320 likes | 497 Views
"Clinical Trials and Clinical Endpoints" . James R. Bradford, DVM, Dipl. ABVP Pharmacia Animal Health. Mycoplasmal Pneumonia. Clinical and production disease Recognized financial impact early ’70’s Research with Lincomycin began in 1974
E N D
"Clinical Trials and Clinical Endpoints" James R. Bradford, DVM, Dipl. ABVP Pharmacia Animal Health
Mycoplasmal Pneumonia • Clinical and production disease • Recognized financial impact early ’70’s • Research with Lincomycin began in 1974 • FDA approval “for the reduction in severity of pneumonia due to Mycoplasma hyopneumoniae” granted in 1978
Mycoplasmal Pneumonia of Swine Is… • A distinct clinical disease with distinct lesions and a recognized cause • Often part of a more severe respiratory disease complex • Potentiator for Pasteurella multocida, some APP, PRRSV (Pijoan, Thacker) • Additive with Swine Influenza Virus (Thacker and Halbur) • Treatable as a single entity or as part of a complex
Clinical Endpoints • % of pigs affected • Number of lobes involved in each pig • % of lung involved • Respiratory score • Cough • Respiratory difficulty
Pivotal Studies • In vitro MIC determination for challenge strain correlated with concentration at site of infection • Challenge trials - dose titration, duration of treatment • Field efficacy trials – dose confirmation, fixed duration
Challenge Model • Must have pigs free of M. hyopneumoniae • Usually very mild disease compared to field challenge • All animals at same stage of infection • Can treat at earliest appearance of clinical signs • May give false sense of efficacy
Treatment Initiation • At onset of clinical signs (Clinical disease present) • Expected to be day 10 PI • Actually day 8 PI – 13.6% of pigs coughing
Clinical Endpoints • % of lobes with lesions – incidence measure • % of total lung with lesions – severity measure
Lesions Observed a a b b a a b b a,b different, p<.05
Conclusion • In the challenge model, lincomycin at 220 and 330 ppm resulted in a significant reduction in severity and incidence of lesions caused by M. hyopneumoniae. • The optimum treatment regime based on lesion and performance data was 220 ppm for 21 days.
Field Trials • Herds with history of problems with MPS • Pigs at an age already likely infected with MPS
4 Field Trials • Indiana, Florida, Alabama, and Minnesota • Pigs 8-12 weeks of age • 6 cohort pigs killed and necropsied to confirm disease • 3 sites tested 4 inclusion rates: 0,110, 220, 330 ppm • 1 site tested 0, 220 ppm only
Clinical Observations • Gross Pathology • Number of lobes involved • Estimated percent of total lung involved • Microscopic Pathology • Right cardiac lobe sampled based on lesion location for histopathologic scoring • Production Parameters (ADG and ADFI)
% Pigs with MPS Lesions An estimate of the number of pigs exposed for sufficient time to develop lesions
% Lobes Affected –All Pigs a ab b b % a,b different, p<.05 Lincomycin suppressed the advancement of the disease process.
Mean % Total Lung Involved All Pigs a ab % b b a,b different, p<.10 220 ppm reduced severity by 49%, 110 ppm by 27%(ns)
Lesions Scored Microscopically for Aging of MP Lesion % of Pigs a,b,cMeans in the same column with different superscripts differ significantly (p<.05)
Trial Conclusion • Lincomycin administered in the feed at 220 ppm for 21 days is effective in the reduction of pneumonia lesions associated with Mycoplasma hyopneumoniae.
Conclusions Based on 25 Years Experience • It is possible to measure clinical endpoints of mycoplasmal pneumonia both in clinical trials and in field trials. • The approval process to provide substantial proof of efficacy was was rigorous and has stood the test of time. • Production parameters are an important auxiliary component of the research process, but not the approval process.
If We Designed a Plan Today….. • Similar approach • Laboratory – in vitro determination of efficacy correlated with drug at the site of infection • Challenge – validated challenge models run in production-like facilities for dose and duration selection • Field trials – field efficacy trials with dose and duration confirmation
If We Designed a Plan Today….. • Field efficacy trials – • Multi-location – production units • History of respiratory disease with M.hyopneumoniae as a key component • Co-infections with PRRSv acceptable/welcome • Experimental unit ? – pen, room, barn, site
If We Designed a Plan Today….. • Clinical Endpoints • % lung involved and % pigs affected would still be critical measurements • % lung involved could be measured more accurately today with grids and computer calculation and could be measured on a sample of pigs killed over the course of the trial • Fluorescent antibody test would provide better confirmation of cause of pneumonia
Lincomix effects on culling Pharmacia - Bradford 9/00