What Does "Early Treatment" Mean, In the Context of COVID-19?

It’s always good to define our terms, so I took the most conservative path I could: I collected all the Randomized Controlled Trials (RCTs) published in the New England Journal of Medicine that claimed to be treating COVID-19 early. If I missed any, let me know. (If you feel like doing the same exercise on a different journal like JAMA, that would be fantastic.)

So what did I find? Well, to start with, I found seven trials published between November 2021 and May 2022. Let’s walk through them:

Sotrovimab

Definition of early treatment:

Adult patients (≥18 years of age) who had a positive result on reverse-transcriptase–polymerase-chain-reaction or antigen SARS-CoV-2 testing and an onset of Covid-19 symptoms within the previous 5 days were screened for eligibility; screening was performed within 24 hours before the administration of sotrovimab or placebo.

In short: up to 5+1 days from onset of symptoms until treatment.

Median: ~2.5+1 (educated guess).

Early Convalescent Plasma

Definition of early treatment:

The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression.

In short: up to 7 days from onset of symptoms until treatment.

Median: 4 days.

Early Remdesivir

Definition of early treatment:

Eligible patients had at least one ongoing symptom consistent with Covid-19, with onset of the first symptom within 7 days before randomization (given that hospitalization typically occurs at or after 7 days of symptoms)

Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2 and 3) or placebo

In short: up to 7+1 days from onset of symptoms until treatment.

Median: 5+1 days.

Molnupiravir

Definition of early treatment:

In this trial, oral molnupiravir was found to be effective for the treatment of Covid-19, without evident safety concerns, when initiated within 5 days after the onset of signs or symptoms

Points for style:

Antiviral therapies that reduce the risk of Covid-19 progression are needed. Since trials have shown the need for initiation of treatment as soon as possible after the onset of symptoms,7-9 such therapies would ideally be readily available and easily administered by the patients themselves.10,11

In short: up to 5 days from onset of symptoms until treatment.

Median: ~3 days (educated guess).

Ivermectin (TOGETHER Trial)

Definition of early treatment:

On presentation to one of the trial outpatient care clinics, potential participants were screened to identify those meeting the eligibility criteria. Inclusion criteria were an age of 18 years or older; presentation to an outpatient care setting with an acute clinical condition consistent with Covid-19 within 7 days after symptom onset.

(There is some question as to whether treatment was administered on day 0 or day 1 after randomization, so we’ll err on the side of caution for now.)

In short: up to 7+1 days from onset of symptoms until treatment.

Mean: they say 3.8+1 days, but I have reason to believe this is overly optimistic.

Early Outpatient Convalescent Plasma

Definition of early treatment:

Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization

In short: up to 8+1 days from onset of symptoms until treatment.

Median: 6+1 days.

Paxlovid

Definition of early treatment:

Our data show that treatment with nirmatrelvir plus ritonavir early in Covid-19 illness can decrease progression to severe disease and quickly reduce SARS-CoV-2 viral load.

The primary objective of the trial was to assess the efficacy of nirmatrelvir plus ritonavir as compared with placebo by comparing the percentage of patients with Covid-19–related hospitalization or death from any cause through day 28 in the two groups. This comparison was performed in the modified intention-to-treat population, which included patients whose treatment began within 3 days after the onset of Covid-19 signs and symptoms and excluded patients who at randomization had received or were expected to receive monoclonal antibody treatment (see Table S2 for definitions of all analysis populations)

While the trial admitted patients with up to 5 days days of symptoms, the patients counted in the primary endpoint were only those treated with 3 days of symptoms or less.

In short: up to 3 days from onset of symptoms until treatment.

Median: 3 days.

To Sum Up

In this fairly quick survey, I found six early treatment trials, with treatment given within 3-9 days. The order from shortest to longest time per trial is:

1. Paxlovid (Max: 3/5 days, Median: 3 days: IQR: -)

2. Molnupiravir (Max: 5 days, Median: 3 days, IQR: -)

3. Sotrovimab (Max: 6 days, Median: 3.5, IQR: -)

4. Convalescent Plasma (Max: 7 days, Median: 4 days, IQR: [2-5])

5. Ivermectin (Max: 8 days, Mean: 5 days, IQR: - )

5. Remdesivir (Max: 8 days, Median: 6 days, IQR [4-7])

7. Outpatient Convalescent Plasma (Max: 9 days, Median: 7 days, IQR [5-8])

Notice any patterns? No? Me neither!

Just kidding. The top three are all high-budget trials for high-profit drugs. The outlier is remdesivir, but then again, the outlier is always remdesivir. One day I’ll pick up this thread again; one of the most bizarre corners of pandemic-era bureaucratic activity:

The Remdesivir Riddle

What else can we learn here? Up to seven days of symptoms before initiation of treatment, with a median of four days is where the middle-of-the-pack trial is. The latest we found in NEJM is nine days max with a median of seven.

Why did I write this, you ask? Well, I’m working on something else, and I needed this to be written somewhere without making that piece even longer. Hope you found this piece interesting enough.

And, hold on to your seats… :)