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Efficacy and Safety of Actovegin in Post-stroke Cognitive Impairment (PSCI) (ARTEMIDA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01582854
Recruitment Status : Completed
First Posted : April 23, 2012
Results First Posted : February 22, 2016
Last Update Posted : February 22, 2016
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Post-Stroke Cognitive Impairment (PSCI)
Interventions Drug: Actovegin
Drug: Placebo
Enrollment 503
Recruitment Details Participants took part in the study at 33 investigative sites in Belarus, Kazakhstan and Russia from 28 June 2012 to 26 November 2014.
Pre-assignment Details Participants who had suffered ischaemic stroke were enrolled equally in 1 of 2 treatment groups, actovegin 2000 mg solution (up to 20 infusions) followed by 200 mg tablets 3 times a day or placebo.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months. Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Period Title: Overall Study
Started 248 255
Completed 212 221
Not Completed 36 34
Reason Not Completed
Death             8             5
Adverse Event             2             3
Withdrawal by Participant             8             11
Lost to Follow-up             1             2
Physician Decision             0             1
Recurrent Stroke             13             8
Disallowed Concomitant Medication             3             2
Carotid or Neurosurgery             0             1
General Anaesthesia             0             1
Other Miscellaneous Reason             1             0
Arm/Group Title Actovegin Placebo Total
Hide Arm/Group Description Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months. Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months. Total of all reporting groups
Overall Number of Baseline Participants 248 255 503
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 248 participants 255 participants 503 participants
70.3  (6.65) 69.6  (7.18) 69.9  (6.92)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
≤ 65 years 78 97 175
> 65 years 170 158 328
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Female
120
  48.4%
142
  55.7%
262
  52.1%
Male
128
  51.6%
113
  44.3%
241
  47.9%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Asian 3 3 6
Black or African American 1 1 2
White 240 248 488
Other 4 3 7
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Russia 190 195 385
Kazakhstan 2 2 4
Belarus 56 58 114
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 248 participants 255 participants 503 participants
167.6  (7.47) 167.2  (7.89) 167.4  (7.68)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 248 participants 255 participants 503 participants
78.3  (13.76) 78.0  (13.73) 78.1  (13.73)
Number of Years of Education  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 248 participants 255 participants 503 participants
12.2  (3.41) 12.3  (3.40) 12.3  (3.40)
Diabetes  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Yes 40 57 97
No 208 198 406
Ischaemic Heart Disease or Peripheral Artery Disease  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Yes 245 253 498
No 3 2 5
Previous Ischaemic Stroke  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Yes 40 38 78
No 208 217 425
Smoking Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Never smoked 172 195 367
Current smoker 53 37 90
Ex-smoker 23 23 46
Alcohol Consumption  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Never drank 117 126 243
Occasional drinker 131 128 259
Daily drinker 0 1 1
Fertility Status of Female Participants   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 248 participants 255 participants 503 participants
Surgically Sterile/Hysterectomized 3 5 8
Post-menopausal 117 137 254
[1]
Measure Description: Female participants with available fertility status data only: 120 and 142 participants in each treatment arm, respectively.
1.Primary Outcome
Title Change From Baseline in Alzheimer's Disease Assessment Scale + Cognitive Subscale Extended Version (ADAS-cog+) at Month 6
Hide Description

The ADAS-cog measures cognitive performance by combining the ratings of 11 items. The cognitive domains mainly addressed by ADAS-cog are: memory (short term), language, ability to orientate (reflects memory), construction/planning of simple designs and performance. The extended version of the ADAS-cog (ADAS-cog+) includes 3 additional items: a 2-number cancellation task to test for attention, a delayed recall task to test for memory consolidation and a maze test for executive performance. Each item is scored and then the item scores are totaled. Total scores range from 0 (best) to 90 (worst). Higher scores indicate greater cognitive impairment. A negative change from Baseline indicates improvement.

Analysis of Covariance (ANCOVA) model was used for analyses that included treatment, pooled centre, and their interaction as factors and Baseline ADAS-cog+ score as a covariate.

Time Frame Baseline and Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analysis. Missing individual item scores (where only some item scores missing) imputed with worst possible score and missing total scores (where all item scores missing) imputed by last observation carried forward.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 224 234
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-6.8  (0.58) -4.6  (0.58)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-3.9 to -0.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.82
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in ADAS-cog+ at Month 3 and Month 12
Hide Description

The ADAS-cog measures cognitive performance by combining the ratings of 11 items. The cognitive domains mainly addressed by ADAS-cog are: memory (short term), language, ability to orientate (reflects memory), construction/planning of simple designs and performance. The extended version of the ADAS-cog (ADAS-cog+) includes 3 additional items: a 2-number cancellation task to test for attention, a delayed recall task to test for memory consolidation and a maze test for executive performance. Each item is scored and then the item scores are totaled. Total scores range from 0 (best) to 90 (worst). Higher scores indicate greater cognitive impairment. A negative change from Baseline indicates improvement.

ANCOVA model was used for analyses that included treatment, pooled centre, and their interaction as factors and Baseline ADAS-cog+ score as a covariate.

Time Frame Baseline and Months 3 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analysis. Missing individual item scores (where only some item scores missing) imputed with worst possible score.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
Change from Baseline at Month 3 (n=224, 234) -5.4  (0.53) -4.3  (0.52)
Change from Baseline at Month 12 (n=211, 219) -8.2  (0.66) -4.5  (0.66)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.122
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -1.1
Confidence Interval (2-Sided) 95%
-2.6 to 0.3
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.74
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -3.7
Confidence Interval (2-Sided) 95%
-5.5 to -1.9
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.93
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline in Montreal Cognitive Assessment Scale (MoCA) at End of Infusion Period, Months 3, 6 and 12
Hide Description

The MoCA is a rapid screening test to assess mild cognitive impairment. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Time to administer the MoCA is approximately 10 minutes. The total possible score is 0 to 30 points; a score of 26 or above is considered normal. A positive change from Baseline (BL) indicates improvement.

ANCOVA model was used for analyses that included treatment and pooled centres as factors, plus years of education and baseline MoCA score as covariates.

Time Frame Baseline, End of Infusion and Months 3, 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
Change from BL at End of Infusion (n=242, 247) 2.1  (0.15) 1.8  (0.15)
Change from Baseline at Month 3 (n=224, 234) 3.4  (0.20) 2.7  (0.20)
Change from Baseline at Month 6 (n=217, 228) 3.8  (0.21) 3.1  (0.21)
Change from Baseline at Month 12 (n=211, 220) 3.9  (0.25) 2.9  (0.24)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments End of Infusion Period
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.111
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.3
Confidence Interval (2-Sided) 95%
-0.1 to 0.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.20
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.016
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
0.1 to 1.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.27
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 6
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.013
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.7
Confidence Interval (2-Sided) 95%
0.2 to 1.3
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.29
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.0
Confidence Interval (2-Sided) 95%
0.3 to 1.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.34
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of ADAS-cog+ Responders at Time Points 3, 6 and 12 Months
Hide Description Responder was defined as an improvement of 4 or more from baseline on the ADAS-cog+ scale using observed data. The proportion of responders was compared between treatments using a chi-square test.
Time Frame Baseline and Months 3, 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Measure Type: Number
Unit of Measure: percentage of responders
Month 3 (n=215, 223) 59.1 48.9
Month 6 (n=208, 216) 62.5 52.3
Month 12 (n=200, 207) 69.0 58.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.032
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Difference
Estimated Value 10.2
Confidence Interval (2-Sided) 95%
0.9 to 19.5
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 6
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.034
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Difference
Estimated Value 10.2
Confidence Interval (2-Sided) 95%
0.8 to 19.5
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.035
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Difference
Estimated Value 10.1
Confidence Interval (2-Sided) 95%
0.8 to 19.3
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Participants With a Diagnosis of Dementia
Hide Description Diagnosis of dementia will be evaluated after 6 and 12 months classified according to International Statistical Classification of Diseases and related Health Problems 10th Revision (ICD-10) [Classification of Mental and Behavioural Disorders, Diagnostic Criteria for Research]. The proportion of participants with dementia was compared between treatments using a Fisher’s exact test.
Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 218 228
Measure Type: Number
Unit of Measure: percentage of participants
Month 6 7.3 10.5
Month 12 8.7 12.7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 6
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.251
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Difference
Estimated Value -3.2
Confidence Interval (2-Sided) 95%
-8.5 to 2.1
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.221
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Method of Estimation Estimation Parameter Percent Difference
Estimated Value -4.0
Confidence Interval (2-Sided) 95%
-9.7 to 1.7
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Change From Baseline in National Institutes of Health Stroke Scale (NIHSS) at End of Infusion Period, Months 3, 6 and 12
Hide Description The NIHSS is a tool to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 (normal) to 4 (some level of impairment). The individual scores from each item are summed in order to calculate total possible NIHSS score from 0 (best) to 42 (worst). A negative change from Baseline indicates improvement. ANCOVA model was used for analyses that included treatment and pooled centre as factors and Baseline NIHSS score as a covariate.
Time Frame Baseline and End of Infusion and Months 3, 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
Change from BL at End of Infusion (n=243, 248) -1.8  (0.10) -1.7  (0.10)
Change from Baseline at Month 3 (n=224, 235) -2.9  (0.10) -2.7  (0.10)
Change from Baseline at Month 6 (n=219, 228) -3.2  (0.10) -3.2  (0.10)
Change from Baseline at Month 12 (n=211, 220) -3.5  (0.10) -3.4  (0.10)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments End of Infusion Period
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.239
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-0.4 to 0.1
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 3
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.136
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-0.5 to 0.1
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 6
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.890
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-0.3 to 0.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Actovegin, Placebo
Comments Month 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.455
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.1
Confidence Interval (2-Sided) 95%
-0.4 to 0.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.14
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Barthel Index at Months 3 and 6
Hide Description The Barthel Index consists of 10 items that measure a person's daily functioning, specifically the activities of daily living and mobility. The items include: feeding, transfers (bed to chair and back), grooming, toilet use, bathing, mobility (walking on level surface), going up and down stairs, dressing, continence of bowels and bladder. Each performance item is rated, with a given number of points assigned to each level or ranking. Individual scores are summed for a total possible scores ranging from 0 (worst) to 100 (best) with higher scores indicating more independent daily living.
Time Frame Months 3 and 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Median (Full Range)
Unit of Measure: score on a scale
Month 3 (n=224,235)
100.0
(55.0 to 100.0)
100.0
(9.0 to 100.0)
Month 6 (n=219,228)
100.0
(55.0 to 100.0)
100.0
(50.0 to 100.0)
8.Secondary Outcome
Title EuroQol EQ-5D (EQ-5D) at Month 6
Hide Description EQ-5D is a standardized measure of health status consisting of 5 dimensions: mobility, self -care, usual activities, pain/discomfort and anxiety/depression. The participant rates their level of function in each area using a 5 point scale where 1=no problems (best) to 5=extreme problems (worst). The percentage of participants in each category is reported.
Time Frame Month 6
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 219 224
Measure Type: Number
Unit of Measure: percentage of participants
Mobility_No problem 41.5 32.2
Mobility_Slight problem 29.8 31.8
Mobility_Moderate problem 12.5 16.5
Mobility_Severe problem 4.0 7.1
Mobility_Unable 0.4 0.4
Self-care_No problem 58.5 48.6
Self-care_Slight problem 19.8 25.5
Self-care_Moderate problem 7.7 9.8
Self-care_Severe problem 2.0 3.5
Self-care_Unable 0.4 0.4
Usual activities_No problem 32.7 32.9
Usual activities_Slight problem 40.7 34.5
Usual activities_Moderate problem 8.9 17.3
Usual activities_Severe problem 4.0 2.5
Usual activities_Unable 2.0 0.8
Pain or discomfort_No pain 50.0 46.3
Pain or discomfort_Slight pain 30.6 25.5
Pain or discomfort_Moderate pain 6.0 15.3
Pain or discomfort_Severe pain 0.8 0.8
Pain or discomfort_Extreme pain 0.4 0
Anxiety or depression_Not anxious 50.0 48.2
Anxiety or depression_Slightly anxious 31.0 29.4
Anxiety or depression_Moderately anxious 6.0 9.4
Anxiety or depression_Severely anxious 0.8 0.8
Anxiety or depression_Extremely anxious 0.4 0
9.Secondary Outcome
Title EuroQol EQ-5D (EQ-5D) at Month 12
Hide Description EQ-5D is a standardized measure of health status consisting of 5 dimensions: mobility, self -care, usual activities, pain/discomfort and anxiety/depression. The participant rates their level of function in each area using a 5 point scale where 1=no problems (best) to 5=extreme problems (worst). The percentage of participants in each category is reported.
Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 212 220
Measure Type: Number
Unit of Measure: percentage of participants
Mobility_No problem 37.9 36.5
Mobility_Slight problem 31.0 29.4
Mobility_Moderate problem 12.5 11.8
Mobility_Severe problem 3.2 7.5
Mobility_Unable 0.8 0.8
Self-care_No problem 55.2 48.2
Self-care_Slight problem 22.2 23.5
Self-care_Moderate problem 6.0 9.4
Self-care_Severe problem 1.6 3.9
Self-care_Unable 0.4 0.8
Usual activities_No problem 32.7 31.0
Usual activities_Slight problem 39.1 33.7
Usual activities_Moderate problem 9.7 15.7
Usual activities_Severe problem 2.8 4.3
Usual activities_Unable 1.2 1.2
Pain or discomfort_No pain 46.8 46.7
Pain or discomfort_Slight pain 28.6 26.3
Pain or discomfort_Moderate pain 8.5 11.4
Pain or discomfort_Severe pain 1.6 1.2
Pain or discomfort_Extreme pain 0 0.4
Anxiety or depression_Not anxious 48.4 47.1
Anxiety or depression_Slightly anxious 31.5 27.1
Anxiety or depression_Moderately anxious 4.8 10.6
Anxiety or depression_Severely anxious 0.8 0.8
Anxiety or depression_Extremely anxious 0 0.4
10.Secondary Outcome
Title EuroQol EQ-5D (EQ-5D) General Health at Months 6 and 12
Hide Description The EuroQoL included a visual analogue scale where the subject marks how they feel at that moment on a scale from 0 (the worst health that can be imagined) to 100 (the best health that can be imagined).
Time Frame Months 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Mean (Standard Deviation)
Unit of Measure: score on a scale
Month 6 (n=219, 224) 67.3  (16.04) 65.0  (16.82)
Month 12 (n=212, 220) 67.8  (15.87) 65.6  (17.51)
11.Secondary Outcome
Title Beck Depression Inventory, Version II (BDI-II) at Months 3, 6 and 12
Hide Description

The BDI-II is a 21-question multiple-choice self-report inventory for measuring the severity of depression. is composed of items relating to symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and lack of interest in sex. Each answer is scored on a scale 0 (best) to 3 (worst). Total scores range from 0 to 63 with higher scores indicating more severe depression.

BDI II scale:

  • 0-13 minimal depression
  • 14-19 mild depression
  • 20-28 moderate depression
  • 29-63 severe depression
Time Frame Months 3, 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Mean (Standard Deviation)
Unit of Measure: score on a scale
Month 3 (n=224, 234) 12.5  (11.02) 11.6  (8.08)
Month 6 (n=219, 227) 11.3  (8.88) 11.5  (10.58)
Month 12 (n=212, 220) 10.7  (7.10) 11.5  (8.24)
12.Secondary Outcome
Title Percentage of Participants With a Diagnosis of Dementia
Hide Description Diagnosis of dementia will be evaluated after 6 and 12 months classified according to International Statistical Classification of Diseases and related Health Problems 10th Revision (ICD-10) [Classification of Mental and Behavioural Disorders, Diagnostic Criteria for Research].
Time Frame Month 6 and 12
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Intent-to-treat population, all enrolled participants who received at least one dose of study drug, with data available for analyses at the given time-point.
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description:
Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months.
Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
Overall Number of Participants Analyzed 248 255
Measure Type: Number
Unit of Measure: percentage of participants
Month 6 7.3 10.5
Month 12 8.7 12.7
Time Frame First dose of study drug to 10 days after last dose of study drug (up to approximately 6.5 months).
Adverse Event Reporting Description Any adverse events and abnormal laboratory findings irrespective of the relation to study treatment were documented. Safety population included all participants who received at least 1 dose of study drug based on treatment received. 2 participants in the placebo arm received actovegin and are included in the actovegin arm for safety analyses.
 
Arm/Group Title Actovegin Placebo
Hide Arm/Group Description Actovegin 2000 mg solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin 200 mg, tablets, orally, 3 times a day for up to 6 months. Actovegin placebo-matching solution, intravenous (IV) infusion for up to 20 days followed by 2 actovegin placebo-matching, tablets, orally, 3 times a day for up to 6 months.
All-Cause Mortality
Actovegin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Actovegin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   22/250 (8.80%)   17/253 (6.72%) 
Cardiac disorders     
Myocardial infarction  1 [1]  1/250 (0.40%)  1/253 (0.40%) 
Acute myocardial infarction  1  0/250 (0.00%)  1/253 (0.40%) 
Angina unstable  1  0/250 (0.00%)  1/253 (0.40%) 
Atrial fibrillation  1  0/250 (0.00%)  1/253 (0.40%) 
Cardiopulmonary failure  1 [1]  1/250 (0.40%)  0/253 (0.00%) 
Coronary artery disease  1  0/250 (0.00%)  1/253 (0.40%) 
Ischaemic cardiomyopathy  1  0/250 (0.00%)  1/253 (0.40%) 
Ventricular fibrillation  1  0/250 (0.00%)  1/253 (0.40%) 
Gastrointestinal disorders     
Diverticulum intestinal  1  0/250 (0.00%)  1/253 (0.40%) 
Gastritis erosive  1  0/250 (0.00%)  1/253 (0.40%) 
Proctitis  1  1/250 (0.40%)  0/253 (0.00%) 
General disorders     
Death  1 [2]  0/250 (0.00%)  1/253 (0.40%) 
Infections and infestations     
Endocarditis bacterial  1 [3]  0/250 (0.00%)  1/253 (0.40%) 
Pneumonia  1 [1]  1/250 (0.40%)  0/253 (0.00%) 
Metabolism and nutrition disorders     
Type 2 diabetes mellitus  1  0/250 (0.00%)  1/253 (0.40%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Astrocytoma  1  0/250 (0.00%)  1/253 (0.40%) 
Metastases to liver  1  0/250 (0.00%)  1/253 (0.40%) 
Pancreatic carcinoma metastatic  1  0/250 (0.00%)  1/253 (0.40%) 
Nervous system disorders     
Ischaemic stroke  1 [4]  13/250 (5.20%)  5/253 (1.98%) 
Brain oedema  1 [5]  1/250 (0.40%)  2/253 (0.79%) 
Cerebral haemorrhage  1 [1]  1/250 (0.40%)  0/253 (0.00%) 
Cerebrovascular accident  1  0/250 (0.00%)  1/253 (0.40%) 
VIIth Nerve Paralysis  1  0/250 (0.00%)  1/253 (0.40%) 
Renal and urinary disorders     
Calculus urinary  1  1/250 (0.40%)  0/253 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary embolism  1 [6]  2/250 (0.80%)  0/253 (0.00%) 
Vascular disorders     
Arteriosclerosis  1 [3]  0/250 (0.00%)  1/253 (0.40%) 
Hypertensive crisis  1  1/250 (0.40%)  0/253 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
[1]
One treatment-emergent death occurred during treatment with actovegin and is not related.
[2]
One treatment-emergent death occurred during treatment with placebo and is not related. No specific cause of death was identified or reported by the investigator.
[3]
One treatment-emergent death occurred during treatment with placebo and is not related.
[4]
One treatment-emergent death occurred during treatment with actovegin and is not related and two treatment-emergent deaths occurred during treatment with placebo (1 of which also had Brain oedema and Hypostatic pneumonia) and are not related.
[5]
One treatment-emergent death occurred during treatment with actovegin and is not related and two treatment-emergent deaths occurred during treatment with placebo (1 participant also had Ischaemic stroke and Hypostatic pneumonia) and are not related.
[6]
Two treatment-emergent deaths occurred during treatment with actovegin and are not related.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Actovegin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   31/250 (12.40%)   31/253 (12.25%) 
Cardiac disorders     
Atrial fibrillation  1  5/250 (2.00%)  3/253 (1.19%) 
Infections and infestations     
Respiratory tract infection viral  1  5/250 (2.00%)  8/253 (3.16%) 
Metabolism and nutrition disorders     
Dyslipidaemia  1  8/250 (3.20%)  2/253 (0.79%) 
Nervous system disorders     
Amnesia  1  0/250 (0.00%)  7/253 (2.77%) 
Dementia  1  5/250 (2.00%)  9/253 (3.56%) 
Headache * 1  7/250 (2.80%)  7/253 (2.77%) 
Vascular disorders     
Hypertension  1  5/250 (2.00%)  3/253 (1.19%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 17.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Name/Title: Medical Director, Clinical Science
Organization: Takeda
Phone: +1-877-825-3327
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01582854     History of Changes
Other Study ID Numbers: AV-2500-301-RD
U1111-1132-3434 ( Registry Identifier: WHO )
First Submitted: April 20, 2012
First Posted: April 23, 2012
Results First Submitted: January 23, 2016
Results First Posted: February 22, 2016
Last Update Posted: February 22, 2016