Comparative Effectiveness and Safety of Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon-Alpha, and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon-Alpha in Patients with Mild to Moderate Novel Coronavirus Disease 2019: A Study Protocol
The emergence of novel coronavirus disease 2019 (COVID-19), caused by the 2019 novel coronavirus (2019-nCoV), has posed significant global health challenges. Originating in Wuhan, China, the rapid spread of COVID-19 coincided with the 2020 Spring Festival, a period characterized by extensive domestic travel, facilitating widespread transmission. By early 2020, over 40,000 cases were confirmed in China, with a mortality rate of approximately 2.3%. The virus, genetically related to SARS-CoV and MERS-CoV, induces respiratory illness marked by fever, cough, dyspnea, and characteristic ground-glass opacities on chest imaging. Despite similarities to previous coronaviruses, no proven antiviral therapies for COVID-19 existed at the onset of the outbreak, prompting urgent investigations into potential treatments.
In response, the National Health Commission of China and the National Administration of Traditional Chinese Medicine issued guidelines advocating the use of interferon-alpha (IFN-α), lopinavir/ritonavir (LPV/r), and ribavirin for COVID-19 management. These recommendations were extrapolated from prior studies on SARS and MERS, where combinations of ribavirin with IFN-α or LPV/r showed promise in reducing viral replication and disease severity in animal models. However, clinical evidence supporting their efficacy in COVID-19 remained absent, highlighting the need for rigorous randomized controlled trials (RCTs). This study protocol outlines a prospective RCT comparing three antiviral regimens for mild to moderate COVID-19: ribavirin plus IFN-α (arm A), LPV/r plus IFN-α (arm B), and triple therapy with ribavirin, LPV/r, and IFN-α (arm C).
Study Design and Objectives
This open-label, single-center, randomized controlled trial aims to enroll 108 patients with mild to moderate COVID-19 at Chongqing Public Health Medical Center. Patients are randomized in a 1:1:1 ratio using block randomization (block size = 9) to one of three treatment arms. The primary objective is to compare the time to viral RNA negativity, defined as two consecutive negative RT-PCR tests for 2019-nCoV from respiratory specimens ≥24 hours apart. Secondary outcomes include viral clearance rate at day 14, 28-day mortality, progression to severe COVID-19, and safety profiles.
Inclusion and Exclusion Criteria
Eligible patients are aged 18–65 years with laboratory-confirmed COVID-19 via RT-PCR from nasopharyngeal/oropharyngeal swabs, sputum, or bronchoalveolar lavage. Mild to moderate disease is characterized by fever, cough, dyspnea, radiographic evidence of pneumonia, respiratory rate 93%, and PaO₂/FiO₂ >300 mmHg. Exclusion criteria include pregnancy, severe hepatic/renal dysfunction (AST/ALT >5× upper limit of normal; creatinine clearance <50 mL/min), hypersensitivity to study drugs, HIV infection, or comorbidities such as severe cardiovascular, pulmonary, or hematologic diseases.
Intervention Protocols
All regimens are administered for 14 days:
- Arm A: Ribavirin (intravenous 2 g loading dose, followed by 400–600 mg orally every 8 hours, adjusted for weight) plus IFN-α1b (5 million IU or 50 μg via nebulization twice daily).
- Arm B: LPV/r (400 mg/100 mg orally twice daily) plus IFN-α1b (dose as above).
- Arm C: Triple therapy combining ribavirin, LPV/r, and IFN-α1b at the aforementioned doses.
Dosing protocols align with Chinese guidelines and prior SARS/MERS studies, balancing antiviral efficacy with tolerability. Ribavirin’s dose adjustments account for hemolytic anemia risks, while LPV/r’s pharmacokinetic enhancement via ritonavir necessitates monitoring for gastrointestinal adverse effects.
Data Collection and Follow-Up
Participants undergo a 28-day follow-up with assessments at days 0, 2, 4, 7, 14, 21, and 28. Serial respiratory samples (nasopharyngeal swabs, sputum) are tested for 2019-nCoV RNA. Blood samples are analyzed for hematologic, hepatic, renal, and inflammatory markers (lymphocyte subsets, coagulation profiles, cardiac enzymes). Chest imaging is repeated at each visit to monitor radiographic progression. Safety assessments include documentation of adverse events (AEs), such as anemia, transaminitis, or thyroid dysfunction, and treatment discontinuation rates.
Statistical Analysis
Sample size calculation (n = 108) assumes 80% power, 95% confidence, and 10% dropout rate. Time-to-event analyses using Cox proportional hazards models will compare viral clearance and mortality between arms. Categorical outcomes (e.g., viral negativity at day 14) are evaluated via chi-square tests or ANOVA, while Kaplan-Meier curves illustrate survival and AE rates. Multivariate Cox models adjust for covariates like age, comorbidities, and baseline viral load. A two-tailed p-value <0.05 signifies statistical significance.
Challenges and Considerations
The trial faces logistical hurdles, including declining COVID-19 incidence in Chongqing due to stringent public health measures, potentially delaying enrollment. Additionally, frequent patient interactions raise infection risks for healthcare workers, necessitating strict personal protective equipment (PPE) protocols. Controversy surrounds triple therapy (arm C), as some clinicians caution against multi-drug regimens due to overlapping toxicities and unproven benefits. However, precedent from MERS case reports supports exploring combination therapies to enhance antiviral activity.
Ethical and Regulatory Compliance
Approved by the Ethics Committee of Chongqing Public Health Medical Center (No. 2020-002-01-KY) and registered with the Chinese Clinical Trial Registry (ChiCTR2000029387), the trial adheres to Good Clinical Practice guidelines. Informed consent ensures participant autonomy, with data anonymization to protect confidentiality.
Implications and Future Directions
This trial represents a critical step toward evidence-based COVID-19 management. By evaluating repurposed antivirals, it addresses an urgent unmet need while avoiding delays associated with novel drug development. Positive findings could validate combination therapies, informing global treatment guidelines. Conversely, negative results would highlight the necessity of exploring alternative agents, such as remdesivir or immunomodulators. Regardless of outcomes, the study’s rigorous methodology provides a template for future pandemic research.
doi.org/10.1097/CM9.0000000000000790
Was this helpful?
0 / 0