Clinical trial NCT05026801: Azithromycin Plus Hydroxychloroquine for COVID-19 Infection
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Respiratory Tract Infection Viral
Keywords: Coronavirus
Lead sponsor: Iterum Therapeutics, International Limited
Sponsor class: INDUSTRY
Collaborators: name: Waterbury Hospital
First posted: 2021-08-30
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Approximately 200 patients with symptoms of a RTI who test positive for SARS-CoV-2 by polymerase chain reaction (PCR) will receive a combination of azithromycin 500 mg and chloroquine 500 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. A sequential probability ratio test will be employed in which comparisons between each regimen will be made with every Day 3 PCR endpoint; if the p value crosses a p=0.001 threshold for any pairwise comparison, the less efficacious arm will be closed to further enrollment and superiority will be declared.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Microbiologic response
timeFrame: Day 3 (+/- 1 day)
Secondary outcomes:
measure: Combined clinical and microbiologic response
timeFrame: Day 3 (+/- 1 day)
Other outcomes:
Locations:
city: Waterbury
country: United States
facility: Waterbury Hospial
state: Connecticut
Study officials:
affiliation: Iterum Therapeutics
name: Michael Dunne, MD
role: PRINCIPAL_INVESTIGATOR
References: