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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02446171
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arms: 4
• Duration (Months): 2
• Patients Per Site Per Month: 22

Study Details

Study Description

Brief Summary

This clinical study is an open-label, randomized, 4-period, 4-treatment, crossover, single-center, single-dose bioavailability study with alternate methods of administration of crushed naloxegol tablets, 25 mg and of a naloxegol solution formulation, 25 mg, compared to whole naloxegol tablets, 25 mg, in healthy subjects.

The main objective of this study is to determine the bioavailability of each of three alternative methods of naloxegol administration compared to whole naloxegol tablets given orally by assessment of the primary pharmacokinetic (PK) parameters of naloxegol

Condition or Disease	Intervention/Treatment	Phase
Bioavailability; Healthy Subjects	Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; Drug: Naloxegol 25 mg (10 mL oral solution); Drug: Naloxegol 25 mg tablet, given orally	Phase 1

Detailed Description

This is an open-label, randomized, 4-period, 4-treatment, crossover, single-center, single-dose bioavailability study with alternate methods of administration of naloxegol: crushed and suspended in water and administered orally (Treatment A),crushed and suspended in water administered via nasogastric tube (Treatment B), solution administered orally (Treatment C) and tablet swallowed as a whole (Treatment D).

Alternative ways of administering a tablet may be useful to help patients who, for different reasons, have difficulties with swallowing a whole tablet. Administration of dispersed (crushed) tablets suspended in water is a common way of administering drugs to these patients. A useful method in patients whose condition prevents swallowing is administration of dispersed tablets through nasogastric tubes. Additionally a solution formulation may be an attractive option for some patients including the pediatric population. The main aim in this clinical study is to investigate whether the blood concentrations of naloxegol (pharmacokinetic) after each treatment A, B and C is comparable to that after treatment D. Additionally, the safety and tolerability shall be assessed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Open-Label, Randomized, 4-Period, 4-Treatment, Crossover, Single-Center, Single-Dose Bioavailability Study With Alternate Methods of Administration of Crushed Naloxegol Tablets, 25 mg and of a Naloxegol Solution Formulation, 25 mg, Compared to Whole Naloxegol Tablets, 25 mg, in Healthy Subjects
• Study Start Date: May 1, 2015
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatments A-D-B-C sequence Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4	Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; naloxegol 25 mg (1 tablet) crushed, suspended in water, given orally; Other Names: Treatment A (Test product) ; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; naloxegol 25 mg (1 tablet) crushed, suspended in water, given via nasogastric tube; Other Names: Treatment B (Test product) ; Drug: Naloxegol 25 mg (10 mL oral solution); naloxegol 25 mg (10 mL oral solution); Other Names: Treatment C (Test product) ; Drug: Naloxegol 25 mg tablet, given orally; naloxegol 25 mg (1 tablet) whole tablet, given orally; Other Names: Treatment D (Reference product)
Experimental: Treatments B-A-C-D sequence Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4	Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; naloxegol 25 mg (1 tablet) crushed, suspended in water, given orally; Other Names: Treatment A (Test product) ; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; naloxegol 25 mg (1 tablet) crushed, suspended in water, given via nasogastric tube; Other Names: Treatment B (Test product) ; Drug: Naloxegol 25 mg (10 mL oral solution); naloxegol 25 mg (10 mL oral solution); Other Names: Treatment C (Test product) ; Drug: Naloxegol 25 mg tablet, given orally; naloxegol 25 mg (1 tablet) whole tablet, given orally; Other Names: Treatment D (Reference product)
Experimental: Treatments C-B-D-A sequence Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4	Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; naloxegol 25 mg (1 tablet) crushed, suspended in water, given orally; Other Names: Treatment A (Test product) ; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; naloxegol 25 mg (1 tablet) crushed, suspended in water, given via nasogastric tube; Other Names: Treatment B (Test product) ; Drug: Naloxegol 25 mg (10 mL oral solution); naloxegol 25 mg (10 mL oral solution); Other Names: Treatment C (Test product) ; Drug: Naloxegol 25 mg tablet, given orally; naloxegol 25 mg (1 tablet) whole tablet, given orally; Other Names: Treatment D (Reference product)
Experimental: Treatments D-C-A-B sequence Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4	Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; naloxegol 25 mg (1 tablet) crushed, suspended in water, given orally; Other Names: Treatment A (Test product) ; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; naloxegol 25 mg (1 tablet) crushed, suspended in water, given via nasogastric tube; Other Names: Treatment B (Test product) ; Drug: Naloxegol 25 mg (10 mL oral solution); naloxegol 25 mg (10 mL oral solution); Other Names: Treatment C (Test product) ; Drug: Naloxegol 25 mg tablet, given orally; naloxegol 25 mg (1 tablet) whole tablet, given orally; Other Names: Treatment D (Reference product)

Outcome Measures

Primary Outcome Measures

1. Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-infinity). [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.]

   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.

2. Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC 0-t). [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.]

   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.

3. Observed Maximum Plasma Concentration (Cmax). [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.]

   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.

Secondary Outcome Measures

1. Time to Reach Maximum Plasma Concentration (Tmax). [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.]

   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.

2. Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz). [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.]

   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.

3. Mean Dissolution Time (MDT). [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.]

   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.

4. Mean Residence Time (MRT). [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.]

   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.

5. Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F). [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.]

   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.

6. Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F). [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.]

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

7. Percentage of Participants With Adverse Events (AE). [For up to 9 weeks (starting with screening).]

   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.

8. Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure. [Day 2 (24h post-dose), Day 3 (48h post-dose) and Day 4 (72h post-dose).]

   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.

9. Mean Change From Baseline for Vital Signs in Supine Pulse Rate. [Day 2 (24h post-dose), Day 3 (48h post-dose) and Day 4 (72h post-dose).]

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

10. Participants With Significant Findings in Physical Examination. [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).]

    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.

11. Participants With Significant Findings in Columbia-Suicide Severity Rating Scale (C-SSRS). [At Baseline and Days 1-4 of each treatment period.]

    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.

12. Participants With Significant Findings in 12-Lead Electrocardiography (ECG). [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).]

    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.

13. Participants With Significant Findings in Hematology, Clinical Chemistry and Urinalysis. [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.]

    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).

14. Taste Test Assessment. [Within 1 hour after dosing (Treatments A and C only).]

    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".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.

• Females must have a negative pregnancy test at screening and on admission to the clinical unit, must not be lactating and must be of non childbearing potential, confirmed at screening by fulfilling one of the following criteria:

• Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range.

• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy; but not tubal ligation.

• Have a body mass index (BMI) between 18.5 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.

• Able to understand, read and speak the German language.

Exclusion Criteria:

• History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the potential subject at risk because of participation in the study, or influence the results or the potential subject's ability to participate in the study.

• Current smokers or those who have smoked or used nicotine products within the previous 3 months.

• Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.

Drugs include known CYP3A4 and/or P-gp inhibitors and inducers, e.g., diltiazem, verapamil, and erythromycin

• Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life.

For females, hormonal replacement therapy is not allowed.

• Subject with a relevant history of a suicide attempt or suicidal behavior. Any recent suicidal ideation within the last 6 months (a level of 4 or 5), or who are at significant risk to commit suicide, as judged by the investigator using the Columbia-Suicide Severity Rating Scale (C-SSRS).

• Applicable to subjects willing to participate in genetic research: Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection or previous bone marrow transplant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Berlin		Germany

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Rainard Fuhr, Dr. med., PAREXEL International GmbH, Berlin

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bui K, Birmingham B, Diva U, Berger B. An Open-Label, Randomized Bioavailability Study of Alternative Methods of Oral Administration of Naloxegol in Healthy Subjects. Clin Pharmacol Drug Dev. 2017 Jul;6(4):420-427. doi: 10.1002/cpdd.335. Epub 2017 Jan 27.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02446171
• Other Study ID Numbers: D3820C00035
• First Posted: May 18, 2015
• Last Update Posted: Mar 10, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by AstraZeneca: naloxegol tablet crushed; naloxegol oral solution; naloxegol whole tablet; relative bioavailability; Phase I; healthy subjects
• Additional relevant MeSH terms: Naloxegol

Study Results

Participant Flow

Recruitment Details	This study was conducted at PAREXEL International, Early Phase Clinical Unit Berlin, Berlin, Germany.
Pre-assignment Detail	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).

Arm/Group Title	ADBC Sequence	BACD Sequence	CBDA Sequence	DCAB Sequence
Arm/Group Description	Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4.	Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4.	Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4.	Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4.
Period Title: Overall Study
STARTED	11	11	11	11
COMPLETED	11	11	9	11
NOT COMPLETED	0	0	2	0

Baseline Characteristics

Arm/Group Title	ADBC Sequence	BACD Sequence	CBDA Sequence	DCAB Sequence	Total
Arm/Group Description	Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4.	Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4.	Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4.	Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4.	Total of all reporting groups
Overall Participants	11	11	11	11	44
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44 (12)	42 (11)	45 (8)	44 (8)	44 (10)
Sex: Female, Male (Count of Participants)
Female	3 27.3%	2 18.2%	3 27.3%	3 27.3%	11 25%
Male	8 72.7%	9 81.8%	8 72.7%	8 72.7%	33 75%

Outcome Measures

1. Primary Outcome

Title	Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-infinity).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	191 (54.2)	192 (48.0)	179 (54.0)	191 (47.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	98.89
	Confidence Interval	(2-Sided) 90%; 92.40 to 105.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	100.04
	Confidence Interval	(2-Sided) 90%; 93.17 to 107.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	94.37
	Confidence Interval	(2-Sided) 90%; 88.70 to 100.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC 0-t).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	188 (54.4)	190 (47.8)	178 (53.7)	188 (47.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	98.79
	Confidence Interval	(2-Sided) 90%; 92.24 to 105.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	100.44
	Confidence Interval	(2-Sided) 90%; 93.65 to 107.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	94.83
	Confidence Interval	(2-Sided) 90%; 89.20 to 100.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Observed Maximum Plasma Concentration (Cmax).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	39.2 (44.1)	40.1 (45.1)	40.2 (45.7)	39.7 (51.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment A, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	97.05
	Confidence Interval	(2-Sided) 90%; 88.09 to 106.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment B, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	100.56
	Confidence Interval	(2-Sided) 90%; 91.80 to 110.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment C, Treatment D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio#
	Estimated Value	102.5
	Confidence Interval	(2-Sided) 90%; 93.13 to 111.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	42	41	43
Median (Full Range) [h]	0.75	1.50	0.50	1.00

5. Secondary Outcome

Title	Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Mean (Standard Deviation) [h]	9.92 (3.92)	8.78 (4.22)	9.28 (3.40)	9.22 (3.13)

6. Secondary Outcome

Title	Mean Dissolution Time (MDT).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	26
Mean (Standard Deviation) [h]	1.29 (0.951)

7. Secondary Outcome

Title	Mean Residence Time (MRT).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Mean (Standard Deviation) [h]	6.94 (2.00)	6.54 (1.92)	6.21 (1.42)	6.72 (1.68)

8. Secondary Outcome

Title	Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F).
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Geometric Mean (Geometric Coefficient of Variation) [L/h]	131 (54.2)	130 (48.0)	140 (54.0)	131 (47.2)

9. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F).
Description	This was one of the PK parameters to determine the apparent volume of distribution during the terminal phase after extravascular administration.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	41	40	43
Geometric Mean (Geometric Coefficient of Variation) [L]	1738 (55.3)	1513 (55.4)	1731 (58.5)	1640 (54.7)

10. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AE).
Description	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.
Time Frame	For up to 9 weeks (starting with screening).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Number [percentage of participants]	9.5 86.4%	7.0 63.6%	11.6 105.5%	18.6 169.1%

11. Secondary Outcome

Title	Mean Change From Baseline for Vital Signs of Supine Systolic and Diastolic Blood Pressure.
Description	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.
Time Frame	Day 2 (24h post-dose), Day 3 (48h post-dose) and Day 4 (72h post-dose).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Day 2/24h Post-dose (SBP) (N= 42, 43, 43, 43)	-2 (9)	-4 (11)	-1 (8)	0 (8)
Day 3/48h Post-dose (SBP) (N= 42, 43, 43, 42)	4 (9)	-2 (10)	2 (8)	2 (8)
Day 4/72h Post-dose (SBP) (N= 9, 11, 11, 12)	7 (9)	0 (9)	1 (11)	7 (13)
Day 2/24h Post-dose (DBP) (N= 42, 43, 43, 43)	-2 (6)	-4 (7)	-1 (5)	0 (6)
Day 3/48h Post-dose (DBP) (N= 42, 43, 43, 42)	0 (6)	-2 (7)	0 (6)	1 (5)
Day 4/72h Post-dose (DBP) (N= 9, 11, 11, 12)	5 (7)	0 (6)	4 (3)	4 (6)

12. Secondary Outcome

Title	Mean Change From Baseline for Vital Signs in Supine Pulse Rate.
Description	Pulse rate: the measurement of vital signs for pulse rate is presented in the below outcome table.
Time Frame	Day 2 (24h post-dose), Day 3 (48h post-dose) and Day 4 (72h post-dose).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Day 2/24h Post-dose (N= 42, 43, 43, 43)	1 (5)	0 (6)	1 (6)	2 (6)
Day 3/48h Post-dose (N= 42, 43, 43, 42)	5 (6)	4 (7)	5 (8)	5 (6)
Day 4/72h Post-dose (N= 9, 11, 11, 12)	8 (9)	4 (9)	8 (5)	12 (5)

13. Secondary Outcome

Title	Participants With Significant Findings in Physical Examination.
Description	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.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Number [participants]	0 0%	0 0%	0 0%	0 0%

14. Secondary Outcome

Title	Participants With Significant Findings in Columbia-Suicide Severity Rating Scale (C-SSRS).
Description	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.
Time Frame	At Baseline and Days 1-4 of each treatment period.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Number [participants]	0 0%	0 0%	0 0%	0 0%

15. Secondary Outcome

Title	Participants With Significant Findings in 12-Lead Electrocardiography (ECG).
Description	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.
Time Frame	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Number [participants]	0 0%	0 0%	0 0%	0 0%

16. Secondary Outcome

Title	Participants With Significant Findings in Hematology, Clinical Chemistry and Urinalysis.
Description	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).
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment B	Treatment C	Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.	Participants received Naloxegol 25 mg of 10 mL oral solution.	Participants received Naloxegol 25 mg whole tablet orally.
Measure Participants	42	43	43	43
Number [participants]	0 0%	0 0%	0 0%	0 0%

17. Secondary Outcome

Title	Taste Test Assessment.
Description	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".
Time Frame	Within 1 hour after dosing (Treatments A and C only).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Treatment A	Treatment C
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.	Participants received Naloxegol 25 mg of 10 mL oral solution.
Measure Participants	42	43
Sweet	0.0 (0.0)	7.0
Salty	0.0	0.0
Sour	0.0	0.0
Bitter	3.0	0.0
Metallic	1.0	0.0
Hot/Spicy	0.0	0.0
How would you rate the taste of this medicine?	4.0	7.0
If the medicine smells, how does it smell?	4.0	7.0
Would you consider taking this medicine again?	8.0	9.0

Adverse Events

Time Frame	SAEs were reported from the signing of the informed consent and AEs were recorded from randomization until the final follow-up/ early-termination visit.
Arm/Group Title	Treatment A		Treatment B		Treatment C		Treatment D
Arm/Group Description	Participants received Naloxegol 25 mg oral tablet, crushed, suspended in water.		Participants received Naloxegol 25 mg crushed, suspended in water, given via nasogastric tube.		Participants received Naloxegol 25 mg of 10 mL oral solution.		Participants received Naloxegol 25 mg whole tablet orally.
All Cause Mortality
	Treatment A		Treatment B		Treatment C		Treatment D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment A		Treatment B		Treatment C		Treatment D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/43 (0%)		0/43 (0%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Treatment A		Treatment B		Treatment C		Treatment D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/42 (9.5%)		3/43 (7%)		5/43 (11.6%)		8/43 (18.6%)
Ear and labyrinth disorders
Tinnitus	1/42 (2.4%)		0/43 (0%)		0/43 (0%)		0/43 (0%)
Gastrointestinal disorders
Vomiting	0/42 (0%)		1/43 (2.3%)		1/43 (2.3%)		1/43 (2.3%)
Abdominal pain	1/42 (2.4%)		0/43 (0%)		0/43 (0%)		1/43 (2.3%)
Nausea	1/42 (2.4%)		0/43 (0%)		1/43 (2.3%)		0/43 (0%)
General disorders
Fatigue	0/42 (0%)		0/43 (0%)		0/43 (0%)		3/43 (7%)
Infections and infestations
Nasopharyngitis	1/42 (2.4%)		0/43 (0%)		0/43 (0%)		0/43 (0%)
Oral herpes	0/42 (0%)		0/43 (0%)		0/43 (0%)		1/43 (2.3%)
Musculoskeletal and connective tissue disorders
Back pain	0/42 (0%)		0/43 (0%)		1/43 (2.3%)		0/43 (0%)
Nervous system disorders
Headache	1/42 (2.4%)		1/43 (2.3%)		3/43 (7%)		3/43 (7%)
Dysgeusia	0/42 (0%)		0/43 (0%)		0/43 (0%)		1/43 (2.3%)
Paraesthesia	0/42 (0%)		1/43 (2.3%)		0/43 (0%)		0/43 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/42 (0%)		0/43 (0%)		1/43 (2.3%)		0/43 (0%)
Dysphonia	0/42 (0%)		0/43 (0%)		1/43 (2.3%)		0/43 (0%)
Skin and subcutaneous tissue disorders
Eczema	0/42 (0%)		0/43 (0%)		0/43 (0%)		1/43 (2.3%)
Hyperhidrosis	0/42 (0%)		0/43 (0%)		1/43 (2.3%)		0/43 (0%)
Pruritus	0/42 (0%)		1/43 (2.3%)		0/43 (0%)		0/43 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.