A Study to Evaluate the Effect of the Potent Cytochrome P-450 3A4 (CYP3A4) Inhibitor Itraconazole on the Pharmacokinetics (PK) of TAK-954 in Healthy Adult Participants

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03173170
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 1.8
• Patients Per Site Per Month: 5.6

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of TAK-954.

Condition or Disease	Intervention/Treatment	Phase
Healthy Participants	Drug: TAK-954; Drug: Itraconazole	Phase 1

Detailed Description

The drug being tested in this study is called TAK-954. TAK-954 is being tested in healthy participants in order to evaluate the effect of the potent CYP3A4 inhibitor itraconazole on the single-dose PK of TAK-954.

The study will enroll approximately 10 participants. Participants will receive the following treatment sequences:

• TAK-954 0.2 mg; Itraconazole 200 mg + TAK-954 0.2 mg

Participants will be given an intravenous infusion of TAK-954 on Day 1 of First Intervention Period (6 days) followed by minimum 7-day washout period, after which participants will be given Itraconazole capsule on Days 1 to 8 along with TAK-945 infusion on Day 4 of Second Intervention Period (9 days).

This single center trial will be conducted in the United States. The overall duration to participate in this study is 7 to 8 weeks. Participants will visit the clinic on Day -1 and remained confined until Day 6 (First Intervention Period) and Day 9 (Second Intervention Period). Participants will return for a Follow-up Visit 10 to 14 days after last dose of study drug (approximately up to Day 34).

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Single-Sequence, Open-Label, 2-Period Crossover Trial to Evaluate the Effect of the Potent Cytochrome P-450 3A4 Inhibitor Itraconazole on the Pharmacokinetics of TAK-954 in Healthy Adult Subjects
• Actual Study Start Date: May 31, 2017
• Actual Primary Completion Date: Jul 24, 2017
• Actual Study Completion Date: Jul 24, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TAK-954 0.2 mg + Itraconazole 200 mg and TAK-954 0.2mg TAK-954 0.2 milligram (mg), infusion, intravenously, once on Day 1 of First Intervention Period, followed by a minimum of 7-day washout period, further followed by Itraconazole 200 mg, capsule, orally, once daily on Days 1 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.	Drug: TAK-954; TAK-954 Infusion; Drug: Itraconazole; Itraconazole Capsule

Outcome Measures

Primary Outcome Measures

1. Cmax: Maximum Observed Plasma Concentration for TAK-954 [TAK-954 0.2 mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose; Itraconazole 200 mg and TAK-954 0.2 mg: Day 4 pre-dose and at multiple time points (up to 120 hours) post-dose]

2. AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-954 [TAK-954 0.2 mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose; Itraconazole 200 mg and TAK-954 0.2mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Is a man or woman (with no child bearing potential) aged 18 to 55 years, inclusive, at the Screening Visit.

2. Has a body mass index (BMI) from greater than or equal to (>=) 18 and less than or equal to (<=) 30 kilogram per square meter (kg/m^2) and has a body weight greater than (>) 50 kilogram (kg) at the Screening Visit.

3. Is a nonsmoker who has not used tobacco- or nicotine-containing products (example, nicotine patch) for at least 6 months before administration of the initial dose of trial drug/invasive procedure.

Exclusion Criteria:

1. Has a positive alcohol or drug screen.

2. Had major surgery, donated or lost 1 unit of blood (approximately 500 milliliter (mL)) within 8 weeks of the first dose of study drug.

3. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce] per day).

4. Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.

5. Has a substance abuse disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pharmaceutical Research Associates, Inc.	Lenexa	Kansas	United States	66219

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - May 3, 2017
• Statistical Analysis Plan - Aug 8, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03173170
• Other Study ID Numbers: TAK-954-1004; 2017-000713-22; U1111-1195-7682
• First Posted: Jun 1, 2017
• Last Update Posted: Jan 15, 2019
• Last Verified: Jul 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Itraconazole

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in United States from 31 May 2017 to 24 July 2017.
Pre-assignment Detail	Healthy participants were enrolled in this single sequence 2-period crossover study to receive TAK-954 0.2 milligram (mg) in Intervention Period 1 followed by itraconazole 200 mg + TAK-954 0.2 mg in Intervention Period 2.

Arm/Group Title	TAK-954 0.2 mg + Itraconazole 200 mg and TAK-954 0.2mg
Arm/Group Description	TAK-954 0.2 mg, infusion, intravenously, once on Day 1 of First Intervention Period, followed by a minimum of 7-day washout period, further followed by itraconazole 200 mg, capsule, orally, once daily on Days 1 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.
Period Title: First Intervention Period (6 Days)
STARTED	10
COMPLETED	10
NOT COMPLETED	0
Period Title: First Intervention Period (6 Days)
STARTED	10
COMPLETED	10
NOT COMPLETED	0
Period Title: First Intervention Period (6 Days)
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	TAK-954 0.2 mg + Itraconazole 200 mg and TAK-954 0.2mg
Arm/Group Description	TAK-954 0.2 mg, infusion, intravenously, once on Day 1 of First Intervention Period, followed by a minimum of 7-day washout period, further followed by itraconazole 200 mg, capsule, orally, once daily on Days 1 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.7 (10.34)
Sex: Female, Male (Count of Participants)
Female	1 10%
Male	9 90%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	10 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 20%
White	8 80%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	10 100%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	73.72 (11.534)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	174.4 (10.17)
Body mass index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	24.2 (2.90)

Outcome Measures

1. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for TAK-954
Time Frame	TAK-954 0.2 mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose; Itraconazole 200 mg and TAK-954 0.2 mg: Day 4 pre-dose and at multiple time points (up to 120 hours) post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) set included all participants who received at least 1 dose of study drug and had at least 1 measurable plasma concentration.

Arm/Group Title	TAK-954 0.2 mg	Itraconazole 200 mg and TAK-954 0.2 mg
Arm/Group Description	TAK-954 0.2 mg, infusion, intravenously, once on Day 1 of First Intervention Period.	Itraconazole 200 mg, capsule, orally, once daily on Days 1 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.
Measure Participants	10	10
Geometric Mean (Standard Deviation) [nanogram/milliliter (ng/mL)]	2.642 (0.4426)	2.840 (0.6497)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-954 0.2 mg, Itraconazole 200 mg and TAK-954 0.2 mg
	Comments	A paired t-test on the natural log-transformed parameters was performed. The means and difference of means for the log-transformed parameters were exponentiated to obtain the point estimates of the itraconazole effect and 90 percent (%) confidence intervals (CIs).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.0622
	Confidence Interval	(2-Sided) 90%; 0.9569 to 1.1792
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-954
Time Frame	TAK-954 0.2 mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose; Itraconazole 200 mg and TAK-954 0.2mg: Day 1 pre-dose and at multiple time points (up to 120 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK set included all participants who received at least 1 dose of study drug and had at least 1 measurable plasma concentration. PK analysis set where Day 1 and 4 assessments were available.

Arm/Group Title	TAK-954 0.2 mg	Itraconazole 200 mg and TAK-954 0.2mg
Arm/Group Description	TAK-954 0.2 mg, infusion, intravenously, once on Day 1 of First Intervention Period.	Itraconazole 200 mg, capsule, orally, once daily on Days 1 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.
Measure Participants	10	10
Geometric Mean (Standard Deviation) [hour*nanogram per milliliter (hr*ng/mL)]	28.59 (6.550)	43.15 (10.265)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-954 0.2 mg, Itraconazole 200 mg and TAK-954 0.2 mg
	Comments	A paired t-test on the natural log-transformed parameters was performed. The means and difference of means for the log-transformed parameters were exponentiated to obtain the point estimates of the itraconazole effect and 90% CIs.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	1.4892
	Confidence Interval	(2-Sided) 90%; 1.3851 to 1.6012
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of study drug up to Day 9 of Second Intervention Period
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-954 0.2 mg		Itraconazole 200 mg		Itraconazole 200 mg and TAK-954 0.2 mg
Arm/Group Description	TAK-954 0.2 mg, infusion, intravenously, once on Day 1 of First Intervention Period.		Itraconazole 200 mg, capsule, orally, once daily on Days 1 to 3 of Second Intervention Period.		Itraconazole 200 mg, capsule, orally, once daily on Days 4 to 8 along with TAK-954 0.2 mg, infusion, intravenously on Day 4 of Second Intervention Period.
All Cause Mortality
	TAK-954 0.2 mg		Itraconazole 200 mg		Itraconazole 200 mg and TAK-954 0.2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Serious Adverse Events
	TAK-954 0.2 mg		Itraconazole 200 mg		Itraconazole 200 mg and TAK-954 0.2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	TAK-954 0.2 mg		Itraconazole 200 mg		Itraconazole 200 mg and TAK-954 0.2 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		0/10 (0%)		1/10 (10%)
Gastrointestinal disorders
Anal incontinence	1/10 (10%)		0/10 (0%)		0/10 (0%)
Diarrhoea	1/10 (10%)		0/10 (0%)		0/10 (0%)
Nervous system disorders
Headache	3/10 (30%)		0/10 (0%)		1/10 (10%)
Presyncope	1/10 (10%)		0/10 (0%)		0/10 (0%)

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.