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Safety and Efficacy Study of Ladostigil in Mild to Moderate Probable Alzheimer's Disease

Primary Purpose

Alzheimer's Disease, Dementia, Memory Loss

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
ladostigil hemitartrate
Sponsored by
Avraham Pharmaceuticals Ltd
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer's Disease focused on measuring Alzheimer's Disease, Dementia, Memory Loss, Cognitive Impairment, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Neurodegenerative Diseases, Delirium, Dementia, Amnestic, Cognitive Disorders, Mental Disorders, Depression, Anxiety

Eligibility Criteria

60 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • AD diagnosis according to NINCDS-ADRDA criteria
  • Mild to moderate AD according to MMSE 14-24 inclusive
  • MRI or CT assessment within 6 months before baseline, corroborating the clinical diagnosis and excluding other potential causes of dementia especially cerebrovascular lesions
  • Absence of major depressive disease according to CSDD of less than or equal to 18
  • Modified Hachinski Ischemic Scale equal to or below 4
  • Education for eight or more years
  • Previous decline in cognition for more than six months as documented in patient medical records
  • A caregiver available and living in the same household or interacting with the patient daily and available if necessary to assure administration of investigational product
  • Patients living at home or nursing home setting without continuous nursing care
  • General health status acceptable for participation in a 12-month clinical trial and ability to swallow oral medication
  • No history of treatment with rivastigmine
  • For patients with either donepezil or galantamine anti-cholinesterase inhibitor treatment prescribed, stopped treatment four weeks prior to screening
  • For patients with memantine treatment prescribed, stopped treatment four weeks prior to screening

Exclusion Criteria:

  • Other primary degenerative dementias (e.g. dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Jacob-Creutzfeldt disease)
  • Other neurodegenerative conditions (Parkinson's disease. amyotrophic lateral sclerosis, etc)
  • Other central nervous system diseases (severe head trauma, tumors, subdural hematoma, etc)
  • A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder
  • Seizure disorders
  • Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc)
  • Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations
  • Other unstable, chronic or clinically significant medical conditions involving major organs like kidney, liver, lungs and heart/vasculature
  • Hospitalization or change of chronic concomitant medications one month prior to screening or during screening period

Sites / Locations

  • Medizinische Univeritat Graz, Universitatsklinik fur Neurologie, Auenbruggerplatz 22
  • Privatordination Horn, HamerlingstraBe 15
  • Allgemeines Krankenhaus der Stadt Linz, KrankenhausstraBe 9
  • Privatordination, Lainzerstrasse 20
  • General Hospital Pula, Negrijeva 6
  • General Hospital Zabok, Bracak 8
  • Clinical Hospital Center Zagreb, Kispaticeva 12
  • Clinical Hospital Dubrava, Avenija Gojka Suska 6
  • Polyclinic Neuron, Salata 12
  • Psychiatric Hospital Vrapce, Bolnicka cesta 32
  • Klinische Forschung Hamburg GmbH, Hoheluftaussee 18
  • Klinische Forschung Schwerin GmbH, FriedrichstraBe 1
  • Studienzentrum Nordwest, Lange StraBe 23-25
  • Military Medical Academy, Crnotravska 17
  • Clinical Centre of Serbia, Dr. Subotica 6
  • CAE Oroitu Centro Atencion Especializada C/Jata, 9
  • Centro Geroinnova Barcelona, Calle Mandoni n 17
  • Fundacio ACE, Institut Catala de Neurosciencies Aplicadas, C/Margues de Sentmenat 35-37
  • Institud d' Assistencia Sanitaria de Girona, Edifici La Republica - C/Dr. Castany, s/n

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ladostigil hemitartrate

Placebo

Arm Description

Ladostigil capsules 80 mg

Placebo capsules

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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)
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.

Full Information

First Posted
May 1, 2011
Last Updated
July 13, 2020
Sponsor
Avraham Pharmaceuticals Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT01354691
Brief Title
Safety and Efficacy Study of Ladostigil in Mild to Moderate Probable Alzheimer's Disease
Official Title
A 6-Month Prospective, Multi-Center, Double-Blind, Placebo-Controlled, Randomized, Adaptive-Trial-Design Study to Evaluate the Safety and Efficacy of 80mg b.i.d Ladostigil in Patients With Mild to Moderate Probable Alzheimer's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
March 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Avraham Pharmaceuticals Ltd

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer's Disease, Dementia, Memory Loss, Cognitive Impairment
Keywords
Alzheimer's Disease, Dementia, Memory Loss, Cognitive Impairment, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Neurodegenerative Diseases, Delirium, Dementia, Amnestic, Cognitive Disorders, Mental Disorders, Depression, Anxiety

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
200 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ladostigil hemitartrate
Arm Type
Experimental
Arm Description
Ladostigil capsules 80 mg
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo capsules
Intervention Type
Drug
Intervention Name(s)
ladostigil hemitartrate
Intervention Description
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.
Primary Outcome Measure Information:
Title
ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale
Description
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
Secondary Outcome Measure Information:
Title
Neuropsychiatric Inventory (NPI)
Description
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
Title
Cornell Scale for Depression in Dementia (CSDD)
Description
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
Title
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
Description
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
Title
Mini-Mental State Examination
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: AD diagnosis according to NINCDS-ADRDA criteria Mild to moderate AD according to MMSE 14-24 inclusive MRI or CT assessment within 6 months before baseline, corroborating the clinical diagnosis and excluding other potential causes of dementia especially cerebrovascular lesions Absence of major depressive disease according to CSDD of less than or equal to 18 Modified Hachinski Ischemic Scale equal to or below 4 Education for eight or more years Previous decline in cognition for more than six months as documented in patient medical records A caregiver available and living in the same household or interacting with the patient daily and available if necessary to assure administration of investigational product Patients living at home or nursing home setting without continuous nursing care General health status acceptable for participation in a 12-month clinical trial and ability to swallow oral medication No history of treatment with rivastigmine For patients with either donepezil or galantamine anti-cholinesterase inhibitor treatment prescribed, stopped treatment four weeks prior to screening For patients with memantine treatment prescribed, stopped treatment four weeks prior to screening Exclusion Criteria: Other primary degenerative dementias (e.g. dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Jacob-Creutzfeldt disease) Other neurodegenerative conditions (Parkinson's disease. amyotrophic lateral sclerosis, etc) Other central nervous system diseases (severe head trauma, tumors, subdural hematoma, etc) A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder Seizure disorders Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc) Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations Other unstable, chronic or clinically significant medical conditions involving major organs like kidney, liver, lungs and heart/vasculature Hospitalization or change of chronic concomitant medications one month prior to screening or during screening period
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Reinhold Schmidt, MD
Organizational Affiliation
MEDIZINISCHE UNIVERSITAT GRAZ
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medizinische Univeritat Graz, Universitatsklinik fur Neurologie, Auenbruggerplatz 22
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
Privatordination Horn, HamerlingstraBe 15
City
Horn
ZIP/Postal Code
3580
Country
Austria
Facility Name
Allgemeines Krankenhaus der Stadt Linz, KrankenhausstraBe 9
City
Linz
ZIP/Postal Code
4020
Country
Austria
Facility Name
Privatordination, Lainzerstrasse 20
City
Wein
ZIP/Postal Code
1130
Country
Austria
Facility Name
General Hospital Pula, Negrijeva 6
City
Pula
ZIP/Postal Code
52100
Country
Croatia
Facility Name
General Hospital Zabok, Bracak 8
City
Zabok
ZIP/Postal Code
49210
Country
Croatia
Facility Name
Clinical Hospital Center Zagreb, Kispaticeva 12
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
Clinical Hospital Dubrava, Avenija Gojka Suska 6
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
Polyclinic Neuron, Salata 12
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
Psychiatric Hospital Vrapce, Bolnicka cesta 32
City
Zagreb
ZIP/Postal Code
10090
Country
Croatia
Facility Name
Klinische Forschung Hamburg GmbH, Hoheluftaussee 18
City
Hamburg
ZIP/Postal Code
20253
Country
Germany
Facility Name
Klinische Forschung Schwerin GmbH, FriedrichstraBe 1
City
Schwerin
ZIP/Postal Code
19055
Country
Germany
Facility Name
Studienzentrum Nordwest, Lange StraBe 23-25
City
Westerstede
ZIP/Postal Code
26655
Country
Germany
Facility Name
Military Medical Academy, Crnotravska 17
City
Belgrade
ZIP/Postal Code
11000
Country
Serbia
Facility Name
Clinical Centre of Serbia, Dr. Subotica 6
City
Belgrad
ZIP/Postal Code
11000
Country
Serbia
Facility Name
CAE Oroitu Centro Atencion Especializada C/Jata, 9
City
Algorta
ZIP/Postal Code
48993
Country
Spain
Facility Name
Centro Geroinnova Barcelona, Calle Mandoni n 17
City
Barcelona
ZIP/Postal Code
08004
Country
Spain
Facility Name
Fundacio ACE, Institut Catala de Neurosciencies Aplicadas, C/Margues de Sentmenat 35-37
City
Barcelona
ZIP/Postal Code
08014
Country
Spain
Facility Name
Institud d' Assistencia Sanitaria de Girona, Edifici La Republica - C/Dr. Castany, s/n
City
Salt
ZIP/Postal Code
17190
Country
Spain

12. IPD Sharing Statement

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Safety and Efficacy Study of Ladostigil in Mild to Moderate Probable Alzheimer's Disease

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