A Single-Dose Positron Emission Tomography (PET) Study to Determine the Effect of TAK-041 on Amphetamine-Induced Dopamine Release in the Central Nervous System (CNS)

• Sponsor: Neurocrine Biosciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02959892
• Collaborator: Takeda (Industry)
• Enrollment: 12
• Location: 1
• Arms: 2
• Actual Duration (Months): 8.6
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine brain penetration of single oral doses of TAK-041 and its effects on amphetamine-induced dopamine release in the Central Nervous System (CNS).

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Amphetamine; Drug: TAK -041; Drug: [11C] (+)-4-propyl-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO)	Phase 1

Detailed Description

The drug being tested in this study is called TAK-041. This study will look at brain penetration of single oral doses of TAK-041 and its effects on amphetamine-induced dopamine release in the CNS.

The study will enroll participants until 12 evaluable participants complete all study procedures. The first 4 participants enrolled in this study will receive a dose of 20 mg TAK-041 and 0.50 milligram per kilogram (mg/kg) dose of amphetamine. The dose for subsequent participants will be determined based on the results of amphetamine-induced dopamine release in the first 4 participants (5 to 40 for TAK-041 and 0.25 or 0.50 mg/kg for the amphetamine).

This single-center trial will be conducted in the United Kingdom. The overall time to participate in this study is approximately 92 days. Participants will remain confined to the clinic for 3 to 4 days during 2 confinement periods. Participants will make monthly visits during Days 8-64 and a final visit 30 days later.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1, Open-Label, Positron Emission Tomography Study in Healthy Subjects to Determine the Effect of TAK-041 on Amphetamine-Induced Dopamine Release in the CNS After Single-Dose Oral Administration
• Actual Study Start Date: Dec 5, 2016
• Actual Primary Completion Date: May 30, 2017
• Actual Study Completion Date: Aug 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-041 20 mg [11C] PHNO 180 megabecquerel (MBq), injection, intravenously, prior to positron emission tomography (PET) scan on Day 1, followed by amphetamine (AMPH) 0.5 milligram per kilogram (mg/kg), tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	Drug: Amphetamine; Amphetamine tablets.; Drug: TAK -041; TAK-041 oral suspension.; Drug: [11C] (+)-4-propyl-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO); [11C]PHNO injection.
Experimental: TAK-041 40 mg [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	Drug: Amphetamine; Amphetamine tablets.; Drug: TAK -041; TAK-041 oral suspension.; Drug: [11C] (+)-4-propyl-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO); [11C]PHNO injection.

Outcome Measures

Primary Outcome Measures

1. Change in Non-displaceable Binding Potential (BP-ND) in the TAK-041+AMPH Condition Compared to AMPH Alone [Baseline (Day 1 of Confinement Period 1) and Day 2 post-AMPH dose in Confinement Period 1]

   The AMPH-induced change in binding potential relative to the non-displaceable component in the basal ganglia (putamen [Pu], ventral striatum [VSt]) which was the region of interest (ROI) was calculated as the percentage of reduction in specific binding from Baseline to postdose following AMPH.

Secondary Outcome Measures

1. Change in BP-ND in the TAK-041+AMPH Condition Compared to AMPH Alone as a Function of the Dose of TAK-041 Administered [Baseline (Day 1 of Confinement Period 1), and Day 1 post-TAK-041 and AMPH dose in Confinement Period 2]

   The effect of predosing with TAK-041 on the AMPH challenge was calculated as the relative change in the percentage reduction in specific binding in ROI in the AMPH+TAK-041 condition compared to AMPH alone.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Is in good health as determined by physical examination, electrocardiogram (ECG), and laboratory evaluations.

2. Weighs at least 45 kilogram (kg) and has a body mass index (BMI) from 18.0 to 30.0 kilogram per square meter (kg/m^2), inclusive, at Screening.

Exclusion Criteria:

1. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as regular consumption of more than 21 units per week) within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. One unit is equivalent to 8 grams of pure alcohol, which is equivalent to 10 milliliter (mL) of pure ethanol (alcohol) or approximately a half-pint of beer, 1 measure of spirits, or 1 glass of wine.

2. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in on Day -1. Cotinine test is positive at Screening or Check-in (Day -1).

3. Has poor peripheral venous access.

4. Has donated or lost 450 mL or more of his blood volume (including plasmapheresis), or had a transfusion of any blood product within 90 days prior to Confinement Period 1.

5. Has had previous research-related exposure to ionizing radiation such that, in combination with the exposure from this study, their exposure will be greater than (>)10 millisievert (mSv) for the previous year.

6. Has a contraindication to magnetic resonance imaging (MRI) based on the standard MRI screening questionnaire. Contraindications include ferromagnetic foreign bodies (example, shrapnel, ferromagnetic fragments in the orbital area), certain implanted medical devices (example, aneurysm clips, cardiac pacemakers), or claustrophobia.

7. Has findings on the screening brain MRI scan that will potentially compromise participant safety or the scientific integrity of the study data if the participant were to participate in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hammersmith Medicines Research	London		United Kingdom	NW107EW

Sponsors and Collaborators

• Neurocrine Biosciences
• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Statistical Analysis Plan - May 27, 2019
• Study Protocol - Feb 21, 2017

More Information

Publications

None provided.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT02959892
• Other Study ID Numbers: TAK-041-1002; U1111-1184-1947; 2016-002346-23
• First Posted: Nov 9, 2016
• Last Update Posted: Mar 19, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Neurocrine Biosciences: Drug therapy
• Additional relevant MeSH terms: Amphetamine; Naxagolide

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in United Kingdom from 05 December 2016 to 23 August 2017.
Pre-assignment Detail	Healthy participants were enrolled in this study to receive TAK-041 in one of the 2 treatment groups: TAK-041 20 milligram (mg) or TAK-041 40 mg.

Arm/Group Title	TAK-041 20 mg	TAK-041 40 mg
Arm/Group Description	[11C] (+)-4-propyl-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) 180 megabecquerel (MBq), injection, intravenously, prior to positron emission tomography (PET) scan on Day 1, followed by amphetamine (AMPH) 0.5 milligram per kilogram (mg/kg), tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.
Period Title: Overall Study
STARTED	6	6
COMPLETED	5	5
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	TAK-041 20 mg	TAK-041 40 mg	Total
Arm/Group Description	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	Total of all reporting groups
Overall Participants	6	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.2 (10.98)	46.2 (8.16)	39.7 (11.45)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	6 100%	6 100%	12 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 33.3%	1 16.7%	3 25%
White	4 66.7%	5 83.3%	9 75%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	179.0 (7.46)	177.5 (7.12)	178.3 (7.00)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	85.22 (4.585)	87.90 (7.714)	86.56 (6.210)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	26.65 (1.814)	27.88 (1.375)	27.26 (1.662)
Smoking History (Count of Participants)
Never smoked	4 66.7%	4 66.7%	8 66.7%
Current smoker	0 0%	0 0%	0 0%
Ex-smoker	2 33.3%	2 33.3%	4 33.3%
Alcohol History (Count of Participants)
Never drunk	1 16.7%	1 16.7%	2 16.7%
Current drinker	5 83.3%	5 83.3%	10 83.3%
Alcohol Consumption of Less Than or Equal to (<=) 21 Units per Week (Count of Participants)
Count of Participants [Participants]	5 83.3%	5 83.3%	10 83.3%
Caffeine History (Count of Participants)
Had caffeine consumption	4 66.7%	6 100%	10 83.3%
Had no caffeine consumption	2 33.3%	0 0%	2 16.7%

Outcome Measures

1. Primary Outcome

Title	Change in Non-displaceable Binding Potential (BP-ND) in the TAK-041+AMPH Condition Compared to AMPH Alone
Description	The AMPH-induced change in binding potential relative to the non-displaceable component in the basal ganglia (putamen [Pu], ventral striatum [VSt]) which was the region of interest (ROI) was calculated as the percentage of reduction in specific binding from Baseline to postdose following AMPH.
Time Frame	Baseline (Day 1 of Confinement Period 1) and Day 2 post-AMPH dose in Confinement Period 1

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received a dose of study drug ([11C]PHNO, AMPH, or TAK-041) as part of this study.

Arm/Group Title	TAK-041 20 mg	TAK-041 40 mg
Arm/Group Description	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.
Measure Participants	6	6
Pu	17 (11)	36 (8)
VSt	14 (14)	23 (20)

2. Secondary Outcome

Title	Change in BP-ND in the TAK-041+AMPH Condition Compared to AMPH Alone as a Function of the Dose of TAK-041 Administered
Description	The effect of predosing with TAK-041 on the AMPH challenge was calculated as the relative change in the percentage reduction in specific binding in ROI in the AMPH+TAK-041 condition compared to AMPH alone.
Time Frame	Baseline (Day 1 of Confinement Period 1), and Day 1 post-TAK-041 and AMPH dose in Confinement Period 2

Outcome Measure Data

Analysis Population Description

The safety analysis set consisted of all participants who were enrolled and received a dose of study drug ([11C]PHNO, AMPH, or TAK-041) as part of this study.

Arm/Group Title	TAK-041 20 mg	TAK-041 40 mg
Arm/Group Description	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.
Measure Participants	6	6
Pu	17 (11)	36 (8)
Vst	14 (14)	23 (20)

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug and no more than 92 days after the last dose of study drug
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	TAK-041 20 mg		TAK-041 40 mg
Arm/Group Description	[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 20 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.		[11C] PHNO 180 MBq, injection, intravenously, prior to PET scan on Day 1, followed by AMPH 0.5 mg/kg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 2 of Confinement Period 1, followed by a 5 to 45 days of interval period, further followed by TAK-041 40 mg, suspension, orally, once, followed by AMPH 0.5 mg, tablet, orally, once and [11C] PHNO 180 MBq, injection, intravenously, prior to PET scan post-AMPH dose on Day 1 of Confinement Period 2.
All Cause Mortality
	TAK-041 20 mg		TAK-041 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Serious Adverse Events
	TAK-041 20 mg		TAK-041 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	TAK-041 20 mg		TAK-041 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/6 (16.7%)
Infections and infestations
Pharyngitis	0/6 (0%)	0	1/6 (16.7%)	1
Herpes Zoster	0/6 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.