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

Study Overview
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Brief Summary
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The aim of this trial is to provide evidence that Actovegin has a symptomatic effect in subjects with post stroke cognitive impairment (PSCI) during a six month treatment period compared to subjects administered placebo. Subjects received IV infusions whilst in hospital, and tablets once discharged. Subjects were followed up for a further six months after their treatment had been stopped to explore if the cognitive symptoms of the subjects treated with Actovegin showed sustained improvement. The trial also explored the possible prevention of dementia with Actovegin in patients who had suffered a recent ischaemic stroke, as well as the effect of Actovegin on other stroke outcomes. Safety information on Actovegin was collected.

Detailed Description
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The drug tested in this study is called actovegin. Actovegin was tested to treat people who have post stroke cognitive impairment. This study looked at the improvement of cognitive symptoms in people who take actovegin compared to placebo. The study enrolled 503 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study: Actovegin-2000 mg intravenous solution; 2- 200 mg tablets 3 times a day Placebo intravenous solution; tablets (dummy inactive) - this is a solution or tablet that looks like the study drug but has no active ingredient All participants received daily intravenous infusions in the hospital (up to a maximum of 20 infusions) followed by 2-200 mg tablets three times a day for the remainder of the 6-month treatment period. This multi-centre trial was conducted in Belarus, Kazakhstan and Russia. The overall time to participate in this study was 12 months. Participants made multiple visits to the clinic plus a final visit after receiving their last dose of study drug for a follow-up assessment.

Official Title
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A 12-month, International, Parallel Group, Randomised, Multi-centre, Double-blind, Placebo-controlled Trial to Examine the Effect of Actovegin® Treatment Given First Intravenously and Subsequently Orally Over 6 Months, in Subjects With Post-stroke Cognitive Impairment (PSCI).

Conditions
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Post-Stroke Cognitive Impairment (PSCI)

Intervention / Treatment
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* Drug: Actovegin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Participant has suffered a recent supra-tentorial ischaemic stroke supported by computed tomography (CT) scan or magnetic resonance imaging (MRI) findings (in accordance with local practice). Participant is male or female, aged 60 years or above. Participant has a score on the National Institute of Health Stroke Scale (NIHSS) between 3 and 18 (inclusive). Participant is capable of completing the Montreal Cognitive Assessment (MoCA) and has a score of ≤ 25 points with adjustment for level of education (4-9 school years ≤ 23 points, 10-12 years ≤ 24 points, >12 years ≤ 25 points). Main Exclusion Criteria: Participant has a medical history of dementia. Participant has a known medical history of major depression or psychotic disorder. Participant is indicated for treatment with thrombolytics or carotid surgery as the current standard of care. Randomisation Criteria: Inclusion Criteria. Ability to perform Alzheimer's Disease Assessment Scale + Cognitive Subscale Extended Version (ADAS-cog+). Exclusion Criteria. Clinically there is suspicion of progressive stroke.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Actovegin<br>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. | Drug: Actovegin<br>* Actovegin solution for infusion and Actovegin tablets<br>|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Actovegin placebo-matching solution for infusion and Actovegin placebo-matching tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale + Cognitive Subscale Extended Version (ADAS-cog+) at Month 6 | 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. | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in ADAS-cog+ at Month 3 and Month 12 | 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. | Baseline and Months 3 and 12 | 
| Change From Baseline in Montreal Cognitive Assessment Scale (MoCA) at End of Infusion Period, Months 3, 6 and 12 | 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. | Baseline, End of Infusion and Months 3, 6 and 12 | 
| Percentage of ADAS-cog+ Responders at Time Points 3, 6 and 12 Months | 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. | Baseline and Months 3, 6 and 12 | 
| Percentage of Participants With a Diagnosis of Dementia | 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. | Month 6 | 
| Change From Baseline in National Institutes of Health Stroke Scale (NIHSS) at End of Infusion Period, Months 3, 6 and 12 | 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. | Baseline and End of Infusion and Months 3, 6 and 12 | 
| Barthel Index at Months 3 and 6 | 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. | Months 3 and 6 | 
| EuroQol EQ-5D (EQ-5D) at Month 6 | 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. | Month 6 | 
| EuroQol EQ-5D (EQ-5D) at Month 12 | 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. | Month 12 | 
| EuroQol EQ-5D (EQ-5D) General Health at Months 6 and 12 | 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). | Months 6 and 12 | 
| Beck Depression Inventory, Version II (BDI-II) at Months 3, 6 and 12 | 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 | Months 3, 6 and 12 | 
| Percentage of Participants With a Diagnosis of Dementia | 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]. | Month 6 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-Stroke Cognitive Impairment (PSCI), Stroke, Actovegin, Cognition disorders