Interventional, randomized, double-blind, parallel-group, placebo-controlled study of add-on eptinezumab treatment to brief educational intervention for the preventive treatment of migraine in patients with dual diagnosis of migraine and Medication Overuse Headache

Eptinezumab is approved for migraine prevention and a substantial proportion of
migraine patients have a dual diagnosis of migraine and MOH. These patients
generally constitute the most burdensome population, accounting for
approximately 80% of all health care costs generated by the patients with CM.
MOH is a global health problem with a prevalence in the general adult
population of different countries ranging from 0.5% to 7.6%. Robust data from
Scandinavia indicate a prevalence of 1% to 2%, representing around 50% of all
patients with chronic daily headache. There is a substantial proportion of
patients with a dual diagnosis of migraine and MOH worldwide5, who do not
respond to, or cannot tolerate, existing treatments. None of the new CGRP mAbs
have been investigated as add-on treatment to education or medication
withdrawal. Therefore, it is of high clinical relevance to explore if BI would
benefit from combination with a preventive treatment that has rapid onset of
action and long-lasting effect.
This study is a placebo-controlled study in patients with a dual diagnosis of
migraine and MOH. The study is intended to evaluate the effect on MMDs, of
eptinezumab as add-on treatment to BI, for the prevention of migraine and
treatment of MOH in patients with a dual diagnosis of migraine and MOH.

This study has been transitioned to CTIS with ID 2024-510729-24-00 check the CTIS register for the current data.

Primary Objective
• To evaluate the efficacy of eptinezumab as add-on to BI for the prevention of
migraine and treatment of MOH

Secondary Objectives
• To evaluate the efficacy of eptinezumab as add-on to BI on health-related
quality of life and work productivity
• To evaluate the efficacy of eptinezumab during the 12-week open label
extension period

Exploratory Objectives
• To investigate the efficacy of eptinezumab as add-on to BI on level of daily
physical activity and sleep using a wearable digital device (subset
• To investigate efficacy of eptinezumab as add-on to BI on the level of
analgesic dependence

Safety Objective
• To evaluate the safety and tolerability of eptinezumab

• This is a phase 4, interventional, multi-national, multi-site, randomized,
double-blind, parallel-group, placebo controlled study designed to demonstrate
the efficacy and safety of add-on eptinezumab treatment to BI, performed at
baseline, for the prevention of migraine and treatment of MOH in patients with
a dual diagnosis of migraine and MOH. The 12-week placebo-controlled period
will be followed by a 12-week open-label period where all patients will receive
eptinezumab to provide further relief and gain exploratory data on the
durability of a potential remission of the MOH and CM. The safety and
tolerability of eptinezumab will be also further assessed in this open-label
period.
• Patients will be instructed at the Baseline Visit to stop taking acute
headache medications during a semi structured educational conversation.
However, acute headache medications are allowed for patients in severe need
with an advice to not exceed 9 days per month. These headache medications
include paracetamol, triptans, ergotamine, combination of non-opioid
analgesics, individual non-opioid analgesics and NSAIDs. The use of
barbiturates and/or opioid analgesics should not exceed 4 days per month.
• Eligible patients will be randomly allocated via a randomization system to
one of the two treatment groups: BI and eptinezumab 100 mg, or BI and placebo,
in a ratio of 1:1.
• Randomization will be stratified by country and number of previous preventive
treatment failures (<=2; >2) occurring up to 5 years prior to Baseline Visit by
using IRT system. Treatment failure is defined as treatment discontinuation
due to lack of efficacy (no clinically meaningful improvement at the
recommended or prescribed dose for at least 3 months), side effects, or general
poor tolerability of the treatment.
• The total study duration from Screening Visit to Safety Follow-up Visit is
approximately 36 weeks and includes a screening period (4 weeks), a
placebo-controlled period (12 weeks), an open-label period (12 weeks), and a
safety follow-up period (8 weeks).
• Patients will attend on-site visits at the Screening Visit, visits with IMP
intravenous (IV) infusions (Baseline Visit and Week 12 Visit), and EoS Visit at
Week 24. All other visits will be conducted as telephone or telemedicine
visits.
• Patients will complete a daily headache eDiary from Screening Visit until
EoS/Withdrawal Visit

• Reference therapy: BI for MOH
* BI is a semi-structured educational conversation with the purpose on
helping the patients to stop the medication overuse. The BI starts with five
questions of the SDS:H (including an indication of the patient*s willingness
and confidence to change his/her medication overuse). Then patient is shown a
short-structured scheme bases presentation either on a flip-over or slides with
information about MOH and the association between medication overuse and
chronic headache. The interview will end with an agreed plan on how to stop
the medication overuse.
The intervention will take approximately 10 minutes to complete and is
performed at Baseline Visit before IMP infusion.

• IMP
* Dosage form
• Eptinezumab - 100 mg, Concentrate for Solution for Infusion
100 mg/mL added to 100 mL of 0.9% normal saline
• Placebo - 100 mL of 0.9% normal saline
The IMP will be administered at Baseline Visit and Week 12 Visit (Visit 5), by
intravenous infusion over 30 minutes (+15 minutes).

Patients are asked to undergo procedures described on pages 12 - 15 of the
study protocol. These procedures include physical and neurological examination,
blood draw (i.e. HIV, Hepatitis B and C testing, etc.) urine sampling (i.e.
drug screen, etc.), vital signs, ECG, completion of an eDiary and several
questionnaires, answer questions of investigator and study team and
administration of study drug. Additionally, female subjects of childbearing
potential will have pregnancy tests. Subject*s participation in this study will
last approximately 36 weeks (about 9 months). This duration includes a
screening period (4 weeks), a placebo-controlled period (12 weeks), an
open-label period (12 weeks), and a safety follow-up period (8 weeks).The study
medication is a registered medication. Possible known side effects are
described in the SmPC and patient information and can also occur during this
study.

Eptinezumab may cause side effects.
• Redness and swelling of the inside of the nose and back of the throat
(nasopharyngitis) (may happen to up to 1 in 10 people).
This was most often seen after the first infusion of eptinezumab. The
number of people with this problem went down after the first dose and remained
about the same.
• Allergic reactions and reactions to the eptinezumab infusion (may happen to
up to 1 in 10 people):
Symptoms of allergic reactions can include swelling, itching, flushing, and
rash. Most allergic reactions happened during the infusion and were not
serious, but often led to stopping of eptinezumab. Although uncommon (may
happen to up to 1 in 100 people), serious or severe allergic reactions (which
are also called anaphylactic reactions) may happen. These allergic reactions
can happen quickly during the eptinezumab infusion. Symptoms of serious or
severe allergic reactions may include difficulty breathing, a fast or weak
pulse or a sudden drop in blood pressure, swelling of the lips or tongue,
hives, and a severe itchy rash.
Other symptoms that may occur due to eptinezumab infusion include respiratory
symptoms (such as blocked or runny nose, throat irritation, cough, sneezing,
shortness of breath, and fatigue (feeling tired). These symptoms are usually
not serious and don't last long.
Eptinezumab can also have other side effects that we do not know about at the
moment.

Discomforts participants may experience with checks or measurements during the
study:
• To give the study drug, an IV catheter is inserted into a vein and kept there
for about 30 to 45 minutes.
• There are potential risks associated with inserting the IV catheter into a
vein and giving the study drug through this catheter. Some people may have
nausea, anxiety, feeling faint, or some temporary discomfort during the
catheter placement.
• the participant may have pain, bleeding at the insertion location, or
bleeding under the skin causing a bruise where blood is drawn, or the catheter
is inserted.
• There is a possibility that the insertion location could get infected, with
swelling, redness, and pain.
• Possible side effects from blood draws include feeling faint, redness and
swelling of the vein, pain, and bruising or bleeding at the place where blood
is drawn. These normally disappear a few days afterwards.
• It is rare but possible to have a serious infection of the bloodstream or
heart valves, or a blood clot in the lungs. If these rare but serious
conditions occur, you would have to go to the hospital for treatment.

Blood pressure measurement
• the participant may have some discomfort as the cuff inflates and squeezes
your arm, but it should only last a few seconds. Sometimes there are tiny red
spots that appear after the test, just below the location of the cuff; they
should be painless.

Electrocardiogram
• The sticky pads used may be cold when applied and sometimes cause some
discomfort (slight redness or itching). If there is hair in the area where
patches need to be applied, this area will be shaved in order to complete the
electrocardiogram. Shaving may cause irritation.

Participating in the study may lead to a reduction in migraine days for the
participants, but an improvement is not guaranteed for all participants.