Candidates: Combination of Plaquenil® (hydroxychloroquine sulfate) and Zithromax® or Z-Pak (azithromycin); monotherapies Chloroquine phosphate (formerly Aralen®); Chloroquine hydrochloride (formerly Aralen Hydrochloride®); Zithromax (azithromycin); Zmax (azithromycin extended release)
Category: ANTIVIRAL
Type: Plaquenil and the chloroquine treatments are antimalarial drugs; plaquanil has also been approved by the FDA for lupus erythematosus and rheumatoid arthritis. Chloroquine, for extraintestinal amebiasis. Zithromax and Zmax are antibacterials indicated for adults with acute bacterial sinusitis, and community-acquired pneumonia. Zithromax is also indicated for acute bacterial exacerbations of chronic obstructive pulmonary disease.
Status: Taiwan Liposome (TLC) said November 3 that a manuscript describing how inhalable liposomal hydroxychloroquine (TLC19) may provide clinical benefit and serve as a potential treatment for COVID-19 had been peer-reviewed and accepted by the journal Clinical and Translational Science (CTS), an official journal of the American Society of Clinical Pharmacology and Therapeutics (ASCPT). The accepted manuscript titled “A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Pre-clinical Pharmacokinetic Study”, can be found on the ASCPT website.
A Phase I randomized, vehicle-controlled, blinded study evaluating the safety, tolerability, and pharmacokinetics of inhaled TLC19 in healthy volunteers is ongoing, TLC added.
On August 14, TLC submitted an IND to the Taiwan FDA for TLC19 Hydroxychloroquine Liposome Inhalation Suspension for the treatment of COVID-19. TLC19 uses TLC’s existing proprietary liposome technology to encapsulate ~1/100 of the oral hydroxychloroquine (HCQ) dose into an inhalable formulation for direct deposit into the airways and lungs. TLC reasons that TLC19 can achieve antiviral effect with a miniscule dose compared to oral HCQ while lowering blood and heart exposure, giving TLC19 the potential to treat COVID-19 without many of the side effects seen in some studies.
TLC cited a preprint study in bioRxiv showing that the company achieved proof of concept in rats for its inhalable liposomal HCQ as a potential treatment for COVID-19. The study compared equivalent doses of inhalable liposomal HCQ to intravenous, unformulated HCQ, showing that inhalable liposomal HCQ achieved increased exposure (~30-fold) and half-life (~2.5-fold) in the lungs while also achieving lower blood and heart exposure. The study also suggested that a sustained release of liposomal HCQ might allow for higher concentrations in the lungs than an aerosolized, non-liposomal HCQ formulation, thus requiring significantly lower doses to achieve sufficient and locally sustained drug exposure.
TLC19 is administered using a vibration mesh nebulizer. TLC is working to accelerate development of TLC19 with MicroBase Technology, which specializes in developing inhalation devices to treat respiratory diseases, through an ISO 17025 accredited laboratory capable of aerosol performance analysis.
The U.S. International Development Finance Corp. (DFC) tweeted on August 7 that it was pausing the $765 million loan it agreed to issue Eastman Kodak on July 28 toward the manufacture of active pharmaceutical ingredients for generic drugs that, according to The Wall Street Journal, include hydroxychloroquine. The pause followed allegations of “unusual trading activity” by Sen. Elizabeth Warren (D-MA), after Kodak’s closing share price rocketed from $2.62 the day before the IFC announcement, to $7.94 the day of the announcement and $33.20 the following day.
Warren requested that the U.S. Securities and Exchange Commission (SEC) probe whether insider trading laws were broken. The Journal reported, based on unnamed sources, that the SEC has begun the investigation; the SEC declined comment. Eastman Kodak responded August 7 by appointing a special committee of independent directors of its Board—Jason New and William G. Parrett—to oversee an internal review of loan-related “recent activity by the company and related parties.” The committee will conduct the internal review through the law firm Akin Gump Strauss Hauer & Feld.
The loan would mark the first use of new authority delegated by an executive order of President Donald Trump that allowed DFC to partner with the U.S. Department of Defense (DoD) toward supporting the nation’s response to COVID-19 under the Defense Production Act (DPA). The Trump administration reasons that ramping up domestic production of drug ingredients will accelerate production of drugs for COVID-19 and other disorders and reduce dependence on other countries.
On July 16, a research team led by David R. Boulware, MD, MPH, of University of Minnesota concluded in a study published in Annals of Internal Medicine that a five-day course of hydroxychloroquine “failed to show a substantial clinical benefit in improving the rate of resolution of COVID-19 symptoms” in adult outpatients assessed in the Phase III COVID-19 PEP trial (NCT04308668).
The randomized, double-blind, placebo-controlled trial—conducted between March 22 and May 20—was designed to test if hydroxychloroquine can prevent symptomatic COVID-19 after known exposure to SARS-CoV-2, and if early preemptive hydroxychloroquine therapy can prevent disease progression in patients with known symptomatic COVID-19 disease, decreasing hospitalizations and symptom severity. The trial enrolled 491 patients who received
The trial’s primary endpoint was the change in symptom severity score over 14 days in those given hydroxychloroquine versus placebo for 423 participants with available longitudinal data on symptom severity. Boulware and colleagues reported that patients randomized to hydroxychloroquine showed only a 12% relative improvement over placebo. They compared hydroxychloroquine to the influenza treatment Tamiflu (oseltamivir), which has shown a 25% to 35% relative reduction in symptom severity score in clinical studies.
At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194). However, adverse effects were more common in those receiving hydroxychloroquine (43% [92 of 212]) than placebo (22% [46 of 211]), with gastrointestinal symptoms the most commonly reported adverse effect among hydroxychloroquine patients: 31% (66 of 212) reported upset stomach or nausea, and 24% (50 of 212) reported abdominal pain, diarrhea, or vomiting.
The WHO said July 4 it discontinued the hydroxychloroquine and Kaletra® (lopinavir/ritonavir) arms of its Solidarity clinical trial. The WHO accepted a recommendation from the study’s International Steering Committee, which cited interim trial results showing that hydroxychloroquine and lopinavir/ritonavir produced little or no reduction in the mortality of hospitalized COVID-19 patients compared to standard of care. However, the interim results did not provide solid evidence of increased mortality, either.
The WHO said researchers observed some associated safety signals in the clinical findings of the European add-on clinical trial Discovery, which had been studying the same drugs as Solidarity. The signals will be reported in the same peer-reviewed publication as interim Solidarity trial results.
On July 2, Henry Ford Health System researchers published a favorable study of hydroxychloroquine in the International Journal of Infectious Diseases. The multi-center retrospective analysis of 2,541 patients hospitalized between March 10 and May 2 across the system’s six hospitals, the study found 13% of those treated with hydroxychloroquine alone died, as did 20.1% treated with a combination of azithromycin and hydroxychloroquine died, and 22.4% of those treated only with azithromycin died—all compared to 26.4% of patients dying who were not treated with either medication.
The vast majority received the drug soon after admission; 82% within 24 hours and 91% within 48 hours of admission. All patients in the study were 18 or over with a median age of 64 years; 51% were men and 56% African American. While none of the patients had documented serious heart abnormalities, patients were monitored for a heart condition routinely pointed to as a reason to avoid the drug as a treatment for COVID-19, Henry Ford said.
Patients treated with hydroxychloroquine at Henry Ford met specific protocol criteria as outlined by the hospital system’s Division of Infectious Diseases—one of several factors that may have influenced results.
“Concomitant steroid use in patients receiving hydroxychloroquine was more than double the non-treated group. This is relevant considering the recent RECOVERY trial that showed a mortality benefit with dexamethasone among individuals requiring supplemental oxygen or mechanical ventilation, potentially biasing this study’s results in favor of hydroxychloroquine,” Todd C. Lee, MD, MPH, FIDSA, and colleagues observed in an Editorial commentrary published July 2 by the same journal, the peer-reviewed, open-access online publication of the International Society of Infectious Diseases.
The NIH said June 20 that its National Heart, Lung, and Blood Institute (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.
Three days earlier, 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.
On June 15, the FDA repealed the emergency use authorization (EUA) it granted in March to anti-malarial drugs chloroquine phosphate and its less toxic metabolite hydroxychloroquine sulfate as treatments for COVID-19, citing a lack of consistent replication of earlier promising results and a randomized controlled clinical trial that showed no clinical benefit for hydroxychloroquine.
Rear Admiral Denise M. Hinton, the FDA’s Chief Scientist, granted the Biomedical Advanced Research and Development Authority (BARDA)’s request to undo the emergency use authorization it granted March 28 to hydroxychloroquine and chloroquine at BARDA’s request. Real Admiral Hinton 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. “The RECOVERY Trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalized with COVID-19.”
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).
Also cited by Rear Admiral Hinton was a study published May 14 in BMJ, Wei Tang, MD, of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, led a team of Chinese researchers that concluded: “Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate COVID-19.
The RECOVERY trial was among reasons cited by the World Health Organization on June 17 for stopping the hydroxychloroquine arm of its Solidarity Trial; other factors included data gathered in Solidarity, as well as a Cochrane review of other evidence of hydroxychloroquine showing that the drug does not result in the reduction of mortality of hospitalised COVID-19 patients, when compared with standard of care. More than 3,500 patients had been recruited for Solidarity in 35 countries.
Earlier in June, The Lancet retracted another study that cast an unfavorable light on the safety of chloroquine and its less toxic metabolite, hydroxychloroquine. The study was led by Mandeep R. Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School.
In the Lancet study, Mehra and colleagues concluded they “were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19.” That study was based on a data analysis from 671 hospitals in six continents, from which Mehra and colleagues identified 96,032 patients hospitalized with COVID-19 between Dec 20, 2019, and April 14. The data was analyzed by Surgisphere, which refused to transfer its full dataset, client contracts, and full ISO audit report to the Lancet’s third-party reviewers, contending that it would violate client agreements and confidentiality requirements. The authors then requested the paper be retracted, stating that they could no longer vouch for the data.
“In my hope to contribute to this research during a time of great need, I did not do enough to ensure that the data source was appropriate for this use,” Mehra told The New York Times.
The study prompted France and Italy to halt the use of hydroxychloroquine as a treatment for COVID-19, two days after the WHO paused the hydroxychloroquine arm of its Solidarity trial due to concerns about the drug’s safety. Also as a result, the University of Oxford’s 40,000-participant double-blind, randomized, clinical trial assessing chloroquine phosphate or hydroxychloroquine sulfate compared with placebo (NCT04303507) was paused, while Belgium’s Federal Agency for Medicines and Health Products cautioned against using hydroxychloroquine to treat COVID-19 outside of registered clinical trials.
The Lancet study was one of two Mehra-led COVID-19 studies to be retracted on June 4. The other study published in The New England Journal of Medicine (NEJM) concluding that the use of either ACE inhibitors or statins was associated with better survival among patients with COVID-19: “However, these associations should be considered with extreme caution. Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding.”
On June 3, a research team led by David R. Boulware, MD, MPH, of University of Minnesota concluded in a study published in NEJM that high doses of hydroxychloroquine did not prevent illness compatible with COVID-19 when initiated within four days after a high-risk or moderate-risk exposure: “This randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for Covid-19.” The trial—said to be the first randomized, double-blind, placebo-controlled study of hydroxychloproquine—recruited 821 U.S. and Canadian participants via social and traditional media, with almost all data self-reported by the participants.
However, in an accompanying NEJM editorial, Myron S. Cohen, MD, Director of the Institute for Global Heath and Infectious Diseases at University of North Carolina at Chapel Hill, cautioned: “The results reported by Boulware et al. are more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined.”
Also to be determined is when the Phase III Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine trial (HERO-HCQ; NCT04334148) might be completed. The trial is expected to take months longer to complete than the five to six months originally planned, Susanna Naggie, MD, vice dean for clinical research and an associate professor at Duke University School of Medicine, told USA Today on June 7.
Naggie said researchers have struggled to recruit patients, enrolling only 800 of the planned 15,000 healthcare worker participants at risk of COVID-19 exposure. Patients are randomized to placebo or a 600mg Hydroxychloroquine tablet on day 1, followed by a 400mg tablet on days 2-30. The primary endpoint of the double blind, placebo-controlled study is the number of participants with clinical infection with COVID-19.
In May, U.S. Secretary of Veterans Affairs Robert Wilkie told a subcommittee of the U.S. House of Representatives Committee on Appropriations that the Department of Veterans Affairs had “ratcheted down” its use of hydroxychloroquine to treat veterans with COVID-19. Wilkie told the Subcommittee on Military Construction, Veterans Affairs, and Related Agencies on May 28 that VA providers treated three patients with hydroxychloroquine the previous week, down from the high of 404 patients the week of March 29. In total, 1,300 veterans were treated with the drug, Wilkie wrote in a letter to U.S. Senate Minority Leader Chuck Schumer (D-NY).
“People in sound mind asked to be given this experimental treatment. The other option was to do nothing,” Wilkie said. “Everyone is learning this is in real time, and we followed FDA guidelines on this.”
In a research letter published May 28 in JAMA, Muthiah Vaduganathan, MD, MPH of Brigham and Women’s Hospital and five co-authors reported that during the week of March 15 to March 21, hydroxychloroquine/chloroquine prescriptions increased from 2,208 in 2019 to 45,858 for fewer than 28 tablet fills (a 1,977% increase), from 70,472 to 196,606 for 28-60 tablet fills (up 179%), and from 44,245 to 124,833 prescriptions for more than 60 tablet fills (up 182%).
Australia’s Walter and Eliza Hall Institute of Medical Research plans to study hydroxychloroquine in COVID SHIELD, a Phase II/III randomized, double-blinded clinical study assessing the drug as preventive care for frontline healthcare workers fighting the COVID-19 pandemic. Local hospitals across Australia will administer hydroxychloroquine or a placebo to approximately 2,250 participants. The Institute has selected IQVIA to manage COVID SHIELD through virtual clinical tools and technologies that include remote monitoring, eConsent, eTMF, and e-source.
President Donald Trump on May 18 renewed the controversy over hydroxychloroquine by disclosing he had been taking the drug for about a week and a half. “I think it’s good. I’ve heard a lot of good stories,” Trump told reporters during a roundtable discussion with leaders in the restaurant industry held at the White House.
Four days earlier, the National Institute of Allergy and Infectious Diseases (NIAID) said it has begun assessing hydroxychloroquine and azithromycin in a Phase IIb clinical trial (A5395; NCT04358068) being conducted by the NIAID-funded AIDS Clinical Trials Group (ACTG). Teva Pharmaceuticals is donating medications for the study, which will enroll approximately 2,000 adults at participating ACTG sites nationwide. The principal aim of the study is to determine whether hydroxychloroquine and azithromycin can prevent hospitalization and death due to COVID-19. Additionally, investigators will evaluate the safety and tolerability of the experimental treatment for people with SARS-CoV-2 infection.
A team of researchers at New York–Presbyterian Hospital (NYP)–Columbia University Irving Medical Center (CUIMC) on May 7 said an observational study observational study it conducted of 1,376 CUIMC patients with moderate to severe COVID-19 disease showed that hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of intubation or death, the study’s composite end point. “Randomized, controlled trials of hydroxychloroquine in patients with COVID-19 are needed,” the researchers cautioned in their study published in The New England Journal of Medicine, which they said was the largest published study of hydroxychloroquine in COVID-19 patients.
Also in May, the COVID-19 Research Outcomes Worldwide Network (CROWN) Collaborative, an international group of physicians and scientists, is testing chloroquine can prevent COVID-19 infection or decrease its severity in frontline healthcare workers. An estimated 30,000 such workers worldwide will participate in the CROWN CORONATION clinical trial. The collaborative and the trial are funded by the COVID-19 Therapeutics Accelerator, an initiative of public and philanthropic donors intended to support research and development to bring effective, accessible COVID-19 treatments to market as quickly as possible.
The FDA on April 24 issued an advisory to healthcare professionals cautioning against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. The agency cited reports of serious heart rhythm problems in patients with COVID-19 treated with hydroxychloroquine or chloroquine, often in combination with azithromycin and other QT prolonging medicines—as well as increased use of these medicines through outpatient prescriptions. “Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19,” the FDA said. “We will continue to investigate risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate publicly when we have more information.”
The advisory capped a week in which demand for hydroxychloroquine plummeted 62%, to 198,500 tablets from 462,850 tablets the week ending April 17, according to Vizient, a group purchasing organization for about 3,000 U.S. hospitals and health care facilities.
The FDA’s advisory followed weeks of actions and statements about the antimalarial drugs ranging from cautious to positive by federal officials as high as President Donald Trump. Some prominent supporters of Trump have advocated for hydroxychloroquine over other widely-discussed potential COVID-19 treatments, notably Gilead Sciences’ remdesivir, Politico reported May 2.
The heightened caution followed publication April 23 of a preprint study in medRxiv in which researchers in South Carolina and Virginia concluded: “Hydroxychloroquine use with or without co-administration of azithromycin did not improve mortality or reduce the need for mechanical ventilation in hospitalized patients.”
The researchers conducted a retrospective analysis of data from 368 patients (men whose median age was over 65 years) hospitalized with confirmed SARS-CoV-2 infection in all U.S. Veterans Health Administration medical centers until April 11. The analysis showed rates of death in the hydroxychloroquine (HC), HC + azithromycin (AZ), and no HC groups were 27.8%, 22.1%, and 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.
Also in April, a team of Brazilian investigators published preliminary findings in JAMA Network Open from a study of 81 patients with severe SARS-CoV-2 recommending against the higher of two dosages of chloroquine diphosphate (CQ): “The 600 mg dosage of should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir,” the Brazilian researchers concluded.
Eleven patients died by the sixth day of treatment with 600 mg CQ twice daily for 10 days after developing heart arrhythmias, leading researchers to halt that portion of the Phase II trial (CloroCOVID19; NCT04323527). The study also assessed a lower dosage (450 mg twice daily on day 1 and once daily for 4 days). Overall, lethality until day 13 was 39% in the high-dosage group (16 of 41 patients) and 15% in the low-dosage group (6 of 40 patients).
“Hydroxychloroquine has several serious known side effects and should be used with caution. Not everyone can take this medicine. To date, there is insufficient clinical evidence to draw any conclusion over the safety and efficacy of hydroxychloroquine in the management of COVID-19 patients.”
Novartis, whose Sandoz generics and biosimilars division markets a generic version of hydroxychloroquine, has launched a Phase III trial (NCT04358081) designed to assess hydroxychloroquine in hospitalized patients with COVID-19, after reaching agreement with the FDA April 20 to initiate a randomized, double-blind, placebo controlled study, set to recruit approximately 440 patients and use hydroxychloroquine donated by Sandoz.
Earlier in April, Sanofi said it would donate 100 million doses of Plaquenil across 50 countries, adding that it had doubled its incremental production capacity—in addition to production for current indications—across its eight hydroxychloroquine manufacturing sites worldwide, and was on track to quadruple production by the summer.
On April 4, Trump said the U.S. government will place 29 million doses of hydroxychloroquine into the Strategic National Stockpile to allow for use by COVID-19 patients—one of several statements that promoted use of that drug, alone and in combination with Zithromax (“I just hope that hydroxychloroquine wins, coupled with, perhaps, the Z-Pak”)—despite concerns expressed by Anthony Fauci, MD, Director of the NIH’s National Institute of Allergy and Infectious Diseases, that more data was needed on the safety and efficacy of the drugs.
Trump’s remarks came five days after the FDA on March 28 issued an emergency use authorization allowing healthcare providers to make available chloroquine phosphate or hydroxychloroquine sulfate to “patients for whom a clinical trial is not available, or participation is not feasible,” adding “FDA encourages the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of these products in treating COVID-19.”
The Population Research Institute is recuirting 1,500 participants for an open-label, parallel group, randomized controlled trial (NCT04324463) being conducted in collaboration with Bayer.
One other clinical trial is recruiting healthcare workers as patients to assess hydroxychloroquine—an up-to-440-patient randomized study (NCT04331834) by the Barcelona Institute for Global Health. Another trial, an up-to-360 patient no-randomized study (NCT04333225) by Baylor Research Institute, was active but not recruiting as of May 5. Two other trials are being conducted in Australia, where the government of Prime Minister Scott Morrison on April 2 exempted hydroxychloroquine from the nation’s register of therapeutic goods, conditioned on the drug being imported, manufactured, or supplied via contract or arrangement with the health department.
Sanofi has offered French authorities “millions of doses” of Plaquenil, enough to treat up to 300,000 people. Sanofi obtained FDA approval for both Plaquenil (in 1955) and Aralen (in 1949), though the company has discontinued marketing brand-name Aralen. Pfizer gained FDA approval for Zithromax in 1991. All three drugs are marketed as generics by numerous companies worldwide. Among generic manufacturers, Mylan said in March it would restart production of hydroxychloroquine sulfate tablets at its West Virginia manufacturing facility while Teva Pharmaceutical Industries committed to donating more than 10 million doses by this month.
Notably, a study in press March 17 in the journal International Journal of Antimicrobial Agents was a 42-patient study in which 26 patients completed treatment with hydroxychloroquine, six with hydroxychloroquine and azithromycin, and 16 patients served as a control group receiving symptomatic treatment and antibiotics (six halted hydroxychloroquine treatment early).
On March 17, a team led by Professor Didier Raoult, MD, PhD, of l’Institut Hospitalo-Universitaire (IHU) Méditerranée Infection in Marseille, published a study in the journal International Journal of Antimicrobial Agents reporting that “100% of patients treated with hydroxychloroquine and azithromycin combination were virologicaly cured comparing with 57.1% in patients treated with hydroxychloroquine only, and 12.5% in the control group.” In the 42-patient study, 26 patients completed treatment with hydroxychloroquine, six with hydroxychloroquine and azithromycin, and 16 patients served as a control group receiving symptomatic treatment and antibiotics (six halted hydroxychloroquine treatment early).
Raoult—who discussed the results in a YouTube video posted March 17—has been appointed by the French government to research possible COVID-19 treatments. On April 9, French President Emmanuel Macron unexpectedly flew to Marseille and spent more than three hours meeting with Raoult. While Prof. Christine Rouzioux, MD, PharmD, PhD, of Paris Descartes University told BFM TV said the meeting sent a message of support to Raoult, aides to the French president said it showed instead his willingness to listen to a broad range of scientific opinions.
A Chinese research team published positive results for hydroxychloroquine in COVID-19 patients, concluding March 18 in Cell Discovery that: “HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. In combination with its anti-inflammatory function, we predict that the drug has a good potential to combat the disease. This possibility awaits confirmation by clinical trials.”
Another Chinese team concluded that chloroquine and Gilead Sciences’ Remdesivir were “highly effective in the control of 2019-nCoV infection in vitro,” according to a study published February 4 in the Nature-owned journal Cell Research that added: “They should be assessed in human patients suffering from the novel coronavirus disease.” Another Chinese team reported March 4 in Clinical Infectious Diseases that “Hydroxychloroquine was found to be more potent than chloroquine.”
However, neither the French nor Chinese studies were randomized clinical trials. The French investigators also acknowledged the “small sample size” in their conclusion—as cited by critics, along with the side effects of hydroxychloroquine. Critics also cite the death of a man after he and his wife ingested fish tank cleaner containing chloroquine phosphate; the death was disclosed March 23 by healthcare provider Banner Health, which added that his wife was in critical condition at a Banner hospital. Supporters of chloroquine phosphate have countered that the couple ingested a far higher dose than a doctor would have prescribed.
A trial of hydroxychloroquine for COVID-19 in China vs. placebo (NCT04261517) was completed as of April 13, while a study comparing the drug vs. AbbVie’s Kaletra (NCT04307693) was terminated as of May 27 after only 65 participants were recruited. While the ‘1517 study showed positive preliminary outcomes, its sample size was small (N=30, randomized 1:1 to treatment or placebo), and virological clearance rate was for placebo patients (93.3%) vs. hydroxychloroquine (86.7%). Radiological progression showed on 5 hydroxychloroquine patients (33.3) vs. 7 placebo patients (46.7%). A multi-nation trial comparing chloroquine with Kaletra in up to 3,040 patients (NCT04304053) was recruiting patients as of April 16.
In Brazil, an early Phase I trial (NCT04348474) assessing the hydroxychloroquine-azithromycin combination in mild ambulatory COVID-19 patients was suspended in April after Azidus, the contract research organization conducting the study for the Prevent Senior Institute in São Paulo, “lost the interest to conduct this study,” according to the study’s page on ClinicalTrial.gov. However, the daily newspaper Estadão de São Paulo reported April 20 reported that the study was suspended because the National Commission for Ethics in Research (Conep) discovered that the trial was launched before the Institute received approval to carry out tests. A post on the blog Science Integrity Digest by Elisabeth Bik reported numerous problems with the study, including that the study was unclear on how many patients actually had COVID-19, and was not randomized.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types:
● ANTIVIRAL
● VAX
● ANTIBODY
● RNA
