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

• Sponsor: Avraham Pharmaceuticals Ltd (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01429623
• Collaborator: (none)
• Enrollment: 210
• Locations: 12
• Arms: 2
• Duration (Months): 55
• Patients Per Site: 17.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether treatment with the investigational drug ladostigil will delay the onset of Alzheimer's disease(AD) in patients with Mild Cognitive Impairment (MCI). MCI is now recognized as a precursor to AD and clinical tools are available to assess cognitive performance at this earlier stage. Ladostigil is currently under investigation for the treatment of AD. In this study, the investigators will be examining ladostigil at a lower dose level. At this dose level, ladostigil has been shown to reduce signs of early memory loss in animals. Thus, in this study the investigators are attempting to determine if earlier invention with a lower dose of ladostigil will significantly reduce initial memory loss and delay the subsequent progression to more serious cognitive dysfunction.

Condition or Disease	Intervention/Treatment	Phase
Mild Cognitive Impairment; Dementia	Drug: ladostigil hemitartrate; Drug: Placebo	Phase 2

Detailed Description

Ladostigil shows neuroprotective activity, reducing oxidative stress, activating microglia, and inhibiting pro-inflammatory cytokines in pre-clinical models. Study assessed its safety and potential efficacy in a 3-year, randomised, double-blind, placebo-controlled, phase 2 clinical trial in patients with mild cognitive impairment (MCI). Patients from 16 centers in Austria, Germany and Israel with MCI (Albert et al 2011), Clinical Dementia Rating (CDR) = 0.5, Mini-Mental State Examination (MMSE) > 24, Wechsler Memory Scale - Revised Verbal Paired Associates ≤ 18, and medial temporal lobe atrophy were stratified by APOE4 genotype and randomly assigned (1:1 allocation) using blocks of 4, to receive either ladostigil, 10 mg per day, or placebo as identically-appearing capsules. The primary endpoint was onset of Alzheimer's disease (AD). Secondary endpoints were the NTB, DAD, and GDS. Exploratory outcomes were MRI-derived whole brain, hippocampus, and entorhinal cortex volumes; the NeuroTrax Mindstreams computerized cognitive battery; and the CDR. Between February 17, 2012 and August 1, 2013, we randomly allocated 210 patients to placebo (107 patients) or ladostigil (103 patients); 4 patients in each group lacked post baseline assessments. After 36 months 20.4% (21 of 103 patients) of the placebo group and 14.1% (14 of 99 patients) of the ladostigil group progressed to AD (log-rank test p=.16). There were no significant effects on NTB, DAD, or GDS outcomes. There was less decline in whole brain volume in the ladostigil group as compared to placebo (p<.02), but not hippocampus and entorhinal cortex volumes, and CDR and a trend for less decline on the RAVLT total delayed score component of the NTB (p=.09). Fourteen patients taking placebo and 21 taking ladostigil discontinued treatment because of adverse events. Serious adverse events were reported by 26 (25.2%) patients in the ladostigil group and 28 (26.2%) patients in the placebo group. Ladostigil appeared safe, well-tolerated, and may have potential for improving memory and delaying progression to dementia.

Study Design

• Study Type: Interventional
• Actual Enrollment: 210 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 36-month, Multi-centre, Randomized, Double Blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment (MCI)
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ladostigil hemitartrate 10mg ladostigil base	Drug: ladostigil hemitartrate; 10mg ladostigil base administered once daily as hard gelatin capsule; Other Names: ladostigil Ladostigil capsules
Placebo Comparator: Placebo Control drug product excipients	Drug: Placebo; Placebo comparator

Outcome Measures

Primary Outcome Measures

1. Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo [3,6,12,18,24,30 and 36 months]

   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.

Secondary Outcome Measures

1. Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population [3,6,12,18,24,30 and 36 months]

   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".

2. Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population [3,6,12,18,24,30 and 36 months]

   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.

3. Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population [3,6,12,18,24,30 and 36 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women (non-childbearing potential) with a diagnosis of Mild Cognitive Impairment (MCI) according to consensus criteria as defined by Petersen

• Abnormal memory function will be evaluated by Verbal Paired Associates from the Wechsler Memory Scale - Revised. Norm values for healthy adults in two age cohorts are: a) 50-70 years 19.7 (SD=2.9) and b) 75-95 years 18.3 (SD=2.8). Patients that score < or = 23 will be included.

• Clinical Dementia Rating (CDR) score of 0.5 (Memory box score 0.5 or 1, no box score >

• Mini Mental State Examination (MMSE) > 24 and < or = 30

• General cognition and functional performance is sufficiently preserved such that a diagnosis of AD can be excluded by the site physician at the time of the screening visit.

• No significant cerebrovascular disease indicated by Modified Hackinski Ischaemic Score equal to or below 4

• Age 55-85 years based upon correlation of cognition and Scheltens score observed in this age range

• Geriatric Depression Scale (GDS) of < or = 5

• An informer who has frequent contact with the subject (e.g. an average of 10 hours per week or more) is available and agrees to monitor administration of study drug, to observe the subject for adverse events and to accompany the subject to clinical visits during the trial, if the presence of the informer is required.

• All patients have to undergo an MRI scan after the screening visit, i.e. during the screening visit, irrespective of MRIs having been performed prior to entry into the study. MRI findings have to be consistent with a diagnosis of MCI.

• Central rating of medial temporal lobe according to Scheltens scale. The right and left medial temporal structures will be rated separately and an overall estimate will be deduced using the average of the two ratings. An average score > 1 is required to make patients eligible for the study.

• Adequate visual and auditory acuity must be demonstrated to allow for neuropsychological testing.

• Good general health status acceptable for participation in a 36-month clinical trial, with no additional diseases expected to interfere with the study

• ECG without clinically significant abnormalities according to exclusion criteria listed below

• Subject is not pregnant, lactating or of childbearing potential (i.e. women must be two years post menopausal or surgically sterile)

• Signed informed consent by patient and informer prior to any study specific procedure

Exclusion Criteria:

• Failure to perform screening or baseline examinations

• Any significant neurological disease other than suspected MCI

• MRI exclusion criteria which allow for mild concomitant vascular lesions are:

• Thromboembolic infarction

• Other focal lesions which may be responsible for the cognitive status of the patient such as infectious disease, space-occupying lesions, normal pressure hydrocephalus or any other abnormalities associated with significant central nervous disease

• More than one lacunar infarct defined as a focal lesion of CSF signal intensity with a diameter of < 1.5cm in any dimension

• Any lacunar infarct in a strategically important location such as the thalamus, hippocampus of either hemisphere, head of the left caudate

• White matter lesions involving more than 25% of the hemispheric white matter

• Implants such as pacemakers, insulin pumps, cochlear implants, nerve stimulators, implantable cardioverter defibrillators, and other medical implants that have not been certified for MRI

• Ferromagnetic foreign bodies such as shell fragments need to be considered on an individual basis

• Metallic implants that can cause artifacts and RF induced heating such as surgical prostheses or aneurysm clips need to be considered on an individual basis

• Clinical or laboratory findings consistent with:

• Central nervous system diseases such as those resulting from severe head trauma, tumours, subdural haematomas or other space occupying processes, etc

• Seizure disorder

• 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)

• History or evidence of schizophrenia or bipolar disorder (DSM IV criteria); active major depression

• Clinically significant advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as:

• Malignant tumours within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer

• Metastases

• History of myocardial infarction within one year prior to screening or unstable or severe cardiovascular disease including angina or congestive heart failure with symptoms at rest

• Uncontrolled hypertension (systolic pressure > 170mmHg or diastolic pressure > 100mmHg)

• Bradycardia (persistent heart beat < 50/min) or tachycardia ( persistent heart beat > 100/min)

• AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males > 450msec, females > 470msec)

• Clinically significant obstructive pulmonary disease or asthma

• Clinically significant laboratory findings that indicate abnormalities in blood biochemistry, blood haematology or urinalysis

• Uncontrolled diabetes mellitus defined by HbA1c > 8.5

• Clinically significant liver disease, coagulopathy or vitamin K deficiency within the past two years prior to screening

• Renal insufficiency (serum creatinine > mg/dl or creatinine clearance < or = to 45ml/min according to Cockgroft-Gault formula); in case of creatinine clearance < or = 45ml/min, an alternative verification of the renal function must be completed using cystatin C analysis. In case of normal level of cystatin C, the patient can be included in the study.

• Any prior use of medications approved by local authorities for the treatment of Alzheimer's disease (e.g. tacrine, donepezil, rivastigmine, galantamine, memantine or other newly approved medications)

• Disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc)

• Women who are fertile and of child bearing potential

• Chronic daily intake of antidepressants as noted in section 9.5 of the clinical study protocol

• Suspected or known drug or alcohol abuse, i.e. more than approximately 60g alcohol (approximately 1 lter of beer or 0.5 liter of wine) per day as indicated by elevated MCV significantly above normal value at screening

• Suspected or known allergy to any components of the study treatments

• Enrollment in another investigational study or intake of investigational drug within the previous three months

• Any condition (e.g. epilepsy) which in the opinion of the investigator makes the patient unsuitable for inclusion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medizinische Universitat Graz, Abteilung fur Neurologie	Graz		Austria	8036
2	Landeskrankenhaus Hall, Memory Klinik	Hall in Tirol		Austria	6060
3	Privatordination Rainer	Wien		Austria	1130
4	Studienambulanz St. Joseph Krankenhaus Berlin, Emovis GmbH	Berlin		Germany	13088
5	Otto-von-Guericke-Universitat, Universitatsklinik fur Neurologie und fur Stereotaktische	Magdeburg		Germany	30120
6	Studienzentrum Nordwest	Westerstede		Germany	26655
7	Department of Geriatrics and Memory Clinic, Mental Health Center, Israel	Beersheva		Israel	84170
8	Cognitive Neurology Unit, Rambam Health Care Campus	Haifa		Israel	31096
9	Cognitive Clinic, Department of Geriatrics, Carmel Medical Center	Haifa		Israel	34362
10	Department of Physical Medicine and Rehabilitation, Hadassah University Hospital, PO Box 24035	Jerusalem		Israel	91240
11	Memory Clinic, Sheba Medical Center at Tel Hashomer	Ramat Gan		Israel	52621
12	Center for Memory and Attention Disorders, Department of Neurology, Sourasky Medical Center	Tel Aviv		Israel	64239

Sponsors and Collaborators

• Avraham Pharmaceuticals Ltd

Investigators

• Principal Investigator: Tzvi Dwolatzky, MD, Director, Department of Geriatrics and Memory Clinic, Mental Health Center, Israel P.O. Box 4600, Beersheva 84170

Study Documents (Full-Text)

None provided.

More Information

Publications

• DeCarli C, Frisoni GB, Clark CM, Harvey D, Grundman M, Petersen RC, Thal LJ, Jin S, Jack CR Jr, Scheltens P; Alzheimer's Disease Cooperative Study Group. Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol. 2007 Jan;64(1):108-15. Erratum in: Arch Neurol. 2007 Mar;64(3):459.
• Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep;256(3):240-6. Review.

• Responsible Party: Avraham Pharmaceuticals Ltd
• ClinicalTrials.gov Identifier: NCT01429623
• Other Study ID Numbers: CO17730; 2011-004187-30
• First Posted: Sep 7, 2011
• Last Update Posted: Jun 15, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Avraham Pharmaceuticals Ltd: Mild Cognitive Impairment; Early Stage Dementia; Conversion to Alzheimer's disease; Memory Impairment
• Additional relevant MeSH terms: Dementia; Cognitive Dysfunction

Study Results

Participant Flow

Recruitment Details	Recruitment between Feb. 17, 2012 and August 1, 2013.

Arm/Group Title	Ladostigil Hemitartrate	Placebo Control
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	107
Converted to Alzheimer's	14	21
COMPLETED	51	48
NOT COMPLETED	51	59

Baseline Characteristics

Arm/Group Title	Ladostigil Hemitartrate	Placebo Control	Total
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 Participants	103	107	210
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	15 14.6%	16 15%	31 14.8%
>=65 years	88 85.4%	91 85%	179 85.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.3 (6.3)	71.4 (6.8)	71.35 (6.54)
Sex: Female, Male (Count of Participants)
Female	36 35%	41 38.3%	77 36.7%
Male	67 65%	66 61.7%	133 63.3%
Region of Enrollment (participants) [Number]
Austria	23 22.3%	24 22.4%	47 22.4%
Israel	47 45.6%	50 46.7%	97 46.2%
Germany	33 32%	33 30.8%	66 31.4%

Outcome Measures

1. Primary Outcome

Title	Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo
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

Outcome Measure Data

Analysis Population Description

All randomized subjects with at least one post-baseline visit.

Arm/Group Title	Ladostigil Hemitartrate	Placebo Control
Arm/Group Description	10mg ladostigil base ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule	drug product excipients Placebo: Placebo comparator
Measure Participants	99	103
Count of Participants [Participants]	14 13.6%	21 19.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladostigil Hemitartrate, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.16
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; 0.74 to 3.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population
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

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat

Arm/Group Title	Ladostigil Hemitartrate	Placebo Control
Arm/Group Description	10mg ladostigil base ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule	drug product excipients Placebo: Placebo comparator
Measure Participants	99	103
Mean (Standard Deviation) [Change from basline on units on a scale]	.084 (1.70)	.242 (1.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladostigil Hemitartrate, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.61
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.37
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .24
	Estimation Comments

3. Secondary Outcome

Title	Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population
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

Outcome Measure Data

Analysis Population Description

Modified Intent to treat (all randomized subject with at least one post baseline assessment)

Arm/Group Title	Ladostigil Hemitartrate	Placebo Control
Arm/Group Description	10mg ladostigil base ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule	drug product excipients Placebo: Placebo comparator
Measure Participants	99	103
Mean (Standard Deviation) [Change from basline on units on a scale]	.21 (.55)	.17 (.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladostigil Hemitartrate, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.32
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.066
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments

4. Secondary Outcome

Title	Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ladostigil Hemitartrate	Placebo Control
Arm/Group Description	10mg ladostigil base ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule	drug product excipients Placebo: Placebo comparator
Measure Participants	99	103
Mean (Standard Deviation) [Change from basline on units on a scale]	-0.77 (8.43)	-0.40 (5.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ladostigil Hemitartrate, Placebo Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.97
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.79
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.17
	Estimation Comments

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	1/103 (1%)		0/107 (0%)
Serious Adverse Events
	Ladostigil Hemitartrate		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/103 (25.2%)		28/107 (26.2%)
Blood and lymphatic system disorders
Chronic lymphocytic leukaemia	0/103 (0%)	0	1/107 (0.9%)	1
Cardiac disorders
Atrial fibrillation	2/103 (1.9%)	2	0/107 (0%)	0
Acute myocardial infarction	0/103 (0%)	0	4/107 (3.7%)	5
Angina unstable	1/103 (1%)	1	0/107 (0%)	0
Bradycardia	0/103 (0%)	0	1/107 (0.9%)	1
Cardiac arrest	1/103 (1%)	1	0/107 (0%)	0
Cardiac failure congestive	1/103 (1%)	1	0/107 (0%)	0
Coronary artery disease	1/103 (1%)	1	0/107 (0%)	0
Dyspnoea exertional	1/103 (1%)	1	0/107 (0%)	0
Extrasystoles	1/103 (1%)	1	0/107 (0%)	0
Sinus bradycardia	0/103 (0%)	0	1/107 (0.9%)	1
Tachyarrhythmia	1/103 (1%)	1	0/107 (0%)	0
Ventricular tachycardia	1/103 (1%)	1	0/107 (0%)	0
Eye disorders
Cataract	0/103 (0%)	0	1/107 (0.9%)	1
Intraocular pressure increased	0/103 (0%)	0	1/107 (0.9%)	1
Gastrointestinal disorders
Diarrhoea	1/103 (1%)	1	0/107 (0%)	0
Diverticulitis	1/103 (1%)	1	0/107 (0%)	0
Gastric cancer	0/103 (0%)	0	1/107 (0.9%)	1
Inguinal hernia	0/103 (0%)	0	1/107 (0.9%)	1
Metastases to peritoneum	0/103 (0%)	0	1/107 (0.9%)	1
Oesophagitis	1/103 (1%)	1	0/107 (0%)	0
Peritonitis	1/103 (1%)	1	0/107 (0%)	0
Umbilical hernia	1/103 (1%)	1	0/107 (0%)	0
General disorders
Chest pain	0/103 (0%)	0	1/107 (0.9%)	1
Infections and infestations
Appendicitis	1/103 (1%)	1	1/107 (0.9%)	1
Bronchitis	0/103 (0%)	0	1/107 (0.9%)	1
Extradural abscess	1/103 (1%)	1	0/107 (0%)	0
Pneumonia	1/103 (1%)	1	1/107 (0.9%)	1
Sepsis	1/103 (1%)	1	0/107 (0%)	0
Viral infection	1/103 (1%)	1	0/107 (0%)	0
Wound infection	1/103 (1%)	1	0/107 (0%)	0
Injury, poisoning and procedural complications
Cervical vertebral fracture	1/103 (1%)	1	0/107 (0%)	0
Seroma	0/103 (0%)	0	1/107 (0.9%)	1
Metabolism and nutrition disorders
Electrolyte imbalance	1/103 (1%)	1	0/107 (0%)	0
Musculoskeletal and connective tissue disorders
Arthritis	1/103 (1%)	1	0/107 (0%)	0
Fractured coccyx	0/103 (0%)	0	1/107 (0.9%)	1
Humerus fracture	0/103 (0%)	0	1/107 (0.9%)	1
Lower limb fracture	0/103 (0%)	0	1/107 (0.9%)	1
Osteoarthritis	0/103 (0%)	0	1/107 (0.9%)	2
Pelvic floor muscle weakness	0/103 (0%)	0	1/107 (0.9%)	1
Post polio syndrome	0/103 (0%)	0	1/107 (0.9%)	1
Rib fracture	1/103 (1%)	1	0/107 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cancer	0/103 (0%)	0	1/107 (0.9%)	1
Prostate cancer	0/103 (0%)	0	3/107 (2.8%)	3
Squamous cell carcinoma	1/103 (1%)	1	0/107 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/103 (0%)	0	1/107 (0.9%)	1
Cervical spinal stenosis	0/103 (0%)	0	1/107 (0.9%)	1
Dizziness	1/103 (1%)	1	0/107 (0%)	0
Haemorrhage intracranial	0/103 (0%)	0	1/107 (0.9%)	1
Headache	0/103 (0%)	0	1/107 (0.9%)	1
Loss of consciousness	1/103 (1%)	1	0/107 (0%)	0
Syncope	2/103 (1.9%)	2	0/107 (0%)	0
Vertebrobasilar insufficiency	0/103 (0%)	0	1/107 (0.9%)	1
Psychiatric disorders
Confusional state	0/103 (0%)	0	2/107 (1.9%)	2
Renal and urinary disorders
Haematuria	1/103 (1%)	1	0/107 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/103 (1%)	1	1/107 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Haemothorax	0/103 (0%)	0	1/107 (0.9%)	1
Lung cancer metastatic	0/103 (0%)	0	1/107 (0.9%)	1
Pneumonia bacterial	1/103 (1%)	1	0/107 (0%)	0
Skin and subcutaneous tissue disorders
Gangrene	1/103 (1%)	1	0/107 (0%)	0
Tinea pedis	1/103 (1%)	1	0/107 (0%)	0
Surgical and medical procedures
Cataract operation	1/103 (1%)	1	0/107 (0%)	0
Glaucoma surgery	2/103 (1.9%)	5	0/107 (0%)	0
Inguinal hernia repair	1/103 (1%)	1	0/107 (0%)	0
Intraocular lens implant	1/103 (1%)	1	0/107 (0%)	0
Knee arthroplasty	0/103 (0%)	0	1/107 (0.9%)	1
Spinal laminectomy	1/103 (1%)	1	0/107 (0%)	0
Transurethral prostatectomy	1/103 (1%)	1	0/107 (0%)	0
Vascular disorders
Accelerated hypertension	0/103 (0%)	0	1/107 (0.9%)	1
Hypertension	0/103 (0%)	0	1/107 (0.9%)	1
Ischaemic stroke	1/103 (1%)	1	0/107 (0%)	0
Peripheral vascular disorder	1/103 (1%)	2	0/107 (0%)	0
Upper gastrointestinal haemorrhage	0/103 (0%)	0	1/107 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Ladostigil Hemitartrate		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	56/103 (54.4%)		59/107 (55.1%)
Cardiac disorders
Atrial fibrillation	6/103 (5.8%)	6	3/107 (2.8%)	3
General disorders
Fatigue	4/103 (3.9%)	4	7/107 (6.5%)	8
Infections and infestations
Nasopharyngitis	11/103 (10.7%)	14	13/107 (12.1%)	15
Musculoskeletal and connective tissue disorders
Arthralgia	7/103 (6.8%)	10	4/107 (3.7%)	4
Back Pain	5/103 (4.9%)	5	10/107 (9.3%)	10
Nervous system disorders
Headache	7/103 (6.8%)	8	5/107 (4.7%)	5
Psychiatric disorders
Depression	6/103 (5.8%)	6	3/107 (2.8%)	3
Respiratory, thoracic and mediastinal disorders
Cough	7/103 (6.8%)	8	7/107 (6.5%)	7
Surgical and medical procedures
Catarct operation	3/103 (2.9%)	4	7/107 (6.5%)	11

Limitations/Caveats

[Not Specified]

More Information

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.