The U.K.’s push for COVID-19 master protocols pays off again with definitive data on lopinavir-ritonavir

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The U.K.’s RECOVERY trial and broader strategy to encourage master protocol participation are proving their value again, this time with data showing that the lopinavir-ritonavir antiviral cocktail has no clinical benefit in hospitalized patients not on a ventilator.

The readout is the third this month for the randomized, controlled adaptive trial, and lends additional support to the master protocol model as the fastest and most efficient way to generate statistically powered clinical data during the pandemic and beyond (see “Master Protocols Emerge”.)

On Tuesday, the trial’s Steering Committee announced the antiviral failed to improve 28-day mortality, the primary endpoint. AbbVie Inc. (NYSE:ABBV) markets the protease inhibitor combination as Kaletra for HIV.

Among 1,596 patients randomized to receive the generic HIV antiviral lopinavir-ritonavir, 28-day mortality was 22.1% compared with 21.3% for the 3,376 patients who received standard of care. The results were consistent across patient subgroups, and there was no evidence of benefit on risk of progression to mechanical ventilation or length of hospital stay.

The study didn’t draw conclusions about the antiviral’s benefit in patients requiring invasive mechanical ventilation due to challenges administering the drug to the population.

RECOVERY is no longer enrolling patients in the lopinavir-ritonavir arm, and is continuing to enroll patients in the azithromycin antibiotic, tocilizumab immune modulator and convalescent plasma arms. It is also enrolling pediatric patients in the dexamethasone arm after the steroid showed survival benefit in adults.

Master protocol studies bear fruit

With over 11,800 patients enrolled, RECOVERY is the largest clinical trial for COVID-19 and is generating a growing list of readouts that have immediately guided authorization decisions and shaped other trial designs.

Two weeks ago, the trial released data showing that the dexamethasone steroid had a survival benefit in hospitalized patients receiving oxygen, leading to an authorization in the U.K. the same day (see “U.K. Approves Steroid After Master Protocol”).

Less than two weeks earlier, the randomized, controlled master protocol trial found that the controversial drug hydroxychloroquine failed to benefit hospitalized COVID-19 patients. Those results were cited as one of the two reasons FDA revoked its Emergency Use Authorization (see “FDA Revokes Chloroquine Authorizations”).

Actionable data emerging from RECOVERY support the U.K.’s strategy to prioritize master protocols over smaller studies for COVID-19.

In April, the U.K. named three master protocol trials that span the disease stages as national priority trials and encouraged patients to enroll in the studies. In addition to RECOVERY, which primarily targets hospitalized patients, it also prioritized the PRINCIPLE trial in older non-hospitalized ambulatory patients and REMAP-CAP in more severe hospitalized patients (see “U.K. Sets the Bar”).

At least five other adaptive master protocol trials have been disclosed around the world, but they haven’t enrolled as many patients and haven’t received the same prioritization. Industry is still waiting for readouts.

According to ClinicalTrials.gov, 57 trials are evaluating lopinavir-ritonavir in active interventional trials for COVID-19, and at least three other master protocols -- REMAP-CAP, INSERM’s DISCOVERY trial and Australia’s ASCOT trial -- are evaluating the antiviral.

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