Phase 3 Trial of Budesonide for Eosinophilic Esophagitis & COVID-19 Deaths in U.S.

NY Times article:  U.S. Coronavirus Cases Are Rising Sharply, but Deaths Are Still Down

This article explains why deaths from COVID-19 have not increased despite increasing number of infections.  Three main reasons: increased testing -detects many with less severe symptoms, younger population are being infected, and new treatment approaches may be helping.  However, “the dip in coronavirus mortality will not necessarily last. As more people socialize, those with milder infections might end up ferrying the pathogen to vulnerable individuals…Recent upswings in coronavirus case numbers leave experts apprehensive of what’s to come. Death, when it occurs, tends to trail infection by about two to four weeks.”


The Budesonide Oral Suspension (BOS) resulted in 62% of BOS patients meeting the threshold of < 15 eos/hpf compared to 1% of placebo patients. From lead author, Ikuo Hirano: “the results of the BOS trial showed that BOS successfully treated both the symptoms and signs of EoE. The positive results will hopefully lead to an approved, safe and effective therapy for EoE.”

Abstract from ACG Meeting October 2019:

Abstract: Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results From a Phase 3, Randomized, Placebo-Controlled Trial

Introduction: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. 

Methods: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed.

Results: A total of 322 patients were randomized (BOS, n=215; placebo, n=107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n=213; placebo, n=105) (Table). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, p< 0.001; 52.6% vs 39.1%, p=0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n=197) than the placebo group (n=89) (−13.0 vs −9.1; p=0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n=202) than placebo (n=93) (−4.0 vs −2.2; p< 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo.  No life-threatening TEAEs were reported.

Discussion: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

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Island Ford, Sandy Springs

 

 

 

Updated Outcome Data for Necrotizing Enterocolitis

A recent systematic review (IH Jones, NJ Hall. J Pediatr 2020; 220: 86-92) provides contemporary outcomes for infants with necrotizing enterocolitis (NEC). The authors analyzed from 38 articles (from 1375 abstracts); the authors excluded data from developing countries. This review included 21,349 infants with any stage of NEC and 7540 with Bell stage 2a+.

Key findings:

  • Overall mortality was 23.5% in all neonates with confirmed NEC (Bell stage 2a+), 34.5% for infants who underwent surgery
  • Mortality rates were higher for extremely low birthweight infants (<1000 g) at 40.5%; the rate was 50.9% for surgical NEC in this cohort
  • Neurodevelopmental disability was reported in only 4 studies and ranged between 24.8% and 61.1% (n=1209)
  • Intestinal failure was reported with an incidence of 15.2% to 35.0% (n=1370)

A limitation with this study is the lack of agreement on definitions/diagnosis for necrotizing enterocolitis and intestinal failure.

My take: This study shows that NEC still carries a high mortality.

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Sandy Springs

How The IRS Proved That Health Insurance Saves Lives

NY Times: The I.R.S. Sent a Letter to 3.9 Million People, It Saved Some of Their Lives

Recently, economists have shown that an I.R.S. letter encouraging people to sign up for health insurance saved lives.  This letter was an inadvertent randomized trial as 600,000 people who were eligible for the letter did not receive it due to a budget shortfall.

An excerpt:

Three years ago, 3.9 million Americans received a plain-looking envelope from the Internal Revenue Service. Inside was a letter stating that they had recently paid a fine for not carrying health insurance and suggesting possible ways to enroll in coverage…

Obtaining insurance… reduced premature deaths by an amount that exceeded any of their expectations. Americans between 45 and 64 benefited the most: For every 1,648 who received a letter, one fewer death occurred than among those who hadn’t received a letter.

In all, the researchers estimated that the letters may have wound up saving 700 lives…

The results also provide belated vindication for the much-despised individual mandate that was part of Obamacare until December 2017, when Congress did away with the fine for people who don’t carry health insurance…

The uninsured rate for Americans is rising for the first time in a decade, as states tighten eligibility rules for Medicaid, and as the Trump administration cuts back on health care outreach…

Previous research has found a link between expanded health insurance access and fewer deaths. Multiple studies showed a decline in mortality rates after states expanded Medicaid, but none could tie the outcome directly to the policy change, since states typically cannot randomly pick which residents do and don’t receive Medicaid. That makes the Treasury experiment, an unintended result of a budget shortfall, distinctively useful.

My take: This analysis shows that prompting health care coverage by sending a single letter can save lives.  It is unfortunate that we are currently heading in the opposite direction.

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NY Times: “Our Food is Killing Too Many of Us”

NY Times: D Mozaffarian, D Glickman Our Food is Killing Too Many of Us

“Improving American nutrition would make the biggest impact on our health care”

An excerpt:

“Instead of debating who should pay for all this, no one is asking the far more simple and imperative question: What is making us so sick, and how can we reverse this so we need less health care? … our food…

Poor diet is the leading cause of mortality in the United States, causing more than half a million deaths per year. Just 10 dietary factors are estimated to cause nearly 1,000 deaths every day from heart disease, stroke and diabetes alone…

Taxes on sugary beverages and junk food can be paired with subsidies on protective foods like fruits, nuts, vegetables, beans, plant oils, whole grains, yogurt and fish….Levels of harmful additives like sodium, added sugar and trans fat can be lowered through voluntary industry targets or regulatory safety standards

Nutrition standards in schools, which have improved the quality of school meals by 41 percent, should be strengthened; the national Fresh Fruit and Vegetable Program should be extended beyond elementary schools to middle and high schools…

Coordinated federal leadership and funding for research is also essential. This could include, for example, a new National Institute of Nutrition at the National Institutes of Health. Without such an effort, it could take many decades to understand and utilize exciting new areas, including related to food processing, the gut microbiome, allergies and autoimmune disorders, cancer, brain health, treatment of battlefield injuries and effects of nonnutritive sweeteners and personalized nutrition.”

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Crater Lake, OR

 

Bariatric Surgery Survival – 5 Countries, 500,000 Participants

A recent population-based cohort study (JH Kauppila et al. Gastroenterol 2019; 157: 19-27) examined the effects of bariatric surgery on survival from Nordic countries between 1980-2012.

Link: Effects of Obesity Surgery on Overall and Disease-Specific Mortality in a 5-Country Population-Based Study

Among 505,258 obese individuals, 49,977 had bariatric surgery.

Key findings:

  • Overall mortality rates were lower in the surgery group during the first 14 years but higher after 15 years (HR 1.20 with CI 1.02-1.42).  Thus, overall, obese patients who underwent bariatric surgery had longer survival times than obese patients who did not have surgery.  Both groups had higher mortality than the general population
  • The improved survival compared to those without surgery was related to decreased mortality from cardiovascular mortality, diabetes and cancer.  However mortality due to suicide was increased.
  • Limitations: lack of detailed data including BMI, smoking and alcohol consumption

Graphical abstract (available online)

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Tweet Updates: Nutrients Helpful in Foods Rather Than Supplements, More ID Doctors Needed

 

Yesterday’s post highlighted a study which indicated that low quality diets result in signiificant mortality.  The tweets below refer to a study which indicated that supplements generally do not help one achieve a good diet.  For a diet to be effective, the nutrients need to be present in the diet.

 

Bad Diets –>High Mortality

A recent article in Lancet (“Health effects of dietary risks in 195 countries, 1990–2017:
a systematic analysis for the Global Burden of Disease Study 2017″ -open access) estimated that bad diets lead to 11 million deaths per year. Thanks to Ana Ramirez for sending me this article. “High intake of sodium, low intake of whole grains, and low intake of fruits were the leading dietary risk factors for deaths and DALYs globally and in many countries.”

A summary of this study was reported on NPR: Bad Diets Are Responsible For More Deaths Than Smoking, Global Study Finds

An excerpt:

About 11 million deaths a year are linked to poor diet around the globe…

As part of a new study published in The Lancet, researchers analyzed the diets of people in 195 countries using survey data, as well as sales data and household expenditure data. Then they estimated the impact of poor diets on the risk of death from diseases including heart disease, certain cancers and diabetes. (They also calculated the number of deaths related to other risk factors, such as smoking and drug use, at the global level.)…

“Generally, the countries that have a diet close to the Mediterranean diet, which has higher intake of fruits, vegetables, nuts and healthy oils [including olive oil and omega-3 fatty acids from fish] are the countries where we see the lowest number of [diet-related] deaths,” …

What would happen if everyone around the globe began to eat a healthy diet, filling three-fourths of their plates with fruits, vegetables and whole grains? We’d run out…

Improving diets won’t be easy: A range of initiatives may be needed, including nutrition education and increased access to healthy foods, as well as rethinking agricultural production.

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Liver Shorts April 2019

CL Mack et al. JPGN 2019; 68: 495-501. This multicenter prospective open-label phase I/III trial of IVIG in biliary atresia patients status-post Kasai indicated that the infusions were tolerated.  However, though this study was not powered to detect efficacy, survival with native liver was LOWER among patients who had received IVIG (n=29): 58.6% compared to the comparison placebo group 70.5% (n=64).  Thus, despite the theoretical advantages of IVIG which targets aspects of the immune system and improvement in a murine model, in practice IVIG does not appear promising for biliary atresia.

D Kim et al. Hepatology 2019; 69: 1064-74. This study shows that despite improvements in hepatitis C mortality rates associated with newer treatments, there is an overall increase in mortality rates from cirrhosis and hepatocellular carcinoma.  This increase is driven by increasing prevalence and severity of both alcoholic liver disease and nonalchoholic fatty liver disease. The overall cirrhosis-related mortality increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3%. Similarly, the overall HCC-related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at annual increase of 2%. The editorial on page 931 (TG Cotter and MR Charlton) notes that each year there are more than 40,000 deaaths associated with chronic liver disease.

H Park et al. Hepatology 2019; 69: 1032-45. This study, using Truven Health MarketScan Cata, examined the outcomes of more than 26,000 patients with newly-diagnosed hepatitis C virus (HCV) infection.  Among the 30% who received oral direct-acting antiviral (DAA) therapy, there were improved outcomes in those with and without cirrhosis. In those with cirrhosis (n=2157), DAA was associated with a 72% and 62% lower incidences of HCC and DCC [decompensated cirrhosis] respectively. In noncirrhotic HCV patients (n=23,948), DAA was associated with a 57% and 58% lower incidence of HCC and DCC respectively.  In addition to improved health outcomes, DAA treatment resulted in decrease health care costs, especially for patients with cirrhosis.

Z Kuloglu et al. JPGN 2019; 68: 371-6.  In this multicenter Turkish study, the authors identified 810 children (median age 5.6 years) with unexplained transaminase elevation (62%),unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%) and cryptogenic fibrosis or cirrhosis (6%).  LAL-D [lysosomal acid lipase deficiency] activity was deficient in 2 siblings (0.2%); both had LDL ~155.  Overall, even in at risk groups, LAL-D is rare.

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Mortality Risk from Childhood Inflammatory Bowel Disease

A recent study (O Olen et al. Gastroenterol 2019; 156: 614-22) was summarized quite succinctly by NEJM journal watch:

Using the Swedish National Patient Registry data, investigators identified 9442 incident cases of IBD diagnosed in patients under age 18 years from 1964 through 2014. Based on 139,000 person-years of follow-up, results were as follows:

  • There were 259 deaths among people with IBD (133 were from cancer and 54 from digestive disease).
  • The all-cause mortality rate in these patients was 2.1/1000 person-years, compared with 0.7 in matched reference individuals from the general population.
  • The average age at death was 61.7 compared with 63.9 years in the reference group.
  • The hazard ratio for death was 3.2 and was higher in those with ulcerative colitis (HR, 4.0), especially if they had concomitant primary sclerosing cholangitis (HR, 12.2), a first-degree relative with ulcerative colitis (HR, 8.3), or a history of surgery (HR, 4.6).
  • Mortality risks were similar when limited to the period after the introduction of biologics (2002–2014).

My take: This study found that having IBD diagnosed in childhood increased the risk of mortality (~1 extra death for every 700 patients followed for 1 year) especially in patients with concomitant PSC and in patients with severe ulcerative colitis.  The study did not see an effect of the newest therapies but was underpowered to directly assess this effect.

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Chattahoochee River, near Azalea Drive

 

Interleukin 6 and Liver Disease Mortality

Briefly noted: J Remmler et al. Clin Gastroenterol Hepatol 2018; 16: 730-7.  This retrospective study with 474 patients showed that blood levels of interleukin 6 were associated with mortality.  In this cohort, those with levels in the lowest quartile (< 5.3 pg/mL) had zero fatalities within 1 year.  In those with the highest quartile (37 pg/mL or more), had a 67.7% mortality rate within 1 year.  The associated editorial (pg 630-32) notes that IL6 functions include liver regeneration, infection defense, and metabolic homeostasis.  “IL6 is synthesized during inflammatory conditions…persistent activation of the IL6 pathway may have detrimental effects in the livers and in other tissues.”

Pine Mountain Trail