Phase I, Randomized, Parallel-group, Double-Blind, Placebo-Controlled, Single Dose Study to Evaluate the Blockade of CGRP Receptor by AMG 334 in Preventing PACAP-38 Induced Migraine-like Attacks in Migraine Patients

Migraine is a profound disabling disorder, episodic headache disorder with a
one-year prevalence of 15-20%
in the Dutch population. Migraine is in the top 10 of the WHO most disabling
diseases and belongs to the priority list
of under treated, serious disabling brain diseases. Migraine profylaxis is an
area with a large "unmedcial need*.
Calcitonine Gene Related Peptide (CGRP) receptor antagonisme seems a good
candidate to change that. The
investigated product AMG334 is an antagonist of the CGRP receptor by which it
(besides other effects) could diminish
vasodilatation, pain transmission and inflammation in the brain and therefore
could reduce migraine attacks.

See also the submitted document called "AMG 334_20140207_Rationale for Dose
Selection and Amend 4"

The primary objective of this study is to evaluate the inhibition of PACAP-38
induced migraine-like attacks by AMG 334

Secondary objectives:
* To evaluate the inhibition of PACAP-38 induced headaches by AMG 334
* To evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of
a single
intravenous (IV) dose of AMG 334 in migraine patients

Exploratory objectives:
* To evaluate the reduction in severity of PACAP-38 induced migraine-like
attacks and headaches by AMG 334
* To evaluate the duration of PACAP-38 induced migraine-like attacks and
headaches by AMG 334
* To evaluate the safety and tolerability of a single intravenous (IV) dose of
exogenous PACAP-38
* To evaluate CGRP and PACAP-38 levels in migraine patients

This is a randomized, double-blind, placebo-controlled, parallel-group study in
subjects with episodic migraines. This study will evaluate the efficacy of AMG
334 as measured by inhibition of PACAP-38 induced migraine-like attacks (MLA)
after a single dose of AMG 334.

Part A: PACAP-38 Dose Selection Phase:
This phase was already completed in Belgium and the United States. The
Netherlands will only particpate to part B

Part B:
* Phase 1: PACAP-38 challenge phase
The objective of this phase is to evaluate if subjects respond to PACAP-38 with
a migrainelike attack within 24 hours after administration withe PACAP-38. For
that purpose, subjects will be dosed on day 1 with 10 pmol/kg/min PACAP-38
during 10 minutes (total dose of 100 pmol/kg).
Subjects will leave the research center after the post-dose assessments on day
2 and will be asked to return on day 3 and day 8.
For subjects who did not respond to PACAP-38 with a migrainelike attack within
24 hours after dosing, the study will end on day 8 of this phase 1. For those
who did respond, phase 2 will be started.

* Phase 2: Randomization (AMG 334 or Placebo) Phase:
A minimum of 16 and a maximum of 36 subjects will be randomized between two
treatment groups (AMG 334 or placebo). On Day 1, treatment groups will receive
140 mg IV AMG 334 over 30 minutes or matching placebo, in a one to one
allocation ratio. On Day 8, the subjects will be administered the dose of
PACAP-38 determined from the PACAP-38 Dose Selection Phase. All subjects will
remain in-house for 24 hours of observation following PACAP-38 infusion.
Subjects will be monitored and at several timepoints asked questions from the
headache questionnaire (Appendix D of the protocol), to determine if they have
experienced a MLA. After 24 hours of data from the first 16 Randomized (AMG 334
or Placebo) Subjects challenged with PACAP-38 is available, an interim analysis
will be conducted to determine if challenge rates are comparable to historical
rates (~66%) and if AMG 334 has greater efficacy than placebo. If AMG 334 is
found to completely block PACAP-38 induced migraines, or have the same efficacy
as placebo, the study will be terminated. Otherwise, approximately 20
Randomized (AMG 334 or Placebo) Subjects will be added after confirmation that
they are so called PACAP-38 responders at the end of phase 1.

After informed consent has been obtained, all screening procedures and tests
establishing eligibility will be performed within a period of 21 days before
study product administration.

Phase 1:
After predose procedures on Day 1, participants will receive a single dose of
PACAP-38. PACAP-38 is administered as an intravenous (in the vein) infusion: 10
pmol/kg/min PACAP-38 over 10 minutes (total dose 100 pmol/kg).
Participants will be discharged upon completion of the study assessments of Day
2 and asked to return to the unit on Day 3 and on Day 8.
For those who do not responded to PACAP-38 with a migraine like attack within
24 hours after dosing, the study will end on day 8 of this phase 1. For those
who did respond, phase 2 will be started.

Phase 2:
PACAP-38 responders from phase 1 will be randomized to receive either AMG 334
or matching placebo. Subjects will return to the research facility on Day -1,
one day prior to investigational product administration, at which time baseline
procedures will be
completed. After completion of all pre-dose procedures on the day of dosing
(Day 1), subjects will receive AMG 334 or matching placebo. Subjects will
reside at the research facility on Day 1 after dosing for at least 1 hour and
then be discharged. Subjects will then return to the research
facility on Day 8 for the infusion of PACAP-38 and stay for at least 24 hours
post PACAP-38 infusion and then discharged and provided with instructions to
return to the research facility according to the procedures provided in the
Schedule of Assessment (Table 4). Subjects will
be followed 85 days with three extra in-clinic (Day10, 29 and 57) study visits
during that time. For a full list of study procedures, including the timing of
each procedure, please refer to Protocol (dd. 21Oct2016) Section 7 and the
Schedule of Assessments (Table 4).

See E9 in this ABR form and in section 4 of the Subject Information "Possible
side effects and other undesirable effects/discomforts".