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

Phase 3

Completed

• Conditions: Cognitive Dysfunction
• Interventions: Drug: Cytoflavin® solution; Drug: Placebo solution; Drug: Placebo enteric-coated tablet; Drug: Cytoflavin® enteric-coated tablet

• Registration Number: NCT03849664
• Lead Sponsor: POLYSAN Scientific & Technological Pharmaceutical Company

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:

1. To study the efficacy of Cytoflavin® administered in elderly patients age for the prevention of cognitive decline after major surgery.

2. To study the safety and tolerability of Cytoflavin® in elderly patients for after major surgery.

Study Timeline

• Study Start: 2017-06-02
• Study First Submitted: 2019-02-20
• Study First Submitted QC: 2019-02-20
• Study First Posted: 2019-02-21
• Primary Completion: 2019-04-11
• Study Completion: 2019-07-11
• Status Verified: 2023-01
• Last Update Submitted: 2023-01-27
• Last Update Posted: 2023-01-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 200

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo enteric-coated tablet	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).
Cytoflavin®	Cytoflavin® solution	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).
Placebo	Placebo solution	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).
Cytoflavin®	Cytoflavin® enteric-coated tablet	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).

Primary Outcome Measures

Name	Time	Method
Montreal Cognitive Assessment (MoCA) scale score	32 days	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

Name	Time	Method
Montreal Cognitive Assessment (MoCA) follow-up	90 days	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
Anxiety/depression	day 32, day 90	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).
Proportion of postoperative delirium	day 3-6	The proportion of patients who developed postoperative delirium in the first 96 hours after surgery according to the results of CAM-ICU
The Mini-Mental State Examination (MMSE) scale	32 days	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	90 days	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
Median Montreal Cognitive Assessment (MoCA) scale score	day 7, 32, 90	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
Median group Mini-Mental State Examination (MMSE) score	day 7, 32, 90	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.
Length of stay in the ICU	day 32	Length of stay in the ICU
Mortality	day 32	Mortality in the postoperative period in the experimental and control groups
Quality of life score	day 90	Change in the overall score for the EQ-5D questionnaire for assessing the quality of life
Postoperative cognitive decline	day 32, day 90	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
Independence and activity	day 32	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

Trial Locations

Locations (13)

Regional Clinical Hospital № 3; 🇷🇺 Chelyabinsk, Russian Federation

Central Clinical Hospital with a polyclinic of the Office of the President of the Russian Federation; 🇷🇺 Moscow, Russian Federation

Alexandrovskaya City Hospital; 🇷🇺 Saint Petersburg, Russian Federation

City Hospital №15; 🇷🇺 Saint Petersburg, Russian Federation

City Hospital №40 of the Kurortny District; 🇷🇺 Saint Petersburg, Russian Federation

Hospital for War Veterans; 🇷🇺 Saint Petersburg, Russian Federation

Military Medical Academy named after S.M. Kirov; 🇷🇺 Saint Petersburg, Russian Federation

Pokrovskaya City Hospital; 🇷🇺 Saint Petersburg, Russian Federation

GBUZ YAO "Regional Clinical Hospital"; 🇷🇺 Yaroslavl, Russian Federation

Research center of specialized types of medical care "Ural Institute of Cardiology"; 🇷🇺 Yekaterinburg, Russian Federation

Ural State Medical University; 🇷🇺 Yekaterinburg, Russian Federation

I. P. Pavlov 1st St. Petersburg State Medical University; 🇷🇺 Saint Petersburg, Russian Federation

City Hospital №38 named after N.A. Semashko; 🇷🇺 Saint Petersburg, Russian Federation