NIH clinical trial of remdesivir to treat COVID-19 begins

NIH clinical trial of remdesivir to treat COVID-19 begins

Dr KK Aggarwal

President CMAAO, HCFI and Past national President IMA

A randomized, controlled NIH supported clinical trial to evaluate the safety and efficacy of the investigational antiviral remdesivir in hospitalized adults diagnosed with COVID-19 has begun at the University of Nebraska Medical Center in Omaha.

The first trial participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship that docked in Yokohama, Japan and volunteered to participate in the study.

Remdesivir, developed by Gilead Sciences Inc., is an investigational broad-spectrum antiviral treatment. It was previously tested in humans with Ebola virus disease and has shown promise in animal models for treating MERS and SARS, which are caused by other coronaviruses.

Clinical trials of remdesivir are also ongoing in China.

Participants in the NIH-sponsored trial must have laboratory-confirmed SARS-CoV-2 infection and evidence of lung involvement, including rattling sounds when breathing (rales) with a need for supplemental oxygen or abnormal chest X-rays, or illness requiring mechanical ventilation.

Individuals with confirmed infection who have mild, cold-like symptoms or no apparent symptoms will not be included in the study.

In accordance with standard clinical research protocols, eligible patients will provide informed consent to participate in the trial.

All potential participants will undergo a baseline physical exam before receiving treatment. Eligible study participants will then be randomly assigned either to the investigational treatment group or the placebo group.

The study is double-blind, meaning trial investigators and participants would not know who is receiving remdesivir or placebo. Participants in the investigational treatment group will receive 200 milligrams (mg) of remdesivir intravenously on the first day of enrollment to the study. They will receive another 100 mg each day for the duration of hospitalization, for up to 10 days total. The placebo group will receive, at an equal volume, a solution that resembles remdesivir but contains only inactive ingredients.

Clinicians will regularly monitor participants and will assign them daily scores based on a predefined scale of clinical outcomes that considers factors such as temperature, blood pressure and use of supplemental oxygen, among others. Participants also will be asked to provide blood samples and nose and throat swabs approximately every two days. Researchers will test these specimens for SARS-CoV-2.

Initially, investigators will compare participant outcomes on day 15 in both the remdesivir group and the placebo group to see if the investigational drug increased clinical benefit compared to placebo. Outcomes are scored on a seven-point scale ranging from fully recovered to death. Investigators will reevaluate this scale after reviewing data from the first 100 participants.

NIH launches large TB prevention trial for people exposed to multidrug-resistant TB

Dr KK Aggarwal

(NIH): A large phase 3 clinical trial called PHOENIx MDR-TB (Protecting Households on Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Patients) to assess treatments for preventing people at high risk from developing multidrug-resistant tuberculosis (MDR-TB) has begun.

The study is comparing the safety and efficacy of a new MDR-TB drug, delamanid, with isoniazid, the standard anti-TB drug for preventing active MDR-TB disease in children, adolescents and adults at high risk who are exposed to adult household members with MDR-TB. Study participants include those at high risk for MDR-TB because they either have latent TB infection, immune systems suppressed by HIV or other factors, or are younger than age 5 years and therefore have a weak immune system.

The study investigators hypothesize that prophylactic treatment with delamanid will prove better than isoniazid at reducing the likelihood that at-risk household members of individuals with MDR-TB will develop active TB disease.

“It is important to perform randomized, controlled clinical trials on how best to provide preventive care for people who come in close contact with individuals with MDR-TB, since this is a major gap in global public health policy,” said Anthony S. Fauci, M.D. Director of the National Institute of Allergy and Infectious Diseases (NIAID), which is co-funding the study and is part of the National Institutes of Health.

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

Steroids not superior to placebo in patients with mild persistent asthma and low sputum eosinophils

NIH: Inhaled steroids are often used to treat people with mild persistent asthma, but now a new study suggests that mild persistent asthma can be managed safely without daily steroid use.

The study of patients with mild persistent asthma found that inhaled steroids were no more effective than placebo in nearly three-fourths of the study patients, all older than age 12. Inhaled steroids were better than placebo for a subset of the patients who had high levels of eosinophils, in their sputum, but they represented about a fourth of patients enrolled in the trial.

The study funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health was published online on May 19 in the New England Journal of Medicine (NEJM). The findings were also presented at the international conference of the American Thoracic Society in Dallas.

The multicenter study included 295 people over the age of 12 with mild persistent asthma. The researchers further divided the group based on low or high sputum eosinophil levels (low = less than 2%; high = greater than or equal to 2%). The subjects were randomized to three treatment groups for 12-week periods:  inhaled steroids (mometasone), long-acting muscarinic antagonists (LAMA; tiotropium), a nonsteroidal treatment for uncontrolled asthma, or placebo. By the end of the study, every participant had received each treatment.

A surprising finding of the study was that nearly 73% (n=221) of the participants were classified as having low sputum eosinophils.

·         Among those participants who were classified as “Eos-low,” the number who responded better to active treatment with steroids was no different than the number who responded better to placebo, whereas, those who were classified as “Eos-high” were nearly three times as likely to respond to inhaled steroids than placebo.

·         Among those who were ‘Eos-low’ and had a better response to one of the treatments, 60% had superior results on LAMA, versus 40% who had better symptom control on placebo. 

Previous research has shown almost 50% of patients with mild persistent asthma have less than 2% eosinophils in sputum and that most patients with low eosinophils do not respond well to steroid treatment. But, sputum eosinophils are not routinely measured.

The findings of this study now indicate that it may be possible to target particular therapies to subsets of patients, such as those with high or low eosinophil biomarkers, for more effective treatments.

(Source: NIH)

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

LATE, a new type of dementia

National Institutes of Health scientists have identified a new type of dementia and have named it LATE or Limbic-predominant Age-related TDP-43 Encephalopathy as reported April 30, 2019, in the journal Brain.

LATE is an under-recognized condition and the “oldest-old” (80 years and older) are at greatest risk of developing it.

LATE affects multiple areas of cognition, ultimately impairing activities of daily life. It mimics the clinical features of Alzheimer’s disease, but is more slowly progressing. But, LATE combined with Alzheimer’s causes a more rapid decline than either condition alone would.

Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each condition appears differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43 may contribute to that phenomenon.

The autopsy diagnosis has been suggested in three stages, according to where in the brain TDP-43 is detected:

·         Stage 1: amygdala only

·         Stage 2: amygdala and hippocampus

·         Stage 3: amygdala, hippocampus and middle frontal gyrus

TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Recent research has shown misfolded TDP-43 protein as being very common in older adults. Around 25% of people over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.

Unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 pathology is also commonly associated with hippocampal sclerosis. The hippocampal region of brain plays an important role in memory and learning. Therefore, cognitive impairment as the symptoms of hippocampal sclerosis may appear to be very similar to the effects of Alzheimer’s disease.

(Source: NIH, April 30, 2019)

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

NIH statement on World Malaria Day 2019

Statement of B.F. (Lee) Hall, M.D., Ph.D., and Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases

Eliminating malaria — one of the world’s oldest and deadliest diseases — remains a critically important public health and biomedical research challenge. Despite remarkable advances in reducing malaria incidence and deaths since 2000, recent progress has become stagnant and has even reversed in some regions. The World Health Organization (WHO) estimates that in 2017 about 219 million cases of malaria occurred worldwide and approximately 435,000 people died of the disease. Unfortunately, malaria cases increased from 2016 to 2017 in the 10 highest-burden countries in Africa, and the number of cases per 1,000 in populations at risk remained at 59 from 2015 to 2017.

Today, the National Institutes of Health recognizes World Malaria Day and commits to a reinvigorated malaria research program. This year’s World Malaria Day theme, “Zero malaria starts with me,” encourages governments, companies, academic institutions, philanthropies, and others to prioritize malaria, mobilize resources, and empower communities affected by malaria to lead and coordinate response activities. The National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, is working toward “zero malaria” with coordinated global research projects to better understand the disease, improve diagnostics, treatments, and mosquito control interventions, and develop safe and effective vaccines.

NIAID works directly with scientists in malaria-endemic regions to build specialized local clinical research capacity. The NIAID-supported International Centers of Excellence for Malaria Research (ICEMR) program has more than 50 field sites in 17 endemic countries dedicated to multidisciplinary research on the complex interactions between the human host, mosquito vectors, and malaria parasites. ICEMR investigators share genomic and epidemiological data for parasites, mosquitoes, and human hosts through public databases such as PlasmoDB, VectorBase, and ClinEpiDB to assist researchers in developing drugs, vaccines and diagnostics, and in improving public health programs. 

ICEMR researchers are studying how the malaria-causing parasite adapts to antimalarial drug pressure and how that translates to the emergence and spread of drug resistance. Resistance to artemisinin drugs, used in most endemic areas, is emerging in Southeast Asia and appears to be spreading west. The ICEMRs are evaluating how asymptomatic malaria infections may contribute to persistent disease transmission and risk. Investigators also are studying how the behavior of malaria-transmitting mosquitoes is changing in response to insecticide use and environmental and ecosystem changes.

NIAID investigators and NIAID-supported scientists are helping to inform treatment policies in various countries by tracking genetic mutations in malaria parasites that indicate resistance to certain drugs. A team of experts recently identified a molecular marker of resistance to piperaquine (a combination therapy drug) in Cambodia (link is external) using publicly available genome sequence data.

Another international research team supported by NIAID created mutated versions of nearly all of the 5,400 Plasmodium falciparum (P. falciparum) parasite genes to determine which of the organism’s genes are essential to growth and survival. The information will help investigators prioritize targets for future antimalarial drug development. One investigational drug being evaluated, DM1157, is a modified form of the antimalarial drug chloroquine. Similar to chloroquine, it interferes with the malaria parasite’s metabolism; however, it inhibits the parasite’s ability to expel the drug, thereby avoiding the drug resistance seen with chloroquine. A Phase 1 clinical trial to evaluate the drug’s safety began in September 2018.

Cerebral malaria — a severe form of illness that can lead to brain damage, long-term neurological deficits, and death — remains a significant problem in sub-Saharan Africa. ICEMR investigators and their collaborators identified brain swelling as a potential contributor to the high mortality rate among children in Malawi with cerebral malaria. A clinical trial is underway to assess whether measures to reduce brain swelling can improve treatment outcomes. ICEMR investigators in India are studying whether the same findings are seen in adults with cerebral malaria, while NIAID researchers are working to develop novel adjunctive cerebral malaria treatments.

Certain populations, such as pregnant women, are at higher risk of developing severe disease upon contracting malaria. NIAID-supported researchers in Malawi recently found that administering the drug chloroquine as a weekly chemoprophylaxis may prevent malaria in pregnancy. NIAID-supported scientists also found that children with high levels of maternal antibodies to the malaria antigen PfSEA-1 at birth have decreased risk of severe malaria during infancy.

NIAID also supports the development of various investigational malaria vaccines. The Institute has conducted and supported multiple early-stage clinical trials of PfSPZ, a candidate malaria vaccine made of weakened immature malaria parasites. It is designed to prevent malaria infection and is now being evaluated in multiple clinical trials in malaria endemic regions, including in infants and children. Another candidate vaccine based on a recombinant protein is currently in a Phase 1 clinical trial.

NIAID researchers also are working on a vaccine designed to block transmission of the malaria parasite from infected humans to mosquitoes. Although a transmission-blocking vaccine would not prevent malaria infection, by limiting further spread it could reduce new malaria infections over time. Results from a clinical trial in Mali indicate that the investigational vaccine, when formulated with an immunity-boosting adjuvant, shows promise. Plans are underway to evaluate the efficacy of the vaccine in a Phase 2 clinical trial in Mali.

NIAID scientists recently developed a monoclonal antibody from a person vaccinated with PfSPZ that potentially could be used for seasonal control and elimination efforts as well as by tourists, health care workers, and military personnel to prevent malaria infection. A trial evaluating the antibody’s safety and efficacy against a controlled human malaria infection (human challenge study) is planned for early 2020. NIAID experts also are collaborating with Malian scientists to discover additional broadly protective monoclonal antibodies.

Although recent data indicate that malaria control efforts may have stalled, numerous historical examples indicate that with enough commitment and ingenuity malaria elimination can be achieved, even after significant setbacks. NIAID-supported investigators, researchers and their collaborators are accelerating progress toward malaria elimination every day. On this World Malaria Day, we reaffirm our commitment to advancing the best research to reach our goal of “zero malaria.”

(Source: NIH)

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

Acyclovir labeling updated to also include details for treating premature infants infected with herpes virus

Newborns infected with HSV can be appropriately treated with acyclovir, a drug typically prescribed to adults for the treatment of HSV infections.

The drug label for acyclovir now includes information for healthcare providers on recommended usage and dosage in newborns up to 3 months of age. The data that informed this label change came from a Pediatric Trials Network (PTN) open-label study titled “Safety and Efficacy of High-Dose Acyclovir in Infants with HSV or Suspected HSV (BPCA ACY02)” funded by the National Institutes of Health (NIH)’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

“With this label change, healthcare providers have clear guidance on how to use and prescribe this drug for their youngest patients”, said Perdita Taylor-Zapata, M.D., program lead for the Best Pharmaceuticals for Children Act (BPCA) at NICHD.

The study, published in the Pediatric Infectious Diseases Journal, examined the population pharmacokinetics of acyclovir in infants and showed that postmenstrual age (PMA) is associated with clearance and suggested dosing intervals as determined by PMA in infants with relatively normal renal function: 20 mg/kg every 12 hours in infants <30 weeks PMA, 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA, and 20 mg/kg every 6 hours in infants 36–41 weeks PMA (Pediatr Infect Dis J. 2014 Jan;33(1):42-9)

Newborns and premature infants are vulnerable to serious and potentially life-threatening complications from herpes simplex (HSV) infection during pregnancy, labor and delivery or shortly after birth if the mother develops genital herpes near the end of her pregnancy. HSV infection in newborns can cause death or long-term problems such as blindness and damage to the brain and other organs.

(Source: NIH, February 8, 2019; Pediatr Infect Dis J. 2014 Jan;33(1):42-9)

Dr KK Aggarwal

Padma Shri Awardee

President Elect Confederation of Medical Associations in Asia and Oceania   (CMAAO)

Group Editor-in-Chief IJCP Publications

President Heart Care Foundation of India

Past National President IMA

NIH stops clinical trial on combination cholesterol treatment

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has stopped a clinical trial studying a blood lipid treatment 18 months earlier than planned. The trial found that adding high dose, extended–release niacin to statin treatment in people with heart and vascular disease, did not reduce the risk of cardiovascular events, including heart attacks and stroke.

Participants were selected for AIM–HIGH because they were at risk for cardiovascular events despite well–controlled low–density lipoprotein (LDL or bad cholesterol). Their increased risk was due to a history of cardiovascular disease and a combination of low high–density lipoprotein (HDL or good cholesterol) and high triglycerides, another form of fat in the blood. Low HDL and elevated triglycerides are associated with an increased risk of cardiovascular events. While lowering LDL decreases the risk of cardiovascular events, it has not been shown that raising HDL similarly reduces the risk of cardiovascular events. During the study’s 32 months of follow–up, participants who took high dose, extended–release niacin and statin treatment had increased HDL cholesterol and lowered triglyceride levels compared to participants who took a statin alone. However, the combination treatment did not reduce fatal or non–fatal heart attacks, strokes, hospitalizations for acute coronary syndrome, or revascularization procedures to improve blood flow in the arteries of the heart and brain.

The AIM–HIGH trial, which stands for Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health, enrolled 3,414 participants in the United States and Canada with a history of cardiovascular disease who were taking a statin drug to keep their LDL cholesterol low. Study participants also had low HDL cholesterol and high triglycerides, which meant that they were at significant risk of experiencing future cardiovascular events. Niacin, also known as Vitamin B3, has long been known to raise HDL and lower triglycerides. Eligible participants were randomly assigned to either high dose, extended–release niacin (Niaspan) in gradually increasing doses up to 2,000 mg per day (1,718 people) or a placebo treatment (1,696 people). All participants were prescribed simvastatin (Zocor), and 515 participants were given a second LDL cholesterol–lowering drug, ezetimibe (Zetia), in order to maintain LDL cholesterol levels at the target range between 40–80 mg/dL.
Researchers began recruiting participants in early 2006. The study was scheduled to finish in 2012. The average age of the participants was 64 years. Pre-existing medical conditions included coronary artery disease (92 percent); metabolic syndrome, which is a cluster of risk factors for heart disease (81 percent); high blood pressure (71 percent); and diabetes (34 percent). More than half of participants reported having a heart attack prior to entering the study.

The rationale for the AIM–HIGH study was based in part on a large number of observational studies that consistently showed that low HDL cholesterol increases the risk of cardiovascular events in men and women, independent of high LDL cholesterol. In addition, previous small clinical studies showed that relatively high residual cardiovascular risk exists among patients with cardiovascular disease, low HDL cholesterol, and high triglycerides despite intensive management of LDL cholesterol.