A proposed clinical trial for COVID-19 pneumonia

This article was originally published on March 23, 2020 on LinkedIn (see link here):

Anecdotal reports suggest that chloroquine (CQ), an old antimalaria drug and its less toxic derivative, hydroxychloroquine (HCQ), may be effective as antiviral treatments against the novel SARS-Cov2, the coronavirus responsible for the now pandemic COVID-19 infection [LinkLinkLinkLinkLink]. The use of these drugs to treat COVID-19 was based on in vitro data suggesting that CQ and HCQ have antiviral       activity against several viruses [LinkLinkLink, Link] including SARS-Cov2 [LinkLink]. There are preliminary reports from China on 100 patients who were treated with CQ or HCQ and showed symptom improvements [Link]. Another recent report from France includes 24 COVID-19 patients who received HCQ with or without azithromycin [Link]. The patients were enrolled consecutively and were not randomized. Forty-two patients completed the trial with data available up to 6 days post-treatment. Hydroxychloroquine was administered at 600 mg a day for 10 days, a dose significantly higher than that recommended for patients with rheumatic and autoimmune diseases [see HCQ PI]. The authors showed that 70% of HCQ-treated patients had viral clearance, versus 12.5% of the controls. An additional 6 patients received HCQ in combination with azithromycin, a macrolide antibiotic.  All 6 patients (100%) in this group had viral clearance at day 6 versus 57% of those treated with HCQ alone [Link]. 

The reasons for the apparent synergistic effects of azithromycin require further study. In addition to its well-known antibiotic activities, azithromycin has both anti-inflammatory and antiviral activities in lower respiratory tract [Link] as well as activity against zika virus [Link]. However, a possible inhibitory activity against SARS-Cov2 has not been studied. The theoretical enhancement of QT prolongation and serious arrhythmias, when combined with HCQ [see HCQ PI] must be weighed against possible benefits. To mitigate this risk, electrocardiograms must be performed at baseline and periodically during treatment. Dosing must also be optimized, since azithromycin could potentially interfere with HCQ metabolism. Based on physiologically-based pharmacokinetic (PBPK) models, a loading dose of 400 mg twice daily of HCQ sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection [Link]

Although encouraging, the human studies of CQ or HCQ so far have been small and non-randomized. Larger randomized controlled trials are needed to definitively establish the efficacy and potential toxicity of these drugs, in combination with azithromycin or other molecules. Several ongoing clinical trials are testing CQ and HCQ for treatment and prophylaxis of COVID-19 in China, Korea and the US and other countries [LinkLinkLink] and many more are on the way.

Zinc appears to be an interesting ion, whose intracellular transport is facilitated by CQ. Zinc inhibits viral replication, including replication of SARS-Cov virus, by inhibiting RNA-dependent RNA polymerase (replicase) [LinkLink]. Unfortunately, zinc, being a positively charged ion does not enter cells. Addition of a zinc ionophore to the cells results in increased intracellular zinc concentration. Interestingly, CQ was found to act as a zinc ionophore [Link] and enhanced inhibition of viral replication. Therefore, CQ appears to exert antiviral activity via multiple interactions with cellular machinery. In addition to increasing endosomal pH and altering ACE2 glycosylation, it also inhibits RNA-dependent RNA polymerase by increasing intracellular zinc concentration. Due to identical mechanisms of action, HCQ is expected to exert similar effects and in fact has been shown to have slightly higher antiviral activity [Link]. Furthermore, based on the early clinical data, the antiviral actions of HCQ can be amplified when azithromycin is added to the therapeutic regimen [Link]. For maximum efficacy, one could envisage using CQ or HCQ in combination with both zinc and azithromycin. Information is already available on the antiviral effects of different zinc salts and the doses required to alter the course of common cold [LinkLink]. Furthermore, low zinc levels in the elderly are associated with higher incidence of pneumonia [Link], and zinc supplementation is associated with shorter duration of severe pneumonia in children [Link]. Considering that the highest mortality in COVID-19 is seen in the elderly and those in nursing homes [LinkLinkLink], the contributing role of zinc deficiency in increased morbidity and mortality among elderly COVID-19 patients must be considered. 

Here we propose a phase II / III study design concept to test all these compounds in order to obtain data needed to inform clinicians for the most effective treatment regimen for moderate to severe COVID-19 infections. The proposed study would be a randomized placebo-controlled parallel group study to assess the efficacy and safety of one of four regimens in the treatment of patients with moderate to severe COVID-19 pneumonia, requiring hospitalization. Following informed consent, patients with an RT-PCR confirmed diagnosis of COVID-19 will be equally divided into 4 groups: 1) control (supportive care), 2) hydroxychloroquine, 3) hydroxychloroquine + azithromycin, 4) hydroxychloroquine + azithromycin + zinc (e.g. zinc acetate). Precise dosing regimens are not discussed and will have to be determined by the investigators based on the available information (see above). Hydroxychloroquine and azithromycin will be administered for 5 days, while zinc may be continued until viral recovery. Baseline assessments will include Chest X-ray, zinc and coper levels, safety laboratory assessments as well as ECG. Those with prolonged QT interval will be excluded. Assessments, including RT-PCR testing for SARS-Cov2, will be performed daily for the first 6 days, then every 2 days until day 10. Zinc and copper levels will also be measured on day 10 or prior to discharge. The primary endpoint will be proportion of patients with viral clearance by day 10. Secondary endpoints could include time to viral clearance, oxygen requirements, need for mechanical ventilation, time to hospital discharge and mortality. Safety assessments will include AEs, SAEs, hepatic, GI, and renal function tests as well as ECG changes. We hope that this high-level study concept will provide the basis for a multi-center collaborative study to quickly determine the most effective and the safest treatment for SARS-Cov2-associated pneumonia.

Mahmoud Loghman-Adham, MD on behalf of Innopiphany, LLC

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