Azithromycin Plus Hydroxychloroquine for COVID-19 Infection

A Randomized, Double-blinded Phase 3 Multi-center Study of the Clinical and Microbiologic Efficacy of a Combination of Azithromycin and Hydroxychloroquine for Treatment of COVID-19 Infection

This is a randomized, double-blinded, Phase 3, multi-center trial of the clinical and microbiologic response of patients with a respiratory tract infection (RTI) due to coronavirus treated with a combination of azithromycin and hydroxychloroquine.

Approximately 200 patients with symptoms of an RTI who test positive for SARS-CoV-2 by polymerase chain reaction (PCR) will receive a combination of azithromycin 500 mg and hydroxychloroquine 600 mg or matching placebos for six consecutive days. There will be two treatment regimens into which patients are randomized so that all patients will receive some active therapy.

Study Overview

• Status: Withdrawn
• Conditions: Respiratory Tract Infection Viral
• Intervention / Treatment: Drug: Azithromycin plus hydroxychloroquine

Detailed Description

As of March 22, 2020, a total of 311,988 people worldwide have been diagnosed with a respiratory infection caused by SARS-CoV-2 of whom 13,407 have died. In the United States 26,747 patients have tested positive of whom 340 have died. There is at present no established therapy for this infection. After the SARS epidemic in 2002, investigations identified chloroquine as a possible inhibitor of replication of this coronavirus. When the SARS-CoV-2 epidemic started in December of 2019, clinicians began to use chloroquine in an attempt to control the infection in newly diagnosed patients. Investigators from China reported chloroquine phosphate has apparent efficacy in treatment of pneumonia due to SARS-CoV-2. Following this report, investigators in France initiated an open label study of hydroxychloroquine, with the addition of azithromycin, in a small number of subjects with SARS-CoV-2 infection. Relative to no treatment the investigators identified a significant reduction in viral isolation by PCR in the nasal swabs of treated patients, with an additional effect seen when patients were also given azithromycin. Azithromycin, like chloroquine, is a weak base that concentrates in endosomes and lysosomes and raises the pH in those vesicles. It is possible that azithromycin and chloroquine's effect on endosomal processing reduces the inflammatory response by affecting TLR4 signaling through the endosomes.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Waterbury Hospial

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults ≥18 years of age

2. History of a respiratory tract infection (RTI) for more than one but less than six days including two or more of the following signs and symptoms of an RTI:

   • Fever (T ≥ 38.0 C, 100.5 F), cough, sputum production, arthralgia/myalgia, anosmia/ageusia or difficulty breathing.

3. A nasal or throat swab or nasal wash positive by PCR for SARS-CoV-2.
4. Has given written informed consent to participate in the study. Due to the public health issues related to this viral infection, witnessed informed consent may be obtained remotely.

Exclusion Criteria:

Exclusion Criteria:

1. Patients likely, in the opinion of the investigator, to require hospitalization within 48 hours of randomization into the study.
2. Concurrent use of non-study antibacterial drug therapy that would have a potential effect on outcome evaluations in patients with an RTI
3. Concurrent use of any other medications for the purpose of treating a viral infection such as influenza antivirals
4. Inability to swallow oral medication in tablet form
5. Patient has severe chronic kidney disease, or is receiving hemodialysis, or peritoneal dialysis or had a renal transplant
6. Patient is known to have severe neutropenia
7. Patients with a known prolongation of the QT interval or are taking medications which could prolong the QT interval
8. Patient is known to be pregnant
9. Patients with a known history of myasthenia gravis
10. Patients with a history of allergy to azithromycin, hydroxychloroquine or chloroquine
11. Patient is considered unlikely to survive the study period or has a rapidly progressive or terminal illness, including septic shock, associated with a high risk of mortality

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Azithromycin plus hydroxychloroquine; All patients will receive active comparator. One group will receive placebo on D1-3 followed by active comparator D4-9, while the other group will receive active comparator D1-6 followed by placebo D7-9.; Other Names: Placebo
ACTIVE_COMPARATOR: Azithromycin plus hydroxychloroquine; Azithromycin 500 mg plus hydroxychloroquine 600 mg by mouth daily for six consecutive days	Drug: Azithromycin plus hydroxychloroquine; All patients will receive active comparator. One group will receive placebo on D1-3 followed by active comparator D4-9, while the other group will receive active comparator D1-6 followed by placebo D7-9.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiologic response	Presence or absence of SARS-CoV-2 by PCR on nasopharyngeal specimen	Day 3 (+/- 1 day)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined clinical and microbiologic response	Presence or absence of SARS-CoV-2 by PCR on nasopharyngeal specimen and improvement in at least two of the signs and symptoms of RTI	Day 3 (+/- 1 day)

Collaborators and Investigators

• Sponsor: Iterum Therapeutics, International Limited
• Collaborators: Waterbury Hospital
• Investigators: Principal Investigator: Michael Dunne, MD, Iterum Therapeutics

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 8, 2021
• Primary Completion (ACTUAL): August 26, 2021
• Study Completion (ACTUAL): August 26, 2021

Study Registration Dates

• First Submitted: February 8, 2021
• First Submitted That Met QC Criteria: August 26, 2021
• First Posted (ACTUAL): August 30, 2021

Study Record Updates

• Last Update Posted (ACTUAL): October 28, 2021
• Last Update Submitted That Met QC Criteria: October 26, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Coronavirus
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Infections; Communicable Diseases; Virus Diseases; Respiratory Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Azithromycin; Hydroxychloroquine
• Other Study ID Numbers: IT005-501

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual participant data for all primary and secondary outcome measures will be made available.
• IPD Sharing Time Frame: Data will be available within 30 days of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed on a case by case basis. Requestors will be required to sign a Data Access Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No