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.