"clinical trials and clinical endpoints" james r. bradford, dvm, dipl. abvp pharmacia...

"Clinical Trials and Clinical Endpoints"

James R. Bradford, DVM, Dipl. ABVP

Pharmacia Animal Health

Mycoplasmal PneumoniaMycoplasmal 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 Mycoplasmal Pneumonia of Swine Is…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 EndpointsClinical Endpoints

% of pigs affected

Number of lobes involved in each pig

% of lung involved

Respiratory score• Cough

• Respiratory difficulty

Pivotal StudiesPivotal 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 ModelChallenge 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

Treatments – Challenged PigsTreatments – Challenged Pigs

Duration

Inclusion rate

7 days 14 days 21 days

0 ppm 3 pens

110 ppm 3 pens 3 pens 3 pens



Treatment Initiation 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 EndpointsClinical Endpoints

% of lobes with lesions – incidence measure

% of total lung with lesions – severity measure

Lesions ObservedLesions Observed

0

10

20

30

40

50

60

70

80

% lobes % lung

0110220330

a a

bb

a a b b a,b different,

p<.05

Duration of TreatmentDuration of Treatment% Lung with Lesions% Lung with Lesions

024

68

1012

1416

1820

0 110 220 330

7 days14 days21 days

ConclusionConclusion

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 TrialsField Trials

Herds with history of problems with MPS

Pigs at an age already likely infected with MPS

4 Field Trials4 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 ObservationsClinical 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)

Replications per TreatmentReplications per Treatment

Inclusion rate Replications

0 15

110 12

220 15

330 12

% Pigs with MPS Lesions% Pigs with MPS Lesions

0

10

20

30

40

50

60

70

0 110 220 330

% MP

An estimate of the number of pigs exposed for sufficient time to develop lesions

% Lobes Affected –All Pigs% Lobes Affected –All Pigs

0

5

10

15

20

25

30

35

40

0 110 220 330

Affected lobes

Lincomycin suppressed the advancement of the disease process.

%

aab

b b

a,b different, p<.05

Mean % Total Lung Involved Mean % Total Lung Involved All PigsAll Pigs

0

1

2

3

4

5

6

0 110 220 330

Lung involvement

220 ppm reduced severity by 49%, 110 ppm by 27%(ns)

a

ab

bb

a,b different, p<.10

%

Lesions Scored Microscopically Lesions Scored Microscopically for Aging of MP Lesionfor Aging of MP Lesion

Acute Subacute

regressing

Chronic

resolved

Other

Pneumoniasearly late

0 49a 5 6 0a 10

110 22b 19 17 14ab 6

220 5c 8 12 29bc 12

330 0c 4 22 38c 6a,b,cMeans in the same column with different superscripts differ significantly (p<.05)

% of Pigs% of Pigs

Trial ConclusionTrial 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 Conclusions Based on 25 Years ExperienceExperience

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 If We Designed a Plan Today…..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

PHARMACOKINETICSVARIOUS DOSE FORMS

Dose Plasma ELF Times above MICForm g/ml) g/ml) 0.25 (MIC 50) 0.5 (MIC 90)

Inject 3.88 4.61 18.4 9.2

Water 1.32 1.6 (calc) 6.4 3.2

Feed 1.05 1.2 (calc) 5.2 2.6


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


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

0

20

40

60

80

100

6 Wks. 10 Wks. 14 Wks. 18 Wks. 22 Wks.

PRRS

M. hyo

SIV

M. hyo PCR

0

20

40

60

80

100


PRRS

M. hyo

SIV

M. hyo PCR

0

20

40

60

80

100


PRRS

M. hyo

SIV

M. hyo PCR

0

20

40

60

80

100


PRRS

M. hyo

SIV

Lincomix effects on Lincomix effects on cullingculling

Cull Percentage

0

5

10

15

20

25

30

35

40

45

Non-Linco GroupsAverage Cull % = 8.67

Upper Control Point = 25.1

Linco GroupsAverage Cull % = 5.12

Upper Control Point = 17.3

Pharmacia - Bradford 9/00

Lincomix pulled

"clinical trials and clinical endpoints" james r. bradford, dvm, dipl. abvp pharmacia...

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