Amid concerns among Americans that the rush to approve COVID-19 vaccines may lead to corner-cutting and end products that are not up to typical FDA efficacy standards, leading developers Moderna (NASDAQ:MRNA) and Pfizer (NYSE:PFE) have taken the unusual steps of publishing the protocols of the large-scale late-stage trials for their respective candidates.
Moderna’s Phase 3 trial of mRNA-1273, two 100 microgram doses 28 days apart, will recruit ~30K adults, 60-75% younger than 65 years old not at risk for complications and 25-40% at least 65 years old (the single most significant risk factor) or less than 65 at increased risk of COVID-19 complications.
The primary efficacy endpoint is the incidence of first-occurrence COVID-19 cases starting 14 days after the second shot.
A confirmed (via molecular test) COVID-19 case is defined as a participant who has experienced at least TWO of the following symptoms: fever (≥ 38ºC), chills, myalgia (muscle soreness), headache, sore throat, new olfactory and taste disorder(s) OR he/she must have experienced at least ONE of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing OR clinical or radiographic evidence of pneumonia.
The primary efficacy endpoint is the incidence of confirmed COVID-19 cases starting 7 days after the second shot as measured by the number of cases per 1,000 person-years of follow-up.
A confirmed (via molecular test) COVID-19 case is defined as participants experiencing at least ONE of the following symptoms: fever, new or increased cough, new or increased shortness of breath, chills, new or increased myalgia (muscle soreness), new loss of taste or smell, sore throat, diarrhea or vomiting.
Moderna’s criteria are a more restrictive and could potentially show a higher efficacy rate for mRNA-1273 as a result.
The number of COVID-19 cases in people who just reported one symptom is unknown. According to a July report from CDC, almost all (96%) of infected persons reported “at least” one symptom of fever, cough or shortness of breath according to case investigation forms while 31% reported all three. Based on these percentages, the proportion of people reporting only one symptom could lead to a material difference in the efficacy of the two vaccines.
The most common symptoms are cough (50%), fever (43%), muscle soreness (36%), headache (34%), shortness of breath (dyspnea) (29%), sore throat (20%), diarrhea (19%), nausea/vomiting (12%) and loss of taste/smell (10% each) according to the CDC.
The incidence of severe COVID-19 cases is a secondary endpoint in both trials. Both companies appear to have the similar criteria (aside from their base definitions): Confirmed COVID-19 infection as specified above plus any of the following: clinical signs indicative of severe systemic illness, respiratory rate ≥ 30 per minute, heart rate ≥ 125 beats per minute, SpO2 ≤ 93% on room air at sea level or PaO2/FIO2 < 300 mm Hg OR respiratory failure or acute respiratory distress syndrome (ARDS), (defined as needing high-flow oxygen, non-invasive or mechanical ventilation, or extracorporeal membrane oxygen), evidence of shock (systolic blood pressure < 90 mmHg, diastolic BP < 60 mmHg or requiring vasopressors), OR significant acute renal, hepatic or neurologic dysfunction, OR admission to an intensive care unit or death.
Pfizer will measure the incidence of severe cases as the number per 1,000 patient-years of follow-up.