Study design and setting

‘The CAM (Clarithromycin) Effectivity for COVID-19 pneumonia that does not require oxygen administration; multicenter, randomized-controlled, open-label, 3-armed parallel group comparison, exploratory trial’ (CAME COVID study) was initiated in May 2021, following the approval by the Clinical Research Review Board in Nagasaki University in March 2021 and the registration/publication at the Japan Registry of Clinical Trials (jRCT) (registration number: jRCTs071210011) in April 2021. This study is scheduled to culminate in July 2022. Patients have been enrolled since May 2021, and enrolment will culminate in February 2022. This study will be conducted in 10 medical institutions in Japan (Nagasaki University Hospital, Nagasaki Harbor Medical Center, Sasebo City General Hospital, Japan Community Health Care Organization JCHO Isahaya General Hospital, Japanese Red Cross Nagasaki Genbaku Hospital, Hospital of the University of Occupational and Environmental Health, Japan, Wakamatsu Hospital of the University of Occupational and Environmental Health, Japan, Kitakyushu City Yahata Hospital, Fukuoka University Chikushi Hospital, and Saiseikai Nagasaki Hospital). As shown in figure 1, patients who are eligible for this study will be asked to participate in this study, and informed consent will be obtained prior to the registration/randomisation. After written consent is obtained from the eligible patients, they will be enrolled and randomised into group A (administration of clarithromycin 800 mg/day), group B (administration of clarithromycin 400 mg/day) or group C (standard treatment without clarithromycin). The rationale for the doses of clarithromycin is as follows: clarithromycin-naproxen-oseltamivir combination therapy for Influenza A using 1000 mg/day of clarithromycin (500 mg twice daily) was tolerated and reduced mortality and length of hospital stay,17 and 400 mg/day and 800 mg/day of clarithromycin have been approved for bacterial respiratory infectious diseases and non-tuberculous mycobacterial infection, respectively, in Japan, and the safety of these doses of clarithromycin has been confirmed.

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Figure 1

Study design and flow of recruitment, randomisation, study intervention and observation.

Sample size calculation

Since no prior clinical trial has evaluated the effect of clarithromycin on COVID-19 pneumonia, no reference data are available for the statistical sample size calculation for this study. Therefore, this study is planned as an exploratory trial, and the target number of enrolled patients is defined as 60 (20 subjects×3 groups), based on the possible number of patients who could give their consent during the planned enrolment period in this study at the participating medical institutions.

Eligibility criteria

Patients with mild COVID-19 pneumonia who do not require oxygen administration will be included in this study. Mild COVID-19 is defined as SARS-CoV-2 positive and percutaneous arterial oxygen saturation (SpO₂) of 94% or higher in this study. This study will enrol patients with mild COVID-19 and with pneumonia. The detailed inclusion criteria are as follows: (1) patients in whom SARS-CoV-2 is detected by PCR tests or loop-mediated isothermal amplification method within 3 days before the informed consent, (2) patients with pneumonia by routine chest radiography or chest CT, (3) Japanese patients who are aged 20 years or older and (4) patients who give their written consent for participating in the study. The exclusion criteria are as follows: (1) patients who had symptoms of 8 days or longer, (2) patients who were treated with macrolide antimicrobial agents, (3) patients who were treated with steroids (except inhalants) or immunosuppressive agents, (4) patients who are diagnosed with influenza viral infection, (5) patients whose SpO₂ is 93% or less under room air condition, (6) patients with hepatic dysfunction (aspartate aminotransferase or alanine aminotransferase is more than five times the upper limit of normal in each medical institution or Child-Pugh B or C), (7) patients with renal dysfunction (creatinine is more than twice the upper limit of normal in each medical institution, and estimated glomerular filtration rate is less than 30 mL/min/1.73 m²), (8) patients whose peripheral blood neutrophils are less than 1000 /µL, (9) patients who have a history of hypersensitivity to macrolide antimicrobial agents, (10) patients who are pregnant or breast feeding, (11) patients who have a history of vaccination against COVID-19 and (12) patients with other conditions that the investigator thinks may render them inappropriate to participate in the study.

Recruitment and consent

The informed consent document (see online supplemental file 1) would be provided to the candidates who meet all of the inclusion criteria and who do not forsake any of the exclusion criteria to provide a comprehensive explanation of this study. Written consent will be obtained. After obtaining consent, the participants will be enrolled in this study.

Random allocation

After obtaining informed consent, eligible patients are randomly assigned in a 1:1:1 ratio to group A (administration of clarithromycin 800 mg/day), group B (administration of clarithromycin 400 mg/day) or group C (standard treatment without clarithromycin). The randomisation sequence is generated using a computer-based dynamic allocation method with a minimisation procedure to balance the allocation factors (age ≥20 years and less than 40 years, ≥40 years and less than 60 years or ≥60 years) and sex.

Study intervention and observation

All enrolled patients in this study will be hospitalised, since the Infectious Diseases Control Law in Japan designated COVID-19 as category II infectious diseases, which warrants the isolation of the patients, and the COVID-19 infectious disease treatment guidelines by the Ministry of Health, Labour and Welfare in Japan29 warrant hospitalisation of the patients of COVID-19 with pneumonia. The enrolled patients will be subsequently observed for 7 days30 for a comprehensive follow-up during the intervention. Patients assigned to group A will commence with 400 mg of clarithromycin orally twice daily (after breakfast and supper) following hospitalisation. Patients assigned to group B will commence with 200 mg of clarithromycin orally twice daily (after breakfast and supper) following hospitalisation. Patients assigned to group C will commence with the standard care for COVID-19 pneumonia in each medical institution without the administration of clarithromycin following hospitalisation. Since this is an open-label trial, placebo is not used in the group C. In groups A and B, clarithromycin is administered 14 times (twice daily for 7 days). If the administration starts on the morning of day 1 (the day of hospitalisation), clarithromycin will be administered until the evening of day 7. If the administration starts on the evening of day 1, clarithromycin will be administered until the morning of day 8. The study patients are observed on days 1, 2, 3, 4, 5, 6, 7, 8 and 14. The day of hospitalisation is considered the day when observation starts (reference date). During the study intervention period (days 1 to 7 or 8), the patients are not allowed to use macrolide antimicrobial agents, immunosuppressive agents or anticancer agents. Following the completion of the study intervention (day 8), the study patients will be discharged. After day 8 (post-treatment observation period), all the study patients will receive standard care for COVID-19 pneumonia in each medical institution without the administration of clarithromycin.

Table 1 shows the schedule of assessments performed at each observation point, including the mandatory and optional assessments. Inspection of subjects’ characteristics (height, weight, body mass index, onset of COVID-19, detection date of SARS-CoV-2, date of hospitalisation, anamnesis and comorbidity), vital signs (body temperature, systolic blood pressure, diastolic blood pressure, pulse, percutaneous oxygen saturation and frequency of breath), haematology tests (red blood cell, haemoglobin, haematocrit, white cell count, neutrophil, lymphocyte, eosinophil, monocyte, basophil and platelet), general blood biochemical tests (total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-guanosine triphosphate, total cholesterol, total protein, albumin, blood urea nitrogen, creatinine-estimated glomerular filtration rate based on creatinine, lactate dehydrogenase, creatine phosphokinase, brain natriuretic peptide, troponin T, C reactive protein, procalcitonin, ferritin, Na, pH, haemoglobin A1c and glucose), blood coagulation tests (prothrombin time, activated partial thromboplastin time and d-dimer), chest radiography and CT, and inspection of medications of other pharmaceutical agents are conducted by general inspection and interview. The severity of COVID-19 pneumonia is measured by the severity classification according to the COVID-19 infectious disease treatment guidelines by the Ministry of Health, Labour and Welfare in Japan29 (mild: SpO₂ ≥96%, no respiratory symptoms or only with coughing without dyspnoea and without pneumonia findings; moderate I: 93% < SpO₂<96%, with dyspnoea and with pneumonia findings; moderate II: SpO₂ ≤93% and oxygen administration required; and severe: admission to intensive care unit or ventilator required), pneumonia severity index31 and A-DROP defined in the guidelines for the management of community-acquired pneumonia in adults released from the Japanese Respiratory Society,32 the quantity of oxygen administered are recorded daily during hospitalisation, PCR tests for SARS-CoV-2 are conducted using nasopharyngeal swabs, 11) nasal drip tests are conducted for interleukin (IL)1beta, IL-6, IL-8, IL-10, IL-17, tumour necrosis factor-alpha, interferon-gamma, beta-defensin, granulocyte-macrophage colony-stimulating factor and immunoglobulin A, special blood tests are conducted for cytokines, chemokines, IL-33, immunoglobulin M, immunoglobulin G, and immunoglobulin A, medication adherence of the study agent, meal intake, and subjective symptoms measured by the severity score33 are daily answered on the study patients’ diary by the study patients themselves.

Outcomes

The primary endpoint of this study is the number of days required to improve clinical symptoms, measured by the severity score33 by 50% or more from baseline. Secondary endpoints are as follows: (1) days to recover the body temperature to below 37°C following registration, (2) change in inflammatory cytokines in serum and nasal discharge from baseline, (3) proportion of patients in whom all the clinical symptoms measured by the severity score completely disappeared, (4) proportion of patients in whom each clinical symptom measured by the severity score is improved by 50% or more from baseline, (5) reduction rate of the SARS-CoV-2 from baseline, (6) change in serum immunoglobulin G, immunoglobulin M and immunoglobulin A antibodies from baseline, (7) recovery rate of peripheral blood lymphocytes, (8) proportion of patients with oxygen administration, (9) change in other general blood biomarkers and vital signs from baseline and (10) change in pneumonia image by chest radiography or chest CT. The severity score33 is measured by enquiring the effect of seven pneumonia-related symptoms (cough, shortness of breath, fatigue, headaches, anosmia, dysgeusia and general unwellness) on the patients’ daily life on a 4-point Likert scale (0=not affected, 1=little affected, 2=affected and 3=severely affected), and the number of days required to decrease the total score of the five symptoms by 50% or more from baseline will be analysed for the primary endpoint. The questionnaire for the severity score is shown in the online supplemental table 1.

Data collection, data management and monitoring

A case report form is used for data collection. A central registration number is used to identify the participants for anonymisation. Data collection and management are carried out by third-party entities to avoid bias. Data management is performed by Soiken, Data Management Group (Data Center). To manage and ensure quality, the study is monitored by Soiken, Monitoring Group.

Safety evaluation

During this study, the investigators constantly monitor any AEs through regular medical checkups. All the related AEs, not only side effects to the study agents but also any abnormal clinical laboratory test values and any untoward medical occurrence, are reported and documented. If the AEs meet the following criteria, the events are referred to as serious adverse events (SAEs) based on the ICH E2A, ICH E2D and the ‘Ethical Guidelines for Medical and Health Research Involving Human Subjects’ in Japan34: (1) AEs that result in death, (2) AEs that are life-threatening, (3) AEs that require hospitalisation or prolongation of existing hospitalisation, (4) AEs that result in persistent or significant disability or incapability, (5) other AEs that are medically important or critical, (6) AEs that are equivalently severe to criteria (1) to (5) and (7) AEs that are congenital abnormality or birth defects. AEs are followed up until normalisation or recovery to a level not considered to be an AE. The first hospitalisation following the registration to day 8 and prolongation of the first hospitalisation after day 8 without worsening of pneumonia-related symptoms are not considered as AEs/SAEs in this study, since this study enrolled patients of COVID-19 with pneumonia who should be treated by hospitalisation until the complete disappearance of pneumonia-related symptoms, according to the COVID-19 infectious disease treatment guidelines by the Ministry of Health, Labour and Welfare in Japan.29

Statistical analysis

All the tests will be two sided, and a p value of <0.05 will be considered statistically significant. A statistical analysis plan will be developed prior to the database lock. All the statistical analyses will be conducted by independent biostatisticians.

Three analysis sets are defined in this study; the full analysis set (FAS) included all the patients who are registered in this study and assigned to one of the intervention groups. However, patients with a severe protocol violation, such as registration without consent or registration out of the enrolment period, will be excluded from the FAS. The per-protocol set (PPS) excludes patients with a protocol violation from the FAS, such as violation of eligibility criteria, use of prohibited or restricted concomitant drugs, or poor adherence to the study agent (less than 75% or more than 120%). The safety analysis set includes all the patients who are registered in this study and receive at least one dose of the study agent or control treatment.

Patient characteristics at baseline will be presented as frequencies and proportions for categorical data, and summary statistics (number of patients, mean, SD, 95% CI for mean, minimum, the first quartile, median, the third quartile and maximum) for continuous data. Patient characteristics will then be compared using the χ² test or Fisher’s exact test for categorical endpoints and analysis of variance or Kruskal-Wallis test for continuous variables.

The primary endpoint of this study is the number of days required to improve the clinical symptoms measured by the severity score33 by 50% or more from the baseline. The primary endpoint will be analysed using the FAS and PPS. The cumulative incidence curves for the days required to improve the clinical symptoms measured by the severity score will be drawn, and a log-rank test with a closed testing procedure will be conducted for comparison among the three groups. In addition, HRs among the groups will be estimated using the Cox proportional hazard model, and a 95% CI will be calculated. The HR adjusted by allocation factors (age and sex) as covariates will also be estimated.

For the secondary endpoints, summary statistics (number of patients, mean, SD, 95% CI for mean, minimum, the first quartile, median, the third quartile and maximum) for measurements, changes from baseline and per cent changes from baseline will be calculated for continuous data. Frequencies and proportions will be calculated for the categorical data. Two-sample t-test or Wilcoxon rank sum test for intergroup comparisons of the continuous data, one-sample t-test or Wilcoxon signed-rank test for intragroup comparisons of the continuous data and the χ² test or Fisher’s exact test for intergroup comparisons of the categorical data will be performed. Multiplicity will not be adjusted for the secondary endpoints.

For the safety endpoints, summary statistics for the frequency of AEs will be calculated, and Fisher’s exact tests will be performed for intergroup comparisons. Multiplicity will not be adjusted for the safety endpoints.

Patient and public involvement

The patients and the public are not involved in the study, including planning, execution, analysis and evaluation.

Ethics and dissemination

This study and its protocol were approved by the Clinical Research Review Board of Nagasaki University (approval no. CRB20-027) in accordance with the Clinical Trials Act of Japan. The study will be conducted in accordance with the Declaration of Helsinki, the Clinical Trials Act and other current legal regulations in Japan. Written informed consent will be obtained from all participants after a full explanation of the study. The results of this study will be disseminated at medical conferences and through journal publications.