSE) score between 10-24 (inclusive) at screening visit.
8. Clinically significant agitation meeting the IPA Provisional Criteria for Agitation in Cognitive Impairment (Appendix 3), both at screening and baseline visits. The agitation symptoms need to have been present for at least 4 weeks before the screening visit and also have to be sustained up to the baseline visit.
9. NPI agitation/aggression item score ≥ 4 at screening visit (on original NPI scale, as derived from the NPI-C). |
|
| E.4 | Principal exclusion criteria |
1. Any other type of dementia than AD.
2. Modified Hachinski Ischemia Score (MHIS) > 4.
3. Changes in AChE inhibitor (donepezil, rivastigmine or galantamine) dosing within 2 months prior to screening.
4. Changes in memantine dosing within 2 months prior to the screening.
5. Changes in antidepressant dosing or addition of another antidepressant medication within 2 months prior to the screening.
6. Use of antipsychotics at any dose within 1 month prior to screening (even for sleep). In the event of previous use of long-acting injectable antipsychotics the duration of required wash-out (at least 5 times the elimination half-life) needs to be agreed with the medical monitor before enrollment.
7. Use of benzodiazepines, other than short-acting sleep medications, for night at a maximum of 3 nights/week, within 2 months prior to screening.
8. Use of any anticholinergic medication within 2 months prior to screening (including those used to treat overactive bladder and tricyclic antidepressants).
9. Current use (within the 30 days prior to screening) of medications with known relevant alpha-2C AR affinity (e.g. mirtazapine, mianserine, clonidine, guanfacine or tizanidine) or with high noradrenaline transporter affinity (reboxetine, venlafaxine or duloxetine).
10. Current use of other psychotropic agents, unless the dosing has been stable during the last 2 months prior to the screening and is expected to remain stable during the study, and permission has been obtained from the medical monitor before enrolment.
11. Myocardial infarction or other clinically significant ischemic cardiac disease, heart failure, or arrhythmia tendency within the past 2 years.
12. Poorly controlled diabetes mellitus
13. Current or history of malignancy within 5 years before screening (some exceptions)
14. Suicidal ideation in the 6 months before screening or current suicide risk.
15. Known or suspected history of alcoholism or drug abuse.
16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological (e.g. epilepsy) or psychiatric disorder (e.g. lifetime schizophrenia, or bipolar disorder within last 5 years) or any other major concurrent illness that in the opinion of the investigator may interfere with the interpretation of the study results or constitute a health risk for the subject
17. Specific findings in MRI or CT that could in the opinion of the investigator affect cognitive function
18. Supine HR < 48 bpm or > 100 bpm after a 5-minute rest at screening visit.
19. Systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg after a 5-minute rest at screening visit.
20. Symptomatic orthostatic hypotension at screening visit.
21. QTc-Fridericia (QTcF) repeatedly > 450 ms in males or > 470 ms in females at screening visit.
22. Clinically significantly abnormal thyroid-stimulating hormone (TSH), vitamin B12 or folate serum levels at screening.
23. Any other abnormal value in laboratory tests, vital signs or ECG which may in the opinion of the investigator interfere with the interpretation of the study results (e.g. affect cognition) or cause a health risk for the patient
24. Female patients of childbearing potential
25. Pre-planned elective surgery for the study period
26. Known hypersensitivity to the active substance.
27. Blood donation or loss of significant amount of blood within 60 days prior to the screening.
28. Participation in a drug study within 60 days prior to the screening or previous participation in clinical study with ORM-12741.
29. Inability to complete the CDR System test battery despite having undergone 2 training sessions.
30. Resides in a skilled nursing facility.
31. Any other condition that in the opinion of the investigator may interfere with the interpretation of the study results or constitute a health risk for the subject if he/she takes part in the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy evaluation will be done for the sum of the NPI-C agitation and
aggression domains (NPI-C-A+A). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Will be assessed at screening, baseline (day 1 predose) and at the week 4, 8 and 12 visits by a trained clinician rater |
|
| E.5.2 | Secondary end point(s) |
| The key secondary evaluation will be done for the CDR System Quality of Memory. In addition, special priority will be put to preplanned analyses of CGIC-A/A (agitation), CGIC-O (overall clinical condition), CMAI-C total score, NPI-C-D+H and NPI-C dysphoria/depression domains. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The CDR System computerised cognitive test battery will be assessed at screening and baseline (day 1 predose). At week 4, week 8 and week 12 visits.
The CDR Assessment System cognitive test battery will be assessed 1 hour after study treatment administration and at week 8 visit additionally 4h after study treatment.
CMAI-C will be assessed based on the caregiver interview at baseline (day 1) and at the week 4, 8 and 12 visits after NPI-C
mADCS-CGIC - will be assessed at week 4, 8 and 12 visits by mADCS-CGIC scale based on both caregiver and subject interviews.
The following variables will be derived from the NPI/NPI-C rating:
- Sum of the NPI-C delusion and hallucination domain scores
- Individual NPI-C domain scores |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 | No |
| 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 |
| Bulgaria |
| Croatia |
| Czech Republic |
| Finland |
| Germany |
| Macedonia, the former Yugoslav Republic of |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Ukraine |
|
| 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 | 2 |
| 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 | 2 |
| 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 |
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