Safety and Efficacy of the Therapy With BRAINMAX® for the Treatment of Patients With Asthenia After COVID-19

Study Overview
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Brief Summary
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This is prospective multicentre comparative randomized double blind placebo controlled study conducted in 6 medical facilities.The objective of the study is to assess the safety and efficacy of the sequential therapy with BRAINMAX®, solution for intravenous infusion and intramuscular injection, and BRAINMAX®, capsules for the treatment of patients with asthenia after having the novel coronavirus infection (COVID-19)

Detailed Description
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Upon signing the informed consent form and screening, 160 eligible patients from 18 to 65 years of age with asthenia after having the novel coronavirus infection (COVID-19) were randomized at a 1:1 ratio. First group received intramuscularly with the dosage regimen of 5 mL of solution (500 mg of ethyl methyl hydroxypyridine succinate + 500 mg of meldonium) once per day for 10 days; total number of injections for the treatment course is 10 and then orally with the dosage regimen of 2 capsules (500 mg of ethyl methyl hydroxypyridine succinate + 500 mg of meldonium) twice per day for 30 days; total number of capsules for the treatment course is 120. Second group received Placebo in the same way.

Official Title
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Prospective Multicentre Comparative Randomized Double Blind Placebo Controlled Study of Safety and Efficacy of the Therapy With BRAINMAX® for the Treatment of Patients With Asthenia After Having the Novel Coronavirus Infection (COVID-19)

Conditions
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Asthenia, COVID-19

Intervention / Treatment
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* Drug: Ethyl methyl hydroxypyridine succinate + Meldonium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients able to sign the patient informed consent form for the participation in the clinical study Patients of both sexes of 18-65 years of age Patient's negative test result for severe acute respiratory syndrome (SARS) -CoV-2 RNA obtained by polymerase chain reaction (PCR) method within 72 hours COVID-19 diagnosis documented in the history more than 12 weeks ago* Minimum two symptoms of asthenic state: fatigue, atony, dizziness, sleeping disorder, feeling of energy loss and decreased functioning, intellectual function disorder, attention and memory disorder, which appeared during or after COVID-19, retain for more than 12 weeks and cannot be explained by an alternative diagnosis Patients capable of following the requirements of the Clinical Study Protocol Negative pregnancy test result (for women with the active childbearing potential) MFI-20 scale score is more than 30 at the moment of screening. Exclusion Criteria: Allergic reactions to the components of the study product Oxygen saturation by pulse oximetry (SpO2) oxygen saturation ≤ 95% Depression level score by Hamilton Depression Rating Scale (HDRS) at the screening ≥ 8 Intracranial pressure rise (for the reason of venous outflow disorder and intracranial tumours) Severe hepatic failure Severe renal failure Chronic liver and hepatic diseases Thyroid diseases Anaemia Malignant tumour of any localization currently or during 5 years before the inclusion into the study except for completely treated carcinoma in situ Autoimmune diseases Other chronical diseases which, according to the investigator, can cause asthenia G lomerular filtration rate (GFR) parameter at screening < 30 mL/min Pregnancy or lactation period Participation in any other clinical study during the last 3 months Tuberculosis, cancers or positive reaction to the HIV infection, hepatitis B & C, syphilis according to the history data Severe eyesight and/or hearing disorders, serious articulation disorders and/or other deviations able to prevent the patient from adequate cooperation during the study) Mental disorders in the history Alcohol, drug abuse or drug dependence in the history Patients which, according to the investigator, are obviously or probably incapable of understanding and evaluating this study information within the process of the informed consent form signing, including but not limited to with regard to expected risks and possible discomfort Other diseases, symptoms or conditions not listed above, which, according to the investigator, are predicaments for the participation in the clinical study Exclusion of patients from the study Erroneous inclusion (inclusion and exclusion criteria violation). Investigator or Sponsor's decision to exclude the patient from the study because of clinically significant deviation from protocol/protocol violation. Serious adverse events or adverse events which do not meet the seriousness criteria and which if developed, according to the investigator, can make the patient's further participation in the study harmful for the patient's health or wellbeing. Any adverse event (there might be no connection with the study drug intake) requiring the observation, procedures and/or drug treatment not allowed by this study protocol. Patient's refusal to continue the participation in the study or his/her lack of discipline. Allergic reaction to the study drug intake, which require its discontinuation. Patient's wish to prematurely terminate the study for any reason. Loss of contact with the patient and his/her absence for the visit. Necessity to use a therapy prohibited by this protocol. Occurrence of pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ethyl methyl hydroxypyridine succinate + Meldonium<br>Arm 1 (n=80) received intramuscularly with the dosage regimen of 5 mL of solution (500 mg of ethyl methyl hydroxypyridine succinate + 500 mg of meldonium) once per day for 10 days; total number of injections for the treatment course is 10 and then orally with the dosage regimen of 2 capsules (500 mg of ethyl methyl hydroxypyridine succinate + 500 mg of meldonium) twice per day for 30 days; total number of capsules for the treatment course is 120. Second group received Placebo in the same way. | Drug: Ethyl methyl hydroxypyridine succinate + Meldonium<br>* Ethyl methyl hydroxypyridine succinate 100.0 mg/mL, meldonium dihydrate - 100.0 mg/mL (Solution for intravenous and intramuscular administration), then Ethyl methyl hydroxypyridine succinate - 250.0 mg, meldonium dihydrate based on dihydrate without adsorption moisture - 250.0 mg (oral capsules)<br>* Other names: BRAINMAX®;|
| Placebo Comparator: Placebo<br>Arm 2 (n=80) received Placebo in the same way. | Drug: Placebo<br>* Placebo was used in the same way<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthenia on a scale Multidimensional Fatigue Inventory (MFI-20) after the completion of the sequential therapy | Mean decrease of MFI-20 asthenia scale score after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthenia on a scale MFI-20 after the completion of the parenteral therapy | Mean decrease of MFI-20 asthenia scale score after the completion of the parenteral therapy | From baseline to Visit 3 (day 11) | 
| Asthenia on a scale MFI-20 after the completion of the oral therapy | Mean decrease of MFI-20 asthenia scale score after the completion of the oral therapy | From Visit 3 (day 11) to Visit 5 (day 41) | 
| Headache on a visual analogue scale (VAS) after the completion of the sequential therapy | Score dynamics by VAS for the headache evaluation after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Headache on a VAS after the completion of the parenteral therapy | Score dynamics by VAS for the headache evaluation after the completion of the parenteral therapy | From baseline to Visit 3 (day 11) | 
| Headache on a VAS after the completion of the oral therapy | Score dynamics by VAS for the headache evaluation after the completion of the oral therapy | From Visit 3 (day 11) to Visit 5 (day 41) | 
| Sleep Quality on a Pittsburgh sleep quality index (PSQI) after the completion of the sequential therapy | Score dynamics by PSQI questionnaire after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Fatigue on a Fatigue Assessment Scale (FAS-10) scale after the completion of the sequential therapy | Score dynamics by FAS-10 scale after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Fatigue on a FAS-10 scale after the completion of the parenteral therapy | Score dynamics by FAS-10 scale after the completion of the parenteral therapy | From baseline to Visit 3 (day 11) | 
| Fatigue on a FAS-10 scale after the completion of the oral therapy | Score dynamics by FAS-10 scale after the completion of the oral therapy | From Visit 3 (day 11) to Visit 5 (day 41) | 
| Dizziness on a Dizziness Handicap Inventory (DHI) questionnaire after the completion of the sequential therapy | Score dynamics by DHI questionnaire after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Dizziness on a DHI questionnaire after the completion of the parenteral therapy | Score dynamics by DHI questionnaire after the completion of the parenteral therapy | From baseline to Visit 3 (day 11) | 
| Dizziness on a DHI questionnaire after the completion of the oral therapy | Score dynamics by DHI questionnaire after the completion of the oral therapy | From Visit 3 (day 11) to Visit 5 (day 41) | 
| Cognitive function on a Monreal Gognitive Assessment (MoCA) scale after the completion of the sequential therapy | Score dynamics by MoCA scale after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Anxiety on a Beck scale after the completion of the sequential therapy | Score dynamics by Beck scale after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Anxiety on a Beck scale after the completion of the parenteral therapy | Score dynamics by Beck scale after the completion of the parenteral therapy | From baseline to Visit 3 (day 11) | 
| Anxiety on a Beck scale after the completion of the oral therapy | Score dynamics by Beck scale after the completion of the oral therapy | From Visit 3 (day 11) to Visit 5 (day 41) | 
| Regulatory function on a Kerdo vegetation index after the completion of the sequential therapy | Changes in values of Kerdo vegetation index after the completion of the sequential therapy | From baseline to Visit 5 (day 41) | 
| Regulatory function on a Kerdo vegetation index after the completion of the parenteral therapy | Changes in values of Kerdo vegetation index after the completion of the parenteral therapy | From baseline to Visit 3 (day 11) |