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Cerebral Pharmacodynamic Effects of 5-HT1B Receptor Stimulation

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ClinicalTrials.gov Identifier: NCT02932488
Recruitment Status : Terminated (Pilot study with sumatriptan found no significant changes in the primary outcome parameter (change in CBF))
First Posted : October 13, 2016
Last Update Posted : June 27, 2019
Sponsor:
Information provided by (Responsible Party):
Gitte Moos Knudsen, Rigshospitalet, Denmark

Brief Summary:
The purpose of this study is to show that PET-MR imaging can be used for obtaining a pharmacodynamic profile of drugs. By using the 5-HT1B receptor as target we also aim to find effect areas and sizes of the 5-HT1B receptor agonist sumatriptan.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Sumatriptan Phase 1

Detailed Description:

Recent technological advances in multimodal imaging have enabled the simultaneous acquisition of magnetic resonance imaging (MRI) and PET data. Whereas functional MRI (fMRI) provides excellent spatio-temporal resolution for localizing changes in brain activity, PET offers high sensitivity and neurochemical specificity. Together, PET and MRI measures have the potential to help clarify the neurochemical basis of changes in fMRI signal induced by selective exogenous ligands or endogenous neurotransmitter.

In the present study we will target the 5-HT1B receptor for which a selective radioligand exist (11C-AZ10419369). The receptor can be stimulated with the agonist sumatriptan, which is used for alleviating migraine attacks. The mechanism of action of sumatriptan is not precisely known and it is unknown to what degree sumatriptan crosses the blood-brain barrier and exerts its effect in the parenchyma. In this study we can determine the blood brain barrier penetration of sumatriptan and thereby evaluate Effect sizes, distribution of signal changes, and correlation between the occupancy at the 5-HT1B receptor in the parenchyma (measured by changes in BPND) and the hemodynamic response (measured by changes in CBF).

Ahead of the main study a pilot study will be conducted in which increasing doses of sumatriptan will be tested in the same subject to obtain a dose-response curve. At the same time side effects will be observed and scored. This serves to find the dose with maximum effect size but minimal side effects, which can then be used in the main study for all subjects.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Cerebral Pharmacodynamic Effects of 5-HT1B Receptor Stimulation
Study Start Date : September 2016
Actual Primary Completion Date : June 2019
Actual Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sumatriptan

In the pilot study (an MR-only study) subjects will receive up to five doses of sumatriptan in the range of 10 ug/kg to 80 ug/kg. This allows us to establish a dose-response curve for each subject. Administration of sumatriptan in the pilot study will be spaced with approximately one week apart to avoid carry-over effects of the drug.

In the main study (a PET-MR study), the sumatriptan dose with the maximal effect size and minimum side effects will be used for all subjects.

Drug: Sumatriptan
Sumatriptan is a 5-HT1B receptor agonist used for treatment of migraine attacks
Other Name: Imigran




Primary Outcome Measures :
  1. Changes in 5-HT1B receptor binding as measured with [11C]AZ10419369 [ Time Frame: Two binding potentials are obtained from the 120 min scan: Baseline BPND is determined from 0-50 min. Intervention BPND is determined from 50-120 min. ]
    Both measures of receptor binding will be calculated from the same PET-MR acquisition.

  2. Changes in cerebral blood flow measured with pseudo continuous Arterial Spin Labeling [ Time Frame: CBF is measured 15 min prior and 30 min after the injection of sumatriptan giving 45 min of total CBF measurement time. ]
    CBF will be measured continuous and within the acquisition a dynamic change in CBF upon administration of sumatriptan will be obtained.


Secondary Outcome Measures :
  1. Change in [11C]AZ10419369 concentration in blood and plasma [ Time Frame: At 2.5, 20, 49, 51, 90 and 120 min after injection of [11C]AZ10419369 ]
    Blood samples will be drawn throughout the acquisition time and radioactivity in blood and plasma will be measured.

  2. Plasma concentration of sumatriptan [ Time Frame: At -1, 1, 10, 20, 35 and 75 min after injection of sumatriptan ]
    Blood samples will taken to measure the plasma concentration of the drug.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy subjects
  • Age 18-60

Exclusion Criteria:

  • Primary psychiatric disease (DSM IV Axis I or WHO ICD-10 diagnostic classification).
  • Present or former neurological diseases,
  • Severe somatic disease
  • Medication that can interfere with the test results.
  • Doesn't speak Danish fluently or is severely, visually or hearing impaired.
  • Information regarding former learning disabilities.
  • Pregnancy at the time of the scanning
  • Breast feeding
  • MR-scanner incompatibility (metal in soft tissue)
  • Alcohol or drug abuse
  • Allergy to ingredients in used drugs
  • Participation in experiments with radioactivity (>10 mSv) within the last year or considerable work-related exposure to radioactivity.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02932488


Locations
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Denmark
Neurobiology Research Unit, Rigshospitalet
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Gitte Moos Knudsen
Investigators
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Study Chair: Gitte M Knudsen, MD, DMSc Neurobiology Research Unit, Rigshospitalet

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Responsible Party: Gitte Moos Knudsen, Chair, Professor, MD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT02932488     History of Changes
Other Study ID Numbers: NP3
First Posted: October 13, 2016    Key Record Dates
Last Update Posted: June 27, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage) data will be available for neuroscience research community contingent on approval by scientific board.
Keywords provided by Gitte Moos Knudsen, Rigshospitalet, Denmark:
PET-MR
5-HT1B receptor
Sumatriptan
phMRI
[11C]AZ10419369
Additional relevant MeSH terms:
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Sumatriptan
Vasoconstrictor Agents
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs