Evaluation of Prognostic Modification in COVID-19 Patients in Early Intervention Treatment

• ClinicalTrials.gov Identifier: NCT04673214
• Recruitment Status: Recruiting
• First Posted: December 17, 2020
• Last Update Posted: December 22, 2020
• Sponsor: Gilberto Cruz Arteaga
• Collaborator: Coordinación de Investigación en Salud, Mexico
• Information provided by (Responsible Party): Gilberto Cruz Arteaga, Coordinación de Investigación en Salud, Mexico

Tracking Information

• First Submitted Date: December 16, 2020
• First Posted Date: December 17, 2020
• Last Update Posted Date: December 22, 2020
• Actual Study Start Date: December 16, 2020
• Estimated Primary Completion Date: February 2, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 16, 2020)

Estimate clinical symptoms by days of follow-up in patients with COVID-19 under treatment with Azithromycin/Ivermectin/Ribaroxaban/Paracetamol vs. Azithromycin/Ribaroxaban/Paracetamol followed by video call for 14 days from U.M.F 13 and U.M.F 20 [ Time Frame: 14 days ]

Assuming 25% efficacy in modifying the clinical course (Symptoms of fever, cough, headache, myalgia, odynophagia, anosmia, rhinorrhea, arthralgia, chest pain, dyspnea, conjunctivitis) of patients diagnosed with COVID-19 under treatment comparative of early intervention for 14 days followed by video call, with a power of 90%, a type I error rate of 1% and a loss to follow-up of 20%; We calculated a total of 62 patients with COVID-19, that is, 31 cases in group A with Azithromycin / Ivermectin / Ribaroxaban / Paracetamol treatment and 31 in group B with Azithromycin / Ribaroxaban / Paracetamol treatment would be necessary for the analysis. Statistical differences will be evaluated using the Mann-Whitney U test. The analyzes will be performed in SPSS version 21

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 16, 2020)

To assess adverse drug reactions by days of follow-up in patients with COVID-19 under treatment with Azithromycin/Ivermectin/Ribaroxaban /Paracetamol vs. Azithromycin /Ribaroxaban/Paracetamol followed by video call for 14 days from U.M.F 13 and U.M.F 20 [ Time Frame: 14 days ]

Assuming a 25% efficacy in modifying the clinical course (adverse reactions) of patients diagnosed with COVID-19 under a comparative early intervention treatment for 14 days followed by video call, with a power of 90%, an error rate type I of 1% and loss to follow-up of 20%; We calculated a total of 62 patients with COVID-19, that is, 31 cases in group A with Azithromycin / Ivermectin / Ribaroxaban / Paracetamol treatment and 31 in group B with Azithromycin / Ribaroxaban / Paracetamol treatment would be necessary for the analysis. Statistical differences will be evaluated using the Mann-Whitney U test. The analyzes will be performed in SPSS version 21

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Prognostic Modification in COVID-19 Patients in Early Intervention Treatment
• Official Title: Prognostic Modification in Patients With COVID-19 Under Early Intervention Treatment at U.M.F 13 and U.M.F 20
• Brief Summary: The present study is designed for patients with mild COVID-19 phase, to demonstrate if there is a modification in the clinical evolution greater than or equal to 25% in their symptoms, implemented in two groups of patients under an early intervention treatment, a group ( A) will receive Azithromycin / Ivermectin / Ribaroxaban / Paracetamol and another group (B) will receive Azithromycin / Ribaroxaban / Paracetamol followed for 14 days followed by video call

Detailed Description

Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents the causative agent of a potential fatal disease generating a global public health problem. Person-to-person transmission of COVID-19 infection led to the isolation of patients who subsequently received a variety of treatments. Ivermectin treatment for safety is approved for human use by the FDA in parasitic and skin infections. Studies report the therapeutic safety of Ivermectin in humans with COVID-19, describing a 6.1-fold decrease in lethality compared to patients who did not use Ivermectin (1.4 vs. 8.5%, p <0.0001). In this sense, the WHO and PAHO encourage the use of unproven therapies in the context of a randomized clinical trial (RCT). Anticoagulants have reported up to 20% in the reduction of mortality (heparin), Ribaroxaban is effective with the inhibition of PAR1 / PAR2 / PAR4 receptors through the blocking of Factor Xa and the formation of thrombin, having anti-inflammatory effects, decreasing arteriosclerosis and platelet aggregation. There is a Telemedicine working method implemented by the OOAD of the North Federal District, which detects early signs and symptoms of possible complications and offers an early intervention treatment policy for first-level care beneficiaries. Under this method, a quasi-experimental study showed that there is a modification in the frequency of recovered patients of 80-90% in patients diagnosed with COVID-19 after an early intervention treatment with paracetamol, Ivermectin, Azithromycin, Ribaroxaban in patients with COVID -19 from UMF 13 during the period of July-August 2020. Therefore, it is necessary to carry out a randomized clinical trial to confirm this assertion.

Objective: To evaluate the percentage of patients with a diagnosis of COVID-19 who modify their clinical evolution under a comparative treatment of early intervention in beneficiaries of the U.M.F 13 and U.M.F 20 of the I.M.S.S., during the period of December 2020-January 2021.

Material and Methods: A randomized, single-blind, prospective, longitudinal and open experimental study in 62 patients with COVID-19 from UMF No. 13 and No. 20 from November to December 2020. Including 31 patients in group A (Azithromycin / Ivermectin / Ribaroxaban / Paracetamol) and 31 patients in group B (Azithromycin / Ribaroxaban / Paracetamol). With inclusion criteria over 18 years of age, have type 2 diabetes mellitus, Systemic Arterial Hypertension, Obesity or overweight, PCR confirmation of COVID-19. For the video call, the Family Medicine Units have Electronic Equipment Installation for Internet use. Exclusion criteria are patients with severe COVID-19 (they deserve immediate referral to second level of care, hospital). Elimination criteria are Prior informed consent, medication is given randomly to a COVID-19 patient, a follow-up video call will be made at home for 14 days, recording sex, age, education, date of disease onset, taking laboratories (hematic biometry, C-reactive protein, D-dimer, Ferritin, prothrombin time, thromboplastin time, lactic dehydrogenase) taken at the onset of the disease, taking as an outcome variable the modification of the clinical course (clinical symptoms such as headache, cough, fever, conjunctivitis , myalgias, arthralgias, rhinorrhea, odynophagia, anosmia, chest pain, dyspnea) when granting treatment in groups A and B.. Statistical differences will be evaluated using the Mann-Whitney U test with a power of 90% and a type I error rate of 1% for the variable of modification of the clinical course in treatment groups A and B. analysis will be performed in SPSS version 21.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Two groups of patients with COVID-19 will be integrated, a Group A taking the following medications: Paracetamol 500 mg orally 1 tablet every 8 hours for 3 days in case of fever equal to or greater than 38.3 ° C, Azithromycin tablets of 500 mg will take 1 single dose tablet the first day and then half a tablet (250 mg) orally every 24 for 4 days, Ivermectin tablets of 200mcg which will be calculated according to your weight and dose, it will be every 24 hours for 2 days and Rivaroxaban 10 mg tablets will take 1 every 24 hours for 10 days and a Group B will take Paracetamol 500 mg orally 1 tablet every 8 hours for 3 days in case of fever equal to or greater than 38.3 ° C, Azithromycin tablets of 500 mg will take 1 single dose tablet on the first day and then half a tablet orally every 24 hours for 4 days and Rivaroxaban 10 mg tablets will take 1 every 24 hours for 10 days.

Masking: Single (Participant)
Masking Description:

For the conformation of the groups, random numbers generated by lottery will be used in which the patient will take a piece of paper as he arrives and will have the number of the group to which he will be assigned. With a type of block randomization, A (Azithromycin, paracetamol, Ivermectin, and Ribaroxaban) and B (paracetamol, Azithromycin, and Ribaroxaban).

Primary Purpose: Treatment

• Condition: Covid19

Intervention

• Drug: Azithromycin / Ivermectin / Ribaroxaban / Paracetamol
  In the patient with the presence of COVID-19 confirmed by the PCR-COVID-19 positive test, the drug is randomly assigned to belong to group A of Azithromycin / Ivermectin / Ribaroxaban / Paracetamol to be followed for 14 days by video call (approximately 15 to 20 min per day) to the patient and the presence or absence of clinical symptoms, adverse reactions being recorded daily
  Other Name: with Ivermectin
• Drug: Azithromycin / Ribaroxaban / Paracetamol
  In the patient with the presence of COVID-19 confirmed by the PCR-COVID-19 positive test, the drug is randomly assigned to belong to group B of Azithromycin / Ribaroxaban / Paracetamol, to be followed for 14 days by video call (approximately 15 to 20 min per day) to the patient and the presence or absence of clinical symptoms, adverse reactions being recorded daily
  Other Name: without Ivermectin

Study Arms

• Experimental: Triple therapy
  Paracetamol 500 mg orally 1 tablet every 8 hours for 3 days in case of fever equal to or greater than 38.3 ° C, Azithromycin 500 mg tablets will take 1 tablet single dose the first day and then half tablet (250 mg) orally every 24 for 4 days, Ivermectin tablets of 200mcg which will be calculated according to your weight and dose, will be every 24 hours for 2 days and Rivaroxaban tablets of 10 mg will take 1 every 24 hours for 10 days
  Intervention: Drug: Azithromycin / Ivermectin / Ribaroxaban / Paracetamol
• Active Comparator: Double therapy
  Paracetamol 500 mg orally 1 tablet every 8 hours for 3 days in case of fever equal to or greater than 38.3 ° C, Azithromycin 500 mg tablets will take 1 tablet single dose the first day and then half a tablet orally every 24 for 4 days and Rivaroxaban 10 mg tablets will take 1 every 24 hours for 10 days.
  Intervention: Drug: Azithromycin / Ribaroxaban / Paracetamol

Publications *

• Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20.
• Becattini C, Pace U, Rondelli F, Delrio P, Ceccarelli G, Boncompagni M, Graziosi L, Visonà A, Chiari D, Avruscio G, Frasson S, Gussoni G, Biancafarina A, Camporese G, Donini A, Bucci AF, Agnelli G. Rivaroxaban for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Design of the PRO-LAPS II STUDY. Eur J Intern Med. 2020 Feb;72:53-59. doi: 10.1016/j.ejim.2019.11.015. Epub 2019 Dec 7.
• Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. doi: 10.1056/NEJMoa1814630.
• Dugina TN, Kiseleva EV, Chistov IV, Umarova BA, Strukova SM. Receptors of the PAR family as a link between blood coagulation and inflammation. Biochemistry (Mosc). 2002 Jan;67(1):65-74. Review.
• Choudhary R, Sharma AK. Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance. New Microbes New Infect. 2020 Apr 22;35:100684. doi: 10.1016/j.nmni.2020.100684. eCollection 2020 May. Review.
• Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, Curley P, Neary M, Sharp J, Liptrott NJ, Valentijn A, David C, Rannard SP, O'Neill PM, Aljayyoussi G, Pennington SH, Ward SA, Hill A, Back DJ, Khoo SH, Bray PG, Biagini GA, Owen A. Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics. Clin Pharmacol Ther. 2020 Oct;108(4):775-790. doi: 10.1002/cpt.1909. Epub 2020 Jun 14. Review.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 16, 2020): 62
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 12, 2021
• Estimated Primary Completion Date: February 2, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients Eligible for Family Medicine Unit No.20 and Family Medicine Unit No.13 belonging to the North DF of the IMSS.
• Male and female patients
• Patients over 18 years of age.
• Patients with compliance with the operational definition COVID-19 and confirmatory test of P.C.R. positive within the first days of the illness (that are evaluated in first level of medical attention).
• Patients with comorbidities such as Type 2 Diabetes Mellitus, Systemic Arterial Hypertension, Overweight or Obesity.

• That they agree to sign an informed consent

  - Related to Video Call:

• That the Family Medicine Unit No.20 and the Family Medicine Unit No.13 belonging to the North DF of the IMSS have the Installation of Electronic Equipment for Internet use

Exclusion Criteria:

• Severe COVID-19 patients (Ameriten sent immediately to second level of care, hospital) Patients with any Personal Pathological History of Hematological Diseases. • Patients allergic to macrolides (Azithromycin) and Ivermectin.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: GILBERTO CR ARTEAGA, specialist; 55 87 44 22 ext 15320; gilberto.cruz@imss.gob.mx

Contact: ALMA ITALIA GU MARTINEZ, specialist; 55 61 27 00 ext 21315; italia.guerrero@imss.gob.mx

• Listed Location Countries: Mexico

Administrative Information

• NCT Number: NCT04673214
• Other Study ID Numbers: R-2020-785-176
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: SHARED VIA EMAIL IF OTHER RESEARCHERS REQUIRE IT

• Responsible Party: Gilberto Cruz Arteaga, Coordinación de Investigación en Salud, Mexico
• Study Sponsor: Gilberto Cruz Arteaga
• Collaborators: Coordinación de Investigación en Salud, Mexico

Investigators

• Principal Investigator: GILBERTO CR ARTEAGA, specialist; MEXICAN SOCIAL SECURITY INSTITUTE

• PRS Account: Coordinación de Investigación en Salud, Mexico
• Verification Date: December 2020