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

Healthy Subjects Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02446171
• Other study ID #: D3820C00035
• Status: Completed
• Phase: Phase 1
• First received: April 29, 2015
• Last updated: July 28, 2015
• Start date: May 2015
• Est. completion date: July 2015

Study information

• Verified date: July 2015
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices (BfArM), Germany
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: July 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Bioavailability
• Healthy Subjects

Intervention

Drug:
• Naloxegol 25 mg tablet, crushed, suspended in water, given orally
naloxegol 25 mg (1 tablet) crushed, suspended in water, given orally
• Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube
naloxegol 25 mg (1 tablet) crushed, suspended in water, given via nasogastric tube
• Naloxegol 25 mg (10 mL oral solution)
naloxegol 25 mg (10 mL oral solution)
• Naloxegol 25 mg tablet, given orally
naloxegol 25 mg (1 tablet) whole tablet, given orally

Locations

Country	Name	City	State
Germany	Research Site	Berlin

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Taste test assessment	To assess the taste of the different formulations of Naloxegol.	Within 1 hour after dosing (Treatments A and C only)	No
Primary	AUC0 - infinity	AUC: Area under plasma concentration-time curve from time zero extrapolated to 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	No
Primary	AUC(0-t)	Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration	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	No
Primary	Cmax	Observed maximum plasma concentration	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	No
Secondary	tmax	Time to reach maximum plasma concentration	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	No
Secondary	t½?z	Half-life associated with terminal slope (?z) of a semi-logarithmic concentration-time curve	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	No
Secondary	MDT	Mean dissolution time (whole tablet only) (calculated as MRTTreatment D [Reference] - MRTTreatment C [Test])	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	No
Secondary	MRT	Mean residence time	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	No
Secondary	?z	Terminal elimination rate constant	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	No
Secondary	CL/F	Apparent total body clearance after extravascular administration estimated as dose divided by AUC	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	No
Secondary	Vz/F	Apparent volume of distribution during the terminal phase after extravascular administration	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	No
Secondary	Adverse events	Standard AE collection. 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	For up to 9 weeks (starting with screening)	Yes
Secondary	Vital signs: blood pressure	Systolic BP (SBP) (mmHg), Diastolic BP (DBP) (mmHg)	At screening and for each treatment period on admission (Day -1), at pre-dose (0 hours) and post-dose at 24 and 48 hours, as well as at final follow-up (up to 9 weeks)	Yes
Secondary	Vital signs: pulse	Pulse: beats per minute [bpm]	At screening and for each treatment period on admission (Day -1), at pre-dose (0 hours) and post-dose at 24 and 48 hours, as well as at final follow-up (up to 9 weeks)	Yes
Secondary	physical examination	general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, mouth and throat), lymph nodes, thyroid, musculoskeletal and neurological systems	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)	Yes
Secondary	Columbia Suicide Severity Rating Scale (C-SSRS)	To assess suicidal ideation and behavior	C-SSRS will be performed at screening (version Baseline - Screening) and at the final follow-up visit (version Since Last Visit), (maximum 9 weeks apart)	Yes
Secondary	12 lead ECG	12-lead ECG obtained after the subject rested in the supine position for at least 10 minutes	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); (total of 7 ECGs per subject who complete the study)	Yes
Secondary	safety laboratory assessments: Hematology	Hematologic laboratory variables	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	Yes
Secondary	safety laboratory assessments: clinical chemistry	Serum clinical chemistry	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	Yes
Secondary	safety laboratory assessments: urinalysis	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	Yes