A 12 week, multicentre, study investigating the efficacy of ORM-12741 on agitation/aggression symptoms in patients with Alzheimer's Disease.

• Register: EUCTR
• Last refreshed on: 11 June 2018
• Main ID: EUCTR2014-000217-30-DE
• Date of registration: 18/03/2015
• Prospective Registration: Yes
• Primary sponsor: Orion Corporation
• Public title: A 12 week, multicentre, study investigating the efficacy of ORM-12741 on agitation/aggression symptoms in patients with Alzheimer's Disease.
• Scientific title: EFFICACY OF ORM-12741 ON AGITATION/AGGRESSION SYMPTOMS IN PATIENTS WITH ALZHEIMER’S DISEASE: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTICENTRE STUDY OF 12 WEEKS - NEBULA
• Date of first enrolment: 16/06/2015
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000217-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Croatia, Czech Republic, Finland, Germany, Macedonia, the former Yugoslav Republic of, Poland, Romania, Russian Federation, Serbia, Slovakia, Ukraine

Contacts

• Name: Project Management
• Affiliation: Worldwide Clinical Trials

• Name: Project Management
• Affiliation: Worldwide Clinical Trials

Key inclusion & exclusion criteria

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).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 250

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 d

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

The agitation/aggression symptoms in patients with Alzheimer’s disease
MedDRA version: 18.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 100000004852

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: ORM-12741
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ORM-12741
Other descriptive name: ORM-12741 (Immediate Release)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: ORM-12741
Pharmaceutical Form: Modified-release capsule, hard
INN or Proposed INN: ORM-12741
Other descriptive name: ORM-12741 (Modified Release A)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Product Name: ORM-12741
Pharmaceutical Form: Modified-release capsule, hard
INN or Proposed INN: ORM-12741
Other descriptive name: ORM-12741 (Modified Release B)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Primary Outcome(s)

Main Objective: 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.

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

Secondary Objective: 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.

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).

Secondary Outcome(s)

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

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.

Secondary ID(s)

3098012

Source(s) of Monetary Support

Orion Corporation