ABSTRACT
Bovine tuberculosis (bTB), caused by Mycobacterium bovis infection, is a zoonotic disease in cattle that represents a significant ongoing challenge to cattle farming productivity and the livelihoods of livestock farmers in the UK. Vaccination of cattle with BCG could directly target the ability of M. bovis to proliferate within vaccinates, restricting bTB pathogenesis and onward disease transmission, and represent a step change in the tools available to help control bTB in farmed cattle. A Marketing Authorisation (MA) is required before a cattle BCG vaccine could be sold and supplied as a veterinary medicine within the UK and this requires comprehensive data supporting vaccine quality, efficacy and, most importantly, its safety. We carried out two independent Good Laboratory Practice (GLP) studies in which the safety of BCG vaccination in cattle was stringently tested through overdose and repeat vaccine administrations in young calves and pregnant heifers. Mild and generally short-lived reactions to vaccinations were observed in some animals, most commonly increases in body temperature and swelling at vaccine injection sites, but these did not have a negative impact on the overall health status of vaccinates. BCG was not shed in the saliva, faeces, milk or urine from vaccinated animals and its dissemination was limited to injection site tissues and associated lymph nodes. Overall, young calves and pregnant heifers vaccinated with BCG remained in good general health, and the vaccinated pregnant heifers had normal pregnancies and gave birth to healthy calves. Obtaining a Marketing Authorisation for a cattle BCG vaccine is a critical milestone in the progress towards the eventual use of BCG vaccination in cattle as an additional bTB control tool within the UK; these pivotal GLP vaccine safety studies generated the detailed and essential target animal safety data needed to support this.
ABSTRACT
BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil.