Positron Emission Tomography (PET) Study of Brain Calcitonin Gene-Related Peptide (CGRP) Receptor Occupancy After Telcagepant Administration (MK-0974-067)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Migraine

Treatments: Drug: [11C]MK-4232; Drug: telcagepant

Study type: Interventional

Funder types: Industry

Identifiers

NCT01315847

0974-067

Details and patient eligibility

About

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.

Full 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.

Enrollment: 10 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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10 participants in 2 patient groups

Healthy Participants (Part I)

Experimental group

Description:

Baseline PET imaging of the brain using \[11C\]MK-4232 tracer (\~300 megabecquerel \[MBq\]) was performed in healthy participants; this PET data served as the baseline for both Period 1 and 2 of Part I. Subsequently in study Part I, Period 1 the healthy participants received a single 1120 mg dose of telcagepant followed by PET imaging of brain with \[11C\]MK-4232 tracer (\~300 MBq) beginning \~3 hours post telcagepant dose. In Part I, Period 2 the healthy participants received a single 140 mg dose of telcagepant followed by PET imaging of brain with \[11C\]MK-4232 tracer (\~300 MBq) beginning \~2 hours post telcagepant dose. Interval between Part I Period 1 and 2 was to be at least 1 week.

Treatment:

Drug: [11C]MK-4232

Drug: telcagepant

Participants with Migraine (Part III)

Experimental group

Description:

In study Part III, Period 1 baseline PET imaging of the brain using \[11C\]MK-4232 tracer (\~300 MBq) was performed in participants with migraine during a migraine attack (ictal phase). Later in Part III, Period 1 the participants with an ongoing migraine attack (ictal phase) received a single 140 mg dose of telcagepant followed by PET imaging of brain with \[11C\]MK-4232 tracer (\~300 MBq) beginning \~2 hours post telcagepant dose. In Part III, Period 2 baseline PET imaging of the brain using \[11C\]MK-4232 tracer (\~300 MBq) was performed in participants with migraine, however, without a migraine attack ongoing (interictal phase). Later in Part III, Period 2 participants with migraine without a migraine attack ongoing (interictal phase) received a single 140 mg dose of telcagepant followed by PET imaging of brain with \[11C\]MK-4232 tracer (\~300 MBq) beginning \~2 hours post telcagepant dose. Interval between Part III Period 1 and 2 was to be at least 1 week.

Treatment:

Drug: [11C]MK-4232

Drug: telcagepant