Tag: clinical trials

Not Enough Women in Stroke Clinical Trials

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A new study published in Neurology shows that women are underrepresented in stroke clinical trials compared to the proportion who have strokes in the general population. 

“Making sure there are enough women in clinical studies to accurately reflect the proportion of women who have strokes may have implications for future treatment recommendations for women affected by this serious condition,” said study author Cheryl Carcel, MD, of The George Institute for Global Health in Sydney, Australia. “When one sex is underrepresented in clinical trials, it limits the way you can apply the results to the general public and can possibly limit access to new therapies.”

The study analysed 281 stroke trials conducted between 1990 and 2020, with a total of 588 887 participants. Of these, only 37.4 % were women. The average prevalence of stroke in women across the countries included was 48%.

Results were calculated in participation-to-prevalence ratio, a relative measure that weights the percentage of women in a trial compared to their proportion in the total population with that disease. A ratio of one indicates that the percentage of women in the study is the same as the percentage of women with the disease in the general population. An acceptable range for an ideal ratio of female participation is between 0.8 and 1.2.

Overall, women were found to be underrepresented relative to their prevalence in the underlying population, with a consistent ratio of 0.84 over time. They found the greatest differences in trials of intracerebral haemorrhage, with a ratio of 0.73; trials with average participant age under 70, with a ratio of 0.81; non-acute interventions, with a ratio of 0.80; and rehabilitation trials, with a ratio 0.77.

“Our findings have implications for how women with stroke may be treated in the future, as women typically have worse functional outcomes after stroke and require more supportive care,” Dr Carcel said. “We will only achieve more equitable representation of women in clinical trials when researchers look at the barriers that are keeping women from enrolling in studies and actively recruit more women. People who fund the research also need to demand more reliable, sex-balanced evidence.”

Source: American Academy of Neurology

New Drug Molnupiravir Halves COVID Hospitalisation Risk

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Merck today announced that their investigational oral antiviral drug molnupiravir significantly reduced the risk of hospitalisation or death in a Phase III trial in at risk patients with mild-to-moderate COVID. 

Interim analysis showed that molnupiravir reduced the risk of hospitalisation or death by approximately 50%; 7.3% of patients randomised to receive molnupiravir were either hospitalised or died through Day 29 following randomisation, compared with 14.1% of placebo-treated patients. Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo. Study recruitment is being stopped early due to these positive results, and the company plans to submit an application for Emergency Use Authorisation (EUA) to the U.S. FDA as soon as possible.

Molnupiravir is an oral form of a potent ribonucleoside analog that inhibits the replication of SARS-CoV-2. Molnupiravir has been shown to be active in several preclinical models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission. 

All 775 patients had laboratory-confirmed mild-to-moderate COVID, with symptom onset within 5 days of study randomization and were required to have at least one risk factor associated with poor disease outcome at study entry. Across all key subgroups, molnupiravir reduced the risk of hospitalisation and/or death; efficacy was unaffected by timing of symptom onset or underlying risk factor. Additionally, based on the participants with available viral sequencing data (approximately 40% of participants), molnupiravir demonstrated consistent efficacy across viral variants Gamma, Delta, and Mu.

The incidence of any adverse event was comparable in the molnupiravir and placebo groups, as was incidence of drug-related adverse events, and the drug was well tolerated.

In addition, molnupiravir is being evaluated for post-exposure prophylaxis in MOVe-AHEAD, a global, multicenter, randomised, double-blind, placebo-controlled Phase III study, which is evaluating the efficacy and safety of molnupiravir in preventing the spread of COVID within households. 

Source: Merck

Most Trials in Clinical Practice Hold Up Over Time

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According to a new paper in Family Practice, medical practice can often be undermined by later research, randomised trials relevant to primary care generally hold up over time.

Medical reversal describes a problem whereby new research causes doctors to stop using a popular medication, procedure or test based on previous evidence. Vinayak Prasad, associate professor at the University of California, San Francisco, had found that up to 46% of original studies on adopted medical practices led to a reversal or shift in evidence of effect.

Evidence-based medicine lets doctors be confident when their decisions are grounded in high quality research. But decisions supported by robust evidence from randomised controlled trials can be reversed. For example, although aspirin is prescribed commonly to prevent cardiovascular disease, new studies indicate this treatment is unlikely to be effective.

Researchers studied the extent to which evidence from randomised control trials relevant to primary care were contradicted in subsequent research. Examining 408 randomised controlled trials from 2002 to 2005 relevant to primary care, the researchers found that over 12-17 years of follow up time, there were just 35 occurrences of evidence reversal, or roughly two a year. About nine in ten of such randomised control trials were not reversed.

“Conclusions from randomised trials relevant to primary care that also meet criteria for validity are stable over time,” said study lead author Christian Ruchon.

Source: EurekAlert!

New Effort to Improve Diversity in Clinical Trials

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Columbia University and Pfizer Inc. have established the Columbia-Pfizer Clinical Trials Diversity Initiative, which aims to reduce health disparities by increasing the number of minorities in clinical trials and making clinical researchers more diverse.

In the United States, 12% of the population is Black and 18% is Hispanic or Latino but in 2020, only 8% were Black and 11% were Hispanic among the 32 000 patients who participated in clinical trials that led to FDA approval of new drugs. For example, a review of clinical trials between 1999 and 2015 for cystic fibrosis only had a representation of 2.0% for Latinos, 1.0% for Black individuals, and 0.1% for Asians.

“People of different ethnicities can have different responses to the same medicine or treatment, so a lack of diversity among clinical trial participants means doctors cannot know if the treatment will be effective in all the patients they treat,” said Anil K Rustgi, MD, Interim Executive Vice President and Dean of the Faculties of Health Sciences and Medicine at Columbia University and director of the Herbert Irving Comprehensive Cancer Center. “Increasing diversity in trials will improve the treatment of patients from underrepresented groups and is a moral imperative as well as a fundamental medical issue.”

Rod MacKenzie, PhD, Executive Vice President and Chief Development Officer at Pfizer, said, “Diversity of representation in clinical trials is a matter of equity, which is a core Pfizer value. We are deeply committed to ensuring our clinical trials reflect the diversity of the communities like New York in which they are conducted. We look forward to working with Columbia University both to offer any willing individual, regardless of background, the opportunity to participate in and contribute to clinical research, and to expand the roster of diverse clinical researchers who are helping us conduct studies.”

Pfizer will provide a three-year, $10 million grant to Columbia to help establish and expand the Initiative, which will improve the diversity of participants in clinical trials by looking at the barriers that prevent participation by marginalised individuals. The Initiative will expand Columbia’s Community Health Workers Program network to connect with underserved populations and create culturally sensitive engagement tools. The efforts will include researching new ways to increase the accessibility of clinical trials through telemedicine, wearable technology, and home visits.

The Initiative also aims to improve diversity among clinical research faculty and staff. Columbia will help build an additional pipeline of diverse clinical investigators through a new National Diversity Clinical Trials Leadership Program to increase the number of faculty and staff from underrepresented groups as well.

“A diverse research staff not only helps to improve trust in clinical trials among participants from underserved groups but improves the entire clinical trial enterprise by bringing different questions, experience, and perspective to the table,” Dr Rustgi said.

Source: Columbia University Irving Medical Center

How do Patients Who Exit Clinical Trials Early Feel?

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A new study has helped researchers understand the experiences of people who withdraw from clinical cancer trials.

Cancer clinical trials (CCTs) provide patients with an opportunity to receive experimental drugs, tests, and/or procedures that may lead to remissions. Such opportunities can be a great benefit for those who took part, but there is little known of the experiences of participants who withdraw from CCTs.

To address this, a first-of-its-kind study from the University of Pennsylvania School of Nursing (Penn Nursing) was conducted to better understand the post-trial needs of these patients and define responsible transitions when patients exit CCTs.

“Understanding the post-trial needs of patients with cancer and their families represents a measure of ethical respect of the many contributions that patients with cancer make to advancing our scientific knowledge and finding treatments that save lives,” said the study’s lead researcher, Connie M Ulrich, the Lillian S Brunner Chair in Medical and Surgical Nursing, professor of nursing, professor of medical ethics and health policy.

The study revealed three important areas:

  • Patients exiting CCTs feel intense symptoms, emotions, and awareness that their life spans are short and options seem limited.
  • The limited discussions with patients who are exiting on their immediate post-trial care needs can result in many feeling that there is no clear path forward.
  • Good communication that deliberately includes attention to post-trial needs throughout the CCT is needed to help scared and disappointed patients navigate their next steps.

The study is set for publication on the JAMA Network.

Source: University of Pennsylvania

AstraZeneca Updates its US Trial Results

AstraZeneca issued updated phase III trial data for its COVID vaccine on Wednesday after facing questions on its accuracy of its preliminary US study.

The company now says its vaccine is 76% effective in protecting against symptomatic cases of virus. A release issued on Monday reported a symptomatic efficacy rate of 79%, but the next day, the National Institute of Allergy and Infectious Diseases said it had been informed the company may have included information from its US results that provided an “incomplete view of the efficacy data.”

The updated report still says that the vaccine is 100% effective against severe disease and hospitalisation. A number of US health officials have criticised the company for what seemed like cherry-picking of data in an effort to improve the results’ appearance.

At the time, AstraZeneca said the figures were based on a “pre-specified interim analysis” and promised it would share an updated analysis in the coming days.

Dr Anthony Fauci, White House chief medical advisor and director at the NIAID, was more supportive of the company, calling the situation “unfortunate” and said it was likely AstraZeneca would issue a modified statement.

“This is really what you call an unforced error because the fact is this is very likely a very good vaccine,” Fauci told ABC’s Robin Roberts on “Good Morning America” on Tuesday. “This kind of thing does … really cast some doubt about the vaccines and maybe contribute to the hesitancy. It was not necessary.”

The BBC’s medical editor, Fergus Walsh, was told the results may have been rushed out of a desire to address the safety concerns surrounding possible blood clots. These had resulted in AstraZeneca vaccines being withdrawn from circulation in some European countries.

The updated results include 190 symptomatic cases out of over 32 000 participants — about 50 more symptomatic cases than the data set released on Monday.

The findings suggest the vaccine is more effective in patients aged 65 and older, with a newly reported efficacy rate of 85% for that population, up from 80% stated earlier.

AstraZeneca reiterated that there were no safety concerns with the vaccine and that it was well tolerated.

Source: NBC News

New JAK1 Inhibitor Abrocitinib Effective in Atopic Dermatitis

A phase III trial showed that a new oral Janus kinase 1 (JAK1) inhibitor, abrocitinib, bettered placebo, at higher doses, also outperformed dupilumab in treating signs and symptoms of atopic dermatitis.

More patients on the higher dose of abrocitinib had an Eczema Area and Severity Index 75 (EASI-75) response (75% improvement from baseline) as compared with the other three randomised groups, reported Hernan Valdez, MD, of Pfizer in New York City, and colleagues.

“In the JADE COMPARE trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo on the basis of IGA and EASI-75 responses at weeks 12 and 16,” the authors stated. “The 100-mg dose of abrocitinib was not significantly different from dupilumab with respect to the three key secondary endpoints of the trial.”

“The 200-mg dose of abrocitinib was superior to dupilumab with respect to itch response at week 2 but not to an EASI-75 response at week 16; no conclusion could be drawn regarding the difference between the 200-mg dose of abrocitinib and dupilumab with respect to an IGA response… . Longer and larger trials are necessary to determine the efficacy and safety of abrocitinib and to compare it with other JAK inhibitors and with biologic agents used for the treatment of atopic dermatitis,” they added.

Several oral JAK inhibitors besides abrocitinib being clinically evaluatied for AD. According to the authors, targeting JAK1 results in inhibition of signaling by interleukin (IL)-4, IL-13, and other cytokines involved in AD. However, there is a lack of data on head-to-head trials of JAK inhibitors.

Despite the very positive reception of JAK inhibitors for the treatment of AD, there have been some studies which raised safety concerns. Tofacitinib, for example, has been associated with a higher rate of malignancies and major adverse cardiovascular events.

In this phase III trial, 838 patients with moderate or severe AD were randomised to abrocitinib 100 mg or 200 mg, dupilumab, or placebo. The trial had two primary endpoints: investigator’s global assessment (IGA) response at week 12 and EASI-75 response at week 12. Both endpoints were compared versus placebo. Secondary analyses included comparisons of itch response at week 2 versus placebo and dupilumab and IGA and EASI-75 responses versus placebo at week 16.

More patients on either of the two doses of abrocitinib had IGA responses at week 12 compared to placebo. The proportion of patients with an EASI-75 response at 12 weeks was 70.3% with abrocitinib 200mg, 58.7% for abrocitinib 100mg, 58.1% for dupilumab, and 27.1% for placebo. All treatment groups performed significantly better than placebo.

At week 2, 49.1% of patients had itch response with the higher dose of abrocitinib, 31.8% with the lower dose, 26.4% with dupilumab, and 13.8% with placebo. The 200-mg abrocitinib group was superior to dupilumab. 

Adverse events (AEs) occurred more often with 200-mg abrocitinib as compared with the other three groups (61.9% vs 50.0% to 53.4%), the most common of which was nausea.

Source: MedPage Today

Journal information:  Bieber T, et al “Abrocitinib versus placebo or dupilumab for atopic dermatitis” N Engl J Med 2021; DOI: 10.1056/NEJM0a2019380.

Clinical Trial for Ivermectin Delivers Disappointing Results

A randomised clinical trial in Colombia for ivermectin treatment in mild COVID returned disappointing results.

An anti-parasitic normally used for livestock, ivermectin has gathered considerable attention as a possible COVID treatment in recent months, especially locally, with stocks containing the product depleted in the last month. There are no ivermectin-containing products in South Africa for human use. The South African Health Products Regulatory Authority is of the view that the evidence for ivermectin is currently inconclusive.

“To our knowledge, preliminary reports of other randomized trials of ivermectin as treatment for COVID-19 with positive results have not yet been published in peer-reviewed journals,” the researchers wrote.

  The randomised, double-blind, single-center study took place from July 15 to December 21, 2020. Patients were assigned to either receive an oral dose of 300 μg/kg of body weight per day of ivermectin or placebo, for five days. Follow-up took place on days 2, 5, 8, 11, 15, and 21. The primary trial outcome was resolution of symptoms within 21 days.  

However, the study was not without its share of problems. The initial primary outcome was time from randomisation until worsening of symptoms by two points on an ordinal scale, but few patients reached this endpoint in the expected time. This meant the sample size needed to maintain sufficient power was “unattainable.” To accommodate this, the primary endpoint was changed to time from randomisation to symptom resolution by day 21, retaining the original sample size.

To make matters worse, a labelling error occurred, where ivermectin was mistakenly given to all patients from September 29 to October 15, so the protocol was amended, with these patients excluded from the primary analysis. The researchers then recruited more patients to retain the originally calculated study power.

Despite these problems, the researchers said the findings remained valid within the confines of its other limitations. Limitations to the study, the researchers said, included that it was not conducted or completed according to the original design; that it may have been underpowered to detect a smaller, clinically meaningful reduction in the primary endpoint; and virological assessments were not included, only clinical characteristics.

Larger trials would be needed “to understand the effects of ivermectin on other clinically relevant outcomes,” concluded the researchers.

Source: MedPage Today

Journal information: López-Medina E, et al “Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19 — A Randomized Clinical Trial” JAMA 2021; DOI: 10.1001/jama.2031.3071.

Neurocrine’s Anticipated Schizophrenia Drug Flops in Clinical Trial

Pharmaeceutical company Neurocrine’s anticipated schizophrenia drug, luvadaxistat, failed to have an impact on negative symptoms in a key clinical trial, but still showed promising cognitive benefits.

Neurocrine Biosciences had licensed seven of Takeda’s psychiatry drugs last year for over $2 billion. Luvadaxistat was the furthest along, having entered Phase 2 testing in 2017.

The experimental drug is supposed to help schizophrenia patients cope with “negative symptoms”—a range of difficult-to-treat conditions such as lack of motivation, trouble communicating and limited emotion. The drug is designed to block an enzyme that degrades a certain kind of amino acid important for brain function.

However, according to results from a mid-stage study, in comparison to placebo, patients treated with the drug didn’t perform significantly better, as measured by a scale that assesses the severity of negative symptoms.

While there was excitement around the science behind luvadaxistat, Wall Street analysts lost much of their optimism in the programme last month, after Concert Pharmaceuticals halted development of CTP-692, an experimental drug based on the same mechanism, after trials also saw disappointing results

Nevertheless, there remains a path ahead for luvadaxistat as Neurocrine is setting up to analyse the drug’s efficacy for cognitive benefits, as it appears that these results at least were in line with scientific predictions.

Source: BioPharma Dive

Questions Raised over Oxford’s Unusual Vaccine Regimen

The recent announcement of the Oxford’s and AstraZeneca’s vaccine trial being 70% effective up to 90% effective has raised some pointed questions.

The trial had two treatment arms, one receiving two full doses of the AZD1222 vaccine and a half dose plus a full dose, with the doses being administered 28 days apart. The “half dose then full dose”  treatment arm reported the 90% protection. The problem was that the trial was never meant to have such an arm. 

It was noticed that some participants were only receiving a half dose because they were experiencing fewer effects than expected such as arm pain and headache. This was subsequently corrected so that they would still receive the full dose on the second administration.

Of particular concern is that the “90% effectiveness” is based on a much smaller subset of the trial participants, with a correspondingly higher statistical uncertainty. So much so that there is statistical overlap with their lower effectiveness of 62% quoted for the two full doses. Furthermore, the participants were from the initial stages of the vaccine trial, where they were aged 18-55 and therefore have little applicability to the results of the main trial which included older age groups as well. 

The details of exactly why the half-measure doses came to be administered in the first place have not been revealed by Oxford or AstraZeneca. Meanwhile in the US, a Phase III of the trial is being rolled out with 40 000 participants, and the “half dose then full dose” regimen may be included – however, uncertainty about it and whether it isn’t a statistical fluke will have to be cleared up first.

Source: Ars Technica