A Phase 2 interventional study of ladostigil hemitartrate in Alzheimer's Disease, Dementia and Memory Loss, sponsored by Avraham Pharmaceuticals Ltd. Completed at 19 sites in 5 countries. Open to participants aged 60 Years to 85 Years. Per ClinicalTrials.gov, last updated 2020-07-30.
Sponsored by Avraham Pharmaceuticals Ltd · Phase 2, Interventional, and Treatment
For many, Alzheimer's disease is the number one medical issue facing our aging society. It is a late onset neurodegenerative disease, frequently under diagnosed, that impairs memory and cognitive performance. There are no known treatments that can either prevent or reverse its progression. Consequently, there still remains a need to evaluate treatments which can better stabilize the symptoms of this disease. These symptoms frequently include decreased functional capacity and negative psychological attributes (e,g, depression, anxiety) in association with the memory and cognition deficits. This current study is being done to assess an investigational compound that has been designed to not only improved the cognitive status of affected patients but to also better manage all symptoms. Hence, the ultimate goal is to provide patients with an improved quality of life by slowing the progression of this neurodegenerative disease
This is a phase II, proof of concept study to evaluate the safety and efficacy of the investigational compound ladostigil versus placebo in mild to moderate Alzheimer's disease patients. The randomized, double-blind, placebo-controlled phase of the trial will be 26 weeks in duration and will involve two cohorts (i.e. one arm receiving ladostigil and one arm receiving placebo). After the initial 26 week period, all participating subjects will receive 26 weeks of treatment with ladostigil (i.e. the open label phase). A total of five territories will be participating in this trial. These include Austria, Croatia, Germany, Serbia and Spain.
Exclusion Criteria:
Ladostigil capsules 80 mg
Drug: ladostigil hemitartrate
Placebo capsules
Drug: ladostigil hemitartrate
Final dosage strength of 80mg b.i.d will begin at Day 22 following a 21 day dose escalation phase involving 40mg and 60mg b.i.d dosage strengths. Oral, solid dosage.
ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia, The ADAS-Cog consist of 11 questions: Word Recall Task Naming Objects and Fingers Following Commands Constructional Praxis Ideational Praxis Orientation Word Recognition Task Remembering Test Directions Spoken Language Comprehension Word-Finding Difficulty Item scores are summed. Low total scores indicate better cognitive performance. Minimum score 0 is best and maximum is 70 - worst. For the purposes of analyses the change from baseline is computed to each administration of the test.
Time frame: 26 weeks
Neuropsychiatric Inventory (NPI)
The Neuropsychiatric Inventory (NPI) was developed to assess psychopathology in dementia patients. It evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The severity and frequency of each neuropsychiatric symptom are rated on the basis of scripted questions administered to the patient's caregiver. Higher the score the more disturbed, lower score is thus better. Minimum score is 0 and maximum is 80.
Time frame: 52 weeks
Cornell Scale for Depression in Dementia (CSDD)
The Cornell Scale for Depression in Dementia (CSDD) was developed specifically to assess signs and symptoms of major depression in dementia on the basis of a semi-structured interview of a qualified informant. The CSDD evaluates a broad spectrum of depressive signs and synptoms and includes items from other depression scales. Information is obtained from interview of the caregiver as well as from direct observation and interview of the patient CSDD is a 19 item scale assessing depressive status. Higher score more depression. The scale ranges from 0-no depression to 38 maximum depression.
Time frame: 52 weeks
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
The Activities of Daily Living ADCS-ADL is a caregiver-based ADL scale composed of 23 items developed for use in dementia clinical trials. It is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests as well as making judgments and decisions. For each ADL, the caregiver is asked whether the patient attempted the activity during the past four weeks. If the answer is positive, the caregiver is then asked to choose the single most accurate definition of the patient's level of performance. Assessment of functional activity status is a 23 item scale measuring impairment in functioning. The scale total score ranges from 0-profound impairment to 30 normal functioning (no impairments)
Time frame: 52 weeks
Mini-Mental State Examination
The MMSE is a frequently used screening instrument for AD drug studies. The instrument provides for evaluation of orientation, memory, attention, concentration, naming, repetition, comprehension, ability to create a sentence and to copy two intersecting polygons. This examination is frequently used by physicians in the original diagnosis of AD, and in its subsequent progression, because it can be easily performed in the routine care of patients. A lower score indicates more cognitive impairment. The highest (best) score is 30. The Mini-Mental State Examination, MMSE, is a 30-point questionnaire measures cognitive impairment to screen for dementia. Items are totaled. The scale ranges from 0-most impairment to 30 (normal) no impairment.
Time frame: 52 weeks
| Milestone | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| Started | 101 | 99 |
| Itt | 99 | 96 |
| Pp | 79 | 75 |
| Completed | 80 | 77 |
| Not completed | 21 | 22 |
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia, The ADAS-Cog consist of 11 questions: Word Recall Task Naming Objects and Fingers Following Commands Constructional Praxis Ideational Praxis Orientation Word Recognition Task Remembering Test Directions Spoken Language Comprehension Word-Finding Difficulty Item scores are summed. Low total scores indicate better cognitive performance. Minimum score 0 is best and maximum is 70 - worst. For the purposes of analyses the change from baseline is computed to each administration of the test.
| score on scale - baseline to endpoint | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale | -.27 ± 5.41 | 0.19 ± 5.15 |
The Neuropsychiatric Inventory (NPI) was developed to assess psychopathology in dementia patients. It evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The severity and frequency of each neuropsychiatric symptom are rated on the basis of scripted questions administered to the patient's caregiver. Higher the score the more disturbed, lower score is thus better. Minimum score is 0 and maximum is 80.
| score on scale - baseline to endpoint | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| Neuropsychiatric Inventory (NPI) | 2.51 ± 11.27 | 0.66 ± 7.90 |
The Cornell Scale for Depression in Dementia (CSDD) was developed specifically to assess signs and symptoms of major depression in dementia on the basis of a semi-structured interview of a qualified informant. The CSDD evaluates a broad spectrum of depressive signs and synptoms and includes items from other depression scales. Information is obtained from interview of the caregiver as well as from direct observation and interview of the patient CSDD is a 19 item scale assessing depressive status. Higher score more depression. The scale ranges from 0-no depression to 38 maximum depression.
| score on scale - baseline to endpoint | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| Cornell Scale for Depression in Dementia (CSDD) | -0.08 ± 2.81 | -0.45 ± 3.28 |
The Activities of Daily Living ADCS-ADL is a caregiver-based ADL scale composed of 23 items developed for use in dementia clinical trials. It is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests as well as making judgments and decisions. For each ADL, the caregiver is asked whether the patient attempted the activity during the past four weeks. If the answer is positive, the caregiver is then asked to choose the single most accurate definition of the patient's level of performance. Assessment of functional activity status is a 23 item scale measuring impairment in functioning. The scale total score ranges from 0-profound impairment to 30 normal functioning (no impairments)
| score on scale - baseline to endpoint | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | -1.88 ± 9.54 | -1.57 ± 7.72 |
The MMSE is a frequently used screening instrument for AD drug studies. The instrument provides for evaluation of orientation, memory, attention, concentration, naming, repetition, comprehension, ability to create a sentence and to copy two intersecting polygons. This examination is frequently used by physicians in the original diagnosis of AD, and in its subsequent progression, because it can be easily performed in the routine care of patients. A lower score indicates more cognitive impairment. The highest (best) score is 30. The Mini-Mental State Examination, MMSE, is a 30-point questionnaire measures cognitive impairment to screen for dementia. Items are totaled. The scale ranges from 0-most impairment to 30 (normal) no impairment.
| change in score - baseline to endpoint | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| Mini-Mental State Examination | 0.80 ± 2.73 | 0.60 ± 2.59 |
Collected over 26 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ladostigil Hemitartrate | 0/100 (0%) | 7/100 (7%) | 11/100 (11%) |
| Placebo | 2/98 (2%) | 7/98 (7.1%) | 2/98 (2%) |
| Event | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| Urinary InfectionInfections and infestations | 0/100 | 2/98 |
| Acute CholecystitisGastrointestinal disorders | 0/100 | 1/98 |
| Arthritis left ankleMusculoskeletal and connective tissue disorders | 0/100 | 1/98 |
| ObstipationGastrointestinal disorders | 0/100 | 1/98 |
| PneunomiaRespiratory, thoracic and mediastinal disorders | 0/100 | 1/98 |
| POLYTRAUMATISMInjury, poisoning and procedural complications | 0/100 | 1/98 |
| ACUTE MYOCARDIAL INFARCTCardiac disorders | 1/100 | 0/98 |
| Brain StrokeVascular disorders | 1/100 | 0/98 |
| Elbow FractureMusculoskeletal and connective tissue disorders | 1/100 | 0/98 |
| Femur fracture subtrochanMusculoskeletal and connective tissue disorders | 1/100 | 0/98 |
| Event | Ladostigil Hemitartrate | Placebo |
|---|---|---|
| DiarrhoeaGastrointestinal disorders | 6/100 | 2/98 |
| Essential hypertensionCardiac disorders | 6/100 | 0/98 |
| Age, Categorical(Participants) | Ladostigil Hemitartrate | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 15 | 15 | 30 |
| >=65 years | 86 | 84 | 170 |
| Age, Continuous(years) | Ladostigil Hemitartrate | Placebo | Total |
|---|---|---|---|
| Mean | 74.25 ± 6.73 | 74.28 ± 6.92 | 74.26 ± 6.8 |
| Sex: Female, Male(Participants) | Ladostigil Hemitartrate | Placebo | Total |
|---|---|---|---|
| Female | 56 | 60 | 116 |
| Male | 45 | 39 | 84 |
| Race/Ethnicity, Customized(Participants) | Ladostigil Hemitartrate | Placebo | Total |
|---|---|---|---|
| Ethnicity — White or Caucasian | 101 | 99 | 200 |
| Ethnicity — Other | 0 | 0 | 0 |
| Region of Enrollment(participants) | Ladostigil Hemitartrate | Placebo | Total |
|---|---|---|---|
| Austria | 28 | 27 | 55 |
| Serbia | 4 | 2 | 6 |
| Germany | 9 | 8 | 17 |
| Croatia | 44 | 45 | 89 |
| Spain | 16 | 17 | 33 |
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Avraham Pharmaceuticals Ltd