Placebo Responses in Trials
for Multiple
.
.
Sclerosis

®
Ses

Luana Gilio, pho®”, Diego Centonze, mo, pho**,
Mario Stampanoni Bassi, mp, Pho’
KEYWORDS

* Multiple sclerosis * Placebo responses ¢ RCT ¢ Expectations Spasticity ¢ Fatigue

KEY POINTS

* Significant “placebo responses” may complicate the interpretation of randomized
controlled trials (RCTs) in multiple sclerosis (MS), often contributing to study failure.
« Evolving diagnostic criteria have significantly influenced the prognosis of MS, resulting in
improved outcomes in both active and placebo arms in more recent studies.

« Progressive changes in trial populations have important implications for the comparability
of results from different RCTs.

« Placebo effects are largely mediated by patient expectations and can be significantly
influenced by both trial design and the type of treatment.
« Systematic exclusion of placebo responders may limit the generalizability of trial findings,
as shared biological mechanisms may underlie responses to both active treatment and
placebo.

INTRODUCTION

In the rapidly evolving landscape of pharmaceutical development, the methodologies
employed in clinical trials in multiple sclerosis (MS) are undergoing significant

changes, presenting both new opportunities and challenges.'

Randomized controlled trials (RCTs) using placebos have been fundamental to the
approval of new drugs. However, this traditional approach is in decline due to the
increasing impracticability of keeping patients on placebo for the duration of a
study.“ Consequently, there is a notable shift toward using active comparators or

employing alternative statistical methods that analyze historical registry data and

draw causal inferences about drug efficacy without a traditional RCT.

* Neurology Unit, IRCCS Neuromed, Via Atinense 18, Pozzilli 86077, Italy; ° Faculty of Psychology, Uninettuno Telematic International University, Rome 00186, Italy; “ Department of
Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, Rome 00133, Italy
* Corresponding author. Department of Systems Medicine, University of Rome Tor Vergata, Via
Montpellier 1, Rome 00133, Italy.
E-mail address:

centonze@uniroma2.it

Neurol Clin 44 (2026) 91-107

https://doi.org/10.1016/j.ncl.2025.08.004

neurologic.theclinics.com

0733-8619/26/0
2025 Elsevier Inc. All rights are reserved, including those for text and data mining,
Al training, and similar technologies.

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Gilio et al

Abbreviations

ARR
CIS
DMT
EDSS
MS
PRO

annual relapse rate
clinically isolated syndrome
disease-modifying treatment
Expanded Disability Status Scale
multiple sclerosis
_patient-reported outcome

RCT

randomized controlled trial

RRMS relapsing-remitting MS

SNP _ single nucleotide polymorphism
We are observing a progressive increase in the sample size and duration of clinical
trials for new disease-modifying treatments (DMTs) in MS. This trend is attributed not
only to the availability of more effective active comparators, but also to a gradual
change in the demographics of trial populations related to evolving diagnostic
criteria.“ These factors have important implications for the comparison of study outcomes over different periods.”
Trials targeting symptomatic treatments for conditions like spasticity, neuropathic
pain, and fatigue face additional interpretative challenges. Significant placebo responses frequently mask the benefits of the active treatment, often resulting in RCT
failure. These responses are largely driven by the neurobiological and psychological
mechanisms of patient expectations,”° and can be significantly influenced by the

study design, the type of symptoms assessed, and patient characteristics.
'°»

Understanding these dynamics is crucial for advancing drug development and requires a reevaluation of how clinical efficacy is measured and interpreted in contemporary trials.
RANDOMIZED CONTROLLED TRIAL IN MULTIPLE SCLEROSIS

The term “placebo response” refers to any improvement observed in the outcome measures within the arm receiving an inactive treatment. This encompasses effects from the
natural history of the disease, such as the gradual decrease in annual relapse rate (ARR)
observed in relapsing-remitting MS (RRMS), improvements due to a regression to the
mean effect, as well as those more specifically described as “placebo effects,” which
are linked to the patient’s expectations and the biological actions of placebos. Defining

that contribute to this placebo response is crucial for interpreting study

the mechanisms

results, designing new trials, and enabling the comparison of different studies.
In RCTs evaluating various DMTs for MS, a notable improvement in primary clinical
outcomes, such as the ARR, new T2 hyperintense lesions or Gd-enhancing (Gd-+) lesions, and Expanded Disability Status Scale (EDSS), is often seen within the placebo

group. '?-'°
Studies have shown that in MS clinical trials, the ARR notably decreases over the
course of the study within the placebo group, exceeding the reduction typically expected from the natural progression of the disease.'* This phenomenon has been
partially attributed to a regression to the mean effect, which can occur when patients

with more active disease are selectedfor trials. '° Further examination and quantification of this effect were undertaken in a systematic review and meta-analysis specif-

ically focusing on MRI lesion count.'* Moreover, various studies identified a
downward trend in ARR in the placebo arm for MS RCTs published in the last de-

cades.*:'*:'° These aspects introduce significant uncertainty in trial planning, as the
expected ARR may exceed the observed ARR,”:'° and underscore the need for larger
sample sizes in clinical trials to adequately compensate for decreased event rate.

Placebo Responses in Trials for Multiple Sclerosis

To explain the downward trend of ARR observed in MS studies, various mechanisms have been analyzed, including changes in patient baseline characteristics

and study characteristics and more objective definition of relapses.’

It has been

shown that the decrease in ARR in more recent trials could be due to a stronger

regression to the mean effect as a short period of observation is used to estimate
the pre-trial ARR.” Furthermore, evidence exists that both improvements in diagnostic
procedures, including increased accessibility to MRI, and changes in diagnostic

criteria have significantly affected the prognosis of MS.’ This is reflected in the inclusion, in more recent RCTs, of progressively milder patients.°:'® In line with this, a
downward trend has been reported also for disability outcomes in placebo groups

of MS RCTs in the last decades. '° In addition, also using real-world data, a progressive improvement of RRMS prognosis is demonstrated by a significant longer disease
duration required to reach disability milestones. '°
It has been proposed that improved clinical outcomes in both the active and pla-

cebo arms in more recent studies may be partly attributed to the presence of the
Will Roger phenomenon in MS RCTs.°*° This statistical paradox, also known as stage
migration, occurs when the advance in diagnostic procedures (Table 1) allows more
patients with milder orvery early disease to be recognized as affected by a given condition or reclassified into a more severe disease stage, leading to an improvement in

the overall prognosis.*° Accordingly, comparing the Posner and McDonald criteria in a
group of patients with clinically isolated syndrome (CIS), it has been shown that the
proportion of patients with definite MS after 1 year was significantly higher using

the latter (16% vs 46%).°° Furthermore, patients with MS diagnosed according to

the McDonald Criteria had significantly reduced risk of reaching EDSS3 at 7 years
compared with patients diagnosed using the Posner criteria.°°

Other factors, such as the increased availability of highly effective DMTs, may have

also influenced the composition of patient population in more recent RCTs.':°° Patients with highly active disease are less likely to be enrolled in trials to avoid the

risk of receiving placebo and are more likely to be removed from trials after experi-

encing a relapse.*”
Progressive changes in trial population have also important implications for the

comparability of results from different RCTs. Studies using historical controls*° and

methods based on propensity scores®'** have been increasingly applied in MS to minimize the use of placebos. However, among the possible biases affecting the use of historical control groups, the Will Rogers phenomenon may indeed significantly limit the

possibility to compare older studies with more recent RCTs.°°** Propensity score techniques adjust for confounding variables in observational studies, aiming to mimic some
aspects of randomization by balancing covariates between treated and untreated
groups. Although this approach is particularly interesting, several methodological issues

may affect these studies.” ':** In particular, the effectiveness ofthis method depends on
accurately measuring all relevant confounders. Indeed, Sormani and colleagues,”
analyzing data from 2 RCTs (AFFIRM published in 2006 and DEFINE/CONFIRM pub-

lished in 2012), clearly demonstrated a difference in the outcomes of the 2 placebo

arms. These data indicated that propensity score methods should be interpreted with

caution in MS as this approach cannot account for different time period.°”’
SYMPTOMATIC TREATMENTS

RCTs for symptoms like pain, fatigue, and depression are traditionally complicated by
significant improvements in the control arm.° This variability is further compounded by
the observation that placebo responses have been increasing over time.“*~

93

54

Table 1
Evolution of multiple sclerosis criteria
Diagnostic Criteria
Main Characteristics

Impact on Diagnosis Timing

Schumacher et al,?! 1965

Based solely on clinical manifestations

Diagnosis often delayed until a

Poser et al,”?

Introduced cerebrospinal fluid
analysis (OCBs) to support

Slightly earlier diagnosis, but still
reliant on waiting for a second

Main Changes

second relapse occurs.
1983

diagnosis.

relapse.

Introduction of more detailed
diagnostic categories,

distinguishing
between clinically
certain, probable and possible MS.

OcBs: lumbar puncture is introduced
to detect the presence of OCB in
CSF, but it is not a mandatory
criterion.

McDonald et al,2? 2001

More objective and standardized
diagnosis based on

Diagnosis possible after a single
clinical attack if MRI shows DIS and

Introduced MRI to demonstrate DIS
and DIT.

CIS: if MRI shows DIS and DIT, MS can
be diagnosed without waiting for a
second clinical relapse.

neuroradiological biomarkers.

DIT.

Introduction of 2 fundamental
concepts:

DIS:areas
lesions
in at least 2 of the 4 typical
(periventricular, juxtacortical,
infratentorial, spinal cord).
DIT: new MRI lesions appearing at
different times or simultaneous

presence of active and nonactive
lesions.

CSF: Its role is scaled down, useful only
in doubtful or atypical cases, as MRI
provides more direct evidence of
disease.

2
5
2

Polman et al," 2005

Increased emphasis on MRI,
strengthening of the role of OCBs
especially in the absence of
definitive MRI evidence.

More diagnoses after a first attack,

DIS: Simplified the definition of DIS

reducing the wait for a second
relapse.
CIS: Simplification of MRI criteria for
early diagnosis, allowing in the case
of CIS and radiological evidence to
progress more rapidly

for diagnosis by MRI, making the
criteria for identifying the presence
of lesions in specific regions clearer.
_DIT: Added the criterion “a new lesion
on MRI at least 3 months after the

of

MS.

to a diagnosis

first one can demonstrate DIT even
in the absence of a new clinical

episode.”
CSF: Strengthening the role of OCBs
to support diagnosis, especially in
the absence of definitive MR

evidence.

Polman et al,*° 2010

Diagnosis possible with a single attack

if MRI shows lesions typical of

different times.

Increased use of oligoclonal bands
and recognition of symptomatic

lesions in the brainstem and

Faster diagnosis due to new criteria

for temporal dissemination.

CIS: If the initial MRI already shows

both DIS and DIT, MS can be
diagnosed immediately without

medulla have made diagnosis

need
to wait for a second MRI orthea
new relapse, speeding up diagnosis

earlier and more effective than the

and the start of DMT

2005 criteria.

DIS: Symptomatic lesions in the

brainstem and spinal cord now

~

count for DIS. The minimum

a

number of lesions required in each

area
has been specified to reduce
ambiguity.

_DIT: Introduction of a new criterion: a

8

52

8

single MRI showing active lesions

g

GD+ and nonactive lesions is

%

sufficient to confirm DIT,

2.

without the need to wait for a

2

follow-up MRI

CSF:MRInevidence
patients ofwithDISCIS,andwithout
clear
DIT, the
presence of OCBs in CSF may

support the diagnosis of MS.

Fy

a

s

z=
a

(continued on next page)

z
ry
@

g

&

8

Table 1
(continued)

2
5

Diagnostic Criteria

Main Characteristics

Impact on Diagnosis Timing

Main Changes

Thompsonetal,2° 2017

Oligoclonal bands in cerebrospinal

Earlier diagnosis even in cases with

DIS: It is clarified that cortical lesions

fluid can substitute for MRI
evidence of temporal

dissemination.

unclear MRI findings.
Improved diagnosis in patients with

symptoms in the brainstem or spinal

cord.

CIS patients: If DIS is present and CSF
shows OCBs, MS can be diagnosed
directly, even without DIT.

(in addition to juxtacortical lesions)
can be counted for DIS.

DIT:OCBs
Added
the possibility of using
in CSF as an alternative
criterion to DIT, allowing faster
diagnosis, especially in patients
with a first clinical attack and
suggestive MRI.

CSF: Specific OCBs in CSF can replace
DIT in the diagnosis of MS if DIS is
already demonstrated, accelerating
diagnosis in patients with CIS and
suggestive lesions on MRI, even in
the absence of DIT.

Montalban, (initial

recommendations,
ECTRIMS) 2024

More “biological” approach to

diagnosis, allowing for earlier
therapeutic intervention.

Diagnosis increasingly earlier due to

« Inclusion of the optic nerve as the

Possibility of diagnosing MS in
asymptomatic patients with RIS.

DIS.
* Elimination of the DIT requirement

optimized protocols.

fifth anatomic area to demonstrate

Individuals with MRI-detected

Introduction of new MRI

lesions typical of MS but no clinical
symptoms may now receive an MS

biomarkers and signs: the “central
vein sign" and lesions with a

diagnosis.

paramagnetic rim have been added

as optional tools to support
diagnosis in specific cases.

Abbreviations: CIS, clinically isolated syndrome; CSF, cerebrospinal fluid; DIS, dissemination in space; DIT, temporal dissemination; GD+, gadolinium-enhanced; MS,
multiple sclerosis; OCBs, oligoclonal bands; RIS, radiologically isolated syndrome.

2

Placebo Responses in Trials for Multiple Sclerosis

Contextual factors, including greater awareness and improvements in diagnostic and

evaluation procedures, contribute to progressive changes in trial populations.°°°
Furthermore, these symptoms are particularly susceptible to strong placebo effects,

largely driven by patients’ expectations. Several elements may have a significant

impact on placebo effects, such as the drug type or the design of the trial.°"“° Recog-

nizing and accounting for these multifaceted factors is essential for accurately interpreting RCT outcomes and optimizing trial designs in MS research.
Fatigue, pain, and spasticity are very frequent MS symptoms and have a major
impact on quality of life and overall disability. Nevertheless, the identification of effective therapeutic strategies is complicated by significant placebo responses, which
can hinder the ability to demonstrate statistically significant treatment effects. For

instance, trials assessing medications for fatigue commonly report robust placebo re-

sponses that can lead to trial failures.*'“° Similarly, clinical studies on classic spasticity treatments, such as baclofen and tizanidine, have faced challenges in achieving

clear statistical superiority over placebo.**:**
While the exact mechanisms remain unclear, it is evident that multiple factors
contribute to the placebo responses observed in RCTs for MS symptoms. In particular,
patient expectations have been identified as a critical determinant. A study investigating
fampridine treatment in MS found that higher positive expectancy scores were associated with improved clinical outcomes at week 4, though this effect diminished at

6 months® Notably, in RCTs for various symptoms, such as pain, it has been clearly evidenced that higher expectations of improvement are associated with large therapeutic
effects. Accordingly, it is important to assess expectations and ask patients which treatment group they believe
to belong.° In fact, it has been shown that using a scale
toassess
negative and positive expectations helped predicting outcome variability.“>

Both patient expectations and contextual influences may exaggerate perceived improvements in the placebo group complicating the interpretation of results.°:*° Indeed,
participation in a clinical trial can itself induce clinical and biological effects. The “Hawthorne effect” describes improvements arising from individuals’ awareness of being
studied. Such enhancements may result from increased attention, observation,
care, and compliance.”

It has been noted that for symptoms like MS fatigue, the dynamics of patient interactions within the trial context, such as the therapeutic environment with frequent clinical evaluations, can reinforce subjective symptom improvement.*° Therefore, careful
attention should be paid to trial design features that can play a pivotal role in amplifying these effects.
Both study design characteristics and the specific attributes of a drug can play a
crucial role in amplifying placebo effects, as exemplified by trials of THC/CBD oromucosal spray (Sativex). THC/CBD oromucosal spray demonstrated benefits in managing spasticity where oral medications had failed, although it was effective in only
one-third to half of previously treatment-resistant patients. The largest pivotal study

in the development of THC/CBD spray, conducted by Novotna and colleagues,’
employed an enriched design. This type of trial seeks to optimize efficiency by identifying responders during an initial treatment phase and discontinuing nonresponders.

early, thereby reducing risks and saving time and resources in clinical practice.“°-*° In
the Novotna study, nearly half (47%) of the sample exposed to THC/CBD spray during

a 4 week initial trial phase showeda positive response.*’ Notably, when these initial
responders were randomly switched to placebo for the subsequent 12 weeks, they
did not rapidly lose the initial benefits. While their spasticity levels were less improved
compared to those who continued on THC/CBD spray, they still exhibited significant
reductions relative to baseline.

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Gilio et al

It has been observed that the use of enriched design methodologies raises concerns about potential interpretation biases, '” as this design may lead to smaller ther-

apeutic effect in the post enrichment period due to priming effects and enhanced
placebo responses.*’**° In particular, enriched design may allow placebo responders

to enter the active phase of the study; these patients, when switched to placebo,
exhibit a sustained clinical effect that could lead to underestimating the active treatment if the full treatment period, including the initial phase, is not considered in the

analysis. °°
Moreover, under certain conditions, drugs can also modulate patients’ expecta-

tions of treatment effects, thereby indirectly influencing the placebo response. In
the specific case of THC/CBD spray, its therapeutic action is primarily mediated
through binding to endocannabinoid CB1 receptors, and to a lesser extent CB2 receptors, resulting in reduced spasticity via modulation of corticospinal excitability.°'°° Notably, CB1 cannabinoid receptors are also critically involved in
placebo responses, as clearly demonstrated in the context of non-opioid placeboinduced analgesia.°*
° Thus, for some medications the mechanism of action may,
in part, overlap with biologic pathways underlying placebo responses and patient

expectations. In MS, beyond spasticity and pain, the endocannabinoid system
may play a pivotal role in mediating therapeutic outcomes of various treatments,
including those aimed at alleviating depression and anxiety. Additionally, individual

variability in CB1 receptor expression has been proposed to influence also the
response to non-pharmacological interventions such as physical therapy and
neuromodulation.°°

These considerations highlight the complexities of trial design and the interpretation
of efficacy in drug development for MS symptoms. Notably, specific study designs to
minimize placebo responses in RCTs have been proposed.*:°’:°° A possible approach
is to identify placebo responders using a placebo run-in-phase. In these studies, all
patients start treatment with placebo and responders are soon excluded, then the
remaining patients are randomized to placebo or active treatment. Another approach

is the sequential parallel comparative design.°° With this method, placebo nonresponders are early identified and re-randomized.
Improved knowledge of the physiology of placebo responses recently opened
new approaches to identify placebo responders. It has been proposed that individual
genetic variability in genes specifically involved in the biology of placebo effects
may be useful to predict placebo responders in clinical trials. For example, it has
been shown that single nucleotide polymorphisms (SNPs) ofthe fatty acid amide hydrolase affecting the endocannabinoid system modulate placebo induced anesthesia.°° Furthermore, SNPs regulating serotonin signaling or catecholamine levels
may modulate placebo responses in patients with major depression and anxiety
disorder.°'+°°

The use of MRI measures may represent another promising approach to understand individual variability in placebo responses.”” Evidence from studies on pain
showed that greater placebo analgesia was associated with increased activity during

pain anticipation in several brain regions including the DLPFC, VLPFC, OFC, superior
parietal cortices, precuneus, and lateral cerebellum and reduced anticipatory re-

sponses in SIl/temporal regions.°* Moreover, it has been suggested that the connectivity of specific brain regions, particularly the right midfrontal gyrus, may help to
predict placebo responses.”° The evidence in MS is still limited. One study reported
that more segregated brain network topology, and higher degree of tissue loss in
various cortical areas were associated with reduced placebo responses in patients
with MS.°°

Table 2

Principal patient-reported outcome used in multiple sclerosis trials

Domain

PROs

Patients Reported Outcomes

FOCUS

QoL

Msis-29”°

Multiple Sclerosis Impact Scale - 29

Physical and psychological impact of MS on quality of life.

PDDS

Patient-Determined Disease Steps

Disability levels in MS.

NDS
Neurologic Disability Scale
UNDS/UKNDS/
—_UNDS
(Unabridged NDS)/UKNDS (United
Gos
Kingdom NDS)/GNDS (Guy's NDS)

Neurologic disability in MS.

EQ-5D”®

EuroQol-5 Dimensions

Health-related quality of life across five dimensions.

FAMS

Functional Assessment of Multiple Sclerosis

Impact of MS on daily functioning.

HAQUAMS

Hamburg Quality of Life Questionnaire
in Multiple Sclerosis

A disease-specific tool assessing quality of life.

MSQLI’?

Multiple Sclerosis Quality of Life Inventory

A comprehensive set of scales assessing quality of life in

~

Multiple Sclerosis Quality of Life-54

patients with MS.
Health-related quality of life, including physical,

a
a

emotional, and social dimensions.
Assess
socialquality
aspects.of life covering physical, psychological, and

S
3FA

MSQol-54%°

LMSQoL’
MusiQolL®

Multiple Sclerosis International Quality of Life

PRIMUS”?

Primary Progressive Multiple Sclerosis Scale

Evaluate the progression of disability in MSP patients,

MS-HRS™*

Multiple Sclerosis - Health-related Quality

Assess the impact of MS on health-related quality of life,

2

considering both physical and psychological domains.

g

London Multiple Sclerosis Quality of Life

Assess quality of life focusing on physical, emotional, and

social dimensions.

of Life Rating Scale

focusing on physical and functional aspects.

g

a

2

=

weal’

Work Productivity and Activity Impairment

Impact of health problems on work productivity and daily

=

EMIQ*

Experiences of Multiple Sclerosis Impact
Questionnaire

Impact of MS on various aspects of life, including physical,
emotional, and social functioning.

z
uv

Weimar Multiple Sclerosis Questionnaire

Assess the overall quality of life and disease impact in

WeIMus'

activities.

5

fa

cy

individuals, focusing on various physical, emotional, and

8

social aspects.

a
(continued on next page)
Ps
8

3
Ss

Table 2

(continued)

Domain _PROs__Patients
Domain
PROs
Patients Reported Outcomes
Outcomes
Physical disability

FOCUS
FOCUS

HALEMS’®

Hamburg Quality of Life/Questionnaire in
Limb/Gait Disorders

Impact of limb and gait disorders on quality of life.

Msws-12°°

Multiple Sclerosis Walking Scale-12

Impact of MS on walking ability and mobility.

FQ 11°

Cognitive Fatigue Questionnaire

Cognitive assessment of fatigue in individuals with MS.

FSMC*°

Fatigue Scale for Motor and Cognitive Functions

Assess fatigue related to motor and cognitive functions in

Fss°

Fatigue Severity Scale

Severity of fatigue and its impact on daily functioning.

MFIs

Modified Fatigue Impact Scale

Assess the impact of fatigue on daily activities.

FSIQ-RMS°

Fatigue Severity Impact Questionnaire for
Relapsing Multiple Sclerosis

A tool specifically designed to assess the impact of fatigue
on daily functioning in individuals with RRMS.

Cognitive function _ MSNQ’

Multiple Sclerosis Neuropsychological Questionnaire

Cognitive impairment screening.

Mood

BDI?

Beck Depression Inventory

Severity of depressive symptoms.

CES-D*°

Center for Epidemiologic Studies Depression Scale

Measure depressive symptoms in the general population,

Fatigue

MS patients.

commonly used in clinical and research settings.

HADS°

Hospital Anxiety and Depression Scale

Assess
levels of anxiety and depression in patients,
particularly in a hospital setting, without focusing on

STAI®

State-Trait Anxiety Inventory

Assess both state anxiety (temporary condition) and trait

physical symptoms.
anxiety (general tendency).

Therapy

TSQM®:

Treatment Satisfaction Questionnaire for Medication _Analyze patients’ satisfaction with their medication,
focusing on effectiveness, side effects, convenience, and
global satisfaction.

Abbreviations: CES-D, center for epidemiologic studies depression scale; CFQ 11, Chalder Fatigue Scale; EMIQ, early mobility; Impairment Questionnaire; FACT-G,
Functional Assessment of Cancer Therapy-General; FAMS, functional assessment of multiple sclerosis; FSMC, fatigue scale for motor and cognitive functions; FSS,
fatigue severity scale; GNDS, Guy's neurologic disability scale; HADS, hospital anxiety and depression scale; HAQUAMS/HALEMS, Hamburg quality of life questionnaire in multiple sclerosis; MFIS, modified fatigue impact scale; MS, multiple sclerosis; MSIS-29, The multiple sclerosis impact scale; MSNQ, multiple sclerosis neuropsychological questionnaire; MSQLI, multiple sclerosis quality of life inventory; MSQoL-54, Multiple Sclerosis Quality of Life-54; MSWS-12, Multiple Sclerosis
Walking Scale; MusiQoL, multiple sclerosis international quality of life questionnaire; PDDS, patient determined disease steps; PRIMUS, patient reported outcome
indices for multiple sclerosis; PRO, patient reported outcome; PROM, patient reported outcome measure; SF-36, 36-Item Short Form Survey; STAI, State-Trait Anxiety Inventory; TSQM, treatment satisfaction questionnaire for medication; UNDS/UKNDS, UK neurologic disability scale; WEIMuS, Wiirzburg Fatigue Inventory in
Multiple Sclerosis; WPAI, work productivity and activity impairment questionnaire; xBDI, Beck’s Depression Inventory.

fay=5
2
2

Placebo Responses in Trials for Multiple Sclerosis

SUMMARY

Addressing placebo responses in clinical trials of DMTs or symptomatic treatments for
MS requires careful consideration, particularly given their potential influence on study
outcomes.

Patient expectations represent a crucial element influencing placebo responses and
should be thoroughly evaluated regarding both the perceived intervention (treatment
assignment) and anticipated therapeutic effects.° Furthermore, interactions occurring
during the trial—among participants and between participants and study personnel—

may also shape these expectations.” These considerations are particularly relevant in
MS RCTs evaluating symptomatic treatments for pain, spasticity, fatigue, and mood.
Employing strategies to systematically assess patient expectations and to control for
the Hawthorne effect by standardizing study visits and patient interactions can help
mitigate their impact.

Study design significantly influences placebo responses. Approaches specifically
designed to exclude placebo responders, such as the inclusion of a run-in phase,
have proven effective in reducing placebo responses.°’°° However, systematically
excluding placebo responders from RCTs raises concerns regarding the generalizability of the study findings, as the resulting cohort may not represent real-world patient populations.° More specifically, as observed for studies investigating THC/
CBD spray for MS spasticity, key biological mechanisms may mediate the response

to both active treatment and placebo.'°°° In this scenario, patients responding to
the active treatment may also exhibit substantial placebo responses. Thus, study designs excluding placebo responders at an early stage could also eliminate patients

who would otherwise respond robustly to active treatment.'° Given the complexity
of placebo responses mediated by multiple biological pathways, including endocannabinoids, serotonin, and catecholamines, these considerations likely extend to

RCTs evaluating other MS symptoms such as pain and fatigue.°*
An alternative approach to enhancing the detection of significant treatment effects,
without systematically excluding placebo responders, involves adopting alternative

endpoints to define clinical efficacy.
In RCTs, clinical efficacy is typically assessed through objective measures such as
the EDSS, the Multiple Sclerosis Functional Composite, No Evidence of Disease Activity, and MRI findings. However, these metrics may not adequately reflect the real-life
impact of MS on patients.°’ Accordingly, differences in objective measures between
treatment arms—which are often small in RCTs—may not always be clinically meaningful to patients, particularly when key quality-of-life factors such as bladder function, fa-

tigue, and cognitive symptoms are insufficiently considered.°*°° On the other hand,
even minimal changes in objective measures, such as an increase in EDSS from 1.5
to 2, may significantly impact patients’ daily lives but may be missed in RCTs.°°
To better capture clinically relevant changes, patient-reported outcomes (PROs)
have gained increasing attention in MS research.’°-’° PROs provide valuable insights
into patients’ perspectives on symptoms and their impact on quality of life (Table 2).
Emerging evidence supports their integration into RCTs as primary endpoints or complementary measures, allowing for a more comprehensive evaluation of treatment

efficacy. °°
Accordingly, PROs may improve the detection of disease progression in MS and

correlate effectively with objective disability measures.'°’

Furthermore, PROs are

especially useful for assessing symptoms that are challenging to quantify objectively,
such as fatigue and cognitive dysfunction, and are therefore increasingly recognized
as essential outcome measures in MS research.°"'0°"'°°

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Gilio et al

CLINICS CARE POINTS

‘* Assess patient expectations, as they may strongly influence both active and placebo
responses in symptomatic MS therapies.
* Clinician-patient interactions can amplify or attenuate placebo and nocebo effects.
Standardizing follow-up visits and assessments can improve reliability of symptom
evaluation.

* Avoid excluding placebo responders, since the same biological mechanisms that drive
placebo responses may also enhance responses to active treatments.

Integrating patient-reported outcomes (PROs) alongside traditional measures such as EDSS
and MRI improves detection of meaningful changes often missed by objective assessments
and provides a better understanding of real-life impact.

DISCLOSURE

The authors declare the following potential conflicts of interest: D. Centonze is an advisory board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck
Serono, Novartis, Roche, Sanofi-Genzyme, and Teva received honoraria for speaking
or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals,
Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal
investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi,
Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research
was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono,
Novartis, Roche, Sanofi Genzyme, and Teva. L. Gilio and M.S. Bassi nothing to report.
Ministero della Salute (Ministry of Health, Italy): Progetto Ricerca Corrente 2025 to
IRCCS Neuromed.
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