Hydroxychloroquine and Ivermectin for the Treatment of COVID-19 Infection

NCT04391127 | Completed Phase 3

• 1 other identifier: 2020-A-09
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 1

Brief Summary

Background: In December 2019, patients with pneumonia secondary to a new subtype of Coronavirus (COVID-19) were identified in China. In a few weeks the virus spread and cases started practically all over the world. In February 2020, the WHO declared a pandemic. Severe symptoms have been found in patients mainly with comorbidities and over 50 years of age. At this time there is no proven therapeutic alternative. In vitro studies and observational experiences showed that antimalarial drugs (Chloroquine and hydroxychloroquine) had antiviral activity and increased viral clearance. Ivermectin, on the other hand, has been shown in vitro to reduce viral replication and in an observational cohort, greater viral clearance with promising clinical results. So far there is no standard of treatment and clinical trials are needed to find effective treatment alternatives. Objective: To evaluate the safety and efficacy of treatment with hydroxychloroquine and ivermectin for serious COVID-19 infections in no critical hospitalized patients. Material and methods: Randomized controlled trial of patients diagnosed with respiratory infection by COVID-19, who present criteria for hospitalization. Randomization will be performed to receive hydroxychloroquine at a dose of 400 mg every 12 hours for one day and then 200 mg every 12 hours, to complete a 5-day treatment schedule. Group 2: Ivermectin 12 mg every 24 hours for one day (less than 80 kg) or Ivermectin 18 mg every 24 hours for one day (greater than 80 kg) + placebo until the fifth day. Group 3: Placebo. Prior to randomization, the risk of cardiovascular complications determined by corrected QT interval, related to hydroxychloroquine intake will be assessed. If the patient is at high risk, the allocation will be to ivermectin only or to placebo in an independent randomization, if the risk is low, any of the three groups could be assigned. Outcomes: The primary outcome will be discharge from hospital for improvement. The safety outcomes will be requirement of mechanical intubation, septic shock or death. Viral clearance will also be evaluated by means of PCR, which will be taken on the 5th day after admission, day 14 and 21.

Conditions

COVID-19

Outcome Measures

Primary Outcomes (3)

• Mean days of hospital stay

  Days from admission as a suspected case of COVID with hospitalization criteria until discharge

  Three months

• Rate of Respiratory deterioration, requirement of invasive mechanical ventilation or dead

  Respiratory deterioration defined by respiratory rate \> 25 per minute, requirement of high oxygen supply (FiO2 \> 80% ) to maintain oxygen saturation \> 90 %, invasive mechanical ventilation or dead.

  Three months

• Mean of oxygenation index delta

  Daily delta of oxygenation index during the hospitalization

  Three months

Secondary Outcomes (1)

• Mean time to viral PCR negativization

  5, 14, 21 and 28 days after the first positive PCR

Study Arms (2)

Hospitalized patients with COVID-19 QTc < 500 mseg

EXPERIMENTAL

Patients with confirmed COVID-19 infection by RT-qPCR SARS-CoV-2 or suspected by chest computed tomography with criteria of hospitalization because emergency medical criteria, with no need of critical care assistance. The risk of hydroxychloroquine complications will be assessed by QT corrected by Bazett formula. If QTc \< 500 ms could be randomized to hydroxychloroquine, ivermectin or placebo.

Drug: Hydroxychloroquine; Drug: Ivermectin; Drug: Placebo

Hospitalized patients with COVID-19 infection with QTc >500ms

EXPERIMENTAL

Patients with confirmed COVID-19 infection by RT-qPCR SARS-CoV-2 or suspected by chest computed tomography with criteria of hospitalization because emergency medical criteria, with no need of critical care assistance. The risk of hydroxychloroquine complications will be assessed by QT corrected by Bazett formula. If QTc \> 500 ms could be randomized to ivermectin or placebo.

Drug: Ivermectin; Drug: Placebo

Interventions

Hydroxychloroquine DRUG

Hydroxychloroquine: 400 mg PO every 12 hours for one day. Subsequently 200 mg every 12 hours per 4 more days.

Hospitalized patients with COVID-19 QTc < 500 mseg

Ivermectin DRUG

Ivermectin 12 mg PO every 24 hours for one day (in case of weight less than 80 kg) or 18 mg PO every 24 hours for one day (in case of weight over 80 kg) Subsequently this group will take two tablets of placebo 12 hrs after ivermectin ingestion and then one tablet of placebo each 12 hrs per 4 more days.

Hospitalized patients with COVID-19 QTc < 500 mseg; Hospitalized patients with COVID-19 infection with QTc >500ms

Placebo DRUG

Two tablets of placebo PO every 12 hours for one day. Subsequently one tablet of placebo every 12 hours per 4 more days.

Hospitalized patients with COVID-19 QTc < 500 mseg; Hospitalized patients with COVID-19 infection with QTc >500ms

Eligibility Criteria

• Age: 16 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• RT-qPCR SARS-CoV-2 positivity or chest computed Tomography with suspected COVID-19 pneumonia
• Hospitalization by medical emergency staff criteria

You may not qualify if:

• Other confirmed viral active and acute infection

Sponsors & Collaborators

• Centenario Hospital Miguel Hidalgo: lead

Study Sites (1)

Jose Manuel Arreola Guerra

Aguascalientes, 20259, Mexico

Location

Related Publications (11)

• Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.

  PMID: 31978945 BACKGROUND

• Lv DF, Ying QM, Weng YS, Shen CB, Chu JG, Kong JP, Sun DH, Gao X, Weng XB, Chen XQ. Dynamic change process of target genes by RT-PCR testing of SARS-Cov-2 during the course of a Coronavirus Disease 2019 patient. Clin Chim Acta. 2020 Jul;506:172-175. doi: 10.1016/j.cca.2020.03.032. Epub 2020 Mar 27.

  PMID: 32229107 BACKGROUND

• Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med. 2020 Feb 20;382(8):692-694. doi: 10.1056/NEJMp2000929. Epub 2020 Jan 24. No abstract available.

  PMID: 31978293 BACKGROUND

• Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3.

  PMID: 32251768 BACKGROUND

• Gonzalez Canga A, Sahagun Prieto AM, Diez Liebana MJ, Fernandez Martinez N, Sierra Vega M, Garcia Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 2008;10(1):42-6. doi: 10.1208/s12248-007-9000-9. Epub 2008 Jan 25.

  PMID: 18446504 BACKGROUND

• Boldescu V, Behnam MAM, Vasilakis N, Klein CD. Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond. Nat Rev Drug Discov. 2017 Aug;16(8):565-586. doi: 10.1038/nrd.2017.33. Epub 2017 May 5.

  PMID: 28473729 BACKGROUND

• Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012 May 1;443(3):851-6. doi: 10.1042/BJ20120150.

  PMID: 22417684 BACKGROUND

• Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, Jans DA. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res. 2020 May;177:104760. doi: 10.1016/j.antiviral.2020.104760. Epub 2020 Mar 3.

  PMID: 32135219 BACKGROUND

• Ketkar H, Yang L, Wormser GP, Wang P. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis. 2019 Sep;95(1):38-40. doi: 10.1016/j.diagmicrobio.2019.03.012. Epub 2019 Mar 29.

  PMID: 31097261 BACKGROUND

• Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, Labella A, Manson DK, Kubin C, Barr RG, Sobieszczyk ME, Schluger NW. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Jun 18;382(25):2411-2418. doi: 10.1056/NEJMoa2012410. Epub 2020 May 7.

  PMID: 32379955 BACKGROUND

• Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. RETRACTED: 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.

  PMID: 32205204 BACKGROUND

Related Links

• Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus 2019 (n-CoV) on 30 January 2020.
• World Health Organization.Coronavirus disease (COVID-19) outbreak
• Infectious Diseases Society of America. (I. D. America, Producer) Retrieved ABRIL de 2020 from IDSA Guidelines on the Treatment and Management of Patients with COVID-19

MeSH Terms

Conditions

COVID-19

Interventions

Hydroxychloroquine; Ivermectin

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Two non-transparent bottles The first bottle will contain the initial treatment: Two ivermectin tablets, two hydroxychloroquine tablets, or two placebo tablets. The second bottle will contain the follow-up treatment (10 tablets): Two tablets will be indicated, which will be take 12 hours after ingestion of the initial bottle and then one tablet every 12 hours for 4 more days. This bottle will contain placebo and hydroxychloroquine according to the corresponding group.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 12, 2020
• First Posted: May 18, 2020
• Study Start: May 4, 2020
• Primary Completion: November 6, 2020
• Study Completion: November 6, 2020
• Last Updated: November 9, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)