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\begin{document}

\title{Meta-regression to explain the placebo effects in clinical trials of
anti-CGRP monoclonal antibodies for migraine prevention}



\author[1]{Stephane A. Regnier}%
\author[1]{	 Xin Ying  Lee}%
\affil[1]{H Lundbeck A/S}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: Commonly used methods of comparison (e.g., network
meta-analyses) require common comparator(s) across trials, such as
placebo in placebo-controlled trials. Recent literature indicates that
route of administration differences across placebo arms of clinical
trials in pain disorders may contribute to differences in placebo
effect. Methods: We conducted a meta-regression on placebo data from
pivotal clinical trials of anti-calcitonin gene-related peptide
(anti-CGRP) monoclonal antibodies for migraine prevention to quantify
the impact of route of administration, migraine type (episodic/chronic),
and number of prior treatment failures on placebo reduction in monthly
migraine days (MMDs) across weeks 1-12 of treatment. A systematic
literature review of Embase, MEDLINE, the Cochrane Library, and grey
literature conducted in June 2021 identified relevant 14 randomised,
placebo-controlled trials for analysis. Results: After testing models
with different covariates, a meta-regression was fitted to the extracted
placebo data with the covariates of route of administration, migraine
type, and proportion of patients with [?]2 prior preventive treatment
failures. An intravenous route of administration for the placebo arm was
a predictor for higher MMD reduction. Predictors of lower MMD reduction
were migraine type (episodic migraine) and a higher proportion of
patients having [?]2 failed preventive treatments. Conclusions: The
efficacy of intravenous anti-CGRP monoclonal antibodies are likely
underestimated, and differences in the route of administration of
placebo may necessitate use of alternative methods that do not assume
the presence of a common comparator when comparing anti-CGRP monoclonal
antibodies in migraine prevention. Further research into the contextual
effects of the placebo effect is warranted.%
\end{abstract}%



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\textbf{INTRODUCTION}

Migraine, a common disorder affecting more than 1 billion people around
the globe, places a substantial humanistic and socio-economic burden on
affected individuals, their families, and society . For many years, the
only available pharmacologic management methods included using
analgesics or nonsteroidal anti-inflammatory drugs for mild attacks, and
triptans for more severe attacks . More recently, the development of
drugs that prevent migraine by targeting the trigeminal sensory
neuropeptide calcitonin gene-related peptide (CGRP) or its receptor have
caused a seismic shift in migraine management .

To date, four anti-CGRP monoclonal antibodies have been approved in the
US and elsewhere for migraine prevention (erenumab, fremanezumab,
galcanezumab, and eptinezumab), along with two small-molecule inhibitors
(gepants) . However, there are currently no head-to-head trials
comparing the anti-CGRP monoclonal antibodies, resulting in a
proliferation of indirect treatment comparisons (ITCs), such as network
meta-analyses, to assess relative treatment effectiveness . At first
glance, ITCs appear straightforward, since all the anti-CGRP pivotal
trials used the reduction in monthly migraine days (MMDs) as the primary
endpoint and all were placebo controlled. However, there is mounting
evidence to suggest that simple subtraction of placebo response from
active treatment response may result in highly inaccurate estimates of
therapeutic efficacy . There are several contextual aspects to placebo
administration that can greatly impact patient responses to medication
in clinical trials of migraine, including patient expectation , route of
administration , and physician demeanour .

While the use of randomised, controlled trials aims to overcome bias
related to perceptions of drug efficacy, by blinding the investigators
and participants to the treatment received, the issue of route of
administration is less easily addressed. This is of particular interest
when comparing the anti-CGRPs, since three of the available products are
administered subcutaneously (SC) and one (eptinezumab) is administered
intravenously (IV). A key assumption is that the common comparator
(i.e., placebo) is essentially congruent across trials. However, the
results of a recent meta-analysis of treatment administration for
chronic migraine clearly illustrated that SC and IV placebo produce
different responses and therefore cannot be assumed to be directly
interchangeable across studies. As a result, the `true' effect of a
treatment, as measured by its efficacy relative to placebo response,
might be underestimated in clinical trials if the placebo contextual
effect (such as IV administration) is strong.

The objective of this analysis is to understand whether, and to what
extent, the route of administration should be considered when conducting
an ITC between anti-CGRP monoclonal antibodies for the preventive
treatment of migraine by assessing how the placebo effect varied in
trials using SC or IV administration. Given that the pivotal anti-CGRP
studies also varied in terms of migraine type (episodic vs chronic) and
number of prior treatment failures, we also conducted meta-regressions
to control for these factors.

\textbf{METHODS}

Data sources

Data for this analysis were extracted from a systematic literature
review (see \textbf{Figure 1} and \textbf{Appendix S1} ). In brief,
electronic databases including Embase, MEDLINE, and the Cochrane Library
were searched for randomised, controlled trials of migraine-preventive
treatments from inception to June 2021. Additional grey literature
searching encompassed 2020--2021 headache/migraine congresses, the
ClinicalTrials.gov website, and several Health Technology Assessment
websites. Only clinical studies in humans, published in English
language, were selected. While the literature review was not fully
comprehensive, it was judged to be sufficiently complete for the
purposes of informing the current analysis. In addition, data on file
from the DELIVER trial (which was not yet published at the time of
conducting the analysis) was used to supplement the data identified by
the SLR.

\textless{}\textless{}\textless{}Note to Journal Editors: Place Fig. 1
here.\textgreater{}\textgreater{}\textgreater{}

We included data from published, placebo-controlled trials for
anti-CGRPs (18 articles detailing 14 studies) conducted in patients with
either episodic or chronic migraine . Where available, phase 3 or phase
4 randomised, controlled trials with a double-blind period of at least
12 weeks' duration were identified. If such studies were unavailable for
any anti-CGRP, data from phase 2 randomised, controlled studies were
used instead. For this analysis, only data from the placebo arm of each
included trial were evaluated. For a few phase 3, anti-CGRP therapeutic
trials (ARISE, PROMISE-1, and PROMISE-2), the percentage of patients who
had failed [?]2 prior preventive migraine treatments could not be
identified in the literature; thus assumptions were made. The phase 3
ARISE study of erenumab 70 mg vs placebo in patients with episodic
migraine reported only the percentage of patients who had failed 1 or
more prior treatment (n=115/291, 39.5\%) ; however, as this was
comparable with that reported in another phase 3 study of erenumab in
episodic migraine (STRIVE; n=127/391, 39.8\%), it was assumed that the
percentage of patients who had failed [?]2 treatments in ARISE was the
same as the percentage in STRIVE. For the phase 3 studies of eptinezumab
(PROMISE-1 in episodic migraine ; PROMISE-2 in chronic migraine ), the
percentages of patients with [?]2 treatment failures were not captured in
the case report form; thus, it was assumed that there were no patients
with [?]2 treatment failures in either study. The potential implications
of this assumption are presented in the Discussion section. Informed
consent and Institutional Review Board approval were not applicable for
this publication.

Meta-regression

A meta-regression was conducted for placebo response, with the
percentage of patients with [?]2 treatment failures as a covariate for
both episodic and chronic migraine for SC trials. This step was intended
to assess whether the percentage of patients with [?]2 treatment failures
was significant and whether the coefficient estimate was similar between
two types of migraine across several SC trials. A similar assessment was
not feasible for IV trials, as there was only one trial for episodic
migraine and one trial for chronic migraine. Consequently, we conducted
a meta-regression including placebo data from all the anti-CGRP (SC and
IV) clinical trials identified in the systematic literature review to
understand the impact on placebo MMD response of the following
variables: type of migraine (episodic or chronic), percentage of
patients with [?]2 prior treatment failures in each trial, and the route
of administration for treatment (i.e., SC or IV). To assess whether the
route of administration impacted MMD reduction in the placebo arms
differently in episodic or chronic migraine, an interaction term between
the route of administration and type of migraine was introduced into the
meta-regression. Finally, we assessed whether the IV effect differed
between episodic and chronic migraine.

Sensitivity analyses to increase number of data points

Some of the trials identified in the literature review only included
patients who had failed [?]2 prior therapies before enrolment. Several
other trials included both treatment-na\selectlanguage{ngerman}ïve and treatment-experienced
patients. Some trial sponsors published subgroup analyses specific to
those patients who had failed \selectlanguage{english}[?]2 prior treatments. Therefore, we
conducted sensitivity analyses in which these subgroup data were
included alongside the overall phase 3 study population. In other words,
each trial could contribute to two data points in the sensitivity
analyses. Having two data points per trial has critical statistical
limitations, due to double-counting of some patients (namely, patients
who had \selectlanguage{english}[?]2 prior treatment failures); however, this approach was used to
assess the robustness of the results by increasing the number of data
points in the analysis. To address this methodological limitation, the
mean and standard error (SE) for patients with 0 or 1 failed prior
therapies were computed by the authors (see \textbf{Appendix S1} ). The
meta-regression was then rerun and compared with the aforementioned
sensitivity analysis (i.e., with potentially two data points per trial:
placebo effect for patients with 0 or 1 prior failures, and placebo
effect for patients with \selectlanguage{english}[?]2 prior failures).

Statistical analyses

The endpoint used for the analyses was the reduction in MMDs. We used
the published data for each clinical study to extract or calculate the
change from baseline in MMDs over weeks 1\selectlanguage{english}-12. If the average change from
baseline from weeks 1\selectlanguage{english}-12 was not reported in the publication, the mean
changes from baseline to weeks 4, 8, and 12 were calculated, and the SE
of the change from baseline to week 12 was used, since SE values were
comparable across all timepoints.

For the random-effects meta-regressions, we used the rma function from
the `metafor' package in R . A DerSimonian-Laird estimator was used . To
estimate the impact of route of administration on placebo response, the
route of administration was included as a dummy variable, in which the
value was set as 1 if placebo administration was IV (namely for
PROMISE-1, PROMISE-2, and DELIVER) and as 0 if placebo administration
was via a different route of administration (i.e., SC), as shown
in\textbf{Table 1} . Coefficient estimates, SE, and 95\% confidence
intervals (CI) were reported. For \emph{P} -values, a threshold of 0.05
was used to determine if changes in the predictor were significantly
associated with changes in the response. Importantly, given that the
number of trials utilising IV administration was small, \emph{P} -values
were interpreted with caution.

\textbf{RESULTS}

Clinical studies

A total of 18 articles detailing 14 studies were identified from the
systematic literature review for inclusion in the meta-regression. Of
these, 7 studies reported data from patients with episodic migraine only
, 4 from patients with chronic migraine only , and 3 from populations
including both episodic and chronic migraine . An additional 4 articles
reported specific subgroup data for patients with \selectlanguage{english}[?]2 prior treatment
failures . Details of the studies, including patient numbers,
administration method, and mean (SE) change from baseline in MMDs in
weeks 1--12 are shown in \textbf{Table 1} . As expected, only the
eptinezumab studies (PROMISE-1 , PROMISE-2 , and DELIVER ) were
associated with IV administration.

\textless{}\textless{}\textless{}Note to Journal Editors: Place Table 1
here.\textgreater{}\textgreater{}\textgreater{}

Effect of SC placebo on MMDs according to type of migraine and prior
treatment failures

In episodic migraine, the meta-regression showed a relationship
(\emph{P} \textless{}0.001) between the percentage of patients with \selectlanguage{english}[?]2
treatment failures and the reduction in MMDs from baseline with placebo:
placebo-treated patients who failed 2 or more therapies had a lower MMD
reduction (1.78 MMDs), compared with patients who did not previously
fail any therapies and who had almost no placebo response (-0.26 MMDs)
(\textbf{Table 2} and \textbf{Figure 2A} ).

Furthermore, there was a relationship between the percentage of patients
with \selectlanguage{english}[?]2 treatment failures and the reduction in MMDs from baseline with
placebo in chronic migraine, although there was a greater level of
uncertainty (wider CIs and \emph{P} =0.057; \textbf{Table 2}
and\textbf{Figure 2B} ). This may reflect the smaller number of trials
and data points available for chronic migraine compared with episodic
migraine. However, the coefficient estimates of the impact of the
proportion of patients with \selectlanguage{english}[?]2 treatment failures were comparable
between chronic migraine (1.88) and episodic migraine (1.77).

\textless{}\textless{}\textless{}Note to Journal Editors: Place Table 2
here.\textgreater{}\textgreater{}\textgreater{}

\textless{}\textless{}\textless{}Note to Journal Editors: Place Fig. 2
here.\textgreater{}\textgreater{}\textgreater{}

In the sensitivity analyses, which included the data from the
publications of phase 3 trials reporting subgroup analyses of patients
with \selectlanguage{english}[?]2 treatment failures, the point estimate for episodic migraine was
unaffected (see \textbf{Table S1} ) and the CIs were narrowed
(see\textbf{Figure S1} ). Adding the subgroup data for chronic migraine
slightly modified the coefficient estimate of prior treatment failure
(from 1.87 to 1.81), which became closer to that of episodic migraine,
and the \emph{P} -value was less than 0.05; however, the 95\% CI of the
impact of prior treatment failure remained wider in chronic migraine
than in episodic migraine.

Incremental IV placebo effect

The results of the meta-regression of the placebo effect with route of
administration, type of migraine, and percentage of patients with \selectlanguage{english}[?]2
treatment failures are shown in \textbf{Table 3} . The MMD reduction
with IV placebo was 1.34 days lower (95\% CI -1.86, -0.81;\emph{P}
\textless{}0.001) than with SC placebo. When the interaction term
between administration and migraine type was added, the\emph{P} -value
just missed the 5\% threshold (\emph{P} =0.071). Directionally, the data
indicate that an IV route of administration generated a higher
incremental placebo response in chronic migraine (1.96 MMDs) than in
episodic migraine (1.01 MMDs). The IV effect was numerically lower in
patients with \selectlanguage{english}[?]2 prior treatment failures (0.47 MMDs) than in those with
\textless{}2 prior treatment failures, but the\emph{P} -value was 0.44.
After splitting the trial results into \textless{}2 and \selectlanguage{english}[?]2 treatment
failures, the IV effect remained similar (1.37 MMDs; \emph{P}
\textless{}0.001) (see \textbf{Table S2} and\textbf{Table S3} ).

\textless{}\textless{}\textless{}Note to Journal Editors: Place Table 3
here.\textgreater{}\textgreater{}\textgreater{}

\textbf{DISCUSSION}

The results of this analysis show that the placebo response in migraine
clinical studies may vary according to the route of administration, the
type of migraine being investigated (episodic vs chronic), and prior
treatment failures. Importantly, even after accounting for migraine type
and clinical history, patients who received IV placebo had a greater
response (-1.34 MMDs) than those who received SC placebo. Therefore, the
efficacy of eptinezumab, which is administered via the IV route, is
likely to be underestimated in comparisons that assume a common placebo
effect. Notably, our study likely underestimates the IV placebo effect,
which may be even greater, given the conservative estimates made
regarding the number of patients with \selectlanguage{english}[?]2 prior treatment failures in
PROMISE-1 and PROMISE-2 (i.e., if the true percentage of patients with
\selectlanguage{english}[?]2 prior treatment failures was greater than 0, then the IV coefficient
would increase in the meta-regression). Overall, the finding that
intravenous administration was associated with larger placebo response
is consistent with a previous meta-analysis .

Additional sources contributing to the placebo effect included the
frequency of migraine (i.e., episodic vs chronic migraine) and the
number of prior treatment failures. Analysis of eptinezumab studies
where placebo was administered IV found differences between migraine
types, with a higher incremental placebo response in patients with
chronic migraine (2.0 MMDs) compared to patients with episodic migraine
(1.0 MMD); however, the \emph{P} -value for the interaction variable was
above 0.05 (\emph{P} =0.07), possibly because of the very low number of
trials with IV placebo administration, or a ceiling effect due to the
definition of episodic migraine. This is in alignment with another
systematic review and meta-analysis which found differences of 1.5 MMDs
in studies of episodic migraine and 2.23 MMDs in studies of chronic
migraine . The review also found that 67\% of interventional benefit was
due to contextual effects (including placebo effect) rather than direct
effect of anti-CGRP action; however, the analysis did not account for
administration (IV vs SC) . We also found that the IV effect was
numerically lessened for patients with \selectlanguage{english}[?]2 prior treatment failures (0.47
fewer MMDs gained vs treatment-naive patients), but\emph{P}
\textgreater{}0.05. This is in alignment with previous research
describing that the proportion contextual effect (i.e., ratio of mean
MMD change in control group to experimental group) was lower in
anti-CGRP studies in episodic migraine including patients with \selectlanguage{english}[?]3 prior
treatment failures . Interestingly, the relationship between percentage
of treatment failure and geographic location was high (correlation
between percentage of 2+ treatment failures and percentage of North
American patients was -0.91 in EM). Therefore, we cannot rule out that
patient continent of origin rather than percentage of \selectlanguage{english}[?]2 prior treatment
failures was the driver of different placebo responses.

Further research is needed to definitively determine the causes
underlying the greater placebo response associated with IV
administration. One possible explanation is that increased healthcare
contact at the point of administration may contribute to the observed
higher placebo effect in IV trials. The number of clinic visits, the
time taken to administer the IV infusion (30--60 minutes), and the
extended period of post-infusion monitoring (2--4 hours) in the PROMISE
trials allowed the opportunity for greater interaction with clinicians
and nurses, which may impact the subsequent treatment response. Prior
studies of patients with other medical conditions indicate that among
individuals who prefer IV treatment administration, presence of
healthcare professionals and the feeling of greater procedural safety
are important , along with the belief that IV treatment has greater
efficacy than SC .

A myriad of contextual effects---that are rarely measured in randomized
clinical trials---can impact placebo response and explain our results,
including (but not limited to) interactions between the patient and
investigator , patient expectations of treatment and treatment regimen .
There is evidence to suggest that verbal suggestion from investigators
during explanation of clinical trial procedures can influence placebo
response based on patients' expectations and desire for positive
outcomes . In a randomized, balanced placebo design study of rizatriptan
vs placebo for acute migraine treatment, investigators found that drug
labeling influenced patient outcomes, that increasing the likelihood of
receiving active treatment increased the likelihood of pain relief, and
that presenting negative vs neutral vs positive information may have
influenced placebo outcomes . In addition, more frequent interactions
between the patient and investigator may heighten expectations and
response. Time between dosing may influence placebo response, with lower
frequency of dosing possibly linked to a higher expectation of strength
and duration of effect. Patient expectations in those who have failed
several preventive therapies may be lower due to negative conditioning
with previous treatments, which was observed in lower placebo rates in
studies and subgroups of patients with evidence of \selectlanguage{english}[?]2 prior failures.

Limitations

There were several limitations associated with our analysis, based on
both the available data and the methodology used for the
meta-regression. The meta-regression was used to account for
heterogeneity in trials due to differences in patient populations, but
data on certain populations were limited. Differences in
inclusion/exclusion criteria could also include unmeasured confounders
for the placebo effect (see \textbf{Table S4} ). The publication of
subgroup analyses of patients who had failed \selectlanguage{english}[?]2 therapies also
complicated the analysis, and we elected to include these alongside
their `parent' phase 3 data in the meta-regression that included type of
migraine (episodic or chronic), percentage of patients with \selectlanguage{english}[?]2 prior
treatment failures in each trial, and the route of administration for
treatment (i.e., SC or IV) as covariates. \textbf{Table S3} attempts to
address this limitation but having access to the subgroup data for 0 or
1 treatment failures would have been preferable. Finally, we only
included anti-CGRP monoclonal antibodies in this analysis, and it
remains to be determined what impact oral, intranasal, or intramuscular
routes of administration might have on placebo responses to other
pharmacologic treatments, such as gepants or onabotulinumtoxinA .

Conclusions

To conclude, in this meta-regression, we found evidence to suggest that
the efficacy of eptinezumab, an anti-CGRP monoclonal antibody
administered by IV, is likely underestimated in ITCs that assume a
common placebo effect. The contextual placebo effects inherent in
current clinical trial design require further scrutiny, and alternative
comparison methods (other than standard Bayesian network meta-analysis)
may need to be implemented to ensure accurate and unbiased treatment
comparisons.

\textbf{LIST OF ABBREVIATIONS}

CGRP, calcitonin gene-related peptide; CM, chronic migraine; CI,
confidence interval; EM, episodic migraine; ITC, indirect treatment
comparison; IV, intravenous; MMDs, monthly migraine days; SE, standard
error; SC, subcutaneous

\textbf{DECLARATIONS}

\textbf{Ethics approval and consent to participate:} Not applicable.

\textbf{Consent for publication:} Not applicable.

\textbf{Availability of data and materials:} All data generated or
analysed during this study are included in this published article (and
its supporting information).

\textbf{Competing interests: S.A. Regnier} owns stock or stock options
in Novartis. \textbf{S.A. Regnier} and \textbf{X.Y. Lee} are employees
of H. Lundbeck A/S, Copenhagen, Denmark.

\textbf{Funding:} Funding and support were provided by H. Lundbeck A/S,
Copenhagen, Denmark.

\textbf{Author contributions (CRediT)}

\textbf{S.A. Regnier}: conceptualization (equal), data curation (equal),
formal analysis (lead), methodology (equal), project administration
(lead), supervision (lead), validation (equal), visualization (equal),
writing -- original draft preparation (lead), writing -- review \&
editing (equal)\textbf{X.Y. Lee}: conceptualization (equal), data
curation (equal), formal analysis (supporting), methodology (equal),
project administration (supporting), validation (equal), writing --
original draft preparation (supporting), writing -- review \& editing
(equal)

\textbf{Acknowledgements:} The authors thank Sally-Anne Mitchell, PhD,
and Jessica Weaver, PhD, of The Medicine Group, LLC (New Hope, PA, USA)
for providing medical writing support, which was funded by H. Lundbeck
A/S and in accordance with Good Publication Practice guidelines.

\textbf{REFERENCES}

\textbf{TABLE AND FIGURE CAPTIONS}

\textbf{Figure 1.} PRISMA diagram for the literature review.

\selectlanguage{english}+Number of studies included from the original SLR does not align with
the original SLR report because pooled studies excluded in the original
SLR were re-reviewed, and those reporting novel data in prior treatment
failure subgroups have now been included in the SLR. Abbreviations: HTA,
Health Technology Assessment; PRISMA, Preferred Reporting Items for
Systematic Reviews and Meta-Analyses; SLR, systematic literature review.

\textbf{Figure 2.} Graphical illustration of the meta-regression showing
relationship between placebo reduction in monthly migraine days and
treatment failures with subcutaneous administration for (A) episodic
migraine and (B) chronic migraine.

Abbreviations: MMDs, monthly migraine days.

\textbf{Table 1.} Placebo response in clinical trials of anti-CGRPs.

\selectlanguage{english}+Subgroup analysis of patients with \selectlanguage{english}[?]2 prior treatment failures. \selectlanguage{english}++Study
included both episodic and chronic migraine; analysis population
includes patients with episodic migraine only. SSStudy included both
episodic and chronic migraine; analysis population includes patients
with chronic migraine only. Abbreviations: CGRP, calcitonin gene-related
peptide; IV, intravenous; MMDs, monthly migraine days; SE, standard
error.

\textbf{Table 2.} Relationship between MMDs reduction and subcutaneous
treatment failures (3,592 total patients, EM and CM trials).

Abbreviations: CI, confidence interval; CM, chronic migraine; EM,
episodic migraine; MMDs, monthly migraine days; SE, standard error.

\textbf{Table 3.} Placebo reduction in MMDs with administration route,
migraine type, and percentage of patients as covariates.

\selectlanguage{english}+Chronic migraine was used as the reference value. Abbreviations: CI,
confidence interval; IV, intravenous; MMDs, monthly migraine days; SE,
standard error.\selectlanguage{english}
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