H. Pylori Infection Treatments

This month we examine a lawsuit where the physician was not found liable for the harm to the plaintiff. This may seem unusual given what you may read in the headlines, but it’s not. In the great majority of cases, at least 80%, the jury’s ultimate decision is in favor of the doctor.

In fact, most lawsuits against health care professionals never even make it to trial. Most are settled or dismissed before a juror is ever questioned, sometimes very early in the process.

While you can’t always protect yourself from being the subject of a lawsuit, you can practice in a way that minimizes the likelihood of you being found liable in that lawsuit.

Facts of the Case

The case involved a nine-year old boy, JD, who complained of a bad stomachache. His parents took him to the emergency department of the local hospital where he was admitted with severe abdominal pain and distension. The clinicians who examined JD at the hospital suspected the child was suffering from constipation. Later that evening, the child was transferred to a children’s hospital where Dr L, a gastroenterologist, served as the child’s attending physician and oversaw his care.

The child’s symptoms were non-specific but were consistent with constipation. Dr L believed that the child was suffering from extreme constipation and proceeded under that assumption by following the appropriate treatment protocol for constipation. The child’s pain levels were decreasing, which the physician took as a good sign, although the boy did vomit more than once.

Late the next day, however, the child went into hypovolemic shock and was immediately rushed to the intensive care unit where he was ultimately diagnosed with acute pancreatitis. This was just the start of the child’s issues. Unfortunately, the pancreatitis had progressed to a necrotizing form causing a plethora of other complications. The boy required multiple surgeries and was hospitalized for over 4 months. His medical expenses were well over $2 million, and that did not include future expenses.

After the child was finally released from the hospital, his parents consulted a plaintiff’s attorney who filed a lawsuit against Dr L, the gastroenterologist, but did not sue either of the hospitals that had treated JD.

The Trial

Although, as mentioned earlier, the majority of cases settle prior to trial, this was one of the exceptions. The trial lasted a total of 4 days and included testimony from 10 witnesses including 4 medical expert witnesses. The trial hinged on whether Dr L had properly treated and monitored the boy prior to his going into shock. The plaintiff argued that Dr L departed from the appropriate standard of care by failing to order tests or take other action which would have revealed the child’s pancreatitis sooner, preventing it from turning into the necrotizing type of disease.

HealthDay News — For adolescents and young adults diagnosed with ulcerative colitis (UC), the rate of discontinuation of 5-aminosalicylic acid (5-ASA) maintenance treatment is high within the first year, according to a study published online September 4 in the British Journal of General Practice.

Nishani Jayasooriya, MBBS, from St. George’s University Hospitals NHS Foundation Trust in London, and colleagues examined the rates and risk factors for discontinuation and adherence to oral 5-ASA in adolescents and young adults one year after UC diagnosis in an observational cohort study. The impact of sociodemographic and health-related risk factors was assessed.

The researchers found that 152 of 607 adolescents and young adults starting oral 5-ASA maintenance treatment discontinued within one month, and 419 discontinued within one year. Those aged 18 to 24 years had higher discontinuation than younger age groups (74 percent versus 61 and 56 percent in those aged 10 to 14 and 15 to 17 years, respectively). Compared with adolescents, young adults had lower adherence (69 vs 80% in those aged 18 to 24 vs 10 to 14 years). The likelihood of discontinuing treatment was increased for residents in deprived vs affluent postcodes (adjusted hazard ratio, 1.46). A lower likelihood of discontinuation was seen for early corticosteroid use for an acute flare (adjusted hazard ratio, 0.68).

“These findings illustrate the importance of clinicians ensuring careful follow-up within the first year when prescribing lifelong therapies for adolescents and young adults who are diagnosed with UC, particularly adolescents transitioning to young adulthood and those living in deprived areas,” the authors write.

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HealthDay News — Acupuncture is safe and feasible for patients with irritable bowel syndrome with diarrhea (IBS-D), according to a pilot study published online December 29 in JAMA Network Open.

Ling-Yu Qi, from the Beijing University of Chinese Medicine, and colleagues randomly assigned 90 individuals with IBS-D to acupuncture (either specific acupoints [SA] or nonspecific acupoints [NSA]) or a sham acupuncture (NA) group with all groups receiving 12 30-minute sessions over 4 consecutive weeks.

The researchers observed substantial improvements in the response rate at week 4 for all groups (composite response rates of 46.7% in the SA group, 46.7% in the NSA group, and 26.7% in the NA group). However, the difference between the groups was not statistically significant. Adequate relief at week 4 was achieved by 64.3% in the SA group, 62.1% in the NSA group, and 55.2% in the NA group. Two patients (6.7%) in the SA group and 3 patients (10%) in the NSA or NA group reported adverse events.

“These findings suggest that acupuncture is feasible and safe; a larger, sufficiently powered trial is needed to accurately assess efficacy,” the authors write.

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HealthDay News — For women with moderate-to-severe nausea and vomiting of pregnancy (NVP), both acupuncture and doxylamine-pyridoxine are efficacious, and the combination may yield a larger benefit than either treatment alone, according to a study published online June 20 in the Annals of Internal Medicine.

Xiao-Ke Wu, MD, PhD, from the Heilongjiang University of Chinese Medicine in Harbin, and colleagues examined the efficacy and safety of acupuncture, doxylamine-pyridoxine, and a combination of both in 352 women in early pregnancy with moderate-to-severe NVP. Participants received 30 minutes of daily active or sham acupuncture and 14 days of doxylamine-pyridoxine or placebo.

The researchers observed no significant interaction between the interventions. A larger reduction in the Pregnancy-Unique Quantification of Emesis score was seen over the treatment course for acupuncture, doxylamine-pyridoxine, and the combination of both compared with their respective control groups (mean differences, −0.7, −1.0, and −1.6, respectively). The risk for births with children who were small for gestational age was higher with doxylamine-pyridoxine vs placebo.

“The combination of both treatments showed numerically larger and potentially more clinically meaningful benefit than either treatment alone,” the authors write. “This finding is especially significant because there is a pressing need to establish a pregnancy-safe treatment regimen and an integrative guideline for managing severe NVP.”

One author disclosed ties to industry.

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Adagrasib is a highly selective, potent oral small molecule inhibitor of KRAS^G12C designed to sustain target inhibition by irreversibly locking the mutant protein in its inactive state. The application is supported by data from the multicohort phase 2 KRYSTAL-1 study (ClinicalTrials.gov Identifier: NCT03785249), which evaluated adagrasib in heavily pretreated patients with KRAS^G12C-mutated advanced CRC.

Study participants received either adagrasib 600mg orally twice daily as monotherapy (n=44) or in combination with cetuximab administered intravenously once or twice weekly (n=32); median follow-up was 20.1 months and 17.5 months, respectively. The primary endpoint was the objective response rate (ORR). 

Among 28 evaluable patients in the adagrasib plus cetuximab arm, the ORR was 46% (95% CI, 28-66). Median duration of response (DOR) was 7.6 months (95% CI, 5.7-not estimable) and median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.1).

Among 43 evaluable patients in the adagrasib monotherapy arm, the ORR was 19% (95% CI, 8-33). Median DOR was 4.3 months (95% CI, 2.3-8.3) and median PFS was 5.6 months (95% CI, 4.1-8.3). 

The safety profile of adagrasib plus cetuximab was well tolerated. The incidence of Grade 3 or 4 treatment-related adverse events was 34% in the monotherapy arm and 16% in the combination arm. There were no Grade 5 adverse events observed. 

A Prescription Drug User Fee Act target date of June 21, 2024 has been set for this application.

“Pretreated KRAS^G12C-mutated CRC is associated with poor outcomes and the current standard of care offers limited clinical benefit for patients,” said Anne Kerber, senior vice president, head of late clinical development, Hematology, Oncology, Cell Therapy (HOCT) at Bristol Myers Squibb. “It [sNDA acceptance] reinforces our commitment to developing potentially transformative targeted cancer therapies for patients for whom few treatment options exist.”

Adagrasib is currently marketed under the trade name Krazati^® and is approved for the treatment of adults with KRAS^G12C-mutated locally advanced or metastatic NSCLC, who have received at least 1 prior systemic therapy.

HealthDay News — For pediatric Crohn disease (PCD) patients, treatment with methotrexate combined with adalimumab, but not infliximab, is associated with a reduction in treatment failure, according to a study published online March 31 in Gastroenterology.

Michael D. Kappelman, MD, MPH, from the University of North Carolina at Chapel Hill, and colleagues conducted a randomized trial involving PCD patients initiating infliximab or adalimumab who were randomly assigned to methotrexate (156 patients [110 infliximab initiators and 46 adalimumab initiators]) or placebo (141 patients [102 infliximab initiators and 39 adalimumab initiators]).

The researchers found that the time to treatment failure did not differ by study arm in the overall population. No differences were seen between the groups among infliximab initiators, while combination therapy was associated with longer time to treatment failure among adalimumab initiators. There was a trend toward lower antidrug antibodies development observed in the combination therapy arm, which was not significant. No differences were seen in patient-reported outcomes of pain interference and fatigue. More adverse events, but fewer serious adverse events, were seen in the combination therapy arm.

“Our study findings suggest strong consideration of using combination therapy for PCD patients initiating adalimumab but not infliximab,” the authors write. “Dissemination and implementation of these findings should lead to improved outcomes in this patient population, including consideration of deimplementation of combination therapy in infliximab-treated patients.”

Several authors disclosed financial ties to biopharmaceutical companies, including AbbVie, the manufacturer of adalimumab.

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Adalimumab-adbm injection, a biosimilar to Humira^® (adalimumab), has been made available by Boehringer Ingelheim.

Adalimumab-adbm injection is an interchangeable biosimilar and can be substituted for the reference product without requiring a prescription change. The substitution may occur at the pharmacy similar to how generics are substituted for brand name drugs. According to the Company, Adalimumab-adbm injection has been priced at an 81% discount to Humira.  

Adalimumab-adbm injection is indicated for the treatment of adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, moderately to severely active Crohn disease, moderately to severely active ulcerative colitis, moderate to severe plaque psoriasis, moderate to severe hidradenitis suppurativa, and noninfectious intermediate, posterior, and panuveitis.

The product is also approved to treat moderately to severely active Crohn disease in children 6 years of age and older, as well as moderately to severely active polyarticular juvenile idiopathic arthritis in children 2 years of age and older.

Adalimumab-adbm injection is a citrate-free formulation and is supplied as 40mg/0.8mL, 20mg/0.4mL and 10mg/0.2mL prefilled syringes and as a 40mg/0.8mL prefilled autoinjector.

In July 2023, Boehringer Ingelheim launched a branded version of adalimumab-adbm called Cyltezo^®. This product will remain available at a 5% discount to Humira.

“Biosimilars are intended to contribute to the economic sustainability of health care systems, and it is our hope that this dual pricing approach will contribute to that sustainability, improve access to Adalimumab-adbm and help meet the varied needs of people with a variety of chronic inflammatory diseases,” said Stephen Pagnotta, Executive Director and Biosimilar Commercial Lead at Boehringer Ingelheim.

HealthDay News — In a study published August 2 in the American Journal of Roentgenology, a radiomic machine learning model predicted Crohn disease diagnosis with better performance than 2 of 3 expert radiologists.

Richard X. Liu, PhD, from the University of Cincinnati College of Medicine, and colleagues developed a machine learning-based method for predicting ileal Crohn disease using radiomic features of ileal wall and mesenteric fat from noncontrast T2-weighted magnetic resonance (MR) images. Performance of the artificial intelligence (AI) model was compared to the performance of expert radiologists.

The researchers found that for 135 patients, the 3 radiologists had accuracies of 83.7, 86.7, and 88.1% for diagnosing Crohn disease, with consensus accuracy of 88.1%. There was substantial inter-radiologist agreement (κ = 0.78). The bowel core was the best-performing region of interest (area under the receiver operating characteristic curve [AUC], 0.95; accuracy, 89.6%); whole bowel fat core and whole fat had worse performance (whole bowel AUC, 0.86; fat core AUC, 0.70; whole-fat AUC, 0.73). A clinical-only model achieved an AUC of 0.85 and accuracy of 80.0%, while an ensemble model combining bowel-core radiomic and clinical models achieved AUC of 0.98 and accuracy of 93.5%. The bowel-core radiomic-only model had better accuracy than radiologist 1 and radiologist 2, but not radiologist 3 or radiologists’ consensus. The ensemble model achieved better accuracy than radiologists’ consensus.

“Deployment of a radiomic-based model using T2-weighted MR data could decrease inter-radiologist variability and increase diagnostic accuracy for pediatric Crohn disease,” the authors write.

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Amjevita (adalimumab-atto), a citrate-free biosimilar to Humira^® (adalimumab), is now available in the US.

Amjevita, a tumor necrosis factor (TNF) blocker, is indicated for:

• Rheumatoid arthritis (RA): reducing signs/symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA; may be used alone or with methotrexate (MTX) or other non-biologic DMARDs.
• Juvenile idiopathic arthritis (JIA): reducing signs/symptoms of moderately to severely active polyarticular JIA in patients 2 years of age and older; may be used alone or with MTX.
• Psoriatic arthritis (PsA): reducing signs/symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active PsA; may be used alone or with non-biologic DMARDs.
• Ankylosing spondylitis (AS): reducing signs/symptoms in adult patients with active AS.
• Crohn disease (CD): moderately to severely active CD in patients 6 years of age and older.
• Ulcerative colitis (UC): moderately to severely active UC in adult patients.
• Plaque psoriasis (PsO): treating adult patients with moderate to severe chronic PsO who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.

The Food and Drug Administration (FDA) approved Amjevita in September 2016 based on data demonstrating that the biosimilar product and the reference product were highly similar, and that there were no clinically meaningful differences between the agents. Amjevita is not interchangeable with Humira. 

Amjevita is supplied in a 40mg/0.8mL single-dose prefilled SureClick autoinjector, and in 20mg/0.4mL and 40mg/0.8mL single-dose prefilled syringes. 

References

1. Amjevita (adalimumab-atto), first biosimilar to Humira^®, now available in the United States. News release. Amgen. Accessed January 31, 2023. https://www.prnewswire.com/news-releases/amjevita-adalimumab-atto-first-biosimilar-to-humira-now-available-in-the-united-states-301734177.html.
2. Amjevita. Package insert. Amgen; 2022. Accessed January 31, 2022. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Amjevita/amjevita_pi_hcp_english.pdf.

CM-101 is an investigational, first-in-class, monoclonal antibody designed to neutralize CCL24, a soluble protein that regulates biliary inflammation and fibrosis in patients with fibroinflammatory diseases such as PSC.

The designation is supported by data from a phase 2a trial (ClinicalTrials.gov Identifier: NCT05824156), which evaluated the safety and tolerability of CM-101 in adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with stage 1c, 2, or 3 fibrosis. Results showed that treatment with CM-101 achieved consistent, positive improvements in key inflammatory and fibrogenesis-related biomarkers.

The Company is investigating CM-101 in adults with PSC in the ongoing double-blind, placebo-controlled, phase 2 SPRING trial (ClinicalTrials.gov Identifier: NCT04595825). Topline data from the SPRING study is expected to be available in the second half of 2024.

“This FDA Fast Track designation is an important validation of CM-101’s potential to have a major impact on this devastating disease that attacks people in their prime years and lacks any approved treatments,” said Adi Mor, PhD, co-founder, CEO and Chief Scientific Officer of Chemomab. “We designed the CM-101 phase 2 SPRING trial to be supportive of a registrational trial in patients with PSC, and we welcome the enhanced opportunities for working closely with the FDA and for acceleration of the development and review process provided by Fast Track status.”

Antiemetic Treatments

Yuto Shimamura, MD, from Showa University in Tokyo, and colleagues evaluated the feasibility, safety, and effectiveness of ARMA. The analysis included 68 patients with GERD symptoms refractory to acid suppression medications or those dependent on such medications.

The researchers found that clinical success rates (defined as >50% reduction in a validated GERD questionnaire) at 2 to 6 months and 1 year post-ARMA were 60 and 70%, respectively. There were significant improvements seen in the median GERD health-related quality of life score from 26 to 11 at two to six months. Among those who underwent 24-hour pH monitoring (51 patients), median acid exposure time significantly decreased from 5.3 to 0.7%, along with a significant reduction in esophagitis rates. No factors predicted short-term success in a multivariate analysis. Transient stenosis requiring balloon dilation was seen in nine patients (13.2%).

“Both reflux hypersensitivity and confirmed GERD patients, regardless of their response to acid suppression medication, may be suitable candidates,” the authors write.

Several authors disclosed ties to industry.

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