Alzheimer's Disease
Conditions
Brief summary
The purpose of this study is to determine whether ORM-12741 is safe and effective in the treatment of Alzheimer's disease.
Detailed description
The purpose of this study is to determine whether ORM-12741 is safe and effective in the treatment of cognitive and behavioral symptoms in patients with Alzheimer's disease.
Interventions
DRUGORM-12741
60mg twice a day
Placebo twice a day
Sponsors
Orion Corporation, Orion Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained from the patient and legally acceptable representative, if required * Informed consent obtained from the caregiver * Males and and females between 55-90 years * Diagnosis of probable Alzheimer's disease, history of progressive cognitive deterioration * Brain imaging consistent with Alzheimer's disease * Mini-mental state examination score 12-21 * Treated with donepezil, rivastigmine or galantamine * At least mild level of behavioral symptoms
Exclusion criteria
* Other types of dementias * Modified Hachinski Ischemia Score \> 4 * Use of memantine, antipsychotics, anticholinergic medication and benzodiazepines (at a max of 3 nights/week) within 2 months * Changes in antidepressant dosing within 2 months * Use of other psychotropic agents * Myocardial infarction within the past 2 years * Malignancy within the past 5 years * Suicidal ideation, risk of suicide * History of alcoholism or drug abuse within 5 years * Clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological or psychiatric disorder or any other major concurrent illness * Specific findings in brain imaging * Abnormal findings in heart rate, blood pressure, ECG, laboratory tests, physical examination; orthostatic hypotension * Blood donation or participation in a drug study within 60 days * Previous AD immunotherapy treatment * Patient cannot complete the computerised cognitive training * Patients who reside in a skilled nursing facility * Patients who are not able to swallow capsules
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Continuity of Attention | 3 months | The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Continuity of attention measures speed and accuracy and is calculated from 3 attentional tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome. |
| Quality of Memory | 3 months | The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Quality of Memory is a combination of outcome measures Quality of Working Memory & Quality of Episodic Memory. Values are calculated by a computer and higher scores mean better outcome. |
| Speed of Memory | 3 months | The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Speed of Memory is assessed as the sum of speed measures from 2 memory tasks and 2 recognition tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome. |
| Power of Attention | 3 months | The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Power of attention measures speed and attention and is assessed from 3 attentional tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome. |
| Number of Participants With Adverse Events | 3 months | Adverse events from start of ORM-12741 treatment until end of study visit. |
| Quality of Episodic Memory | 3 months | The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Quality of Episodic Memory measures the capability of maintaining information in episodic memory and is assessed as the sum of sensitivity indices from 4 memory tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome. |
| Quality of Working Memory | 3 months | The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Quality of Working Memory measures the capability of maintaining information in working memory and is assessed as the sum of sensitivity indices from 2 memory tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NPI Total Score | 3 months | The total score of Neuropsychiatric Inventory (NPI) was assessed by a caregiver interview. 10 behavioral areas were included: Delusions, Hallucinations, Agitation/Aggression, Depression/Dysphoria, Anxiety, Elation/Euphoria, Apathy/Indifference, Disinhibition, Irritability/Lability, and Aberrant Motor Behaviour. Higher scores mean worse outcome. Minimum value 0, maximum value 120. |
| Caregiver Distress Score | 3 months | Caregiver distress score generated by adding together the scores of individual NPI distress questions of Neuropsychiatric Inventory NPI. Higher scores mean worse outcome. Minimum value 0, maximum value 120. |
| Pharmacokinetics of ORM-12741 | 3 months | ORM-12741 plasma trough concentrations at week 12. |
Countries
Finland
Participant flow
Recruitment details
This study was conducted in 4 countries (18 centres): Finland, Poland, Romania and Spain. Of these, 1 centre screened but did not randomise any subjects. Study period was 27 Apr 2011-21 Sep 2012 (first subject first visit to last subject last visit).
Pre-assignment details
A total of 132 subjects were screened and 100 were randomized to 3 treatment groups. 30 patients were excluded prior randomization due to inclusion/exclusion criteria, 2 due to personal reasons.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose of ORM-12741 ORM-12741: 60mg twice a day | 33 |
| High Dose of ORM-12741 ORM-12741: 200mg twice a day | 33 |
| Placebo Placebo for ORM-12741: Placebo twice a day | 34 |
| Total | 100 |
Baseline characteristics
| Characteristic | Low Dose of ORM-12741 | High Dose of ORM-12741 | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 71.8 years STANDARD_DEVIATION 8.2 | 71.8 years STANDARD_DEVIATION 6.8 | 72.3 years STANDARD_DEVIATION 8.5 | 72.0 years STANDARD_DEVIATION 7.8 |
| Sex: Female, Male Female | 19 Participants | 23 Participants | 17 Participants | 59 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 17 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 33 | 0 / 34 |
| other Total, other adverse events | 8 / 33 | 14 / 33 | 16 / 34 |
| serious Total, serious adverse events | 0 / 33 | 1 / 33 | 0 / 34 |
Outcome results
Primary
Continuity of Attention
The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Continuity of attention measures speed and accuracy and is calculated from 3 attentional tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Continuity of Attention | 85.7 Index score | Standard Deviation 11 |
| High Dose of ORM-12741 | Continuity of Attention | 84.8 Index score | Standard Deviation 15.3 |
| Placebo | Continuity of Attention | 79.7 Index score | Standard Deviation 21.2 |
Primary
Number of Participants With Adverse Events
Adverse events from start of ORM-12741 treatment until end of study visit.
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose of ORM-12741 | Number of Participants With Adverse Events | 18 Participants |
| High Dose of ORM-12741 | Number of Participants With Adverse Events | 21 Participants |
| Placebo | Number of Participants With Adverse Events | 21 Participants |
Primary
Power of Attention
The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Power of attention measures speed and attention and is assessed from 3 attentional tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Power of Attention | 1940.3 msec | Standard Deviation 533.3 |
| High Dose of ORM-12741 | Power of Attention | 1978.0 msec | Standard Deviation 1040.4 |
| Placebo | Power of Attention | 2077.9 msec | Standard Deviation 995.8 |
Primary
Quality of Episodic Memory
The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Quality of Episodic Memory measures the capability of maintaining information in episodic memory and is assessed as the sum of sensitivity indices from 4 memory tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Quality of Episodic Memory | 100.7 Index score | Standard Deviation 92.2 |
| High Dose of ORM-12741 | Quality of Episodic Memory | 85.0 Index score | Standard Deviation 59.6 |
| Placebo | Quality of Episodic Memory | 46.3 Index score | Standard Deviation 62.4 |
Primary
Quality of Memory
The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Quality of Memory is a combination of outcome measures Quality of Working Memory & Quality of Episodic Memory. Values are calculated by a computer and higher scores mean better outcome.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Quality of Memory | 216.53 Index score | Standard Deviation 133.15 |
| High Dose of ORM-12741 | Quality of Memory | 196.37 Index score | Standard Deviation 93.72 |
| Placebo | Quality of Memory | 117.15 Index score | Standard Deviation 104.3 |
Primary
Quality of Working Memory
The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Quality of Working Memory measures the capability of maintaining information in working memory and is assessed as the sum of sensitivity indices from 2 memory tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Quality of Working Memory | 1.20 Index score | Standard Deviation 0.53 |
| High Dose of ORM-12741 | Quality of Working Memory | 1.18 Index score | Standard Deviation 0.47 |
| Placebo | Quality of Working Memory | 0.82 Index score | Standard Deviation 0.59 |
Primary
Speed of Memory
The Cognitive Drug Research (CDR) computerised battery tests is designed to evaluate the effects of novel compounds on the quality of cognitive functioning. Speed of Memory is assessed as the sum of speed measures from 2 memory tasks and 2 recognition tasks on the CDR computerised battery tests. Values are calculated by a computer and higher scores mean better outcome.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Speed of Memory | 8287.8 msec | Standard Deviation 3898.2 |
| High Dose of ORM-12741 | Speed of Memory | 8930.30 msec | Standard Deviation 5379.5 |
| Placebo | Speed of Memory | 8082.2 msec | Standard Deviation 4064.1 |
Secondary
Caregiver Distress Score
Caregiver distress score generated by adding together the scores of individual NPI distress questions of Neuropsychiatric Inventory NPI. Higher scores mean worse outcome. Minimum value 0, maximum value 120.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Caregiver Distress Score | 9.2 score on a scale | Standard Deviation 6 |
| High Dose of ORM-12741 | Caregiver Distress Score | 8.0 score on a scale | Standard Deviation 4.3 |
| Placebo | Caregiver Distress Score | 11.0 score on a scale | Standard Deviation 10.4 |
Secondary
NPI Total Score
The total score of Neuropsychiatric Inventory (NPI) was assessed by a caregiver interview. 10 behavioral areas were included: Delusions, Hallucinations, Agitation/Aggression, Depression/Dysphoria, Anxiety, Elation/Euphoria, Apathy/Indifference, Disinhibition, Irritability/Lability, and Aberrant Motor Behaviour. Higher scores mean worse outcome. Minimum value 0, maximum value 120.
Time frame: 3 months
Population: per protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | NPI Total Score | 14.7 score on a scale | Standard Deviation 9.1 |
| High Dose of ORM-12741 | NPI Total Score | 13.7 score on a scale | Standard Deviation 8.9 |
| Placebo | NPI Total Score | 20.2 score on a scale | Standard Deviation 19 |
Secondary
Pharmacokinetics of ORM-12741
ORM-12741 plasma trough concentrations at week 12.
Time frame: 3 months
Population: M-ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose of ORM-12741 | Pharmacokinetics of ORM-12741 | 18.4 ng/ml | Standard Deviation 13.9 |
| High Dose of ORM-12741 | Pharmacokinetics of ORM-12741 | 61.0 ng/ml | Standard Deviation 45.9 |
| Placebo | Pharmacokinetics of ORM-12741 | 0 ng/ml | Standard Deviation 0 |