A Six Month Phase II/III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of Telcagepant (MK-0974) for Prevention of Menstrually Related Migraine in Female Patients with Episodic Migraine

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that is
believed to play a key role in the early stages of migraine pathogenesis. CGRP
levels in the cranial circulation are increased during a migraine attack and
CGRP itself has been shown to trigger migraine headache. Telcagepant potassium
(hereafter referred to as telcagepant) is a potent, selective competitive
antagonist of the human CGRP receptor and is being developed for acute
treatment of migraine.
Telcagepant has been studied in 5 completed double-blind, placebo-controlled
acute migraine efficacy studies. In these studies, telcagepant has
demonstrated effectiveness in relieving migraine pain and associated symptoms,
and was generally well-tolerated. In three pivotal Phase III efficacy trials,
both 140 mg and 280 mg showed superior efficacy over placebo as measured by 2
hour pain freedom, 2 hour pain relief, 2-24 sustained pain freedom,
photophobia, phonophobia and nausea and was efficacious in patients who
previously reported poor responses to triptans. In addition, telcagepant does
not cause vasoconstriction and was not associated with the adverse events
typically experienced by patients taking triptans, such as chest pain, chest
pressure, paraesthesia, throat tightness and asthenia.

In 60% of female patients, migraine attacks increase during the perimenstrual
period. Triptans have shown efficacy in short-term (mini-) prophylaxis of
menstrual migraine when taken for 5-6 days perimenstrually. Reduction in
migraine frequency in the range of 15-25% over placebo has been observed with
triptans.
The first evidence that telcagepant may have prophylactic efficacy was seen in
the acute efficacy studies. In the pivotal efficacy study for which
zolmitriptan was used as an active control, telcagepant showed similar 2 hour
pain freedom and pain relief as zolmitriptan. However, telcagepant appeared to
have longer duration of action. In the long term safety study there was
evidence that telcagepant decreased headache frequency. Among patients who
experienced pain freedom at 2 hours after administration of the initial dose,
migraine return within 24 hours (an exploratory endpoint) was less common with
telcagepant than with rizatriptan. These finding, taken together, suggest that
telcagepant may have potential to confer a prophylaxis against migraine even
when taken for a short period of time each month.
Finally, in the migraine prophylaxis study, although the study was terminated
early, both telcagepant 140 mg and 280 mg BID treatment groups showed a
nominally significant (p<0.02) reduction in headache frequency after 1 month of
treatment as compared to placebo.

During the clinical development program for telcagepant, elevations in
aminotransferases were observed. The data suggest that the manner in which
telcagepant is administered*how frequently and for how long*is a determinant of
clinical risk. The current study is designed to obtain additional experience
in a clinical trial setting when telcagepant is used at the anticipated maximum
allowed frequency of dosing per month for the acute treatment of migraine. The
large sample size in this study will help inform the risk of aminotransferase
elevation relative to the background rate. For a more extensive explanation;
see section "burden and risks".

• Test the safety of the research drug, telcagepant (MK-0974)
• Test the safety of the research study drug telcagepant (MK-0974) in the
prevention of menstrually related migraines.
• Compare the effectiveness of the research study drug telcagepant (MK-0974) in
the prevention of menstrually related migraines to placebo (look-alike drug
with no active ingredients, sometimes called a "sugar pill").

This is a 6-month, randomized, double-blind, placebo-controlled, parallel-group
study to assess the safety, tolerability, and efficacy of telcagepant 140 mg
for the prevention of menstrually related migraine. Patients who qualify at
the screening visit (Visit 1) will be randomized in a 2:1 ratio to telcagepant
140 mg or placebo to be administered once a day at bedtime for 7 consecutive
days starting at the beginning of each perimenstrual period. Patients will
return to the clinic monthly as soon as possible (i.e. within 1 - 5 days) after
completion of each 7-day dosing period for a follow-up visit. All follow-up
procedures will be conducted according to the Study Flow Chart.

Study drug supply will be provided as 140-mg tablets of telcagepant or matching
placebo. Patients will administer a single daily dose of telcagepant 140 mg or
placebo at bedtime for 7 consecutive days each month, beginning at the onset of
menses, for up to 6 months. If a patient has prodromal symptoms that reliably
predict the onset of menses, they may begin dosing up to 3 days prior to menses
onset.

See E9.
During the clinical development program for telcagepant, elevations in
aminotransferases greater than 3-fold above normal were observed. The majority
of elevations were observed in a migraine prophylaxis study, which was
terminated early due to concerns regarding aminotransferase elevations. The
final analysis showed that these findings occurred at or after at least 2 weeks
of treatment with telcagepant 280 mg or 140 mg twice daily. Two of these
elevations were marked, and were associated with symptoms that could have
represented an acute hepatitis. In each observed case, aminotransferase levels
returned to normal after drug was discontinued, and clinical signs/symptoms
dissapeared.
These findings occurred under treatment conditions that were qualitatively and
quantitatively different from those associated with the expected use of
telcagepant for acute, intermittent migraine. Specifically, both duration of
therapy and plasma drug exposures were greater during continuous daily dosing
than during intermittent dosing (the expected treatment paradigm for acute
intermittent migraine) with either 140 mg or 280 mg. Review of the telcagepant
safety database suggests that there is no increased aminotransferase elevation
beyond the expected background rate of other therapies when use is for less
than 14 consecutive days of therapy.
The data suggest that the manner in which telcagepant is administered*how
frequently and for how long*is a determinant of clinical risk. Plasma
exposures during daily telcagepant administration are higher than exposures
after the same dose administered once. Patients in the migraine prophylaxis
study were exposed to sustained higher circulating concentrations of drug than
those in the intermittently dosed studies, due to the twice daily dosing
paradigm. It is possible, therefore, that circulating drug concentration and
duration of treatment could have played a role in the development of
aminotransferase elevations.
The current study is designed to obtain additional experience in a clinical
trial setting when telcagepant is used at the anticipated maximum allowed
frequency of dosing per month for the acute treatment of migraine. The present
study will examine the safety of 140 mg dosing consecutively 7 days monthly.
The large sample size in this study will help inform the risk of
aminotransferase elevation relative to the background rate.

Since the elevation of aminotransferases could be a possible serious side
effect in this study, the liver enzymes of patients will be monitored carefully
if patients display the associated symptoms.