NIA inks MoU with Thailand for academic collaboration in Thai traditional medicine and Ayurveda

Jaipur: The National Institute of Ayurveda, Jaipur under the Ministry of Ayush of the Government of India and the Department of Thai Traditional and Alternative Medicine of the Ministry of Public Health of the Government of the Kingdom of Thailand signed a Memorandum of Understanding (MoU) on the establishment of an Academic Collaboration in Ayurveda and Thai Traditional Medicine in New Delhi, India at 10th India-Thailand Joint Commission Meeting held at Hyderabad House, New Delhi.

Shri B.K. Singh, Joint Secretary, Ministry of Ayush, Government of India, and Dr. Taweesin Visanuyothin, Director General, Department of Thai Traditional and Alternative Medicine Thailand signed the MoU in the presence of other dignitaries during the event. 

The initiative has been taken to promote, facilitate, and develop academic collaboration in the field of Ayurveda and Thai Traditional Medicine based on equality and mutual benefit of the Participants. This MoU will facilitate the exchange of experts for research and training programs, academic and technical activities, and conducting research, exchange of information, technologies, and best practices of Traditional Medicine.

Also Read:National Institute of Ayurveda invites applications for Certificate e-Course on Dietetics, Nutrition, Immunity

The Participants will take necessary steps to encourage and promote cooperation in facilitating academic and technical activities and conducting research for mutual benefits. Exchanging and accommodating experts, teaching instructors, practitioners, and students for research and training programmes. Exchanging knowledge, experiences, information, technologies, and best practices. Providing scholarships for education.

Promoting the participation of experts in conferences, workshops, seminars, and events held by the Participants and other important areas of cooperation, with the mutual consent of the Participants.

During implementation of this MOU, the Participants, within their capacities will support each other with mutual cooperation and collaborative activities on the basis of equality and mutual benefits by facilitating training courses in Thailand and India, conducting collaborative research studies on diseases of common interest to both Participants and visits and exchanges of policy makers, academics, experts, researchers, practitioners, and students.

NIA and Department of Thai Traditional and Alternative Medicine, Thailand will share information on regulatory mechanisms, best practice, guidelines of practice and courses of study and training; and organize conferences/meetings alternately in India and Thailand and reviewing the progress of the implementation of the MOU and the evaluation of the results of collaborative programmes.

Also Read:PM Modi emphasizes global significance of Ayurveda, Yoga at World Food India inauguration

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Patients of COVID-19 associated AKI may not have long-term kidney function decline: JAMA

A recent study unveiled the long-term consequences of COVID-19 with encouraging news for survivors of COVID-19-associated acute kidney injury (COVID-AKI). The study was published in the Journal of American Medical Association highlighted the lingering effects on kidney function in patients who battled COVID-19.

The retrospective longitudinal multicenter cohort study spanned from March 2020 to June 2022 and analyzed electronic health records of adult hospitalized patients with AKI by comparing the outcomes between those with COVID-19 and influenza-related AKI, as well as AKI from other causes. The study followed up with patients for up to two years post-discharge to assess the incidence of major adverse kidney events (MAKE), including mortality and the worsened kidney function.

The results of this study were from the analysis of 9624 hospitalized patients, including 987 with COVID-AKI. Despite initial concerns regarding the impact of COVID-19 on renal health, the survivors of COVID-AKI expressed lower rates of MAKE when compared to patients with AKI from other causes. The findings revealed a significantly lower risk of mortality and kidney function decline among the individuals who underwent COVID-19 by suggesting a more favorable long-term prognosis for kidney health in this cohort.

The study highlighted distinct demographic and clinical characteristics among patients with COVID-AKI, including a slightly younger age, higher baseline kidney function and more severe illness markers which indicates the unique challenges faced by this population. In summary, the findings of the study suggest that survivors of COVID-AKI may experience better long-term kidney function and lower mortality rates when compared to those with AKI from other causes that offers hope in the fight against the lasting impacts of the pandemic.

Source:

Aklilu, A. M., Kumar, S., Nugent, J., Yamamoto, Y., Coronel-Moreno, C., Kadhim, B., Faulkner, S. C., O’Connor, K. D., Yasmin, F., Greenberg, J. H., Moledina, D. G., Testani, J. M., & Wilson, F. P. (2024). COVID-19−Associated Acute Kidney Injury and Longitudinal Kidney Outcomes. In JAMA Internal Medicine. American Medical Association (AMA). https://doi.org/10.1001/jamainternmed.2023.8225

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Early Colorectal Cancer Screening may Reduce Cancer-Specific Mortality: JAMA

A recent study published in the Journal of American Medical Association revealed that early invitation to Colorectal cancer (CRC) screening could significantly reduce the cancer-specific mortality when compared to late or no invitation. This research spanning from January 2008 to December 2021 to evaluate the impact of routine CRC screening using fecal occult blood testing on cancer-specific mortality.

This study was conducted in the Stockholm-Gotland region of Sweden encompassed a total of 379,448 individuals born from 1938 to 1954 and analyzed data from December 2022 to June 2023.

The participants were categorized into groups based on their invitation to screening as early (2008-2012), late (2013-2015) or no invitation. The early invitation group which constituted 203,670 individuals was compared to the control group of 175,778 individuals who received late or no invitation.

The results demonstrated a significant decrease in CRC mortality among those who underwent early screening. The individuals in the early screening group expressed a reduced risk of CRC mortality by 14% when compared to the control group. Also, the study found a corresponding decrease in excess mortality which further emphasizes the positive impact of early CRC screening.

Despite challenges in evaluating the effectiveness of population-based CRC screening programs, this study provides compelling evidence that supports their efficacy in reducing cancer-specific mortality rates. The mean screening participation rate was 63.3% which indicates a significant uptake of screening within the studied population.

The outcomes underscore the importance of routine CRC screening with fecal occult blood testing as a crucial preventive measure against colorectal cancer. This suggest that the true association between screening and reduced mortality could be even higher, considering potential factors such as testing coexistence in the control group and delayed CRC diagnoses.

Reference:

Blom, J., Saraste, D., Törnberg, S., & Jonsson, H. (2024). Routine Fecal Occult Blood Screening and Colorectal Cancer Mortality in Sweden. In JAMA Network Open (Vol. 7, Issue 2, p. e240516). American Medical Association (AMA). https://doi.org/10.1001/jamanetworkopen.2024.0516

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Some Patients With Fatty Liver Disease May Tolerate Small Amounts of Alcohol Without Getting Sicker: JAMA

Patients diagnosed with steatotic liver disease (formerly called fatty liver disease) are usually advised to stop drinking alcoholic beverages. But a new study led by Cedars-Sinai found that drinking, on average, a small amount of alcohol a day did not lead to further liver damage in patients with mild disease.

The study is published in JAMA Network Open.

“We found that patients in the early stages of steatotic liver disease could consume less than 7.4 grams of alcohol a day without elevating their risk for advanced liver fibrosis which is associated with severe health problems including liver cancer, organ failure and even death,” said Yee Hui Yeo, MD, first author of the study and a clinical fellow in the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai.

“That amount is equivalent to about 6 ounces of beer, 2.5 ounces of wine and less than 1 ounce of a distilled spirit, like vodka or tequila,” Yeo said.

Steatotic liver disease is the most common chronic liver condition in the U.S., according to the American Liver Foundation, which estimates that 1 in 4 adults have the condition, which is often undiagnosed. Patients are advised to abstain from alcohol consumption, which can further damage the organ. But abstinence can be challenging for many people, even those who are light drinkers and or who have alcohol use disorder, according to the study authors.

“A critical gap in our understanding of steatotic liver disease progression has been the lack of concrete data to define a ‘safe’ level of alcohol consumption for those patients who can’t quit drinking. Our study addresses this unmet need by providing empirical evidence on the relationship between alcohol intake levels and the progression of early-stage disease,” Yeo said.

In the cohort study, Yeo-working with medical scientists in China-evaluated data from the U.S. National Health and Nutrition Examination Survey III. Investigators reviewed the health surveys from nearly 3,000 people with steatotic liver disease to identify a safe threshold for alcohol consumption.

Yeo emphasizes the findings are not a recommendation that patients with steatotic liver disease continue to drink but are intended to guide their care if abstinence is challenging.

“There has been ambiguity about the extent to which alcohol consumption exacerbates steatotic liver disease. We want to reduce this uncertainty by providing evidence-based information. We favor abstinence as the safest course of action for these patients. But for those who are not able to stop drinking, these findings provide concrete guidelines for making decisions about their health and lifestyle,” Yeo said.

In addition to limiting alcohol consumption, Yeo advises patients with steatotic liver disease improve their diet, get regular physical exercise and manage risk factors, which include hypertension, obesity, diabetes and prediabetes.

“While it is still best to counsel abstinence for patients with this liver disease, the study defines a threshold beyond which alcohol consumption can increase mortality. The results provide new guidance for clinicians and patients,” said Shelly Lu, MD, the Women’s Guild Chair in Gastroenterology and director of the Division of Digestive and Liver Diseases at Cedars-Sinai.

Reference:

Yeo YH, Zhu Y, Arab JP, et al. Alcohol Intake Thresholds Among Individuals With Steatotic Liver Disease. JAMA Netw Open. 2023;6(12):e2347548. doi:10.1001/jamanetworkopen.2023.47548.

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Ultra-processed food linked to over 30 damaging health outcomes in BMJ research

Consistent evidence shows that higher exposure to ultra-processed foods is associated with an increased risk of 32 damaging health outcomes including cancer, major heart and lung conditions, mental health disorders, and early death.

The findings, published by The BMJ today, show that diets high in ultra-processed food may be harmful to many body systems and underscore the need for urgent measures that target and aim to reduce dietary exposure to these products and better understand the mechanisms linking them to poor health.

Ultra-processed foods, including packaged baked goods and snacks, fizzy drinks, sugary cereals, and ready-to-eat or heat products, undergo multiple industrial processes and often contain colours, emulsifiers, flavours, and other additives. These products also tend to be high in added sugar, fat, and/or salt, but are low in vitamins and fibre.

They can account for up to 58% of total daily energy intake in some high income countries, and have rapidly increased in many low and middle income nations in recent decades.

Many previous studies and meta-analyses have linked highly processed food to poor health, but no comprehensive review has yet provided a broad assessment of the evidence in this area.

To bridge this gap, researchers carried out an umbrella review (a high-level evidence summary) of 45 distinct pooled meta-analyses from 14 review articles associating ultra-processed foods with adverse health outcomes.

The review articles were all published in the past three years and involved almost 10 million participants. None were funded by companies involved in the production of ultra-processed foods.

Estimates of exposure to ultra-processed foods were obtained from a combination of food frequency questionnaires, 24 hour dietary recalls, and dietary history and were measured as higher versus lower consumption, additional servings per day, or a 10% increment.

The researchers graded the evidence as convincing, highly suggestive, suggestive, weak, or no evidence. They also assessed the quality of evidence as high, moderate, low, or very low.

Overall, the results show that higher exposure to ultra-processed foods was consistently associated with an increased risk of 32 adverse health outcomes.

Convincing evidence showed that higher ultra-processed food intake was associated with around a 50% increased risk of cardiovascular disease related death, a 48-53% higher risk of anxiety and common mental disorders, and a 12% greater risk of type 2 diabetes.

Highly suggestive evidence also indicated that higher ultra-processed food intake was associated with a 21% greater risk of death from any cause, a 40-66% increased risk of heart disease related death, obesity, type 2 diabetes, and sleep problems, and a 22% increased risk of depression.

Evidence for the associations of ultra-processed food exposure with asthma, gastrointestinal health, some cancers and cardiometabolic risk factors, such as high blood fats and low levels of ‘good’ cholesterol, remains limited.

The researchers acknowledge that umbrella reviews can only provide high-level overviews and they can’t rule out the possibility that other unmeasured factors and variations in assessing ultra-processed food intake may have influenced their results.

However, their use of rigorous and prespecified systematic methods to evaluate the credibility and quality of the analyses suggests that the results withstand scrutiny.

As such, they conclude: “These findings support urgent mechanistic research and public health actions that seek to target and minimise ultra-processed food consumption for improved population health.”

Ultra-processed foods damage health and shorten life, say researchers in a linked editorial. So what can be done to control and reduce their production and consumption, which is rising worldwide?

They point out that reformulation does not eliminate harm, and profitability discourages manufacturers from switching to make nutritious foods, so public policies and action on ultra-processed foods are essential.

These include front-of-pack labels, restricting advertising and prohibiting sales in or near schools and hospitals, and fiscal and other measures that make unprocessed or minimally processed foods and freshly prepared meals as accessible and available as, and cheaper than, ultra-processed foods.

It is now time for United Nations agencies, with member states, to develop and implement a framework convention on ultra-processed foods similar to the framework on tobacco, and promote examples of best practice, they write.

Finally, they say multidisciplinary investigations “are needed to identify the most effective ways to control and reduce ultra-processing and to quantify and track the cost-benefits and other effects of all such policies and actions on human health and welfare, society, culture, employment, and the environment.”

Reference:

Lane M M, Gamage E, Du S, Ashtree D N, McGuinness A J, Gauci S et al. Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses BMJ 2024; 384 :e077310 doi:10.1136/bmj-2023-077310.

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Veno-Arterial Extracorporeal Life Support for Acute Pulmonary Embolism Improved Outcomes

A recent study published in The Annals of Thoracic Surgery highlights the outcomes of patients who underwent Veno-Arterial Extracorporeal Life Support (VA-ECLS) for various indications by majorly focusing on acute pulmonary embolism (PE). The study by Erik Scott and team examined data from the Extracorporeal Life Support Organization global registry that spanned from 2010 to 2019.

The findings analyzed a cohort of 26,583 patients in total with 978 (3.7%) participants on VA-ECLS for acute PE as the primary diagnosis that revealed significant differences in outcomes based on the indication for VA-ECLS. The patients receiving VA-ECLS for acute PE were found to have a significantly higher likelihood of survival to hospital discharge compared to those supported for other reasons.

The individuals undergoing VA-ECLS for acute PE were 78% more likely to be discharged alive by highlighting the potential efficacy of this intervention in managing acute PE cases. Also, these patients expressed fewer cardiovascular and renal complications when compared to their counterparts who were supported for other indications, suggesting a relatively smoother recovery trajectory.

However, the analysis also unveiled higher rates of mechanical complications among patients who undergo VA-ECLS for acute PE that suggests the need for careful monitoring and management of such issues during treatment.

The outcomes of the study emphasized the significance of guiding clinical decision-making for patients requiring VA-ECLS support, particularly in cases of acute PE. Additional findings underscore the importance of considering VA-ECLS as a crucial intervention for acute PE cases, given the improved survival outcomes observed in this patient population. While further research is mandated to analyze deeper into the nuances of VA-ECLS outcomes across different indications, this study provides valuable insights into the potential benefits and considerations associated with employing VA-ECLS in cases of acute PE.

Reference:

Scott, E. J., Young, S., Ratcliffe, S. J., Wang, X.-Q., Mehaffey, J. H., Sharma, A., Rycus, P., Tonna, J., Yarboro, L., Bryner, B., Collins, M., & Teman, N. R. (2024). Veno-Arterial Extracorporeal Life Support Use in Acute Pulmonary Embolism Shows Favorable Outcomes. In The Annals of Thoracic Surgery. Elsevier BV. https://doi.org/10.1016/j.athoracsur.2024.02.008

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Transillumination method in total knee arthroplasty: New approach with old tools

Murodulla Karimov et al conducted a study to evaluate the possibility of precise intraoperative localization of the lateral genicular arteries by an orthopaedic surgeon using the transillumination method. The study was published in “International Orthopaedics.”

The authors utilized the light of Storz Xenon 300 Light Source for Endoscopy, the tip of which is tightly inserted into the intra-articular side of the lateral retinaculum, while lifting and everting the patella outwards in 90° with towel clips in the medial edge (the limb is in 180° of extension), while the assistant makes fan-like movements from top to bottom and medial to lateral. The arteries are visualized as dark red and identified in the upper-lateral and lower-lateral directions lateral retinaculum, after which the direction of the arteries is marked with a marker. Next, the lateral retinaculum is released distally from the marked edges to the blood vessels, which remain intact.

12 patients underwent cemented TKA with patella-friendly Zimmer Biomet NexGen Legacy Posterior Stabilized prostheses (without patellar resurfacing), seven right knees and five left knees. The mean age of patients in the study group was 66.636 ± 7.003 years. The minimal follow-up period was 13 months (mean—16.363 ± 2.5 months). Functional outcomes were assessed using Knee Society and a specific patellar questionnaire—Kujala Score. Intraoperative detection of insufficient patellar stability and/or patellar maltracking was based on the no-thumb technique. In pre- and postoperative period X-ray investigation, standard standing X-ray and Merchant view were used to evaluate implant position and patellofemoral congruency.

Key findings of the study were:

• In this study, ten out of twelve knee joints (83.3%) had at least one artery visible by the proposed method in the lateral parapatellar area.

• Five out of ten knee joints had more than one artery that could be visualized and identified as an arterial vessel.

• Postoperative Knee Society Score showed significant improvement from a mean 51.181 ± 3.868 to a mean 88.727 ± 3.663.

• Mean hospital length of stay is 8.545 ± 1.863 days.

• X-ray assessment using standard anteroposterior, lateral, and Merchant skyline views showed appropriate implant positioning and patellofemoral congruency.

• The mean Kujala Score in the postoperative period (3 and 6 months) was 67.3 ± 6.75 and 75.6 ± 6.42, respectively.

The authors concluded that – “Lateral release of the patellar retinaculum should be carried out under careful monitoring and visualization of the lateral genicular arteries. Using the proposed transillumination method, an orthopaedic surgeon can perform a lateral release while pre serving the lateral blood supply to the patella, when the medial side has already been sacrificed by the medial parapatellar approach. This method provides an opportunity to avoid iatrogenic devascularization of the patella, postoperative patellar complications, and, importantly, blood loss reduction in TKA.” 

Further reading:

Transillumination method in total knee arthroplasty: new approach with old tools

Murodulla Karimov, Sarvar Madrakhimov

International Orthopaedics (2024) 48:449–454

https://doi.org/10.1007/s00264-023-05977-6

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Rilzabrutinib effective and safe against chronic spontaneous urticaria, finds study

A recent study published in the Journal of Allergy and Clinical Immunology unveiled promising results from a Phase 2 study evaluating the efficacy and safety of rilzabrutinib (SAR444671) in addressing Chronic Spontaneous Urticaria (CSU). CSU is a distressing skin condition often resistant to conventional treatments, is characterized by recurring hives and intense itching, significantly impacting quality of life of the patients.

The RILECSU study encompassed a 52-week investigation involving adults with moderate-to-severe CSU that is inadequately managed by H1 antihistamine treatment alone. The study comprised a 12-week randomized, double-blind, placebo-controlled, dose-ranging phase that was succeeded by a 40-week open-label extension period.

The participants (N=160) were randomly assigned to receive rilzabrutinib at varying doses or a matching placebo. The individuals who were administered with rilzabrutinib at 400mg three times a day (TID) demonstrated significant improvements when compared to the placebo group. A marked reduction in weekly Itch Severity Score (ISS7) and Urticaria Activity Score (UAS7) was observed as early as Week 1, with sustained efficacy through Week 12.

Also, rilzabrutinib expressed a favorable safety profile, with adverse events that ranged from headache, nausea to diarrhea occurring at a higher frequency but remaining manageable. These findings highlight the potential of rilzabrutinib as a promising therapeutic option for the individuals  with the debilitating effects of CSU.

This study emphasized the significance of rilzabrutinib’s rapid onset and tolerability in addressing the unmet needs of CSU patients. The results pave the way for further exploration into the efficacy of rilzabrutinib across diverse patient populations and reinforce the importance of continued research in advancing treatment modalities for chronic skin diseases.

Source:

Maurer, M., Gimenez-Arnau, A., Ferrucci, S., Mikol, V., Sun, I., Mannent, L., & Gereige, J. (2024). Efficacy and Safety of Rilzabrutinib in Patients With Chronic Spontaneous Urticaria: 12-Week Results From the RILECSU Phase 2 Dose-Ranging Study. In Journal of Allergy and Clinical Immunology (Vol. 153, Issue 2, p. AB373). Elsevier BV. https://doi.org/10.1016/j.jaci.2023.11.893

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Once-weekly survodutide safely tied to substantial weight loss in obese individuals: Study

Germany: In adults with a BMI of 27 kg/m2 or greater without diabetes, once-weekly survodutide produced significant reductions in body weight versus placebo from baseline to week 46, findings from a recent phase 2 trial have revealed. Survodutide’s tolerability profile was in line with what would be expected based on its mechanism of action; participants most frequently reported gastrointestinal adverse events.

“All tested survodutide doses significantly reduced body weight in a dose-dependent manner relative to placebo in participants with a BMI of 27 kg/m2 or greater (0·6 mg, ≥2·4 mg),” the researchers reported in their study published in The Lancet Diabetes & Endocrinology.

Survodutide doses 2·4 mg or higher resulted in substantial, clinically relevant bodyweight losses of 5% or more in over half of the participants within 8 weeks of treatment initiation.

Obesity is a chronic and widespread condition that requires long-term management, research into additional targets to improve treatment outcomes remains a priority. Therefore, Anita M Hennige, Boehringer Ingelheim International GmbH, Biberach an der Riß, Germany, and colleagues aimed to investigate the efficacy, safety, and tolerability of glucagon receptor–GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management.

For this purpose, the researchers conducted a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial in 43 centres in 12 countries. Participants aged 18–75 years, BMI ≥27 kg/m2, and without diabetes were enrolled. They were randomly assigned in a ratio of 1:1:1:1:1 to subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance).

The study’s primary endpoint was the percentage change in weight from baseline to week 46. The primary analysis included the modified intention-to-treat population and was based on the dose assigned at randomisation (planned treatment), containing all data censored for COVID-19-related discontinuation. The modified intention-to-treat population was defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint.

The sensitivity analysis was based on the actual dose received during the maintenance phase (actual treatment) and included on-treatment data. The safety analysis included all the participants who received at least one dose of the study drug.

387 participants were enrolled between March 30, 2021, and Nov 11, 2021; 386 participants were treated (0·6 mg, n=77; 2·4 mg, n=78; 3·6 mg, n=77; 4·8 mg, n=77; placebo n=77) and 233 of 386 completed the 46-week treatment period (187 of 309 receiving survodutide; 46 of 77 receiving placebo).

Based on the study, the researchers reported the following findings:

  • When analysed according to planned treatment, mean changes in body weight from baseline to week 46 were −6·2%; −12·5%; −13·2%; −14·9%; −2·8%.
  • Adverse events occurred in 91% of 309 survodutide recipients and 75% of 77 placebo recipients; these were primarily gastrointestinal in 75% of 309 survodutide recipients and 42% of 77 placebo recipients.

“All tested survodutide doses were tolerated, and dose-dependently reduced body weight,” the researchers wrote. The effect of survodutide on body weight was sustained throughout the treatment period.

Reference:

Le Roux, C. W., Steen, O., Lucas, K. J., Startseva, E., Unseld, A., & Hennige, A. M. (2024). Glucagon and GLP-1 receptor dual agonist survodutide for obesity: A randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. The Lancet Diabetes & Endocrinology, 12(3), 162-173. https://doi.org/10.1016/S2213-8587(23)00356-X

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Investigational oral drug sebetralstat provided on-demand relief during tissue swelling attacks from hereditary angioedema: Phase 3 study

USA: A phase III study showed that an investigational oral drug sebetralstat provided on-demand relief during tissue swelling attacks from hereditary angioedema (HAE).

KONFIDENT is the first phase 3 trial for oral on-demand treatment in hereditary angioedema, evaluating a representative population. Safety and efficacy results were presented at the American Academy of Allergy, Asthma & Immunology annual meeting.

“Following self-administration, there was a reduction in the time to the beginning of symptom relief from a median of 6.7 hours with a placebo to 1.6 hours with a 300-mg dose of the plasma kallikrein inhibitor and 1.8 hours with a 600-mg dose,” Paul Audhya, MD, of developer KalVista Pharmaceuticals in Cambridge, Massachusetts, reported in the meeting.

According to findings presented during a late-breaking session, the KONFIDENT trial met key secondary endpoints, with both sebetralstat doses leading to faster reductions in attack severity and shorter times to complete resolution.

Hereditary angioedema is characterized by either a deficiency (type 1 HAE) or dysfunction (type II HAE) of the C1 inhibitor protein, resulting in tissue-swelling episodes that are often painful and sometimes dangerous when an attack affects a patient’s upper airway. Risk factors for attacks included infections and stress.

KalVista is seeking sebetralstat’s approval as the first oral, on-demand therapy for HAE and recently announced that it plans to submit a new drug application to the FDA this year. A host of drugs are approved for the condition as prophylaxis or on-demand treatment, including C1 esterase inhibitors and other plasma kallikrein inhibitors, however, the currently available on-demand options require subcutaneous or intravenous administration.

KONFIDENT is an international, randomized, double-blind, placebo-controlled, 3-way cross-over, phase 3 trial that included participants >_12 years, receiving on-demand therapy with or without long-term prophylaxis. They were randomized to treat <_3 attacks of any severity or location (except severe laryngeal) with 1-2 doses of sebetralstat 300 mg, 600 mg, or placebo.

The primary endpoint was time to the beginning of symptom relief (Patient Global Impression of Change rating of at least ‘‘A Little Better’’ two-time points in a row) within 12 hours.

The key secondary endpoints included time to first decrease in severity from attack onset (>_1 level decrease on Patient Global Impression of Severity [PGI-S] two-time points in a row) within 12 hours and time to attack resolution (PGI-S rating of ‘‘None’’) within 24 hours. Efficacy analyses were based on 252 attacks (84 attacks/treatment group).

After the screening, 136 participants were randomized; 110 experienced at least one attack during the trial, of whom 60% were women, and the median age was 40. Of the 264 total attacks, 87 occurred when patients were assigned to the 300-mg dose of sebetralstat, 93 while on the 600-mg dose, and 84 while assigned placebo.

Patients digitally documented their attacks, including the time of symptom onset and relief from their assigned treatments.

The key findings of the study were as follows:

  • A majority of attacks were treated within an hour of symptoms, and the most common primary attack locations were the abdomen (43%), arms/hands (29%), legs/feet (24%), and the head/face/neck (11%). Most were mild to moderate, while 17% were severe.
  • Second doses of a patient’s assigned medication were allowed 3 hours or more after the first dose if determined to be necessary by the patient. This occurred 38.4% of the time with the 300-mg dose of the study drug, 41.1% with the 600-mg dose, and 55.4% with the placebo.
  • · Treatment-related adverse events (AEs) with sebetralstat (2.3% with the 300-mg dose and 3.2% with the 600-mg dose) were comparable with placebo (4.8%), according to the researchers.
  • Serious treatment-emergent AEs occurred after one attack treated at the 300-mg sebetralstat dose (1.2%) and two attacks treated at the 600-mg dose (2.2%) versus none with placebo. One event at the 300-mg sebetralstat dose was severe.

However, the researchers acknowledged that most participants (92%) were white, which may hinder the general applicability of the findings. 

Source:

American Academy of Allergy, Asthma & Immunology annual meeting 

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