Advances in the Canine Cranial Cruciate Ligament, 2nd edition

Table 43.2Study features to consider to minimize placebo effects and increase the assay sensitivity (identifiable
difference between the treatment and control groups) in the design of a placebo-controlled clinical trial.

Protocol element Criteria Considerations Implications

Patient factors Disease duration Patients with a short disease duration may

have increased likelihood of experiencing a

marked decrease in signs due to natural

waxing and waning of chronic disease [1]

Increased placebo

effect

Disease duration Defining an upper limit may eliminate patients

with refractory conditions that are less likely to

respond to an investigational intervention

Increased treatment

effect

Disease severity Defining minimum baseline outcome measure

scores (pain, function, gait, etc.) is necessary

for performance of a responders’ analysis (RA)

RA is required for

registration studies

[2]

Disease severity Mildly affected patients may regress to

negligible signs due to natural history of

disease [1]

Increased placebo

effect

Disease severity Greater severity may be associated with larger

treatment effects

Increased treatment

effect

Stable body weight Dogs on a weight reduction program can have

improved outcomes, confounding a study [3]

Increased placebo

effect

Prior treatment

response

Animals that have not responded to prior

treatments may be excluded as they may be

less likely to respond to the intervention under

study

Maximize treatment

effects

Study design

factors

Time between

screening and

baseline data

collection

Delaying baseline data collection until after

the screening visit can combat the tendency

for owners to seek out a research study when

their pet’s condition is at its worst and

therefore may regress with time without

intervention [1]

Minimize placebo

effects

Placebo run-in

periods [4,5]

Pre-randomization, blinded participants are

prescribed placebo. Placebo ‘responders’ are

exited from the study prior to randomization

Minimize placebo

effects

Treatment run-in

period [6]

Pre-randomization, blinded participants are

prescribed an active treatment. Treatment

‘non-responders’ are exited from the study

prior to randomization

Maximize treatment

effects

Number of groups Fewer treatment groups (2–3) may reduce

expectations that subjects are receiving an

active treatment [7]

Minimize placebo

effects

Type of

intervention

Intra-articular and topical placebo

interventions may be associated with greater

responses than oral placebo [8]

Sample sizes

increased

Site factors Number of sites Use the minimum number of sites needed for

recruitment goals in order to decrease data

variability and a greater potential for placebo

group improvement [9]

Minimize placebo

effects

Study personnel

training

Expectations can influence active treatment

and placebo group improvement. Training

protocols should be developed to manage

expectations; increase understanding of trial;

and increase the likelihood of reliable data

collection [7]

Minimize placebo

effects

Maximize treatment

effects

References.1.Barnettet al. 2005; 2. Brownet al. 2013a; 3. Wuchereret al. 2013; 4. Daviset al. 1995; 5. Sullivanet al.
2009; 6. Furlanet al. 2011; 7. Dworkinet al. 2012; 8. Bannuruet al. 2015; 9. Hauser ̈ et al. 2011.