Clinical Study Designed to Evaluate the Effect of CimetrA in Patients Diagnosed With COVID-19

Study Overview
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Brief Summary
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A preparation of CimertrA, comprising Artemisinin, Curcumin, and Boswellia, and Vitamin C in a nanoparticular formulation, is proposed as a treatment for the disease associated with the novel coronavirus SARS-CoV-2. This initiative is presented under the urgent circumstances of the fulminant pandemic caused by this lethal disease, which is known as COVID-19 and has spread across the globe causing death and disrupting the normal function of modern society. The grounds for the proposal are rooted in existing knowledge on the components and pharmacological features of this formulation and their relevance to the current understanding of the disease process being addressed. The severe acute respiratory syndrome-associated coronavirus disease 2019 (COVID-19) illness results from the immediate response to the viral infection as well as from a subsequent host inflammatory response. Systemic proinflammatory cytokines and biomarkers are elevated as the disease progresses towards its advanced stages, and correlate with worse chances of survival. Serum cytokine levels that are elevated in patients with Covid-19-associated cytokine storm include interleukin-1β, interleukin-6, IP-10, TNF, interferon-γ, macrophage inflammatory protein (MIP) 1α and 1β, and VEGF. Higher interleukin-6 levels are strongly associated with shorter survival. The relative frequencies of circulating activated CD4+ and CD8+ T cells and plasmablasts are increased in Covid-19. In addition to the elevated systemic cytokine levels and activated immune cells, several clinical and laboratory abnormalities, such as elevated CRP and d-dimer levels, hypoalbuminemia, renal dysfunction, and effusions, are also observed in Covid-19. Laboratory test results reflecting hyper inflammation and tissue damage were found to predict worsening outcomes in Covid-19. CimetrA, comprising Artemisinin, Curcumin, Boswellia, and Vitamin C in a nanoparticular formulation, has been studied on patients with COVID-19 in a randomized double-blind control Phase II study (MGC-006 - under a previous product name - ArtemiC). The study product demonstrated excellent safety and efficacy profiles. Experiments performed in vitro with CimetrA demonstrated the ability to reduce cytokine elevation in response to stimulation of human PBMC preparations. The currently proposed Multi-center multinational-controlled study is designed to include 252 adult patients who suffer from moderate COVID-19 infection. Safety will be assessed through collection and analysis of adverse events, blood and urine laboratory assessments, and vital signs. After the screening visit, the study drug will be administrated twice a day morning and evening (every 12 hours) during (day 1 and day 2) The patients will be randomized in 1:1:1 ratio to study drug (CimetrA) in addition to Standard of Care (Arm 1 (CimetrA-1) or Arm 2 (CimetrA-2)) or Placebo in addition to Standard of Care (Arm 3).

Detailed Description
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The study will take place during the patient's hospitalization due to a COVID-19 infection. The study will last up to 4 weeks, until the conclusion on day 28. In case of hospital discharge within the study period, follow-up will continue per protocol until day 28 wherever the subject will be located, performed via phone call or in-clinic, depending on the status of the patient and study schedule. 252 adult patients who suffer from COVID-19 infection and do not participate in any other clinical trial. The patient must not agree to participate in any new clinical study during the study duration. The study will take place during the patient's hospitalization due to a COVID-19 infection. The study will last up to 4 weeks, until the conclusion on day 28. In case of hospital discharge within the study period, follow-up will continue per protocol until day 28 wherever the subject will be located, performed via phone call or in-clinic, depending on the status of the patient and study schedule. Day 1 Prior to engaging in any study procedures, the subject must meet the inclusion/exclusion criteria by history (which includes a signed declination), and review and sign an ICF. Following procedures will be performed during the visit - Inclusion/Exclusion criteria evaluation Informed Consent Medical History Concomitant Medications Physical Examination Vital Signs Hematology blood test (local, mandatory even if there are available results from the day before) Biochemistry blood test (local, mandatory even if there are available results from the day before) NEWS score PK test (brazil only, central)* Blood test for inflammatory markers (IL-6, IL-1β, IL-12, TNF α, IFN-γ) (local) D-Dimer test (local) VAS scale Urine pregnancy test for women of childbearing potential ECG COVID-19-Impact on Quality of Life Questionnaire (will be completed by the staff based on the patient answer) Randomization in 1:1:1 ratio to study drug (CimetrA) in addition to Standard of Care (Arm 1 (CimetrA-1) or Arm 2 (CimetrA-2)) or Placebo in addition to Standard of Care (Arm 3) Treatment administration (twice a day, morning and evening) Test for detection COVID-19 (within 5 days from admission to hospital) Day 2 Concomitant Medications AE Assessment Physical Examination Vital Signs Hematology blood test (local, mandatory even if there are available results from the day before) Biochemistry blood test (local, mandatory even if there are available results from the day before) NEWS score Blood test for inflammatory markers (IL-6, IL-1β, IL-12, TNF α, IFN-γ) (local) D-Dimer test (local) VAS scale Treatment administration (twice a day, morning and evening) Days 3-6 Concomitant Medications AE assessment Physical Examination Vital Signs Hematology blood test ** Biochemistry blood test ** News score ** Blood test for inflammatory markers (IL-6, IL-1β, IL-12, TNF α, IFN-γ) (local) VAS scale Day 7 Concomitant Medications AE assessment Physical Examination Vital Signs Hematology blood test (local, mandatory even if there are available results from the day before) Biochemistry blood test (local, mandatory even if there are available results from the day before) News score Blood test for inflammatory markers (IL-6, IL-1β, IL-12, TNF α, IFN-γ) (local) D-Dimer test (local) VAS scale COVID-19-Impact on Quality of Life Questionnaire (will be completed by the staff based on the patient answer) Days 8-13 Concomitant Medications AE assessment Physical Examination Vital Signs Hematology blood test ** Biochemistry blood test ** News score ** VAS scale Day 14 Concomitant Medications AE assessment Physical Examination Vital Signs Hematology blood test (local, mandatory even if there are available results from the day before) Biochemistry blood test (local, mandatory even if there are available results from the day before) News score Blood test for inflammatory markers (IL-6, IL-1β, IL-12, TNF α, IFN-γ) (local) D-Dimer test (local) VAS scale Test for detection COVID-19 COVID-19-Impact on Quality of Life Questionnaire (will be completed by the staff based on the patient answer) Day 21 (phone visit) Concomitant Medications AE assessment VAS scale COVID-19-Impact on Quality of Life Questionnaire (will be completed by the staff based on the patient answer) Day 28 - Follow Up (clinic visit) Concomitant Medications AE assessment Physical Examination Vital Signs Hematology blood test (local, mandatory even if there are available results from the day before) Biochemistry blood test (local, mandatory even if there are available results from the day before) News score Blood test for inflammatory markers (IL-6, IL-1β, IL-12, TNF α, IFN-γ) (local) D-Dimer test (local) VAS scale Test for detection COVID-19 Urine pregnancy test for women of childbearing potential ECG COVID-19-Impact on Quality of Life Questionnaire (will be completed by the staff based on the patient answer)

Official Title
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A Phase III, Double-blind , Controlled Clinical Study Designed to Evaluate the Effect of CimetrA in Patients Diagnosed With COVID-19

Conditions
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Corona Virus Infection, Covid19, SARS-CoV Infection

Intervention / Treatment
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* Drug: Placebo administration
* Diagnostic Test: Confirm SARS-CoV-2 infection
* Procedure: Physical Examination
* Procedure: Vital Signs
* Diagnostic Test: Hematology blood test
* Diagnostic Test: Biochemistry blood test
* Other: NEWS score
* Diagnostic Test: PK test
* Diagnostic Test: blood test for inflammatory markers
* Diagnostic Test: D-dimer test
* Other: VAS scale
* Diagnostic Test: Urine pregnancy test for women of childbearing potential
* Procedure: ECG
* Other: COVID-19-Impact on Quality of Life Questionnaire
* Drug: CimetrA-1
* Drug: CimetrA-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed SARS-CoV-2 infection (according to nationally authorized laboratory criteria) Hospitalized patient with COVID-19 of moderate stable or worsening severity not requiring ICU admission. Age: 18 years old and above. Subjects must be under observation or admitted to a controlled facility or hospital (home quarantine is not sufficient). Ability to receive treatment by spray into the oral cavity Exclusion Criteria: Tube feeding or parenteral nutrition. Patients with scores 5 or above per the Ordinal Scale for Clinical Improvement published by the WHO. (i.e., who need oxygen supply beyond use of nozzles or simple mask) Need for admission to ICU during the present hospitalization at any time prior to completion of the recruitment to the study. Any condition which, in the opinion of the Principal Investigator, would prevent full participation in this trial or would interfere with the evaluation of the trial endpoints.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Patients will be randomized in 1:1:1 ratio to one of the three arms.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - CimetrA-1<br>a total dose containing a combination of Artemisinin 12 mg, Curcumin 40 mg, Boswellia 30 mg, and Vitamin C 120 mg in spray administration - divided into 4 separate doses given as an add on therapy, 4 doses over 48 hours (day 1 and day 2), twice a day (morning and evening). | Diagnostic Test: Confirm SARS-CoV-2 infection<br>* patients will be tested for SARS-CoV-2 on days 1, 14 and 28<br>* Other names: Covid-19 test;Procedure: Physical Examination<br>* patients will undergo a physical examination on days 1-14 and day 28<br>Procedure: Vital Signs<br>* patient's vital signs will be measured on days 1-14 and day 28<br>Diagnostic Test: Hematology blood test<br>* patients will provide a blood sample for a hematology blood test on days 1-14 and day 28<br>* Other names: blood tests;Diagnostic Test: Biochemistry blood test<br>* patients will provide a blood sample for a biochemistry blood test on days 1-14 and day 28<br>* Other names: blood tests;Other: NEWS score<br>* patient's NEWS score will be evaluated on days 1-14 and day 28<br>* Other names: scoring;Diagnostic Test: PK test<br>* PK test will be performed on day 1 only (only in Brazil sites)<br>* Other names: pharmacokinetics;Diagnostic Test: blood test for inflammatory markers<br>* patients will provide a blood sample for an inflammatory markers blood test (IL-6, IL-1β, IL-12, TNF α, IFN-γ) on days 1-7, day 14, and day 28<br>* Other names: blood tests;Diagnostic Test: D-dimer test<br>* patients will provide a blood sample for D-dimer blood test on days 1, day 2, day 7, day 14, and day 28<br>* Other names: blood tests;Other: VAS scale<br>* patient's VAS scale will be evaluated on days 1-14, day 21, and day 28<br>* Other names: scoring;Diagnostic Test: Urine pregnancy test for women of childbearing potential<br>* patients will provide a urine sample for a urine pregnancy test on days 1, and day 28<br>* Other names: pregnancy test;Procedure: ECG<br>* patients will undergo an ECG examination on days 1, and day 28<br>Other: COVID-19-Impact on Quality of Life Questionnaire<br>* patients will answer the COVID-19-Impact on Quality of Life Questionnaire on days 1, 7,14,21 and 28<br>Drug: CimetrA-1<br>* patients will receive the study treatment, CimetrA-1 treatment in addition to Standard of Care<br>* Other names: CimetrA-1 drug administration;|
| Experimental: Arm 2 - CimetrA-2<br>a total dose containing a combination of Artemisinin 8.4 mg, Curcumin 28 mg, Boswellia 21 mg, and Vitamin C 84 mg in spray administration - divided into 4 separate doses given as an add on therapy, 4 doses over 48 hours (day 1 and day 2), twice a day (morning and evening). | Diagnostic Test: Confirm SARS-CoV-2 infection<br>* patients will be tested for SARS-CoV-2 on days 1, 14 and 28<br>* Other names: Covid-19 test;Procedure: Physical Examination<br>* patients will undergo a physical examination on days 1-14 and day 28<br>Procedure: Vital Signs<br>* patient's vital signs will be measured on days 1-14 and day 28<br>Diagnostic Test: Hematology blood test<br>* patients will provide a blood sample for a hematology blood test on days 1-14 and day 28<br>* Other names: blood tests;Diagnostic Test: Biochemistry blood test<br>* patients will provide a blood sample for a biochemistry blood test on days 1-14 and day 28<br>* Other names: blood tests;Other: NEWS score<br>* patient's NEWS score will be evaluated on days 1-14 and day 28<br>* Other names: scoring;Diagnostic Test: PK test<br>* PK test will be performed on day 1 only (only in Brazil sites)<br>* Other names: pharmacokinetics;Diagnostic Test: blood test for inflammatory markers<br>* patients will provide a blood sample for an inflammatory markers blood test (IL-6, IL-1β, IL-12, TNF α, IFN-γ) on days 1-7, day 14, and day 28<br>* Other names: blood tests;Diagnostic Test: D-dimer test<br>* patients will provide a blood sample for D-dimer blood test on days 1, day 2, day 7, day 14, and day 28<br>* Other names: blood tests;Other: VAS scale<br>* patient's VAS scale will be evaluated on days 1-14, day 21, and day 28<br>* Other names: scoring;Diagnostic Test: Urine pregnancy test for women of childbearing potential<br>* patients will provide a urine sample for a urine pregnancy test on days 1, and day 28<br>* Other names: pregnancy test;Procedure: ECG<br>* patients will undergo an ECG examination on days 1, and day 28<br>Other: COVID-19-Impact on Quality of Life Questionnaire<br>* patients will answer the COVID-19-Impact on Quality of Life Questionnaire on days 1, 7,14,21 and 28<br>Drug: CimetrA-2<br>* patients will receive the study treatment, CimetrA-2 treatment in addition to Standard of Care<br>* Other names: CimetrA- 2 drug administration;|
| Placebo Comparator: Arm 3 - Placebo<br>composed of the same solvent but without active ingredients, given as an add on therapy in spray administration, 4 doses over 48 hours (day 1 and day 2), twice a day (morning and evening). | Drug: Placebo administration<br>* patients will receive the placebo treatment in addition to Standard of Care<br>Diagnostic Test: Confirm SARS-CoV-2 infection<br>* patients will be tested for SARS-CoV-2 on days 1, 14 and 28<br>* Other names: Covid-19 test;Procedure: Physical Examination<br>* patients will undergo a physical examination on days 1-14 and day 28<br>Procedure: Vital Signs<br>* patient's vital signs will be measured on days 1-14 and day 28<br>Diagnostic Test: Hematology blood test<br>* patients will provide a blood sample for a hematology blood test on days 1-14 and day 28<br>* Other names: blood tests;Diagnostic Test: Biochemistry blood test<br>* patients will provide a blood sample for a biochemistry blood test on days 1-14 and day 28<br>* Other names: blood tests;Other: NEWS score<br>* patient's NEWS score will be evaluated on days 1-14 and day 28<br>* Other names: scoring;Diagnostic Test: PK test<br>* PK test will be performed on day 1 only (only in Brazil sites)<br>* Other names: pharmacokinetics;Diagnostic Test: blood test for inflammatory markers<br>* patients will provide a blood sample for an inflammatory markers blood test (IL-6, IL-1β, IL-12, TNF α, IFN-γ) on days 1-7, day 14, and day 28<br>* Other names: blood tests;Diagnostic Test: D-dimer test<br>* patients will provide a blood sample for D-dimer blood test on days 1, day 2, day 7, day 14, and day 28<br>* Other names: blood tests;Other: VAS scale<br>* patient's VAS scale will be evaluated on days 1-14, day 21, and day 28<br>* Other names: scoring;Diagnostic Test: Urine pregnancy test for women of childbearing potential<br>* patients will provide a urine sample for a urine pregnancy test on days 1, and day 28<br>* Other names: pregnancy test;Procedure: ECG<br>* patients will undergo an ECG examination on days 1, and day 28<br>Other: COVID-19-Impact on Quality of Life Questionnaire<br>* patients will answer the COVID-19-Impact on Quality of Life Questionnaire on days 1, 7,14,21 and 28<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical improvement in treatment groups | Time to sustained clinical improvement, defined as a national Early Warning Score 2 (NEWS2) of 2 Maintained for 24 Hours in comparison to routine treatment (measured on days 7, 14, 28) | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| oxygen dependency | Number of participants with depending on oxygen supplementation through day 28 since onset of symptoms | up to 28 days | 
| change in inflammatory marker levels | Change in inflammatory marker levels - IL-6, IL-1β, IL-12, TNF α, IFN-γ, CRP, NLR (Neutrophil / Lymphocyte ratio) at days 1, 2, 4, 7, 14, 28 | up to day 28 | 
| effective dose determination | Definition of the active dose of CimetrA | up to 28 days | 
| Pharmacokinetic profile | Pharmacokinetic profile of the study drug-AUC(mmol/L·h) | up to 28 days | 
| Pharmacokinetic profile | Pharmacokinetic profile of the study drug-Tmax (Hour) | up to 28 days | 
| Pharmacokinetic profile | Pharmacokinetic profile of the study drug-Cmax (mmol/L) | up to 28 days | 
| Incidence of mechanical ventilation | Incidence of mechanical ventilation | up to 28 days | 
| Incidence of Intensive Care Unit (ICU) stay during COVID-19 complication | Incidence of Intensive Care Unit (ICU) stay during COVID-19 complication | up to 28 days | 
| evaluation of drug related adverse events | Percentage of participants with definite or probable drug related adverse events | up to 28 days | 
| Long term adverse events of COVID-19 | Long term adverse events of COVID-19 on Day 28 | up to 28 days | 
| Quality of life of patients | Quality of life of patients on Days 0, 14 and 28. COVID-19 - Impact on Quality of Life (COV19-QoL) scale questionnaire. The scale was made in order to serve as a tool for controlling the impact of the situation with the COVID19 pandemic in general on findings of various research on mental health.The higher score, the greater impact on quality of life and related domains subjectively perceived by the participants. Scores could be displayed and analyzed for each item separately. recommend the following way of calculating the total score for each participant: summing the scores on all of the items and dividing that result by the number of items (i.e. 6). Hence, the total score will be the average of all the items. The average score is measured between 1-5 scale. | up to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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corona, covid19, covid, coronavirus, corona virus infection, sars-cov-2