Imaging Study to Compare Effects of Darolutamide and Enzalutamide With Respect to Placebo on the Blood Flow in the Brain in Healthy Male Volunteers.

Study Overview
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Brief Summary
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The current study would investigate the effects of a single dose of darolutamide and enzalutamide compared with placebo and compared to each other on human brain blood flow using arterial spin labeling magnetic resonance imaging (ASL-MRI), a non-invasive MRI technique. The change in cerebral blood flow was an indirect measure of brain penetration. The risk of drug-associated CNS-related adverse events was likely to be correlated with the concentration of the drug in the brain. In contrast to enzalutamide, preclinical studies of darolutamide indicate that its brain penetration was much lower. The aim of this study was to determine whether there was a difference between darolutamide and enzalutamide compared to placebo in cerebral blood flow and thus in brain penetration.

Detailed Description
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The primary objective was to investigate drug-induced changes in grey matter cerebral blood flow during single-dose treatment with darolutamide or enzalutamide as compared to placebo using voxel-wise quantification of the grey matter for the entire brain. The secondary objective was to investigate drug-induced changes in regional cerebral blood flow in brain areas related to cognitive function after single-dose treatment.

Official Title
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A Phase I, Randomized, Placebo-controlled, Open-label, Three Period Crossover Study to Investigate the Effect of Darolutamide and Enzalutamide on Cerebral Blood Flow in Healthy Male Volunteers.

Conditions
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Cerebrovascular Circulation

Intervention / Treatment
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* Drug: Darolutamide (BAY1841788)
* Drug: Enzalutamide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are healthy as determined by medical history, physical examination, laboratory tests, and cardiac monitoring. Exclusion Criteria: Existing or recent relevant diseases of vital organs (eg, liver diseases, heart diseases, renal disease, lung disease), central nervous system or other organs (eg, Diabetes mellitus, myasthenia gravis). Known contraindication to magnetic resonance imaging. Any structural variants or pathological abnormalities on structural brain MRI during screening. Any history of seizures including a febrile seizure in childhood, loss of consciousness, transient ischemic attack, or any condition that may pre-dispose to seizure. Participant with any type of neurological problems or history of psychiatric disorder, especially mood disorders including medical history with suicidal ideation and/or suicide attempts, which may disable the participant to consent to the study. Participants who use prescription or oral over the counter medications which might influence the study objectives, dietary/nutritional supplements, (including vitamins, natural and herbal remedies, eg, St. John's wort) within 2 weeks prior to first study intervention administration or during the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Men_EPD<br>Healthy male participants receive drugs in order Enzalutamide, Placebo and Darolutamide. | Drug: Darolutamide (BAY1841788)<br>* 300 mg tablet darolutamide, once orally<br>* Other names: Darolutamide: ODM-201;Drug: Enzalutamide<br>* 4 x 40 mg capsules, once orally<br>* Other names: MDV3100;Other: Placebo<br>* 4 placebo tablets, once orally<br>* Other names: Darolutamide-matching placebo;|
| Experimental: Men_DEP<br>Healthy male participants receive drugs in order Darolutamide, Enzalutamide and Placebo. | Drug: Darolutamide (BAY1841788)<br>* 300 mg tablet darolutamide, once orally<br>* Other names: Darolutamide: ODM-201;Drug: Enzalutamide<br>* 4 x 40 mg capsules, once orally<br>* Other names: MDV3100;Other: Placebo<br>* 4 placebo tablets, once orally<br>* Other names: Darolutamide-matching placebo;|
| Experimental: Men_PDE<br>Healthy male participants receive drugs in order Placebo, Darolutamide and Enzalutamide. | Drug: Darolutamide (BAY1841788)<br>* 300 mg tablet darolutamide, once orally<br>* Other names: Darolutamide: ODM-201;Drug: Enzalutamide<br>* 4 x 40 mg capsules, once orally<br>* Other names: MDV3100;Other: Placebo<br>* 4 placebo tablets, once orally<br>* Other names: Darolutamide-matching placebo;|
| Experimental: Men_DPE<br>Healthy male participants receive drugs in order Darolutamide, Placebo and Enzalutamide. | Drug: Darolutamide (BAY1841788)<br>* 300 mg tablet darolutamide, once orally<br>* Other names: Darolutamide: ODM-201;Drug: Enzalutamide<br>* 4 x 40 mg capsules, once orally<br>* Other names: MDV3100;Other: Placebo<br>* 4 placebo tablets, once orally<br>* Other names: Darolutamide-matching placebo;|
| Experimental: Men_EDP<br>Healthy male participants receive drugs in order Enzalutamide, Darolutamide and Placebo. | Drug: Darolutamide (BAY1841788)<br>* 300 mg tablet darolutamide, once orally<br>* Other names: Darolutamide: ODM-201;Drug: Enzalutamide<br>* 4 x 40 mg capsules, once orally<br>* Other names: MDV3100;Other: Placebo<br>* 4 placebo tablets, once orally<br>* Other names: Darolutamide-matching placebo;|
| Experimental: Men_PED<br>Healthy male participants receive drugs in order Placebo, Enzalutamide and Darolutamide. | Drug: Darolutamide (BAY1841788)<br>* 300 mg tablet darolutamide, once orally<br>* Other names: Darolutamide: ODM-201;Drug: Enzalutamide<br>* 4 x 40 mg capsules, once orally<br>* Other names: MDV3100;Other: Placebo<br>* 4 placebo tablets, once orally<br>* Other names: Darolutamide-matching placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in grey-matter cerebral blood flow of enzalutamide as compared to placebo | Obtained by comparing whole brain grey matter quantitative voxel-by-voxel maps of cerebral blood flow/ perfusion (mL per 100g tissue per min) of enzalutamide to placebo. Measured in grey matter voxels with arterial spin labeling magnetic resonance imaging (ASL-MRI). | At 4 hours after drug | 
| Change in grey-matter cerebral blood flow of darolutamide as compared to placebo | Obtained by comparing whole brain grey matter quantitative voxel-by-voxel maps of cerebral blood flow/ perfusion (mL per 100g tissue per min) of darolutamide to placebo. Measured in grey matter voxels with ASL-MRI. | At 4 hours after drug | 
| Change in grey-matter cerebral blood flow of enzalutamide as compared to darolutamide | Obtained by comparing whole brain grey matter quantitative voxel-by-voxel maps of cerebral blood flow/ perfusion (mL per 100g tissue per min) of enzalutamide to darolutamide. Measured in grey matter voxels with ASL-MRI. | At 4 hours after drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean regional grey-matter cerebral blood flow in brain areas related to cognitive function during treatment of enzalutamide as compared to placebo | Brain areas related to cognitive function comprise hippocampus and frontal cortex. Cerebral blood flow measured with ASL-MRI. | At 4 hours after drug | 
| Change in mean regional grey-matter cerebral blood flow in brain areas related to cognitive function during treatment of darolutamide as compared to placebo | Brain areas related to cognitive function comprise hippocampus and frontal cortex. Cerebral blood flow measured with ASL-MRI. | At 4 hours after drug | 
| Change in mean regional grey-matter cerebral blood flow in brain areas related to cognitive function during treatment of enzalutamide as compared to darolutamide | Brain areas related to cognitive function comprise hippocampus and frontal cortex. Cerebral blood flow measured with ASL-MRI. | At 4 hours after drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy volunteers, Magnetic Resonance Imaging (MRI)