This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new ...therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1–18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively.
Background
Fremanezumab, a fully humanized monoclonal antibody (mAb; IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for the preventive treatment of migraine in ...adults. The efficacy and safety of fremanezumab for migraine prevention have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world effectiveness data are needed to complement clinical trial data. This study assessed the effectiveness of fremanezumab across different subgroups of adult patients with episodic migraine (EM), chronic migraine (CM), or difficult-to-treat (DTT) migraine in real-world clinical settings.
Methods
This retrospective, panel-based online chart review used electronic case report forms. Patient inclusion criteria were a physician diagnosis of EM or CM; age ≥ 18 years at the time of first fremanezumab initiation; ≥ 1 dose of fremanezumab treatment; ≥ 1 follow-up visit since first initiation; and ≥ 2 measurements of monthly migraine days (MMD; with 1 within a month before or at first initiation and ≥ 1 after first initiation). Changes in MMD and monthly headache days were assessed during the follow-up period. These endpoints were evaluated in subgroups of patients by migraine type (EM/CM) and in subgroups with DTT migraine (diagnosis of medication overuse MO, major depressive disorder MDD, generalized anxiety disorder GAD, or prior exposure to a different CGRP pathway–targeted mAb CGRP mAb).
Results
Data were collected from 421 clinicians and 1003 patients. Mean (percent) reductions from baseline in MMD at Month 6 were − 7.7 (77.0%) in EM patients, − 10.1 (68.7%) in CM patients, − 10.8 (80.6%) in the MO subgroup, − 9.9 (68.3%) in the MDD subgroup, − 9.5 (66.4%) in the GAD subgroup, and − 9.0 (68.7%) in the prior CGRP mAb exposure subgroup. Improvements in MDD or GAD severity were reported by 45.5% and 45.8% of patients with comorbid MDD or GAD, respectively.
Conclusions
In this real-world study, fremanezumab demonstrated effectiveness for migraine regardless of migraine type or the presence of factors contributing to DTT migraine (MO, GAD, MDD, or prior exposure to a different CGRP mAb).
Background
The efficacy and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP) and is approved for the ...preventive treatment of migraine in adults, have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world data can further support those clinical trial data and demonstrate the full clinical benefits of fremanezumab. This chart review assessed the effectiveness of fremanezumab for improving clinical outcomes in adult patients with migraine treated according to real-world clinical practice.
Methods
This retrospective, panel-based, online physician chart review study used electronic case report forms with US physicians. Patient inclusion criteria were a physician diagnosis of migraine, fremanezumab treatment initiation at ≥ 18 years of age after US Food and Drug Administration approval, ≥ 1 dose of fremanezumab treatment, and ≥ 2 assessments of monthly migraine days (MMD; 1 within 30 days before treatment initiation and ≥ 1 after initiation). Changes from baseline in MMD, monthly headache days (MHD), and Migraine Disability Assessment (MIDAS) and 6-item Headache Impact Test (HIT-6) scores were assessed over 6 months. These endpoints were evaluated in the overall population and subgroups divided by dosing schedule and number of prior migraine preventive treatment failures.
Results
This study included data from 421 clinicians and 1003 patients. Mean age at fremanezumab initiation was 39.7 years, and most patients were female (75.8%). In the overall population, mean baseline MMD and MHD were 12.7 and 14.0, respectively. Mean (percent) reductions from baseline in MMD and MHD, respectively, were − 4.6 (36.2%) and − 4.7 (33.6%) at Month 1, − 6.7 (52.8%) and − 6.8 (48.6%) at Month 3, and − 9.2 (72.4%) and − 9.8 (70.0%) at Month 6. Mean (percent) reductions from baseline in MIDAS and HIT-6 scores also increased over the 6-month study period, from − 6.2 (21.6%) and − 8.4 (14.0%) at Month 1 to − 18.1 (63.1%) and − 16.2 (27.0%) at Month 6, respectively. Improvements in these outcomes over 6 months were observed across all evaluated subgroups.
Conclusions
This real-world study demonstrated effectiveness of fremanezumab treatment for up to 6 months, irrespective of dosing regimen or number of prior migraine preventive treatment failures, reflecting ongoing, clinically meaningful improvements in patient outcomes.
In this retrospective cohort study, data from an integrated US healthcare system containing both electronic medical record data and linked claims data (from 01/2004 to 12/2020) were used to evaluate ...the clinical burden, treatment patterns, and healthcare resource use (HRU) in patients with von Willebrand disease (VWD). Two patient cohorts were analyzed: the overall VWD population (n = 396) and a subset of these patients (n = 75) who were considered potentially eligible for prophylaxis treatment with von Willebrand factor (VWF) based on a history of severe and frequent bleeding. HRU (hospitalizations, outpatient visits, and emergency department visits) were measured in patients with linked claims data (n = 110, overall VWD patients; n = 23 potentially VWF-prophylaxis-eligible VWD patients). In general, patients with VWD experienced a substantial burden of bleeding events, comorbidities, and HRU. Patients with VWD who were considered potentially eligible for prophylaxis owing to severe and frequent bleeds suffered from a higher clinical burden and HRU than the overall VWD population, and thus may benefit from VWF prophylactic treatment. The findings from this study could help improve clinical outcomes and manage HRU for patients with VWD.
BACKGROUND:
Omadacycline is an amino-methylcycline antibiotic that is indicated for the treatment of adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin ...structure infections (ABSSSI). Like many new antibiotics, there are scant real-world effectiveness data for omadacycline. There is also a high potential that an omadacycline prescription is rejected or reversed, and it is not known whether patients who have an unapproved omadacycline claim are at higher risk for 30-day emergency department (ED)/inpatient (IP) visits.
OBJECTIVE:
To describe the real-world effectiveness of omadacycline and assess the impact of unapproved omadacycline claims among adult outpatients with CABP or ABSSSIs.
METHODS:
The study population included patients who received 1 or more omadacycline outpatient prescriptions from a large US claims database (October 2018 to September 2020) and had a diagnosis for CABP or ABSSSI. The approval status of omadacycline claims was determined. The proportion of all-cause 30-day ED/IP visits among patients with an approved vs unapproved claim was compared.
RESULTS:
404 patients met the inclusion criteria (CABP: 97; ABSSSI: 307). Of the 404 patients, 146 (36%) had an unapproved claim (CABP: 28; ABSSSI: 118). Overall, the proportion of 30-day ED/IP visits (yes/no) for those with an unapproved and approved claim was 28% vs 17%, respectively (
P
< 0.05). The overall adjusted 30-day ED/IP visits incidence difference was 11% (95% CI = 2 - 19), corresponding to an adjusted number needed to treat of 9 (95% CI = 5 - 43).
CONCLUSIONS:
A high incidence (36%) of unapproved omadacydine claims was observed in this study. Patients with unapproved daims had an 11% higher incidence of 30-day all-cause ED/IP visits than patients with approved claims.
DISCLOSURES
This study was funded by Paratek Pharmaceuticals, Inc (King of Prussia, PA). Dr Lodise is a consultant to Paratek Pharmaceuticals, Inc, and has received consultancy payments. Drs Gunter, Sandor, and Berman are employees and shareholders of Paratek Pharmaceuticals, Inc. Dr Mu, Ms Gao, Ms Yang, and Ms Yim are employees of Analysis Group. Analysis Group has received payment from Paratek Pharmaceuticals, Inc, to conduct part of this study.
This study included 404 adult patients with pneumonia or skin and skin structure infections who received an outpatient omadacycline prescription and compared 30-day emergency department (ED)/hospital visits between those who had their omadacycline prescription filled and those who did not. Of the 404 patients in the study, 36% did not have their omadacycline prescription filled. Patients with unfilled omadacycline prescriptions were more likely to have 30-day ED/hospital visits relative to patients with filled prescriptions.
In this observational cohort study of adult outpatients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections, 36% had an unapproved omadacycline claim. Patients with unapproved claims had an 11% higher incidence of 30-day ED/inpatient visits than patients with approved claims. These findings provide health care stakeholders and payers with valuable information on the potential implications of insurance coverage and approval status of omadacycline claims for community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections.
Introduction
Eosinophilic gastritis and eosinophilic enteritis (EoG/EoN) are associated with a substantial clinical burden. However, limited information is available regarding the economic burden of ...EoG/EoN. This study was conducted to compare healthcare resource use (HRU) and costs among patients with EoG/EoN versus without EoG/EoN in the USA.
Methods
Administrative claims data from the IBM MarketScan
®
Commercial Claims and Encounters (CCAE) and Medicare Supplemental and Coordination of Benefits Databases (2009–2019) was used to identify two cohorts of patients. Patients without EoG/EoN were matched 3:1 to patients with EoG/EoN on sex, year of birth, and healthcare plan type. Study measures included demographic characteristics, select comorbidities, all-cause HRU, and costs. Comparisons were made over a 1-year period following EoG/EoN diagnosis for patients with EoG/EoN and an eligible date for patients without EoG/EoN.
Results
A total of 2219 patients with EoG/EoN and 6657 patients without EoG/EoN were analyzed. Significantly higher proportions of patients with EoG/EoN versus without EoG/EoN had comorbid conditions. Rates of all-cause HRU were significantly higher among patients with EoG/EoN versus patients without EoG/EoN (adjusted rate ratio 95% confidence interval: inpatient visits, 6.26 5.26, 7.46; outpatient visits, 1.17 1.16, 1.19; emergency department visits, 2.11 1.98, 2.25; all
p
< 0.001). Patients with EoG/EoN incurred significantly higher costs versus patients without EoG/EoN (adjusted mean cost difference $31,180;
p
< 0.001). Cost differences were largely due to outpatient (adjusted mean cost difference $14,018;
p
< 0.001) and inpatient (adjusted mean cost difference $11,224;
p
< 0.001) costs.
Conclusion
The economic burden associated with EoG/EoN is substantial, with patients with EoG/EoN having a higher rate of HRU and incurring $31,180 more than patients without EoG/EoN on average. Most of the cost difference was attributable to outpatient and inpatient costs. Cost-saving strategies to lower the burden of illness in this patient population are needed.
A cruise ship is a closed-off environment that simulates the basic functioning of a city in terms of living conditions and interpersonal interactions. Thus, the Diamond Princess cruise ship, which ...was quarantined because of an onboard outbreak of COVID-19 in February, 2020, provides an opportunity to define the shedding pattern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient antibody responses before and after the onset of symptoms.
We recruited adult (≥18 years) passengers from Hong Kong who had been on board the Diamond Princess cruise ship docked in Yokohama, Japan in February, 2020. All participants had been found to be negative for SARS-CoV-2 by RT-PCR 4 days before disembarking and were transferred to further quarantine in a public estate in Hong Kong, where they were recruited. Participants were prospectively screened by quantitative RT-PCR (RT-qPCR) of nasopharyngeal and throat swabs, and serum IgG and IgM against internal nucleoprotein and the surface spike receptor-binding protein (RBD) of SARS-CoV-2 at baseline (upon entering quarantine) and on days 4, 8, and 12 of quarantine.
On Feb 22, 2020, 215 adults were recruited, of whom nine (4%; 95% CI 2–8) were positive for SARS-CoV-2 by RT-qPCR or serology and were hospitalised. Of these nine patients, nasopharyngeal swab RT-qPCR was positive in eight patients (89%; 57–99) at baseline. All nine patients were positive for anti-RBD IgG by day 8. Eight (89%; 57–99) were simultaneously positive for nasopharyngeal swab RT-PCR and anti-RBD IgG. One patient who was positive for anti-RBD IgG and had a negative viral load had multifocal peripheral ground-glass changes on high-resolution CT that were typical of COVID-19. Five patients (56%; 27–81) with ground-glass changes on high-resolution CT were found to have higher anti-nucleoprotein-IgG OD values on day 8 and 12 and anti-RBD IgG OD value on day 12 than patients without ground-glass changes. Six (67%; 35–88) patients remained asymptomatic throughout the 14-day quarantine period.
Patients with COVID-19 can develop asymptomatic lung infection with viral shedding and those with evidence of pneumonia on imaging tend to have an increased antibody response. Positive IgG or IgM confirmed infection of COVID-19 in both symptomatic and asymptomatic patients. A combination of RT-PCR and serology should be implemented for case finding and contact tracing to facilitate early diagnosis, prompt isolation, and treatment.
Shaw Foundation Hong Kong; Sanming-Project of Medicine (Shenzhen); High Level-Hospital Program (Guangdong Health Commission).
Effective antiviral therapy is important for tackling the coronavirus disease 2019 (COVID-19) pandemic. We assessed the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ...ribavirin for treating patients with COVID-19.
This was a multicentre, prospective, open-label, randomised, phase 2 trial in adults with COVID-19 who were admitted to six hospitals in Hong Kong. Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group). The primary endpoint was the time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR, and was done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT04276688.
Between Feb 10 and March 20, 2020, 127 patients were recruited; 86 were randomly assigned to the combination group and 41 were assigned to the control group. The median number of days from symptom onset to start of study treatment was 5 days (IQR 3–7). The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days IQR 5–11) than the control group (12 days 8–15; hazard ratio 4·37 95% CI 1·86–10·24, p=0·0010). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups. One patient in the control group discontinued lopinavir–ritonavir because of biochemical hepatitis. No patients died during the study.
Early triple antiviral therapy was safe and superior to lopinavir–ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19. Future clinical study of a double antiviral therapy with interferon beta-1b as a backbone is warranted.
The Shaw-Foundation, Richard and Carol Yu, May Tam Mak Mei Yin, and Sanming Project of Medicine.
Nontarget data acquisition for target analysis (nDATA) workflows using liquid chromatography-high-resolution accurate mass (LC-HRAM) spectrometry, spectral screening software, and a compound database ...have generated interest because of their potential for screening of pesticides in foods. However, these procedures and particularly the instrument processing software need to be thoroughly evaluated before implementation in routine analysis. In this work, 25 laboratories participated in a collaborative study to evaluate an nDATA workflow on high moisture produce (apple, banana, broccoli, carrot, grape, lettuce, orange, potato, strawberry, and tomato). Samples were extracted in each laboratory by quick, easy, cheap, effective, rugged, and safe (QuEChERS), and data were acquired by ultrahigh-performance liquid chromatography (UHPLC) coupled to a high-resolution quadrupole Orbitrap (QOrbitrap) or quadrupole time-of-flight (QTOF) mass spectrometer operating in full-scan mass spectrometry (MS) data-independent tandem mass spectrometry (LC-FS MS/DIA MS/MS) acquisition mode. The nDATA workflow was evaluated using a restricted compound database with 51 pesticides and vendor processing software. Pesticide identifications were determined by retention time (t R, ±0.5 min relative to the reference retention times used in the compound database) and mass errors (δM) of the precursor (RTP, δM ≤ ±5 ppm) and product ions (RTPI, δM ≤ ±10 ppm). The elution profiles of all 51 pesticides were within ±0.5 min among 24 of the participating laboratories. Successful screening was determined by false positive and false negative rates of <5% in unfortified (pesticide-free) and fortified (10 and 100 μg/kg) produce matrices. Pesticide responses were dependent on the pesticide, matrix, and instrument. The false negative rates were 0.7 and 0.1% at 10 and 100 μg/kg, respectively, and the false positive rate was 1.1% from results of the participating LC-HRAM platforms. Further evaluation was achieved by providing produce samples spiked with pesticides at concentrations blinded to the laboratories. Twenty-two of the 25 laboratories were successful in identifying all fortified pesticides (0–7 pesticides ranging from 5 to 50 μg/kg) for each produce sample (99.7% detection rate). These studies provide convincing evidence that the nDATA comprehensive approach broadens the screening capabilities of pesticide analyses and provide a platform with the potential to be easily extended to a larger number of other chemical residues and contaminants in foods.
TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and ...life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD.
Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review.
Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation.
We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.
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