Trial Outcomes & Findings for A Bioavailability Study With Alternate Methods of Administration of Naloxegol Tablets, and Solution (NCT NCT02446171)

NCT ID: NCT02446171

Last Updated: 2017-03-10

Results Overview

Area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 44 participants
• Primary outcome timeframe: Pre-dose (0 hours [within 30 minutes prior to administration of the investigational medicinal product (IMP)]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.
• Results posted on: 2017-03-10

Participant Flow

This study was conducted at PAREXEL International, Early Phase Clinical Unit Berlin, Berlin, Germany.

Participants were randomized in 4 sequence Williams design for 4 periods and 4 treatments: 25 mg naloxegol tablet crushed and suspended in water taken orally(Treatment A), 25 mg naloxegol tablet crushed and suspended in water via nasogastric tube (Treatment B), 2.5 mg/mL oral solution (Treatment C) and 25 mg naloxegol tablet swallowed(Treatment D).

Participant milestones

Measure	ADBC Sequence Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4.	BACD Sequence Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4.	CBDA Sequence Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4.	DCAB Sequence Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4.
Overall Study STARTED	11	11	11	11
Overall Study COMPLETED	11	11	9	11
Overall Study NOT COMPLETED	0	0	2	0

Reasons for withdrawal

Measure	ADBC Sequence Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4.	BACD Sequence Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4.	CBDA Sequence Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4.	DCAB Sequence Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4.
Overall Study Withdrawal by Subject	0	0	2	0

Baseline Characteristics

A Bioavailability Study With Alternate Methods of Administration of Naloxegol Tablets, and Solution

Baseline characteristics by cohort

Measure	ADBC Sequence n=11 Participants Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4.	BACD Sequence n=11 Participants Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4.	CBDA Sequence n=11 Participants Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4.	DCAB Sequence n=11 Participants Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4.	Total n=44 Participants Total of all reporting groups
Age, Continuous	44 years STANDARD_DEVIATION 12 • n=5 Participants	42 years STANDARD_DEVIATION 11 • n=7 Participants	45 years STANDARD_DEVIATION 8 • n=5 Participants	44 years STANDARD_DEVIATION 8 • n=4 Participants	44 years STANDARD_DEVIATION 10 • n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	11 Participants n=21 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	8 Participants n=4 Participants	33 Participants n=21 Participants

PRIMARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to administration of the investigational medicinal product (IMP)]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The Pharmacokinetic (PK) analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

Area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-infinity).	191 h*ng/mL Geometric Coefficient of Variation 54.2	192 h*ng/mL Geometric Coefficient of Variation 48.0	179 h*ng/mL Geometric Coefficient of Variation 54.0	191 h*ng/mL Geometric Coefficient of Variation 47.2

PRIMARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC 0-t).	188 h*ng/mL Geometric Coefficient of Variation 54.4	190 h*ng/mL Geometric Coefficient of Variation 47.8	178 h*ng/mL Geometric Coefficient of Variation 53.7	188 h*ng/mL Geometric Coefficient of Variation 47.4

PRIMARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

Observed maximum plasma concentration (Cmax) is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Observed Maximum Plasma Concentration (Cmax).	39.2 ng/mL Geometric Coefficient of Variation 44.1	40.1 ng/mL Geometric Coefficient of Variation 45.1	40.2 ng/mL Geometric Coefficient of Variation 45.7	39.7 ng/mL Geometric Coefficient of Variation 51.8

SECONDARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

This was one of the PK parameters to determine the time to reach maximum plasma concentration (tmax). Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=42 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=41 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Time to Reach Maximum Plasma Concentration (Tmax).	0.75 h Interval 0.23 to 5.0	1.50 h Interval 0.25 to 5.02	0.50 h Interval 0.25 to 5.0	1.00 h Interval 0.23 to 5.03

SECONDARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

This was one of the PK parameters to determine λz of a t½λz. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz).	9.92 h Standard Deviation 3.92 • Interval 0.23 to 5.0	8.78 h Standard Deviation 4.22 • Interval 0.25 to 5.02	9.28 h Standard Deviation 3.40 • Interval 0.25 to 5.0	9.22 h Standard Deviation 3.13 • Interval 0.23 to 5.03

SECONDARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point. There were zero participants analyzed in Treatment A, B and C, hence data was not determined.

This was one of the PK parameters to determine MDT (whole tablet only) (calculated as MRT Treatment D [Reference] - MRT Treatment C [Test]). Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=26 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D Participants received Naloxegol 25 mg whole tablet orally.
Mean Dissolution Time (MDT).	1.29 h Standard Deviation 0.951 • Interval 0.23 to 5.03	—	—	—

SECONDARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

This was one of the PK parameters to determine MRT. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Mean Residence Time (MRT).	6.94 h Standard Deviation 2.00 • Interval 0.23 to 5.0	6.54 h Standard Deviation 1.92 • Interval 0.25 to 5.02	6.21 h Standard Deviation 1.42 • Interval 0.25 to 5.0	6.72 h Standard Deviation 1.68 • Interval 0.23 to 5.03

SECONDARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

This was one of the PK parameters to determine the apparent total body clearance after extravascular administration estimated as dose divided by AUC. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F).	131 L/h Geometric Coefficient of Variation 54.2 • Interval 0.23 to 5.0	130 L/h Geometric Coefficient of Variation 48.0 • Interval 0.25 to 5.02	140 L/h Geometric Coefficient of Variation 54.0 • Interval 0.25 to 5.0	131 L/h Geometric Coefficient of Variation 47.2 • Interval 0.23 to 5.03

SECONDARY outcome

Timeframe: Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Population: The PK analysis set was a subset of those participants in the safety analysis set and included participants who had received at least 1 dose of study medication and had at least 1 post-dose plasma concentration measurement at a scheduled time point.

This was one of the PK parameters to determine the apparent volume of distribution during the terminal phase after extravascular administration.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=41 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=40 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F).	1738 L Geometric Coefficient of Variation 55.3 • Interval 0.23 to 5.0	1513 L Geometric Coefficient of Variation 55.4 • Interval 0.25 to 5.02	1731 L Geometric Coefficient of Variation 58.5 • Interval 0.25 to 5.0	1640 L Geometric Coefficient of Variation 54.7 • Interval 0.23 to 5.03

SECONDARY outcome

Timeframe: For up to 9 weeks (starting with screening).

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.The term AE is used generally to include any AE whether serious or non-serious. An serious AE (SAE) is an AE that fulfills one or more of the following criteria: results in death, is immediately life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity or substantial disruption of the ability to conduct normal life functions; is a congenital abnormality or birth defect; is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Percentage of Participants With Adverse Events (AE).	9.5 percentage of participants	7.0 percentage of participants	11.6 percentage of participants	18.6 percentage of participants

SECONDARY outcome

Timeframe: Day 2 (24h post-dose), Day 3 (48h post-dose) and Day 4 (72h post-dose).

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

The following variables were collected after the participants had rested in the supine position for at least 5 minutes: Systolic Blood Pressure (SBP) and Diastolic BP. The measurement of vital signs for SBP and DBP are presented in the below outcome table.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. Day 2/24h Post-dose (SBP) (N= 42, 43, 43, 43)	-2 mmHg Standard Deviation 9	-4 mmHg Standard Deviation 11	-1 mmHg Standard Deviation 8	0 mmHg Standard Deviation 8
Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. Day 3/48h Post-dose (SBP) (N= 42, 43, 43, 42)	4 mmHg Standard Deviation 9	-2 mmHg Standard Deviation 10	2 mmHg Standard Deviation 8	2 mmHg Standard Deviation 8
Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. Day 4/72h Post-dose (SBP) (N= 9, 11, 11, 12)	7 mmHg Standard Deviation 9	0 mmHg Standard Deviation 9	1 mmHg Standard Deviation 11	7 mmHg Standard Deviation 13
Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. Day 2/24h Post-dose (DBP) (N= 42, 43, 43, 43)	-2 mmHg Standard Deviation 6	-4 mmHg Standard Deviation 7	-1 mmHg Standard Deviation 5	0 mmHg Standard Deviation 6
Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. Day 3/48h Post-dose (DBP) (N= 42, 43, 43, 42)	0 mmHg Standard Deviation 6	-2 mmHg Standard Deviation 7	0 mmHg Standard Deviation 6	1 mmHg Standard Deviation 5
Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. Day 4/72h Post-dose (DBP) (N= 9, 11, 11, 12)	5 mmHg Standard Deviation 7	0 mmHg Standard Deviation 6	4 mmHg Standard Deviation 3	4 mmHg Standard Deviation 6

SECONDARY outcome

Timeframe: Day 2 (24h post-dose), Day 3 (48h post-dose) and Day 4 (72h post-dose).

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

Pulse rate: the measurement of vital signs for pulse rate is presented in the below outcome table.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Mean Change From Baseline for Vital Signs in Supine Pulse Rate. Day 2/24h Post-dose (N= 42, 43, 43, 43)	1 beats per minute (bpm) Standard Deviation 5	0 beats per minute (bpm) Standard Deviation 6	1 beats per minute (bpm) Standard Deviation 6	2 beats per minute (bpm) Standard Deviation 6
Mean Change From Baseline for Vital Signs in Supine Pulse Rate. Day 3/48h Post-dose (N= 42, 43, 43, 42)	5 beats per minute (bpm) Standard Deviation 6	4 beats per minute (bpm) Standard Deviation 7	5 beats per minute (bpm) Standard Deviation 8	5 beats per minute (bpm) Standard Deviation 6
Mean Change From Baseline for Vital Signs in Supine Pulse Rate. Day 4/72h Post-dose (N= 9, 11, 11, 12)	8 beats per minute (bpm) Standard Deviation 9	4 beats per minute (bpm) Standard Deviation 9	8 beats per minute (bpm) Standard Deviation 5	12 beats per minute (bpm) Standard Deviation 5

SECONDARY outcome

Timeframe: A full physical examination at screening and the final follow-up visit (maximum 9 weeks apart). Abbreviated physical examination on admission (on Day -1 of each treatment period) and at 48-hours post-dose to each treatment period (for up to 4 weeks).

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

A complete physical examination included an assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, mouth and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. Physical examination was performed to check for any significant abnormality in participants.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Participants With Significant Findings in Physical Examination.	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: At Baseline and Days 1-4 of each treatment period.

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

The C-SSRS is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events, and provided a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation and deterrents), all of which are significantly predictive of completed suicide. The C-SSRS was performed to determine the presence of suicidality.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Participants With Significant Findings in Columbia-Suicide Severity Rating Scale (C-SSRS).	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: At screening, first admission to the clinical unit (Visit 2, Day -1), 1.25 hours after each dose (Visits 2-5, Day 1), as well as at the final follow-up visit (up to 9 weeks).

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

A 12-lead ECG was obtained after the participant rested in supine position for at least 10 minutes. The study physician was to judge the overall interpretation as normal or abnormal. If abnormal, it was decided as to whether or not the abnormality was clinically significant and the reason for the abnormality was recorded.

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Participants With Significant Findings in 12-Lead Electrocardiography (ECG).	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: At screening and at the final follow-up visit (maximum 9 weeks apart); in addition, for the first and third treatment period at pre-dose.

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

Participants were assessed through each laboratory variables for any significant abnormalities. Hematology assessments included white blood cell count, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and others. Clinical chemistry assessment included testing levels of sodium, potassium, urea, creatinine, albumin, calcium, glucose (fasting) and others. Urinalysis assessment included glucose, protein, blood and microscopy (if positive for blood or protein).

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 Participants Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 Participants Participants received Naloxegol 25 mg whole tablet orally.
Participants With Significant Findings in Hematology, Clinical Chemistry and Urinalysis.	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Within 1 hour after dosing (Treatments A and C only).

Population: The safety analysis set included all participants who had received at least one dose of Naloxegol and for whom any safety post-dose data were available.

A standardized questionnaire was provided to participants and were asked to complete the questionnaire for the liquid formulations tested, i.e., Naloxegol crushed tablet, oral (Treatment A) and Naloxegol oral solution (Treatment C), without assistance or influence from site personnel. For each formulation, the questionnaire was identical and required the participant's opinion. Sweet, salty, sour, bitter, metallic, hot/spicy were rated on a scale of 0 to 10, where 0 means not at all and 10 means extreme. The overall rating of the taste was rated on a scale of 0 to 10, where 0 means "I dislike it extremely much" and 10 means "I like it extremely much". The smell of the medicine was based on a scale of 0 to 10, where 0 means extremely bad and 10 means extremely nice. The question on whether the participants would consider ever taking the medicine again was based on a scale of 0 to 10, where 0 means "Never - under no circumstances" and 10 means "Yes, definitely".

Outcome measures

Measure	Treatment A n=42 Participants Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 Participants Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D Participants received Naloxegol 25 mg whole tablet orally.
Taste Test Assessment. Sweet	0.0 units on a scale Full Range 0.0 • Interval 0.0 to 2.0	7.0 units on a scale Interval 1.0 to 10.0	—	—
Taste Test Assessment. Salty	0.0 units on a scale Interval 0.0 to 7.0	0.0 units on a scale Interval 0.0 to 4.0	—	—
Taste Test Assessment. Sour	0.0 units on a scale Interval 0.0 to 5.0	0.0 units on a scale Interval 0.0 to 6.0	—	—
Taste Test Assessment. Bitter	3.0 units on a scale Interval 0.0 to 8.0	0.0 units on a scale Interval 0.0 to 5.0	—	—
Taste Test Assessment. Metallic	1.0 units on a scale Interval 0.0 to 7.0	0.0 units on a scale Interval 0.0 to 4.0	—	—
Taste Test Assessment. Hot/Spicy	0.0 units on a scale Interval 0.0 to 1.0	0.0 units on a scale Interval 0.0 to 2.0	—	—
Taste Test Assessment. How would you rate the taste of this medicine?	4.0 units on a scale Interval 0.0 to 8.0	7.0 units on a scale Interval 1.0 to 10.0	—	—
Taste Test Assessment. If the medicine smells, how does it smell?	4.0 units on a scale Interval 3.0 to 5.0	7.0 units on a scale Interval 5.0 to 9.0	—	—
Taste Test Assessment. Would you consider taking this medicine again?	8.0 units on a scale Interval 0.0 to 10.0	9.0 units on a scale Interval 1.0 to 10.0	—	—

Adverse Events

Treatment A

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Treatment B

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Treatment C

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Treatment D

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Treatment A n=42 participants at risk Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Treatment B n=43 participants at risk Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Treatment C n=43 participants at risk Participants received Naloxegol 25 mg of 10 mL oral solution.	Treatment D n=43 participants at risk Participants received Naloxegol 25 mg whole tablet orally.
Nervous system disorders Headache	2.4% 1/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	7.0% 3/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	7.0% 3/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Nervous system disorders Dysgeusia	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Nervous system disorders Paraesthesia	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Gastrointestinal disorders Vomiting	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Gastrointestinal disorders Abdominal pain	2.4% 1/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Gastrointestinal disorders Nausea	2.4% 1/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
General disorders Fatigue	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	7.0% 3/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Infections and infestations Nasopharyngitis	2.4% 1/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Infections and infestations Oral herpes	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Ear and labyrinth disorders Tinnitus	2.4% 1/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/42 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	2.3% 1/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.	0.00% 0/43 • SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.

Additional Information

Ian Wogan

AstraZeneca AB

Phone: +1 301 398 0670

Email: ClinicalTrialTransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a publication (e.g., in a scientific journal) based on the results of this study is envisaged, approval from AstraZeneca will be obtained and a draft manuscript will be submitted to AstraZeneca for scrutiny and comment. The choice of conduit will be mutually agreed on by the Principal Investigator and AstraZeneca.
• Publication restrictions are in place

Restriction type: OTHER