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A 3 Year Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment

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ClinicalTrials.gov Identifier: NCT01429623
Recruitment Status : Completed
First Posted : September 7, 2011
Results First Posted : June 15, 2017
Last Update Posted : June 15, 2017
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 Mild Cognitive Impairment
Dementia
Interventions Drug: ladostigil hemitartrate
Drug: Placebo
Enrollment 210
Recruitment Details Recruitment between Feb. 17, 2012 and August 1, 2013.
Pre-assignment Details  
Arm/Group Title Ladostigil Hemitartrate Placebo Control
Hide Arm/Group Description

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

Period Title: Overall Study
Started 102 [1] 107 [2]
Converted to Alzheimer's [3] 14 [4] 21 [5]
Completed 51 48
Not Completed 51 59
Reason Not Completed
Death             1             0
Adverse Event             7             14
Withdrawal by Subject             19             13
Physician Decision             2             3
Protocol Violation             3             2
Assorted             1             2
Conversion to Alzheimer's disease             14             21
No post baseline data             4             4
[1]
103 allocated, 1 withdrew consent prior to first dose, 4 lacked post baseline data
[2]
107 allocated, 4 lacked post baseline data
[3]
Upon conversion to Alzheimer's disease, the primary endpoint, subjects removed from study
[4]
14 of 99
[5]
21 of 103
Arm/Group Title Ladostigil Hemitartrate Placebo Control Total
Hide Arm/Group Description

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

Total of all reporting groups
Overall Number of Baseline Participants 103 107 210
Hide Baseline Analysis Population Description
103 were randomized to ladostigil, however 1 subject withdrew consent before first dose.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 103 participants 107 participants 210 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
15
  14.6%
16
  15.0%
31
  14.8%
>=65 years
88
  85.4%
91
  85.0%
179
  85.2%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 103 participants 107 participants 210 participants
71.3  (6.3) 71.4  (6.8) 71.35  (6.54)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 103 participants 107 participants 210 participants
Female
36
  35.0%
41
  38.3%
77
  36.7%
Male
67
  65.0%
66
  61.7%
133
  63.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 103 participants 107 participants 210 participants
Austria 23 24 47
Israel 47 50 97
Germany 33 33 66
1.Primary Outcome
Title Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo
Hide Description

Total number of conversions from Mild Cognitive Impairment to Alzheimer's disease across entire 3 year study period. Conversion is determined, or defined, by a Clinical Dementia Rating (CDR) score of greater than or equal to one.

Composite rating ranges from 0 no symptoms of dementia to 3 Severe symptoms of dementia.

Time Frame 3,6,12,18,24,30 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized subjects with at least one post-baseline visit.
Arm/Group Title Ladostigil Hemitartrate Placebo Control
Hide Arm/Group Description:

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

Overall Number of Participants Analyzed 99 103
Measure Type: Count of Participants
Unit of Measure: Participants
14
  14.1%
21
  20.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.16
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.55
Confidence Interval (2-Sided) 95%
0.74 to 3.25
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population
Hide Description Mean value change (from baseline) in Geriatric Depression Scale (GDS) across entire study period. The GDS ranges from 0 to 30. Scores of 0-9 are considered "normal", 10-19 "mildly depressed", and 20-30 "severely depressed".
Time Frame 3,6,12,18,24,30 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Modified Intent to Treat
Arm/Group Title Ladostigil Hemitartrate Placebo Control
Hide Arm/Group Description:

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

Overall Number of Participants Analyzed 99 103
Mean (Standard Deviation)
Unit of Measure: Change from basline on units on a scale
.084  (1.70) .242  (1.87)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.61
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value .37
Parameter Dispersion
Type: Standard Error of the Mean
Value: .24
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population
Hide Description Mean value change (from baseline) in Neuropsychiatric Test Battery (NTB) across entire study period. The NTB included the following well known cognitive tests: Rey Auditory Verbal Learning Test (RAVLT), Controlled Word Association Test (COWAT), Category Fluency Test (CFT), WMS-R Digit Span, and Trail Making Part A and B. The mean value was comprised of the z score of each of these tests with all z scores in the direction of higher scores better functioning. Range -3 to +3.
Time Frame 3,6,12,18,24,30 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Modified Intent to treat (all randomized subject with at least one post baseline assessment)
Arm/Group Title Ladostigil Hemitartrate Placebo Control
Hide Arm/Group Description:

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

Overall Number of Participants Analyzed 99 103
Mean (Standard Deviation)
Unit of Measure: Change from basline on units on a scale
.21  (.55) .17  (.43)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.32
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.066
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.085
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population
Hide Description Mean value change (from baseline) in Disability Assessment in Dementia (DAD) across entire study period. DAD evaluates the basic and instrumental activities in daily activities of elderly people with dementia. Higher scores reflect better functioning. DAD ranges from 0 to 100.
Time Frame 3,6,12,18,24,30 and 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ladostigil Hemitartrate Placebo Control
Hide Arm/Group Description:

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

Overall Number of Participants Analyzed 99 103
Mean (Standard Deviation)
Unit of Measure: Change from basline on units on a scale
-0.77  (8.43) -0.40  (5.11)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ladostigil Hemitartrate, Placebo Control
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.97
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value .79
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.17
Estimation Comments [Not Specified]
Time Frame 36 months
Adverse Event Reporting Description Treatment emergent adverse events (i.e., occurring after first drug administration)
 
Arm/Group Title Ladostigil Hemitartrate Placebo Control
Hide Arm/Group Description

10mg ladostigil base

ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule

drug product excipients

Placebo: Placebo comparator

All-Cause Mortality
Ladostigil Hemitartrate Placebo Control
Affected / at Risk (%) Affected / at Risk (%)
Total   1/103 (0.97%)      0/107 (0.00%)    
Hide Serious Adverse Events
Ladostigil Hemitartrate Placebo Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   26/103 (25.24%)      28/107 (26.17%)    
Blood and lymphatic system disorders     
Chronic lymphocytic leukaemia * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Cardiac disorders     
Atrial fibrillation * 1 [1]  2/103 (1.94%)  2 0/107 (0.00%)  0
Acute myocardial infarction * 1  0/103 (0.00%)  0 4/107 (3.74%)  5
Angina unstable * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Bradycardia * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Cardiac arrest * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Cardiac failure congestive * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Coronary artery disease * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Dyspnoea exertional * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Extrasystoles * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Sinus bradycardia * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Tachyarrhythmia * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Ventricular tachycardia * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Eye disorders     
Cataract * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Intraocular pressure increased  1  0/103 (0.00%)  0 1/107 (0.93%)  1
Gastrointestinal disorders     
Diarrhoea * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Diverticulitis * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Gastric cancer * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Inguinal hernia * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Metastases to peritoneum * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Oesophagitis * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Peritonitis * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Umbilical hernia * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
General disorders     
Chest pain * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Infections and infestations     
Appendicitis * 1  1/103 (0.97%)  1 1/107 (0.93%)  1
Bronchitis * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Extradural abscess * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Pneumonia * 1  1/103 (0.97%)  1 1/107 (0.93%)  1
Sepsis * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Viral infection * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Wound infection * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Injury, poisoning and procedural complications     
Cervical vertebral fracture * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Seroma * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Metabolism and nutrition disorders     
Electrolyte imbalance * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Arthritis * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Fractured coccyx * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Humerus fracture * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Lower limb fracture * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Osteoarthritis * 1  0/103 (0.00%)  0 1/107 (0.93%)  2
Pelvic floor muscle weakness * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Post polio syndrome * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Rib fracture * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Ovarian cancer * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Prostate cancer * 1  0/103 (0.00%)  0 3/107 (2.80%)  3
Squamous cell carcinoma * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Nervous system disorders     
Cerebrovascular accident * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Cervical spinal stenosis * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Dizziness * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Haemorrhage intracranial * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Headache * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Loss of consciousness * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Syncope * 1  2/103 (1.94%)  2 0/107 (0.00%)  0
Vertebrobasilar insufficiency * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Psychiatric disorders     
Confusional state * 1  0/103 (0.00%)  0 2/107 (1.87%)  2
Renal and urinary disorders     
Haematuria * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Reproductive system and breast disorders     
Benign prostatic hyperplasia * 1  1/103 (0.97%)  1 1/107 (0.93%)  1
Respiratory, thoracic and mediastinal disorders     
Haemothorax * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Lung cancer metastatic * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Pneumonia bacterial * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Skin and subcutaneous tissue disorders     
Gangrene * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Tinea pedis * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Surgical and medical procedures     
Cataract operation * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Glaucoma surgery * 1  2/103 (1.94%)  5 0/107 (0.00%)  0
Inguinal hernia repair * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Intraocular lens implant * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Knee arthroplasty * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Spinal laminectomy * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Transurethral prostatectomy * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Vascular disorders     
Accelerated hypertension * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Hypertension * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
Ischaemic stroke * 1  1/103 (0.97%)  1 0/107 (0.00%)  0
Peripheral vascular disorder * 1  1/103 (0.97%)  2 0/107 (0.00%)  0
Upper gastrointestinal haemorrhage * 1  0/103 (0.00%)  0 1/107 (0.93%)  1
1
Term from vocabulary, MedDRA (12.0)
*
Indicates events were collected by non-systematic assessment
[1]
Events rated as serious
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Ladostigil Hemitartrate Placebo Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   56/103 (54.37%)      59/107 (55.14%)    
Cardiac disorders     
Atrial fibrillation * 1  6/103 (5.83%)  6 3/107 (2.80%)  3
General disorders     
Fatigue * 1  4/103 (3.88%)  4 7/107 (6.54%)  8
Infections and infestations     
Nasopharyngitis * 1  11/103 (10.68%)  14 13/107 (12.15%)  15
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  7/103 (6.80%)  10 4/107 (3.74%)  4
Back Pain * 1  5/103 (4.85%)  5 10/107 (9.35%)  10
Nervous system disorders     
Headache * 1  7/103 (6.80%)  8 5/107 (4.67%)  5
Psychiatric disorders     
Depression * 1  6/103 (5.83%)  6 3/107 (2.80%)  3
Respiratory, thoracic and mediastinal disorders     
Cough * 1  7/103 (6.80%)  8 7/107 (6.54%)  7
Surgical and medical procedures     
Catarct operation * 1  3/103 (2.91%)  4 7/107 (6.54%)  11
1
Term from vocabulary, MedDRA (12.0)
*
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
Phone: +972544643889
EMail: Jonathan.Rabinowitz@biu.ac.il
Layout table for additonal information
Responsible Party: Avraham Pharmaceuticals Ltd
ClinicalTrials.gov Identifier: NCT01429623    
Other Study ID Numbers: CO17730
2011-004187-30 ( EudraCT Number )
First Submitted: September 3, 2011
First Posted: September 7, 2011
Results First Submitted: January 31, 2017
Results First Posted: June 15, 2017
Last Update Posted: June 15, 2017