Hydroxychloroquine and Nitazoxanide Combination Therapy for COVID-19

April 22, 2020 updated by: Prof. Dr. Kamal Mohammed Okasha, Tanta University

Clinical Trial Evaluating Safety and Efficacy of Hydroxychloroquine and Nitazoxanide Combination as Adjuvant Therapy in Covid-19 Newly Diagnosed Egyptian Patients: A Tanta University Hope

In December 2019, a new infectious respiratory disease emerged in Wuhan, Hubei province, China. An initial cluster of infections was linked to Huanan seafood market, potentially due to animal contact. Subsequently, human-to-human transmission occurred and the disease, now termed coronavirus disease 19 (COVID-19) rapidly spread within China and all over the world. A novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), which is closely related to SARS-CoV, was detected in patients and is believed to be the etiologic agent of the new lung disease. The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded positive sense RNA virus that is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV).

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Selected Drugs

Hydroxychloroquine (an analog of chloroquine) has been demonstrated to have an anti-SARS-CoV activity in vitro. Hydroxychloroquine clinical safety profile is better than that of chloroquine (during long-term use) and allows higher daily dose and has fewer concerns about drug-drug interactions. Hydroxychloroquine has long-term safety (600 mg/day for 12 to 18 months was safe). Hydroxychloroquine effectively inhibited both the entry, transport and the post-entry stages of SARS-CoV-2, similar to the chloroquine, and one study found Hydroxychloroquine to be a more potent agent than chloroquine in inhibiting SARS-CoV-2 in vitro. Hydroxychloroquine acts as a weak base that can change the pH of acidic intracellular organelles including endosomes/lysosomes, essential for the membrane fusion. Besides, the significant decrease in the production of pro-inflammatory markers and cytokines with Hydroxychloroquine has made this agent a successful disease modifying anti-inflammatory agent in the treatment of various autoimmune diseases. An additional issue to be considered in severely sick patients is cytokine storm associated with disease severity of SARS-CoV-2.

There are no currently available data from randomized clinical trials (RCTs) to inform clinical guidance on the use, dosing, or duration of Hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection. Although optimal dosing and duration of Hydroxychloroquine for treatment of COVID-19 are unknown, some U.S. clinicians have reported anecdotally different Hydroxychloroquine dosing such as 400 mg twice daily on day one, then daily for 5 days; 400 mg twice daily on day one, then 200 mg twice daily for 4 days; 600 mg twice daily on day one, then 400 mg daily on days 2-5. In a recent clinical trial, Hydroxychloroquine sulfate 200 mg, three times per day during ten days was used in patients with COVID-19.

Nitazoxanide is originally developed as an antiprotozoal agent and has a broad-spectrum antiviral activity undergoing development for the treatment of influenza and other viral respiratory infections. In addition to its antiviral activity, Nitazoxanide inhibits the production of pro-inflammatory cytokines TNF-α, IL-2, IL-4, IL-5, IL-6, IL-8 and IL-10 in peripheral blood mononuclear cells. Nitazoxanide could improve outcomes in patients infected with MERS-CoV by suppressing overproduction of pro-inflammatory cytokines, including IL-6. Nitazoxanide has been tested in clinical setting for the treatment of acute uncomplicated influenza, where the subjects received either 600 or 300 mg of Nitazoxanide or placebo orally twice daily for five days and were followed for 28 days. Subjects who received Nitazoxanide 600 mg twice daily experienced shorter times to alleviation of symptoms compared with subjects who received 300 mg Nitazoxanide twice daily, which in turn, was shorter than placebo.

According to the National Health Commission of the People's Republic of China, there is lack of effective antiviral therapy against COVID-19. Nearly all patients who suffered from COVID-19-associated pneumonia accepted oxygen therapy and WHO recommended extracorporeal membrane oxygenation (ECMO) to patients with refractory hypoxemia. Rescue treatment with convalescent plasma and immunoglobulin G are delivered to some critical cases according to their condition.

The rationale of the use of Hydoxychloroquine and Nitazoxanide combination for treatment of COVID-19 infected patients is based on the antiviral and anti-inflammatory activity of the selected drugs. Since the two drugs exhibit different modes of action, it would be of value in containing the viral infection through targeting different sites in the pathophysiology of the disease.

Diagnostic criteria

The viral research institution in China has conducted preliminary identification of the SARS-CoV-2 through the classical Koch's postulates and observing its morphology through electron microscopy. So far, the golden clinical diagnosis method of COVID-19 is nucleic acid detection in the nasal and throat swab sampling or other respiratory tract samplings by real-time PCR and further confirmation by next-generation sequencing.

Side effects of Hydroxychloroquine

  • The most common adverse effects are mild nausea and occasional stomach cramps with mild diarrhea, reduced appetite and vomiting
  • The most serious adverse effects are retinopathy and heart problems
  • Long term use may cause liver toxicity Contraindications of Hydroxychloroquine
  • Heart conditions, diabetes or psoriasis.
  • The drug transfers into breast milk so should be used with care by pregnant or nursing women

Interactions of Hydroxychloroquine

  • Antacids may decrease the absorption of Hydroxychloroquine.
  • Both neostigmine and pyridostigmine antagonize the action of Hydroxychloroquine.
  • There may be a link between Hydroxychloroquine and hemolytic anemia in those with glucose-6-phosphate dehydrogenase deficiency.
  • Digoxin; concomitant administration with Hydroxychloroquine may result in increased serum digoxin levels.
  • Insulin or antidiabetic drugs; concomitant administration with Hydroxychloroquine may enhance the effects of the hypoglycemic treatment.
  • Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing ventricular arrhythmias if used concurrently with other arrhythmogenic drugs.
  • Mefloquine and other drugs that lower the convulsive threshold, when co-administered with Hydroxychloroquine, there may be an increased risk of convulsions.
  • Concurrent use of Hydroxychloroquine with antiepileptics may impair the antiepileptic activity.
  • Cyclosporin when used concomitantly with Hydroxychloroquine, an increased plasma cyclosporin level was reported.

Side effects of Nitazoxanide

The most common adverse effects are GIT as nausea and occasional stomach cramps with mild diarrhea, reduced appetite and vomiting. Nervous system side effects as headache, dizziness, somnolence, insomnia, tremor, and hypesthesia have been reported in less than 1% of the patients.

Contraindications of Nitazoxanide

There are no data on the excretion of Nitazoxanide into human milk. The manufacturer recommends that caution be used when administering Nitazoxanide to nursing women.

Tizoxanide (the active metabolite of Nitazoxanide) is highly bound to plasma protein (> 99.9%). Therefore, it is necessary to monitor for adverse reactions when administering Nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin).

Warning

Nitazoxanide should be used with caution in patients with significant renal and hepatic impairment.

Research Objectives

The pandemic disease COVID-19 is particularly of major importance in Egypt where a heavy population lives. There is an acute need for comprehensive, continuous, and cost-effective health care delivery for infected people. Early detection and strategies for prevention of progression of COVID-19 would make a major difference for these patients and would also be economically beneficial for a resource-constrained country.

This research proposal was employed as a practical strategy for providing a suitable drug combination for possible treatment of COVID-19 infected patients. This drug combination may help to prevent the progression of respiratory complications. This can be achieved through different goals as follows:

  1. Screening of different drugs related to different pharmacological classes depending on its possible activity against COVID-19 virus.
  2. Providing cost-effective and easy-to-implement treatment strategy for infected patients and/or patients with high risk of developing respiratory failure.
  3. Finally, this clinical strategy remains an important goal in improving the Egyptian health state which can save people life and save a lot of money.

Scope of Work

The scope of work will be conducted through:

  1. Use of new drug combination of Hydroxychloroquine and Nitazoxanide for treatment of COVID-19 infected people. Since the two drugs exhibit different modes of action, it would be of value in containing the viral infection through targeting different sites in the pathophysiology of the disease.
  2. Evaluation of the effect of new drug combination on the symptomatic treatment of newly diagnosed COVID-19 patients through a clinical trial designed according to WHO (clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected) interim guidance published at 13 March 2020.
  3. Investigating the impact of new drug combination on the prevention of severe compilations such as acute respiratory distress syndrome (ARDS).

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Phase 2
  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Confirmed cases of COVID-19 (Positive RT-PCR)
  • Newly diagnosed symptomatic patients.
  • Adults (18-65 Years old)
  • Both sexes

Exclusion Criteria:

  • Patients with abnormal liver function (ALT, AST), chronic kidney disease or dialysis (CrCl< 30 ml/min)
  • Pregnant women or women who are breastfeeding
  • Immunocompromised patients taking medication upon screening
  • Subjects with comorbid condition like hypertension, cardiovascular disease, diabetes mellites, asthma, COPD, malignancy
  • Patients having allergy to Hydroxychloroquine and/or Nitazoxanide
  • Patients with contraindication towards the study medication including retinopathy, G6PD deficiency and QT prolongation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Hydroxychloroquine plus Nitazoxanide
200 mg of Hydroxychloroquine orally three times daily for 10 days plus 500 mg of Nitazoxanide orally twice daily for 6 days
Combination product: Hydroxychloroquine plus Nitazoxanide
Both hydroxychloroquine & nitazoxanide will be administered orally to participating patients
Other Names:
  • drug therapy
ACTIVE_COMPARATOR: Standard care
Standard care delivered in the COVID-19 isolation hospitals.
Other: Standard care
Oxygen administered via ventilator. In addition, antipyretic "paracetamol" may be added if necessary

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with COVID-19-negative PCR
Time Frame: within 10 days to become PCR negative
PCR analysis of COVID-19 RNA in patients
within 10 days to become PCR negative

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with improved respiratory rate
Time Frame: within 30 days
improved breaths per minute for the patients
within 30 days
Number of patients with improved PaO2
Time Frame: within 30 days
Change in PaO2 in mmHg of the patients
within 30 days
Number of patients with normalized Serum IL6
Time Frame: within 30 days
Serum IL6 in pg/mL of the patients
within 30 days
Number of patients with normalized Serum TNFα
Time Frame: within 30 days
Serum TNFα in pg/mL of the patients
within 30 days
Number of patients with normalized Serum iron
Time Frame: within 30 days
Serum iron in microgram/dL of the patients
within 30 days
Number of patients with normalized Serum ferritin
Time Frame: within 30 days
Serum ferritinin microgram/L of the patients
within 30 days
Number of patients with normalized International normalized ratio "INR" for prothrombin time
Time Frame: within 30 days
International normalized ratio "INR" for prothrombin time of 2
within 30 days
Number of patients with normalized complete blood count "CBC"
Time Frame: within 30 days
CBC for lymphocyte count in cells/microliter
within 30 days
The Mortality rate among treated patients
Time Frame: within 30 days
Mortality rate [number of dead patients/total number of treated patients]
within 30 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tanta University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

May 1, 2020

Primary Completion (ANTICIPATED)

October 1, 2020

Study Completion (ANTICIPATED)

December 1, 2020

Study Registration Dates

First Submitted

April 18, 2020

First Submitted That Met QC Criteria

April 22, 2020

First Posted (ACTUAL)

April 24, 2020

Study Record Updates

Last Update Posted (ACTUAL)

April 24, 2020

Last Update Submitted That Met QC Criteria

April 22, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HCQ/NTZ

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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