A Study to Evaluate Drug-Drug Interaction of TAK-788 With Itraconazole and Rifampin in Healthy Adult Participants

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03928327
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Actual Duration (Months): 3.5
• Patients Per Site Per Month: 6.9

Study Details

Study Description

Brief Summary

The purpose of this study is to characterize the effect of itraconazole (Part 1) and rifampin (Part 2) on the single-dose pharmacokinetics (PK) of TAK-788 and its active metabolites (AP32960 and AP32914) in healthy adult participants.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: TAK-788; Drug: Itraconazole; Drug: Rifampin	Phase 1

Detailed Description

The drug being tested in this study is called TAK-788 (Mobocertinib). The study assessed the drug-drug interaction of TAK-788 with either a strong cytochrome P-450 (CYP)3A inhibitor, itraconazole (Part 1) or with a strong CYP3A inducer, rifampin (Part 2) in healthy adult participants.

The study enrolled 24 healthy participants. The study was designed to consist of 2 parts:

Part 1- TAK-788 assessment with itraconazole Part 2- TAK-788 assessment with rifampin. Part 1 had 2 cohorts:

Part 1: Participants (n = 12) received a single oral dose of 20 mg capsule of TAK-788 on Day 1 of Period 1 followed by 200 mg itraconazole oral solution once daily (QD) in Period 2 on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule were coadmistered on Day 5 of Period 2.

In Part 2 participants (n = 12) received a single oral 160 mg dose of TAK-788 capsules in Period 1 of Day 1 followed by 600 mg capsules of rifampin QD in Period 2 Days 1 to Day 13 and a single dose of 160 mg TAK-788 capsules was coadministered on Day 7 of Period 1. There was a washout period of 7 days between the dose of TAK-788 on Period 1 and the first dose of rifampin in Period 2.

This single-center trial was conducted in the United States. The overall time to participate in this study was approximately 120 days (including screening period). Participants were contacted by telephone 30 days after the last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 1 Study of Oral TAK-788 to Evaluate the Drug-Drug Interaction With Itraconazole and Rifampin in Healthy Adult Subjects
• Actual Study Start Date: May 2, 2019
• Actual Primary Completion Date: Aug 16, 2019
• Actual Study Completion Date: Aug 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1, Treatment Sequence AB TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast (Treatment A). Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 (Treatment B). There was a washout period of 7 days between the two treatments.	Drug: TAK-788; TAK-788 Capsules; Other Names: Mobocertinib ; Drug: Itraconazole; Itraconazole Oral solution
Experimental: Part 2, Treatment Sequence CD TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast (Treatment C). Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 (Treatment D). There was a washout period of 7 days between the two treatments.	Drug: TAK-788; TAK-788 Capsules; Other Names: Mobocertinib ; Drug: Rifampin; Rifampin Capsules

Outcome Measures

Primary Outcome Measures

1. Treatment B vs Treatment A (Part 1), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914 [Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose]

   The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.

2. Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914 [Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose]

   The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.

3. Treatment B Vs Treatment A (Part 1), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914 [Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose]

   The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour*nanomolar.

4. Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914 [Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose]

   The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour*nanomolar.

5. Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-788 [Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose]

6. Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32960 [Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose]

7. Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32914 [Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose]

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

1. Continuous non smoker who has not used nicotine containing products for at least 3 months prior to the first dose and throughout the study based on participant self-reporting.

2. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms (ECGs), as deemed by the Investigator or designee. Has liver function tests (LFTs) including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin within the upper limit of normal at screening and at first check-in.

3. Normal baseline spirometry for forced vital capacity (FVC) and forced expiratory volume (FEV1)/FVC within 7 days prior to the first dosing based on the following normal FVC and FEV1/FVC range: a. 20 - 39 years of age: ≥ 80% and b. 40 - 55 years of age: ≥ 75%

4. Body mass index (BMI) ≥18.0 and ≤32.0 kg/m^2, at screening.

Key Exclusion Criteria:

1. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.

2. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds.

3. Presence of an acute lung infection, within 3 months of screening.

4. History or presence of any previous lung disease.

5. Part 1 only: History or presence of any of the following, deemed clinically significant by the PI or designee, and as confirmed by the Sponsor:

• Ventricular dysfunction or risk factors for Torsades de Pointes (e.g., heart failure, cardiomyopathy, family history of Long QT Syndrome);

• Uncorrected hypokalemia (potassium levels <3.7) and/or hypomagnesemia (magnesium levels <1.9);

• Myasthenia gravis.

1. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).

2. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.

3. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.

4. QTcF interval is >460 msec (males) or >470 msec (females) or ECG findings are deemed abnormal with clinical significance by the Investigator or designee at screening.

5. Estimated creatinine clearance <90 mL/min at screening

6. Unable to refrain from or anticipates the use of:

• Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing and throughout the study. Medication listed as part of acceptable birth control methods will be allowed. Thyroid hormone replacement medication may be permitted if the subject has been on the same stable dose for the immediate 3 months prior to the first dosing. Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study, only after initial dosing.

• Any drugs known to be inhibitors or inducers of CYP3A enzymes and/or P-gp, including St. John's Wort, within 28 days prior to the first dosing and throughout the study. Appropriate sources (e.g., Flockhart Table™) will be consulted to confirm lack of pharmacokinetic (PK)/pharmacodynamics interaction with study drugs.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Celerion	Tempe	Arizona	United States	85283

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Apr 16, 2019
• Statistical Analysis Plan - Jun 6, 2019

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03928327
• Other Study ID Numbers: TAK-788-1006
• First Posted: Apr 26, 2019
• Last Update Posted: Aug 21, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug Therapy
• Additional relevant MeSH terms: Itraconazole; Rifampin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study in the United States from 02 May 2019 to 16 August 2019.
Pre-assignment Detail	Healthy participants were enrolled in this 2-period study to receive: TAK-788 20 mg (Treatment A) along with itraconazole 200 mg (Treatment B) and TAK-788 160 mg (Treatment C) with rifampin 600 mg (Treatment D) in sequential manner to evaluate drug-drug interaction.

Arm/Group Title	Part 1, Treatment Sequence AB	Part 2, Treatment Sequence CD
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast (Treatment A). Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 (Treatment B). There was a washout period of 7 days between the two treatments.	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast (Treatment C). Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 (Treatment D). There was a washout period of 7 days between the two treatments.
Period Title: Period 1
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Part 1, Treatment Sequence AB	Part 2, Treatment Sequence CD	Total
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast (Treatment A). Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 (Treatment B). There was a washout period of 7 days between the two treatments.	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast (Treatment C). Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 (Treatment D). There was a washout period of 7 days between the two treatments.	Total of all reporting groups
Overall Participants	12	12	24
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	37.7	40.3	39
Sex: Female, Male (Count of Participants)
Female	4 33.3%	8 66.7%	12 50%
Male	8 66.7%	4 33.3%	12 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 75%	10 83.3%	19 79.2%
Not Hispanic or Latino	3 25%	2 16.7%	5 20.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 8.3%	0 0%	1 4.2%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 8.3%	0 0%	1 4.2%
White	10 83.3%	12 100%	22 91.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%	12 100%	24 100%
Weight (Kg) [Mean (Full Range) ]
Mean (Full Range) [Kg]	85.53	79.78	82.65
Height (cm) [Mean (Full Range) ]
Mean (Full Range) [cm]	172.8	165.8	169.3
Body Mass Index (BMI) (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	28.573	28.955	28.764

Outcome Measures

1. Primary Outcome

Title	Treatment B vs Treatment A (Part 1), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914
Description	The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.
Time Frame	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Arm/Group Title	Part 1, Treatment A	Part 1, Treatment B
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.
Measure Participants	12	12
Geometric Mean (Geometric Coefficient of Variation) [nM]	13.7 (30.7)	39.2 (21.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1, Treatment A, Part 1, Treatment B
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Squares (LS) Mean Ratio
	Estimated Value	2.86
	Confidence Interval	(2-Sided) 90%; 2.48 to 3.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	Linear mixed-effects model was used for analysis, using fixed-effect(treatment), random-effect(participants). Geometric mean ratios(GMR), 90% confidence interval(CI) calculated using exponentiation of treatment least squares means(LSMs) difference.

2. Primary Outcome

Title	Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914
Description	The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.
Time Frame	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Arm/Group Title	Part 2, Treatment C	Part 2, Treatment D
Arm/Group Description	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Measure Participants	12	12
Geometric Mean (Geometric Coefficient of Variation) [nM]	177 (34.1)	14.9 (68.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1, Treatment A, Part 1, Treatment B
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90%; 0.07 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Linear mixed-effects model was used for analysis, using fixed-effect (treatment) and random-effect (participants). GMR and 90% CI was calculated using exponentiation of treatment LSMs difference.

3. Primary Outcome

Title	Treatment B Vs Treatment A (Part 1), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914
Description	The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour*nanomolar.
Time Frame	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile. Overall number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Part 1, Treatment A	Part 1, Treatment B
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.
Measure Participants	8	10
Geometric Mean (Geometric Coefficient of Variation) [hr*nM]	298 (35.2)	1820 (18.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1, Treatment A, Part 1, Treatment B
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	6.27
	Confidence Interval	(2-Sided) 90%; 5.20 to 7.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Linear mixed-effects model was used for analysis, using fixed-effect (treatment) and random-effect (participants). GMR and 90% CI was calculated using exponentiation of treatment LSMs difference.

4. Primary Outcome

Title	Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914
Description	The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour*nanomolar.
Time Frame	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile. Overall number analyzed is the number of participants with data available for analyses. Overall number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Part 2, Treatment C	Part 2, Treatment D
Arm/Group Description	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Measure Participants	12	11
Geometric Mean (Geometric Coefficient of Variation) [hr*nM]	3610 (43.2)	194 (70.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1, Treatment A, Part 1, Treatment B
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 90%; 0.04 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Linear mixed-effects model was used for analysis, using fixed-effect (treatment) and random-effect (participants). GMR and 90% CI was calculated using exponentiation of treatment LSMs difference.

5. Primary Outcome

Title	Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-788
Time Frame	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Arm/Group Title	Part 1, Treatment A	Part 1, Treatment B	Part 2, Treatment C	Part 2, Treatment D
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Measure Participants	12	12	12	12
Median (Full Range) [hr]	6.00	8.00	6.00	4.00

6. Primary Outcome

Title	Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32960
Time Frame	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile.

Arm/Group Title	Part 1, Treatment A	Part 1, Treatment B	Part 2, Treatment C	Part 2, Treatment D
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Measure Participants	12	12	12	12
Median (Full Range) [hr]	6.00	8.00	6.00	2.00

7. Primary Outcome

Title	Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32914
Time Frame	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose

Outcome Measure Data

Analysis Population Description

PK Set included participants who complied sufficiently with the protocol and display an evaluable PK profile. Overall number analyzed is the number of participants with data available for analyses.

Arm/Group Title	Part 1, Treatment A	Part 1, Treatment B	Part 2, Treatment C	Part 2, Treatment D
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.	Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.	TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.	Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
Measure Participants	9	8	12	8
Median (Full Range) [hr]	6.00	8.00	6.00	4.00

Adverse Events

Time Frame	From first dose up to 30 days post last dose of study drug (Up to 45 days)
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	Part 1, Treatment A		Part 1, Treatment B		Part 2, Treatment C		Part 2, Treatment D
Arm/Group Description	TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast in Period 1.		Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 in Period 2.		TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast in Period 1.		Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 in Period 2.
All Cause Mortality
	Part 1, Treatment A		Part 1, Treatment B		Part 2, Treatment C		Part 2, Treatment D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Serious Adverse Events
	Part 1, Treatment A		Part 1, Treatment B		Part 2, Treatment C		Part 2, Treatment D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Part 1, Treatment A		Part 1, Treatment B		Part 2, Treatment C		Part 2, Treatment D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		4/12 (33.3%)		9/12 (75%)		10/12 (83.3%)
Ear and labyrinth disorders
Ear pain	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal distension	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Abdominal pain	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Abdominal pain lower	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Diarrhoea	0/12 (0%)		2/12 (16.7%)		2/12 (16.7%)		3/12 (25%)
Flatulence	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Lip dry	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Nausea	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		2/12 (16.7%)
Oral discomfort	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Vomiting	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
General disorders
Chest discomfort	0/12 (0%)		0/12 (0%)		0/12 (0%)		2/12 (16.7%)
Chills	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		1/12 (8.3%)
Feeling hot	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)
Infections and infestations
Urinary tract infection	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Limb injury	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		1/12 (8.3%)
Nervous system disorders
Burning sensation	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Dizziness	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)
Dysgeusia	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Headache	0/12 (0%)		1/12 (8.3%)		1/12 (8.3%)		2/12 (16.7%)
Paraesthesia	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)
Sensory disturbance	0/12 (0%)		1/12 (8.3%)		0/12 (0%)		0/12 (0%)
Renal and urinary disorders
Micturition urgency	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Reproductive system and breast disorders
Menstruation delayed	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Dry throat	0/12 (0%)		0/12 (0%)		2/12 (16.7%)		0/12 (0%)
Dyspnoea	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Oropharyngeal pain	0/12 (0%)		0/12 (0%)		0/12 (0%)		2/12 (16.7%)
Skin and subcutaneous tissue disorders
Dry skin	1/12 (8.3%)		0/12 (0%)		3/12 (25%)		0/12 (0%)
Generalised erythema	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)
Pruritus	0/12 (0%)		0/12 (0%)		0/12 (0%)		2/12 (16.7%)
Pruritus generalised	0/12 (0%)		0/12 (0%)		2/12 (16.7%)		0/12 (0%)
Rash	0/12 (0%)		0/12 (0%)		0/12 (0%)		2/12 (16.7%)
Rash papular	0/12 (0%)		0/12 (0%)		0/12 (0%)		1/12 (8.3%)
Vascular disorders
Flushing	0/12 (0%)		0/12 (0%)		1/12 (8.3%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.