The NIH’s National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO) have both halted clinical studies of hydroxychloroquine conducted as part of larger multi-drug trials based on efficacy, while Novartis ended its Phase III due to its inability to recruit enough patients.
The clinical setbacks—announced Saturday by the NIH, Friday by Novartis, and last Wednesday by the WHO—come less than a week after the FDA repealed its emergency use authorization (EUA) for the controversial antimalarial drug, citing in part a lack of consistent replication of earlier promising results, and a randomized controlled clinical trial that showed no clinical benefit for hydroxychloroquine.
The NIH said that NHLBI halted its Outcomes Related to COVID-19 Treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) Study (NCT04332991), which was being conducted by the NHLBI’s Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network.
The NHLBI acted on the recommendation of the trial’s data and safety monitoring board, which determined after its fourth interim analysis that while there was no harm, hydroxychloroquine was very unlikely to be beneficial to hospitalized patients with COVID-19.
The blinded, placebo-controlled randomized clinical trial aimed to enroll more than 500 adults hospitalized with COVID-19 or in an emergency department with anticipated hospitalization. ORCHID participants had been randomly assigned to receive hydroxychloroquine 400 mg twice daily for two doses (day one), then 200 mg twice daily for the subsequent eight doses (days two to five) or a placebo twice daily for five days.
More than 470 were enrolled at the time the study was halted. Patients randomized to the experimental intervention had also received hydroxychloroquine. Participants will now continue to receive standard of care and follow up as indicated for their condition, the NIH said.
A day before the NIH’s announcement, Novartis cited “acute enrollment challenges” in announcing that it was suspending its planned 440-patient Phase III trial (NCT04358081) designed to assess hydroxychloroquine in hospitalized patients with COVID-19.
Novartis, whose Sandoz generics and biosimilars division markets a generic version of hydroxychloroquine, reached agreement with the FDA April 20 to initiate a randomized, double-blind, placebo controlled study, which had been set to use hydroxychloroquine donated by Sandoz. The company said no safety issues had been reported, and emphasized that it reached no conclusions on the efficacy of hydroxychloroquine from its study.
Hydroxychloroquine is among the approximately 100 drugs and vaccines that GEN is “Keeping an Eye On” in its COVID-19 DRUG & VACCINE CANDIDATE TRACKER, which now counts nearly 250 candidates in development against the virus.
WHO Cites Lack of Benefit
On June 17, the World Health Organization halted the hydroxychloroquine arm of its Solidarity clinical trial after advisers concluded that the drug showed no benefit compared to standard of care in reducing deaths, Ana Maria Henao-Restrepo, MD, medical officer in WHO’s Department of Immunization Vaccines and Biologicals, WHO medical officer, told reporters.
The trial’s other treatment arms are: standard care; Gilead Sciences’ remdesivir; AbbVie’s Kaletra (lopinavir/ritonavir); and Kaletra combined with interferon.
The halted WHO, Novartis, and NIH studies capped a week of setbacks for hydroxychloroquine that began June 15, when the FDA repealed the EUA it granted in March to hydroxychloroquine and another chemically related anti-malarial drug, chloroquine phosphate as treatments for COVID-19.
Rear Admiral Denise M. Hinton, the FDA’s chief scientist, cited data from the 11,000-plus patient, Phase II/III RECOVERY trial (NCT04381936), which assessed hydroxychloroquine among six potential treatments for COVID-19. In June, investigators stopped enrolling participants in the 1,542-patient hydroxychloroquine arm.
“There is no beneficial effect of hydroxychloroquine in patients hospitalized with COVID-19,” Profs. Peter Horby, MD, PhD, and Martin Landray, MB ChB, PhD, FRCP, both of the University of Oxford, concluded.
In addition to hydroxychloroquine, the RECOVERY trial also evaluated azithromycin, Abbvie’s Kaletra (Lopinavir-Ritonavir), an unspecified corticosteroid, convalescent plasma, and Roche/Genentech’s Actemra® (tocilizumab).
Since the onset of the COVID-19 pandemic, hydroxychloroquine gained both global attention and intense clinical scrutiny after President Donald Trump first advocated its use in combination with azithromycin—declaring in a March 21 tweet that the hydrochloroquine-azithromycin combination has “a real chance to be one of the biggest game changers in the history of medicine.”
Last month, Trump disclosed that he had taken the drug to protect from infection with the SARS-CoV-2 virus.