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

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ClinicalTrials.gov Identifier: NCT01354691
Recruitment Status : Completed
First Posted : May 17, 2011
Results First Posted : July 30, 2020
Last Update Posted : July 30, 2020
Sponsor:
Information provided by (Responsible Party):
Avraham Pharmaceuticals Ltd

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Alzheimer's Disease
Dementia
Memory Loss
Cognitive Impairment
Intervention Drug: ladostigil hemitartrate
Enrollment 200
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Period Title: Overall Study
Started 101 99
ITT 99 96
PP 79 75
Completed 80 77
Not Completed 21 22
Arm/Group Title Ladostigil Hemitartrate Placebo Total
Hide Arm/Group Description

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Total of all reporting groups
Overall Number of Baseline Participants 101 99 200
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 99 participants 200 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
15
  14.9%
15
  15.2%
30
  15.0%
>=65 years
86
  85.1%
84
  84.8%
170
  85.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 101 participants 99 participants 200 participants
74.25  (6.73) 74.28  (6.92) 74.26  (6.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 99 participants 200 participants
Female
56
  55.4%
60
  60.6%
116
  58.0%
Male
45
  44.6%
39
  39.4%
84
  42.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Ethnicity Number Analyzed 101 participants 99 participants 200 participants
White or Caucasian
101
 100.0%
99
 100.0%
200
 100.0%
Other
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 101 participants 99 participants 200 participants
Austria 28 27 55
Serbia 4 2 6
Germany 9 8 17
Croatia 44 45 89
Spain 16 17 33
1.Primary Outcome
Title ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description:

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Overall Number of Participants Analyzed 99 96
Mean (Standard Deviation)
Unit of Measure: score on scale - baseline to endpoint
-.27  (5.41) 0.19  (5.15)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.67
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
2.Secondary Outcome
Title Neuropsychiatric Inventory (NPI)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description:

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Overall Number of Participants Analyzed 99 96
Mean (Standard Deviation)
Unit of Measure: score on scale - baseline to endpoint
2.51  (11.27) 0.66  (7.90)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.21
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
3.Secondary Outcome
Title Cornell Scale for Depression in Dementia (CSDD)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description:

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Overall Number of Participants Analyzed 93 86
Mean (Standard Deviation)
Unit of Measure: score on scale - baseline to endpoint
-0.08  (2.81) -0.45  (3.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.78
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
4.Secondary Outcome
Title Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description:

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Overall Number of Participants Analyzed 99 96
Mean (Standard Deviation)
Unit of Measure: score on scale - baseline to endpoint
-1.88  (9.54) -1.57  (7.72)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =0.83
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
5.Secondary Outcome
Title Mini-Mental State Examination
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description:

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

Overall Number of Participants Analyzed 99 96
Mean (Standard Deviation)
Unit of Measure: change in score - baseline to endpoint
0.80  (2.73) 0.60  (2.59)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value =.77
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Time Frame 26 weeks
Adverse Event Reporting Description

Enrolled patients Ladostigil 101(100.0%) Placebo 99(100.0%) ITT Population Ladostigil 99(98.02%) Placebo 96(96.97%) PP Population Ladostigil 79(78.22%) Placebo 75(75.76%) Safety Population Ladostigil 100(99.01%) Placebo 98(98.99%)

one patient discontinued the study in each group before administration of drug that is why the Safety Population is: Ladostigil 100(99.01%) Placebo 98(98.99%)

 
Arm/Group Title Ladostigil Hemitartrate Placebo
Hide Arm/Group Description

Ladostigil capsules 80 mg

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.

Placebo capsules

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.

All-Cause Mortality
Ladostigil Hemitartrate Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/100 (0.00%)      2/98 (2.04%)    
Hide Serious Adverse Events
Ladostigil Hemitartrate Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/100 (7.00%)      7/98 (7.14%)    
Cardiac disorders     
ACUTE MYOCARDIAL INFARCT * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
Gastrointestinal disorders     
Acute Cholecystitis * 1  0/100 (0.00%)  0 1/98 (1.02%)  1
Obstipation * 1  0/100 (0.00%)  0 1/98 (1.02%)  1
Infections and infestations     
Urinary Infection * 1  0/100 (0.00%)  0 2/98 (2.04%)  2
Injury, poisoning and procedural complications     
Sun Stroke * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
POLYTRAUMATISM * 1  0/100 (0.00%)  0 1/98 (1.02%)  1
Musculoskeletal and connective tissue disorders     
Elbow Fracture * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
Femur fracture subtrochan * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
Arthritis left ankle * 1  0/100 (0.00%)  0 1/98 (1.02%)  1
Respiratory, thoracic and mediastinal disorders     
Sick Sinus Syndrome * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
Thoracic Pain * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
Pneunomia * 1  0/100 (0.00%)  0 1/98 (1.02%)  1
Vascular disorders     
Brain Stroke * 1  1/100 (1.00%)  1 0/98 (0.00%)  0
1
Term from vocabulary, MedDRA (10.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ladostigil Hemitartrate Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   11/100 (11.00%)      2/98 (2.04%)    
Cardiac disorders     
Essential hypertension * 1  6/100 (6.00%)  6 0/98 (0.00%)  0
Gastrointestinal disorders     
Diarrhoea * 1  6/100 (6.00%)  6 2/98 (2.04%)  3
1
Term from vocabulary, MedDRA (10.0)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Jonathan Rabinowitz, PhD
Organization: Bar Ilan University
EMail: jonathan.rabinowitz@biu.ac.il
Layout table for additonal information
Responsible Party: Avraham Pharmaceuticals Ltd
ClinicalTrials.gov Identifier: NCT01354691    
Other Study ID Numbers: CR100101/CO15570
First Submitted: May 1, 2011
First Posted: May 17, 2011
Results First Submitted: July 2, 2018
Results First Posted: July 30, 2020
Last Update Posted: July 30, 2020