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Efficacy and Safety of Cytoflavin® Used in Elderly Patients for the Prevention of Cognitive Decline After Major Surgery

Primary Purpose

Cognitive Dysfunction

Status
Completed
Phase
Phase 3
Locations
Russian Federation
Study Type
Interventional
Intervention
Cytoflavin® solution
Cytoflavin® enteric-coated tablet
Placebo solution
Placebo enteric-coated tablet
Sponsored by
POLYSAN Scientific & Technological Pharmaceutical Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cognitive Dysfunction focused on measuring postoperative cognitive decline

Eligibility Criteria

60 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Signed informed consent
  2. Men and women aged 60-80 years, inclusive.
  3. Planned cardiac surgery, which does not assume the use of a cardiopulmonary bypass.
  4. Planned or delayed orthopedic surgery (hip joint endoprosthetics, osteosynthesis for fractures of the proximal third of the hip, etc.), under general or combined anesthesia.
  5. Legal capacity of the patient
  6. Absence of dementia (MoCA≥17, MMSE≥19)
  7. Lack of reproductive potential or
  8. Consent to use adequate methods of contraception

Exclusion Criteria:

  1. Hypersensitivity to any component of the study drug
  2. Emergency surgery
  3. Repeated surgery or reoperation
  4. Anesthesia risk ASA≥5
  5. Severe visual or hearing impairment which impedes the performance of neuropsychological tests
  6. Operation under general anesthesia in the previous 3 months
  7. Severe renal failure requiring replacement of renal function (dialysis)
  8. Severe hepatic failure (class C and above in Child-Pugh)
  9. Chronic obstructive pulmonary disease
  10. Terminal stage of other chronic incurable diseases
  11. Decompensated diabetes
  12. A history of oncological diseases, mental illness, HIV infection, syphilis, tuberculosis, alcohol or drug addiction
  13. The use of 5 or more units of alcohol per week in the previous 3 months
  14. Diagnosis of mental or neurodegenerative disease (e.g. schizophrenia, Parkinson's disease, clinically manifest depression)
  15. Permanent intake of psychotropic drugs (neuroleptics, tranquilizers, antidepressants)
  16. Course intake of nootropic drugs in the previous 3 months
  17. Communicative, sensory, motor, or any other deficiency that does not allow the patient to adequately assess their behavior and correctly fulfill the conditions of the study protocol.
  18. The presence in the history of any significant, according to the physician-researcher, condition that prevents the inclusion of the patient in the study.
  19. Participation in any clinical study in the previous 3 months
  20. Employees of the study centres and their family members.

Sites / Locations

  • Regional Clinical Hospital № 3
  • Central Clinical Hospital with a polyclinic of the Office of the President of the Russian Federation
  • Alexandrovskaya City Hospital
  • City Hospital №15
  • City Hospital №38 named after N.A. Semashko
  • City Hospital №40 of the Kurortny District
  • Hospital for War Veterans
  • I. P. Pavlov 1st St. Petersburg State Medical University
  • Military Medical Academy named after S.M. Kirov
  • Pokrovskaya City Hospital
  • GBUZ YAO "Regional Clinical Hospital"
  • Research center of specialized types of medical care "Ural Institute of Cardiology"
  • Ural State Medical University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Cytoflavin®

Placebo

Arm Description

Patients of group I will receive the experimental drug Cytoflavin®, manufactured by POLYSAN (Russia), on the day before surgery, during the surgical intervention, and in the postoperative period. Cytoflavin® solution(Inosine + Nicotinamide + Riboflavin + Succinic Acid) will be administered IV for 7 days, and Cytoflavin® enteric-coated tablets (Inosine + Nicotinamide + Riboflavin + Succinic Acid) will be administered for 25 days (in total 32 days of treatment).

Patients of group II will receive placebo (manufactured by POLYSAN, Russia), on the day before surgery, during the surgical intervention, and in the postoperative period. Placebo solution will be administered IV for 7 days, and placebo enteric-coated tablets will be administered for 25 days (in total 32 days of treatment).

Outcomes

Primary Outcome Measures

Montreal Cognitive Assessment (MoCA) scale score
The MoCA test is a one-page 30-point test, ranging between 0 and 30, where 0 is the worst and 30 is the best result; a score of 26-30 or over is considered to be normal. Outcome measure is the change in the MoCA scale score by the end of the treatment course compared with the preoperative score.

Secondary Outcome Measures

The Mini-Mental State Examination (MMSE) scale
MMSE test is a 30-point questionnaire; any score greater than or equal to 24 points (out of 30) indicates a normal cognition; below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. Outcome measure will be the change of MMSE scale score by the end of the treatment course compared to the preoperative score
The Mini-Mental State Examination (MMSE) follow-up score
MMSE test is a 30-point questionnaire; any score greater than or equal to 24 points (out of 30) indicates a normal cognition; below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. Outcome measure will be the change of MMSE scale score by the end of the follow-up period
Montreal Cognitive Assessment (MoCA) follow-up
The MoCA test is a one-page 30-point test, ranging between 0 and 30, where 0 is the worst and 30 is the best result; a score of 26-30 or over is considered to be normal. Outcome measure is the change of the MoCA scale score by the end of the follow-up period
Median group Mini-Mental State Examination (MMSE) score
MMSE test is a 30-point questionnaire; any score greater than or equal to 24 points (out of 30) indicates a normal cognition; below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. Outcome measure will be the difference between median group total scores on the MMSE scale.
Median Montreal Cognitive Assessment (MoCA) scale score
The MoCA test is a one-page 30-point test, ranging between 0 and 30, where 0 is the worst and 30 is the best result; a score of 26-30 or over is considered to be normal. Outcome measure is the difference in median group values of the MOCA scale
Proportion of postoperative delirium
The proportion of patients who developed postoperative delirium in the first 96 hours after surgery according to the results of CAM-ICU
Length of stay in the ICU
Length of stay in the ICU
Mortality
Mortality in the postoperative period in the experimental and control groups
Postoperative cognitive decline
The proportion of patients with a decrease in the results of two or more neuropsychological tests by more than 20% by the end of the treatment course and by the end of the follow-up period compared the baseline values
Quality of life score
Change in the overall score for the EQ-5D questionnaire for assessing the quality of life
Independence and activity
The proportion of patients dependent in at least two daily functions according to the results of the Katz Daily Activity Index at the end of the treatment course
Anxiety/depression
The group average score by Hospital Anxiety and Depression Scale (HADS) at the end of the treatment course and at the end of the follow-up period. The HADS is a fourteen item scale, a person can score between 0 and 21 for either anxiety or depression, where scores on each scale can be interpreted in ranges: normal (0-7), mild (8-10), moderate (11-14) and severe (15-21).

Full Information

First Posted
February 20, 2019
Last Updated
January 27, 2023
Sponsor
POLYSAN Scientific & Technological Pharmaceutical Company
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1. Study Identification

Unique Protocol Identification Number
NCT03849664
Brief Title
Efficacy and Safety of Cytoflavin® Used in Elderly Patients for the Prevention of Cognitive Decline After Major Surgery
Official Title
A Multicentre Double-blind Placebo-controlled Randomized Study of Efficacy and Safety of Cytoflavin®, Intravenous Administration and Enteric-coated Tablets, Used in Elderly Patients for Prevention of Cognitive Decline After Major Surgery
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Completed
Study Start Date
June 2, 2017 (Actual)
Primary Completion Date
April 11, 2019 (Actual)
Study Completion Date
July 11, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
POLYSAN Scientific & Technological Pharmaceutical Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Postoperative cognitive impairment develops in the early and continues in the late postoperative period; it is manifested by impaired memory, attention, concentration and other higher cortical functions (thinking, speech). Early studies demonstrated the positive impact of perioperative administration of Cytoflavin (Inosine + Nicotinamide + Riboflavin + Succinic Acid), which prevented impairments of intelligence, speech, and attention after cardiac surgery, both in conditions of cardiopulmonary bypass and on a working heart. The aim of the present study is to evaluate the safety and efficacy of Cytoflavin for the prevention of cognitive disorders after major surgeries performed in elderly patients.
Detailed Description
Cytoflavin® (Inosine + Nicotinamide + Riboflavin + Succinic Acid) is a combination drug, which improves coronary and cerebral blood flow, activates metabolic processes in the central nervous system, restores impaired consciousness, promotes regression of neurological symptoms and improvement of cognitive functions of the brain. It has a quick awakening effect in post-anesthetic depression of consciousness. The positive effect of Cytoflavin® on cognitive function has been previously shown in patients with dyscirculatory encephalopathy and acute stroke, as well as in a population of patients during cardiac surgery in cardiopulmonary bypass and working heart. The present study aims to evaluate the opportunity of prevention of postoperative cognitive decline by administration of Cytoflavin® at a sequential regimen, starting from intravenous infusions and followed by oral intake during 1 month. Study objectives: To study the efficacy of Cytoflavin® administered in elderly patients age for the prevention of cognitive decline after major surgery. To study the safety and tolerability of Cytoflavin® in elderly patients for after major surgery.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cognitive Dysfunction
Keywords
postoperative cognitive decline

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
200 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cytoflavin®
Arm Type
Experimental
Arm Description
Patients of group I will receive the experimental drug Cytoflavin®, manufactured by POLYSAN (Russia), on the day before surgery, during the surgical intervention, and in the postoperative period. Cytoflavin® solution(Inosine + Nicotinamide + Riboflavin + Succinic Acid) will be administered IV for 7 days, and Cytoflavin® enteric-coated tablets (Inosine + Nicotinamide + Riboflavin + Succinic Acid) will be administered for 25 days (in total 32 days of treatment).
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients of group II will receive placebo (manufactured by POLYSAN, Russia), on the day before surgery, during the surgical intervention, and in the postoperative period. Placebo solution will be administered IV for 7 days, and placebo enteric-coated tablets will be administered for 25 days (in total 32 days of treatment).
Intervention Type
Drug
Intervention Name(s)
Cytoflavin® solution
Other Intervention Name(s)
Inosine + Nicotinamide + Riboflavin + Succinic Acid solution
Intervention Description
Single drip infusion of 20 ml of Cytoflavin® solution in 200 ml of 0.9%NaCl intravenously once a day
Intervention Type
Drug
Intervention Name(s)
Cytoflavin® enteric-coated tablet
Other Intervention Name(s)
Inosine+Nicotinamide+Riboflavin+Succinic Acid tablet
Intervention Description
2 tablets, orally, with 100 ml of drinking water, 30 minutes before meals, 2 times a day, with an interval of 8-10 hours (but no later than 18:00).
Intervention Type
Drug
Intervention Name(s)
Placebo solution
Other Intervention Name(s)
riboflavin; meglumine, soduim hydroxide, water
Intervention Description
Single drip infusion of 20 ml of placebo solution in 200 ml of 0.9%NaCl intravenously once a day
Intervention Type
Drug
Intervention Name(s)
Placebo enteric-coated tablet
Other Intervention Name(s)
povidone, calcium stearate, hypromellose, polysorban, dyes
Intervention Description
2 tablets, orally, with 100 ml of drinking water, 30 minutes before meals, 2 times a day, with an interval of 8-10 hours (but no later than 18:00).
Primary Outcome Measure Information:
Title
Montreal Cognitive Assessment (MoCA) scale score
Description
The MoCA test is a one-page 30-point test, ranging between 0 and 30, where 0 is the worst and 30 is the best result; a score of 26-30 or over is considered to be normal. Outcome measure is the change in the MoCA scale score by the end of the treatment course compared with the preoperative score.
Time Frame
32 days
Secondary Outcome Measure Information:
Title
The Mini-Mental State Examination (MMSE) scale
Description
MMSE test is a 30-point questionnaire; any score greater than or equal to 24 points (out of 30) indicates a normal cognition; below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. Outcome measure will be the change of MMSE scale score by the end of the treatment course compared to the preoperative score
Time Frame
32 days
Title
The Mini-Mental State Examination (MMSE) follow-up score
Description
MMSE test is a 30-point questionnaire; any score greater than or equal to 24 points (out of 30) indicates a normal cognition; below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. Outcome measure will be the change of MMSE scale score by the end of the follow-up period
Time Frame
90 days
Title
Montreal Cognitive Assessment (MoCA) follow-up
Description
The MoCA test is a one-page 30-point test, ranging between 0 and 30, where 0 is the worst and 30 is the best result; a score of 26-30 or over is considered to be normal. Outcome measure is the change of the MoCA scale score by the end of the follow-up period
Time Frame
90 days
Title
Median group Mini-Mental State Examination (MMSE) score
Description
MMSE test is a 30-point questionnaire; any score greater than or equal to 24 points (out of 30) indicates a normal cognition; below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. Outcome measure will be the difference between median group total scores on the MMSE scale.
Time Frame
day 7, 32, 90
Title
Median Montreal Cognitive Assessment (MoCA) scale score
Description
The MoCA test is a one-page 30-point test, ranging between 0 and 30, where 0 is the worst and 30 is the best result; a score of 26-30 or over is considered to be normal. Outcome measure is the difference in median group values of the MOCA scale
Time Frame
day 7, 32, 90
Title
Proportion of postoperative delirium
Description
The proportion of patients who developed postoperative delirium in the first 96 hours after surgery according to the results of CAM-ICU
Time Frame
day 3-6
Title
Length of stay in the ICU
Description
Length of stay in the ICU
Time Frame
day 32
Title
Mortality
Description
Mortality in the postoperative period in the experimental and control groups
Time Frame
day 32
Title
Postoperative cognitive decline
Description
The proportion of patients with a decrease in the results of two or more neuropsychological tests by more than 20% by the end of the treatment course and by the end of the follow-up period compared the baseline values
Time Frame
day 32, day 90
Title
Quality of life score
Description
Change in the overall score for the EQ-5D questionnaire for assessing the quality of life
Time Frame
day 90
Title
Independence and activity
Description
The proportion of patients dependent in at least two daily functions according to the results of the Katz Daily Activity Index at the end of the treatment course
Time Frame
day 32
Title
Anxiety/depression
Description
The group average score by Hospital Anxiety and Depression Scale (HADS) at the end of the treatment course and at the end of the follow-up period. The HADS is a fourteen item scale, a person can score between 0 and 21 for either anxiety or depression, where scores on each scale can be interpreted in ranges: normal (0-7), mild (8-10), moderate (11-14) and severe (15-21).
Time Frame
day 32, day 90

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent Men and women aged 60-80 years, inclusive. Planned cardiac surgery, which does not assume the use of a cardiopulmonary bypass. Planned or delayed orthopedic surgery (hip joint endoprosthetics, osteosynthesis for fractures of the proximal third of the hip, etc.), under general or combined anesthesia. Legal capacity of the patient Absence of dementia (MoCA≥17, MMSE≥19) Lack of reproductive potential or Consent to use adequate methods of contraception Exclusion Criteria: Hypersensitivity to any component of the study drug Emergency surgery Repeated surgery or reoperation Anesthesia risk ASA≥5 Severe visual or hearing impairment which impedes the performance of neuropsychological tests Operation under general anesthesia in the previous 3 months Severe renal failure requiring replacement of renal function (dialysis) Severe hepatic failure (class C and above in Child-Pugh) Chronic obstructive pulmonary disease Terminal stage of other chronic incurable diseases Decompensated diabetes A history of oncological diseases, mental illness, HIV infection, syphilis, tuberculosis, alcohol or drug addiction The use of 5 or more units of alcohol per week in the previous 3 months Diagnosis of mental or neurodegenerative disease (e.g. schizophrenia, Parkinson's disease, clinically manifest depression) Permanent intake of psychotropic drugs (neuroleptics, tranquilizers, antidepressants) Course intake of nootropic drugs in the previous 3 months Communicative, sensory, motor, or any other deficiency that does not allow the patient to adequately assess their behavior and correctly fulfill the conditions of the study protocol. The presence in the history of any significant, according to the physician-researcher, condition that prevents the inclusion of the patient in the study. Participation in any clinical study in the previous 3 months Employees of the study centres and their family members.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tatiana V Kharitonova, MD, PhD
Organizational Affiliation
St. Petersburg Research Institute of Emergency Medicine n.a. I.I. Dzhanelidze
Official's Role
Study Director
Facility Information:
Facility Name
Regional Clinical Hospital № 3
City
Chelyabinsk
Country
Russian Federation
Facility Name
Central Clinical Hospital with a polyclinic of the Office of the President of the Russian Federation
City
Moscow
Country
Russian Federation
Facility Name
Alexandrovskaya City Hospital
City
Saint Petersburg
Country
Russian Federation
Facility Name
City Hospital №15
City
Saint Petersburg
Country
Russian Federation
Facility Name
City Hospital №38 named after N.A. Semashko
City
Saint Petersburg
Country
Russian Federation
Facility Name
City Hospital №40 of the Kurortny District
City
Saint Petersburg
Country
Russian Federation
Facility Name
Hospital for War Veterans
City
Saint Petersburg
Country
Russian Federation
Facility Name
I. P. Pavlov 1st St. Petersburg State Medical University
City
Saint Petersburg
Country
Russian Federation
Facility Name
Military Medical Academy named after S.M. Kirov
City
Saint Petersburg
Country
Russian Federation
Facility Name
Pokrovskaya City Hospital
City
Saint Petersburg
Country
Russian Federation
Facility Name
GBUZ YAO "Regional Clinical Hospital"
City
Yaroslavl
Country
Russian Federation
Facility Name
Research center of specialized types of medical care "Ural Institute of Cardiology"
City
Yekaterinburg
Country
Russian Federation
Facility Name
Ural State Medical University
City
Yekaterinburg
Country
Russian Federation

12. IPD Sharing Statement

Citations:
Citation
Kovalenko A.L., Nagibovich O.A., Vishnevsky A.Yu., Belekhov G.A., Gubaidullin R.R., Popov D.V., Agafiina A.S. Use of a Neurometabolism-Targeting Drug in Prevention of Postoperative Cognitive Dysfunction. General Reanimatology. 2022;18(2):12-21. https://doi.org/10.15360/1813-9779-2022-2-12-21
Results Reference
background
Links:
URL
https://doi.org/10.15360/1813-9779-2022-2-12-21
Description
Related Info

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Efficacy and Safety of Cytoflavin® Used in Elderly Patients for the Prevention of Cognitive Decline After Major Surgery

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