Alzheimer's Disease
Conditions
Brief summary
To evaluate the long-term safety and tolerability of idalopirdine (Lu AE58054) as adjunctive therapy to donepezil in patients with mild-moderate Alzheimer's Disease (AD).
Detailed description
This is an interventional, multi-national, multi-site, open-label extension study in patients with mild to moderate AD who completed the 24-week lead-in study 14861A (NCT01955161) or 14862A (NCT02006641). Patients received 28-weeks of open-label treatment with idalopirdine 60 mg/day (option to reduce to 30 mg/day) as adjunctive treatment to donepezil. Approximately 100 patients, who had completed the initial 28-week period (OLEX), were included in a 24 week open-label treatment period with memantine (OLEX-MEM) that evaluated the safety and tolerability of concomitant memantine therapy in patients who were already on a stable treatment with idalopirdine and donepezil and for whom memantine treatment was clinically indicated.
Interventions
DRUGIdalopirdine 60 mg
once daily, encapsulated tablets, orally
Sponsors
H. Lundbeck A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* the patient has completed Visit 7 (Completion Visit) in the lead-in double-blind, placebo controlled clinical studies 14861A/NCT01955161 or 14862A/NCT02006641 For patients in the OLEX-MEM: * The patient has completed Visit 6 (Week 28) of the OLEX. * The patient, according to the judgement of the investigator, requires initiation of treatment with memantine as per local label/SmPC/treatment guidelines.
Exclusion criteria
* The patient has a moderate or severe ongoing adverse event from the lead-in study considered a potential safety risk by the investigator. * The patient has experienced seizures before Completion Visit in the lead-in study. * The patient has evidence of clinically significant disease. * The patient's donepezil treatment is likely to be interrupted or discontinued during the study. * The patient is receiving therapy with another acetylcholinesterase inhibitors (AChEI). Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Adverse Events (TEAEs) in the OLEX | Baseline II (start of OLEX, week 0) to end of OLEX (week 28) | A TEAE is an adverse event that starts or increases in intensity after the date of Baseline II. |
| Number of TEAEs in the OLEX-MEM | From Baseline III (start of OLEX-MEM, Week 28) to end of OLEX-MEM (Week 52) | A TEAE is an adverse event that starts or increases in intensity after the date of Baseline III (start of OLEX-MEM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Daily Functioning | Baseline II (start of OLEX, Week 0) to Week 28 | Change from Baseline II to Week 28 in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL23) total score. The ADCS-ADL23 is a 23-item clinician-rated inventory to assess activities of daily living (conducted with a caregiver or informant). Each item comprises a series of hierarchical sub-questions, ranging from the highest level of independent performance to a complete loss for each activity. Total score of the 23 items ranges from 0 to 78 (higher score indicates lower disability). |
| Change in Cognition | Baseline II (start of OLEX, Week 0) to Week 28 | Change from Baseline II to Week 28 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. The ADAS-cog is a 11-item neuropsychological test that assess the severity of cognitive impairment. The items determine the patient's orientation, memory, language, and praxis. Total score of the 11 items range from 0 to 70 (lower score indicates lower cognitive impairment). |
| Change in Cognitive Aspects of Mental Function | Baseline II (start of OLEX, Week 0) to Week 28 | Change from Baseline II to Week 28 in Mini Mental State Examination (MMSE). The MMSE is an 11-item test to assess the cognitive aspects of mental function. The subtests assess orientation, memory, attention, language, and visual construction. The scores for each item is dichotomous (1 = response is correct, 0 = response is incorrect). Total score of the 11 items ranges from 0 to 30 (higher score indicates lower deficit). |
| Change in Behavioural Disturbance | Baseline II (start of OLEX, Week 0) to Week 28 | Change from Baseline II to Week 28 in Neuropsychiatric Inventory (NPI) total score. The NPI is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is rated for frequency (a 4-point scale from 1 \[occasionally\] to 4 \[very frequent\]) and severity (a 3-point scale from 1 \[mild\] to 3 \[marked\]). The total NPI score is the frequency ratings multiplied by the severity ratings and ranges from 0 to 144 (higher score indicates worse outcome). |
| Clinical Global Impression Score | Week 28 | Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) score at Week 28. The ADCS-CGIC is a semi-structured interview to assess clinically relevant changes in patients with AD. The items determine cognition, behavior, social and daily functioning. Severity at baseline is rated on a 7-point scale from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). The clinically relevant change from baseline is rated on a 7-point scale from 1 (marked improvement) to 7 (marked worsening). |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Hungary, Israel, Italy, Lithuania, Poland, Portugal, Romania, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Open-label extension study in patients with mild to moderate AD who completed the 24-week lead-in study 14861A (NCT01955161) or 14862A (NCT02006641)
Participants by arm
| Arm | Count |
|---|---|
| Idalopirdine 60 mg Idalopirdine 60 mg adjunct to 10 mg donepezil. The dose of idalopirdine could be decreased from 60 mg to 30 mg if 60 mg was not well tolerated. The dose of donepezil was to be maintained throughout the study. | 1,462 |
| Total | 1,462 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| OLEX | Adverse Event | 66 | 0 |
| OLEX | Death | 11 | 0 |
| OLEX | Lack of Efficacy | 3 | 0 |
| OLEX | Lost to Follow-up | 6 | 0 |
| OLEX | Other: Caregiver unavailable | 3 | 0 |
| OLEX | Other: Coordinator decision | 1 | 0 |
| OLEX | Other: Disallowed medication | 8 | 0 |
| OLEX | Other: Insufficient compliance | 2 | 0 |
| OLEX | Other: Moved to nursing home | 1 | 0 |
| OLEX | Other: Withdrawal of caregiver consent | 1 | 0 |
| OLEX | Other: Worsening of condition | 1 | 0 |
| OLEX | Protocol Violation | 6 | 0 |
| OLEX | Results of the lead-in studies | 58 | 0 |
| OLEX | Withdrawal before treatment | 1 | 0 |
| OLEX | Withdrawal by Subject | 60 | 0 |
| OLEX-MEM | Adverse Event | 0 | 6 |
| OLEX-MEM | Lost to Follow-up | 0 | 1 |
| OLEX-MEM | Other: Moved to nursing home | 0 | 3 |
| OLEX-MEM | Protocol Violation | 0 | 2 |
| OLEX-MEM | Withdrawal by Subject | 0 | 7 |
Baseline characteristics
| Characteristic | Idalopirdine 60 mg |
|---|---|
| Age, Continuous | 73.7 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 209 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1224 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | NA Participants |
| Race (NIH/OMB) Asian | 63 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants |
| Race (NIH/OMB) More than one race | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 62 Participants |
| Race (NIH/OMB) White | 1318 Participants |
| Region of Enrollment Argentina | 119 participants |
| Region of Enrollment Belgium | 13 participants |
| Region of Enrollment Brazil | 30 participants |
| Region of Enrollment Bulgaria | 52 participants |
| Region of Enrollment Canada | 51 participants |
| Region of Enrollment Chile | 79 participants |
| Region of Enrollment Croatia | 11 participants |
| Region of Enrollment Czechia | 135 participants |
| Region of Enrollment Denmark | 11 participants |
| Region of Enrollment Estonia | 44 participants |
| Region of Enrollment Finland | 13 participants |
| Region of Enrollment France | 71 participants |
| Region of Enrollment Germany | 52 participants |
| Region of Enrollment Hungary | 10 participants |
| Region of Enrollment Israel | 5 participants |
| Region of Enrollment Italy | 82 participants |
| Region of Enrollment Lithuania | 34 participants |
| Region of Enrollment Poland | 139 participants |
| Region of Enrollment Portugal | 12 participants |
| Region of Enrollment Romania | 6 participants |
| Region of Enrollment South Africa | 39 participants |
| Region of Enrollment South Korea | 40 participants |
| Region of Enrollment Spain | 50 participants |
| Region of Enrollment Taiwan | 15 participants |
| Region of Enrollment Ukraine | 47 participants |
| Region of Enrollment United Kingdom | 66 participants |
| Region of Enrollment United States | 236 participants |
| Sex: Female, Male Female | 922 Participants |
| Sex: Female, Male Male | 540 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 1,462 | 0 / 101 |
| other Total, other adverse events | 182 / 1,462 | 7 / 101 |
| serious Total, serious adverse events | 91 / 1,462 | 2 / 101 |
Outcome results
Primary
Number of TEAEs in the OLEX-MEM
A TEAE is an adverse event that starts or increases in intensity after the date of Baseline III (start of OLEX-MEM).
Time frame: From Baseline III (start of OLEX-MEM, Week 28) to end of OLEX-MEM (Week 52)
Population: All patients who took at least one dose of IMP or memantine in the OLEX-MEM.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idalopirdine 60 mg | Number of TEAEs in the OLEX-MEM | 93 TEAEs |
Primary
Number of Treatment Emergent Adverse Events (TEAEs) in the OLEX
A TEAE is an adverse event that starts or increases in intensity after the date of Baseline II.
Time frame: Baseline II (start of OLEX, week 0) to end of OLEX (week 28)
Population: All patients who took at least one dose of IMP in the OLEX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idalopirdine 60 mg | Number of Treatment Emergent Adverse Events (TEAEs) in the OLEX | 2130 TEAEs |
Secondary
Change in Behavioural Disturbance
Change from Baseline II to Week 28 in Neuropsychiatric Inventory (NPI) total score. The NPI is a 12-item structured interview with a caregiver to assess behavioural disturbances. The NPI comprises 10 behavioural and 2 neurovegetative items. Each item consists of a screening question and several sub-questions that are rated no (not present) or yes (present). Each item is rated for frequency (a 4-point scale from 1 \[occasionally\] to 4 \[very frequent\]) and severity (a 3-point scale from 1 \[mild\] to 3 \[marked\]). The total NPI score is the frequency ratings multiplied by the severity ratings and ranges from 0 to 144 (higher score indicates worse outcome).
Time frame: Baseline II (start of OLEX, Week 0) to Week 28
Population: All patients in who took at least one dose of IMP in the OLEX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idalopirdine 60 mg | Change in Behavioural Disturbance | 1.80 units on a scale | Standard Error 0.35 |
| Idalopirdine 60 mg (OLEX); Patients From lead-in Study 14862A | Change in Behavioural Disturbance | 1.36 units on a scale | Standard Error 0.34 |
Secondary
Change in Cognition
Change from Baseline II to Week 28 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score. The ADAS-cog is a 11-item neuropsychological test that assess the severity of cognitive impairment. The items determine the patient's orientation, memory, language, and praxis. Total score of the 11 items range from 0 to 70 (lower score indicates lower cognitive impairment).
Time frame: Baseline II (start of OLEX, Week 0) to Week 28
Population: All patients in who took at least one dose of IMP in the OLEX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idalopirdine 60 mg | Change in Cognition | 3.01 units on a scale | Standard Error 0.22 |
| Idalopirdine 60 mg (OLEX); Patients From lead-in Study 14862A | Change in Cognition | 2.67 units on a scale | Standard Error 0.23 |
Secondary
Change in Cognitive Aspects of Mental Function
Change from Baseline III to Week 52 in Mini Mental State Examination (MMSE). The MMSE is an 11-item test to assess the cognitive aspects of mental function. The subtests assess orientation, memory, attention, language, and visual construction. The scores for each item is dichotomous (1 = response is correct, 0 = response is incorrect). Total score of the 11 items ranges from 0 to 30 (higher score indicates lower deficit).
Time frame: Baseline III (start of OLEX-MEM, Week 28) to Week 52
Population: All patients who took at least one dose of IMP or memantine in the OLEX-MEM.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idalopirdine 60 mg | Change in Cognitive Aspects of Mental Function | -0.55 units on a scale | Standard Error 0.26 |
Secondary
Change in Cognitive Aspects of Mental Function
Change from Baseline II to Week 28 in Mini Mental State Examination (MMSE). The MMSE is an 11-item test to assess the cognitive aspects of mental function. The subtests assess orientation, memory, attention, language, and visual construction. The scores for each item is dichotomous (1 = response is correct, 0 = response is incorrect). Total score of the 11 items ranges from 0 to 30 (higher score indicates lower deficit).
Time frame: Baseline II (start of OLEX, Week 0) to Week 28
Population: All patients in who took at least one dose of IMP in the OLEX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idalopirdine 60 mg | Change in Cognitive Aspects of Mental Function | -1.28 units on a scale | Standard Error 0.1 |
| Idalopirdine 60 mg (OLEX); Patients From lead-in Study 14862A | Change in Cognitive Aspects of Mental Function | -1.02 units on a scale | Standard Error 0.11 |
Secondary
Change in Daily Functioning
Change from Baseline II to Week 28 in Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL23) total score. The ADCS-ADL23 is a 23-item clinician-rated inventory to assess activities of daily living (conducted with a caregiver or informant). Each item comprises a series of hierarchical sub-questions, ranging from the highest level of independent performance to a complete loss for each activity. Total score of the 23 items ranges from 0 to 78 (higher score indicates lower disability).
Time frame: Baseline II (start of OLEX, Week 0) to Week 28
Population: All patients in who took at least one dose of IMP in the OLEX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idalopirdine 60 mg | Change in Daily Functioning | -3.71 units on a scale | Standard Error 0.28 |
| Idalopirdine 60 mg (OLEX); Patients From lead-in Study 14862A | Change in Daily Functioning | -3.88 units on a scale | Standard Error 0.32 |
Secondary
Clinical Global Impression Score
Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) score at Week 28. The ADCS-CGIC is a semi-structured interview to assess clinically relevant changes in patients with AD. The items determine cognition, behavior, social and daily functioning. Severity at baseline is rated on a 7-point scale from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). The clinically relevant change from baseline is rated on a 7-point scale from 1 (marked improvement) to 7 (marked worsening).
Time frame: Week 28
Population: All patients in who took at least one dose of IMP in the OLEX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Idalopirdine 60 mg | Clinical Global Impression Score | 4.58 units on a scale | Standard Error 0.005 |
| Idalopirdine 60 mg (OLEX); Patients From lead-in Study 14862A | Clinical Global Impression Score | 4.61 units on a scale | Standard Error 0.05 |