Clinical trial NCT01315847: Positron Emission Tomography (PET) Study of Brain Calcitonin Gene-Related Peptide (CGRP) Receptor Occupancy After Telcagepant Administration (MK-0974-067)
Official title: A Three-Part Positron Emission Tomography Study of Brain CGRP Receptor Occupancy Levels Following Administration of MK-0974, Using [11C]MK-4232 as an Imaging Agent
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Migraine
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2011-03-15
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the receptor occupancy (RO) associated with telcagepant (MK-0974) administration based on displacement of \[11C\]MK-4232 from the CGRP receptors in the brain using PET. The study enrolled healthy participants (Part I) and migraine patients (Part III). Due to a protocol amendment, study Part II was not conducted.

Detailed description: For the 1120 mg (i.e., maximal) telcagepant dose, \[11C\]MK-4232 was administered and PET scan was started \~3 hours post telcagepant to coincide with the Tmax of the 1120 mg dose. For the 140 mg (i.e., therapeutic) telcagepant dose, \[11C\]MK-4232 was administered and PET scan was started \~2 hours post telcagepant to correspond with the timing of clinical efficacy measurements of telcagepant for migraine treatment in Phase III studies.

Eligibility criteria: Inclusion Criteria:

* Participant (Part III only) agrees to use (or have their partner use) a highly effective method of birth control within the projected duration of the study
* Participant has a Body Mass Index (BMI) ≤32 kg/m2 at the prestudy visit
* Participant (Part III only) has had a history of migraine with or without aura \>1 year with at least 1 and ≤8 moderate or severe migraine attacks per month in the last 3 months prior to screening
* Participant is judged to be in good health (apart from migraine) based on medical history, physical examination, vital sign measurements, and laboratory safety tests
* Participant has no clinically significant abnormality on electrocardiogram (ECG)
* Participant has been a nonsmoker and/or has not used nicotine or nicotine containing products for at least approximately 6 months
* Participant is willing to comply with the study restrictions and willing to allow the investigators to place an arterial catheter in the radial artery.

Exclusion Criteria:

* Participant is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 years (participant with situational depression in the past 6 to 12 months, but not currently, may be enrolled at the discretion of the investigator)
* Participant has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study
* Participant has an estimated creatinine clearance of ≤80 mL/min
* Participant has a history of stroke, chronic seizures, or major neurological disorder
* Participant has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases
* Participant has a history of neoplastic disease except 1) adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix 2) other malignancies which have been successfully treated ≥10 years prior to the prestudy (screening) visit where, in the judgment of both the investigator and treating physician, appropriate follow-up has revealed no evidence of recurrence from the time of treatment through the time of the prestudy (screening) visit
* For Part III only: Participant is a nursing mother, has difficulty distinguishing his/her migraine attacks from tension or interval headaches, has a history of predominantly mild migraine attacks or migraines usually resolved spontaneously in less than 4 hours, has basilar or hemiplegic migraine headache, has more than 15 headache-days per month or has taken medication for acute headache on more than 10 days per month in any of the 3 months prior to screening, is taking migraine prophylactic medication, was \>50 years of at age of migraine onset, has, in the opinion of the investigator, other confounding pain syndromes, psychiatric conditions such as uncontrolled major depression, dementia or significant neurological disorders other than migraine, has liver function tests, specifically alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and Alkaline Phosphatase are above the upper limit of normal at the prestudy (screening) visit or at recheck within 4 weeks prior to Day 1, is taking strong or moderate Cytochrome P450 3A4 (CYP3A4) inhibitors such as Ketoconazole, Diltiazem or Verapamil
* Participant is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies
* Participant consumes excessive amounts of alcohol
* Participant consumes excessive amounts, defined as greater than 6 servings of caffeinated beverages per day
* Participant has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks prior to the prestudy visit
* Participant has a history of significant multiple and/or severe allergies (including latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food
* Participant is currently a regular user (including "recreational use") of any illicit drugs or has a history of drug (including alcohol) abuse within approximately 2 years
* Participant has participated in a PET study or other study involving administration of a radioactive substance or ionizing radiation within 12 months prior to the prestudy visit
* Participant has implanted or embedded metal objects or fragments in the head or body that would present a risk during the magnetic resonance imaging (MRI) scanning
* Participant suffers from claustrophobia and would be unable to undergo MRI or PET scanning
* Any concern by the investigator regarding the safe participation of the participant in the study, and the ability of the subject to tolerate the procedures.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) (Part I)
timeFrame: Up 14 days after the last dose of telcagepant and/or [11C]MK-4232 in Part I of study (Up to approximately 14 weeks)
measure: Number of Participants With AEs (Part III)
timeFrame: Up 14 days after the last dose of telcagepant and/or [11C]MK-4232 in Part III of study (Up to approximately 6 months)
measure: Brain Calcitonin Gene-related Peptide (CGRP) Receptor Occupancy (RO) Post Telcagepant Obtained by PET Imaging Using [11C]MK-4232 Tracer at Baseline and After a Maximum Dose of Telcagepant (1120 mg) in Healthy Participants (Part I, Period 1)
timeFrame: Part I Baseline, at ~0-90 minutes after [11C]MK-4232 dose; and Part I, Period 1 post telcagepant, at ~0-90 minutes after [11C]MK-4232 dose
measure: Average Telcagepant Plasma Concentration During PET Imaging Using [11C]MK-4232 Tracer After a Maximum Dose of Telcagepant (1120 mg) in Healthy Participants (Part I, Period 1)
timeFrame: Part I, Period 1 post telcagepant, at ~0-90 minutes after [11C]MK-4232 dose
measure: Brain CGRP RO Post Telcagepant Obtained by PET Imaging Using [11C]MK-4232 Tracer at Baseline and After a Therapeutic Dose of Telcagepant (140 mg) in Healthy Participants (Part I, Period 2)
timeFrame: Part I Baseline, at ~0-90 minutes after [11C]MK-4232 dose; and Part I, Period 2 post telcagepant, at ~0-90 minutes after [11C]MK-4232 dose
measure: Average Telcagepant Plasma Concentration During PET Imaging Using [11C]MK-4232 Tracer After a Therapeutic Dose of Telcagepant (140 mg) in Healthy Participants (Part I, Period 2)
timeFrame: Part 1, Period 2 post telcagepant, at ~0-90 minutes after [11C]MK-4232 dose
measure: Brain CGRP RO Post Telcagepant Obtained by PET Imaging Using [11C]MK-4232 Tracer at Baseline and After a Therapeutic Dose of Telcagepant (140 mg) in Participants With Migraine During a Migraine Attack (Ictal Phase)(Part III, Period 1)
timeFrame: Part III, Period 1 Baseline, at ~0-90 minutes after [11C]MK-4232 dose; and Part III, Period 1 post telcagepant, at ~0-90 minutes after [11C]MK-4232 dose
measure: Brain CGRP RO Post Telcagepant Obtained by PET Imaging Using [11C]MK-4232 Tracer at Baseline and After a Therapeutic Dose of Telcagepant (140 mg) in Participants With Migraine During Period When Migraine is Absent (Interictal Phase)(Part III, Period 2)
timeFrame: Part III, Period 2 Baseline, at ~0-90 minutes after [11C]MK-4232 dose; and Part III, Period 2 post telcagepant, at ~0-90 minutes after [11C]MK-4232 dose
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Hostetler ED, Joshi AD, Sanabria-Bohorquez S, Fan H, Zeng Z, Purcell M, Gantert L, Riffel K, Williams M, O'Malley S, Miller P, Selnick HG, Gallicchio SN, Bell IM, Salvatore CA, Kane SA, Li CC, Hargreaves RJ, de Groot T, Bormans G, Van Hecken A, Derdelinckx I, de Hoon J, Reynders T, Declercq R, De Lepeleire I, Kennedy WP, Blanchard R, Marcantonio EE, Sur C, Cook JJ, Van Laere K, Evelhoch JL. In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232. J Pharmacol Exp Ther. 2013 Nov;347(2):478-86. doi: 10.1124/jpet.113.206458. Epub 2013 Aug 23.