A Phase I Study to Assess PK of AZD7986 Alone & With Verapamil, Itraconazole or Diltiazem in Healthy Subjects

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02653872
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 4
• Actual Duration (Months): 2.7
• Patients Per Site Per Month: 5.6

Study Details

Study Description

Brief Summary

This is a phase 1, non-randomized, fixed sequence, 3-period, drug-drug interaction study to assess the pharmacokinetics (PK) of AZD7986 in healthy subjects when administered alone and in combination with multiple doses of verapamil and itraconazole or diltiazem

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects	Drug: AZD7986; Drug: Verapamil; Drug: Itraconazole; Drug: Diltiazem	Phase 1

Detailed Description

This study will be an open-label, non-randomised, fixed sequence, 3-period study conducted at a single study centre to assess the PK of AZD7986 in healthy subjects when administered alone and in combination with multiple doses of verapamil and itraconazole or diltiazem. An adaptive design with an interim analysis of the PK data from Periods 1 and 2 will be used to determine which of itraconazole or diltiazem will be administered in combination with AZD7986 in Period 3.

Treatments to be administered in a fixed order separated by a washout period:

period 1 - single AZD7986 (25 mg) on Day 1 (1 hour before food), washout 7 days period 2 - verapamil (240 mg extended release formulation) daily 1 hour before food (Day 1 to 10) and a single dose of AZD7986 (25 mg) 1 hour before food (Day 5), washout period 14 days period 3 - subject to interim pharmacokinetic analysis of AZD7986 alone compared with AZD7986 and verapamil combined, either itraconazole (200 mg, oral solution formulation 10mg/mL) administered twice on Day 1 and daily on days 2 to 11 (1 hour before food) plus AZD7986 (25mg) single dose on Day 6 (1 hour before food); or diltiazem (360 mg, extended release formulation) on Days 1 to 13 (1 hour before food) plus AZD7986 (25 mg) 1 hour before food on Day 8.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Open-label, Non-randomized, Fixed Sequence Study Assessing the Pharmacokinetics of AZD7986 When Administered Alone and With Multiple Doses of Verapamil and Itraconazole or Diltiazem in Healthy Subjects
• Actual Study Start Date: Jan 22, 2016
• Actual Primary Completion Date: Apr 13, 2016
• Actual Study Completion Date: Apr 13, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD7986 (alone) Treatment period 1 AZD7986 (15 mg/mL) 25 mg dosage administered alone	Drug: AZD7986; Oral solution, single dose, dilution from concentrate
Active Comparator: Verapamil (with AZD7986) Treatment period 2 Daily administration of verapamil (240 mg, extended release formulation) on Days 1 to 10 plus administration of single dose AZD7986 (25 mg) on Day 5	Drug: AZD7986; Oral solution, single dose, dilution from concentrate; Drug: Verapamil; Extended release tablet for oral use
Active Comparator: Itraconazole (with AZD7986) Treatment Period 3 Itraconazole (200 mg, oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily Days 2 to 11 plus single dose AZD7986 (25 mg, tbc) on Day 6	Drug: AZD7986; Oral solution, single dose, dilution from concentrate; Drug: Itraconazole; Oral solution
Active Comparator: Diltiazem (with AZD7986) Treatment period 3 Diltiazem (360 mg, extended release formulation) administered Days 1 to 13 plus single dose AZD7986 (25 mg) on Day 8	Drug: AZD7986; Oral solution, single dose, dilution from concentrate; Drug: Diltiazem; Extended release capsule

Outcome Measures

Primary Outcome Measures

1. Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax). [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

2. Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC). [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of verapamil and itraconazole on the PK of AZD7986.

3. Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]). [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

4. Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz). [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

5. Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

6. Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F). [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

7. Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F). [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.

8. Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the area under the plasma concentration-time curve from time over the dosing interval tau (24 hours) of Verapamil, itraconazole and OH-itraconazole (a metabolite of Itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.

9. Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole. [Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose]

   To assess the time to reach maximum observed concentration of Verapamil, Itraconazole and OH-itraconazole (a metabolite of itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.

2. Healthy male and/or female subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venepuncture.

3. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 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(> 40 milli-International unit [mIU]/mL).

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

1. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.

2. Provision of signed, written and dated informed consent for optional genetic/biomarker research.

3. Hormone replacement therapy is not allowed for females to exclude any drug drug interaction between the hormone replacement therapy and AZD7986.

Exclusion Criteria:

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

2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.

3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of AZD7986.

4. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, as judged by the investigator.

5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.

6. Any clinically significant abnormal findings in vital signs after at least 10 minutes of rest, defined as the following:

• Systolic blood pressure < 100 mmHg or > 140 mmHg;

• Diastolic blood pressure < 50 mmHg or > 90 mmHg; or

• Pulse rate < 50 or > 85 beats per minute.

1. Any clinically important abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically important abnormalities in the 12 Lead ECG as considered by the investigator that may interfere with the interpretation of ECG interval measured from the onset of the QRS complex (electrical activity or ventricular contraction on the ECG where Q represents the downward deflection, R represents upward deflection and S represents a downward one) to the end of the T wave corrected for heart rate (QTc) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.

2. Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450 ms or shortened QTcF < 340 ms or family history of long QT syndrome.

3. PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).

4. PR (PQ) interval prolongation > 200 ms, intermittent second or third degree atrioventricular (AV) block (Wenckebach block while asleep is not exclusive), or AV dissociation.

5. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.

6. Known or suspected history of drug abuse, as judged by the investigator.

7. Current smokers or those who have smoked or used nicotine products within the 3 months before screening.

8. Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the investigator.

9. Positive screen for drugs of abuse or cotinine at screening or on each admission to the study centre or positive screen for alcohol on each admission to the study unit.

10. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7986.

11. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate,) as judged by the investigator.

12. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of AZD7986.

13. Use of any prescribed or non-prescribed medication including antacids and other drugs for gastric acid-related disorders, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of AZD7986 or longer if the medication has a long half-life.

Note: Hormonal replacement therapy is not allowed for females.

1. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.

2. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of AZD7986 in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest.

Note: Subjects consented and screened, but not dosed in this study or a previous phase I study, are not excluded.

1. Subjects who have previously received AZD7986.

2. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.

3. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.

4. Subjects who cannot communicate reliably with the investigator.

5. Subjects who are vegans or have medical dietary restrictions.

6. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

7. Subject has increased risk of infection:

• History and/or presence of tuberculosis (TB); positive result for interferon gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), subjects who have resided in regions where tuberculosis and mycosis are endemic during 90 days before screening, or who intend to visit such a region during the duration of the study i.e., deserts areas, Eastern Europe, Central and South America, Africa except Egypt, Russia, Asia, Indonesia. The test may be repeated if the initial test result is indeterminate.

• Oral body temperature of > 37.7°C on Day -1, or as judged by the investigator.

• Blood neutrophil count < 1.7 x109/L (Screening and Day -1 morning sample).

• Is in high risk-group for HIV infection within the last 6 months (i.e., men who have had unprotected sex with men, women who have had sex without a condom with men who have sex with men, people who have had sex without a condom with a person who has lived or travelled in Africa, people who inject drugs, people who have had sex without a condom with somebody who has injected drugs, people who have caught another sexually transmitted infection, people who have received a blood transfusion while in Africa, Eastern Europe, the countries of the former Soviet Union, Asia or Central and Southern America).

• Other latent or chronic infections (e.g., recurrent sinusitis, genital or ocular herpes, urinary tract infection) or at risk of infection (surgery, trauma, or significant infection) within 90 days of screening, or history of skin abscesses within 90 days of screening.

• Clinically significant lower respiratory tract infection not resolved within 4 weeks prior to screening, as determined by the investigator.

• Subjects with active malignancy or neoplastic disease in the previous 5 years other than superficial basal cell carcinoma.

• Disease history suggesting abnormal immune function.

• Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to dosing.

• High-sensitivity C-reactive protein above upper limit of laboratory reference range at screening and on Day -1.

1. Subjects with a history or signs of current gingivitis/periodontitis or a history or current hyperkeratosis of palms and soles will be excluded. (Due to the fact that many subjects lacking functional DPP1 enzyme have been described to have periodontitis and palmoplantar hyperkeratosis.)

2. Subjects with total urinary protein/urine creatinine ratio outside the normal range.

3. Drugs affecting CYP3A4 should be refrained from use for 3 weeks prior to study commencement and thereafter until study completion.

In addition, the following is considered a criterion for the exclusion from the optional genetic component of the study:

1. History of bone marrow transplant

2. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

3. Hypersensitivity to the verapamil or to any of the excipients.

4. History of serious cardiac events such as myocardial infarction.

5. History of sino-atrial block; sick sinus syndrome; chronic or uncompensated heart failure (including left ventricular heart failure).

6. History of atrial flutter, atrial fibrillation or Wolff-Parkinson-White syndrome.

7. Known hypersensitivity to diltiazem or to any of the excipients.

8. Known hypersensitivity to itraconazole or to any of the excipients.

9. Elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	London		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Annelize Koch, MBChB, FFPM, Parexel

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02653872
• Other Study ID Numbers: D6190C00003
• First Posted: Jan 12, 2016
• Last Update Posted: Feb 23, 2018
• Last Verified: Jul 1, 2017

• Keywords provided by AstraZeneca: Non-randomized; Verapamil; Itraconazole; Diltiazem; Safety; Tolerability; Pharmacokinetics
• Additional relevant MeSH terms: Itraconazole; Verapamil; Diltiazem

Study Results

Participant Flow

Recruitment Details	This study was conducted at PAREXEL Early Phase Clinical Unit - London
Pre-assignment Detail	Fifteen healthy male subjects were enrolled in the study to assess the pharmacokinetics (PK) of AZD7986 when administered alone (Treatment Period 1) and in combination with multiple doses of verapamil (Treatment Period 2) and itraconazole (Treatment Period 3).

Arm/Group Title	All Participants
Arm/Group Description	All 15 participants who were enrolled in the study and who received at least a single dose of the study drug in three treatment periods in a fixed sequence and were separated by a washout period.
Period Title: Overall Study
STARTED	15
Treatment Period 1:	15
Treatment Period 2:	15
Treatment Period 3:	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All 15 participants who were enrolled in the study and who received at least a single dose of the study drug in three treatment periods in a fixed sequence and were separated by a washout period.
Overall Participants	15
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	33 (12)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	15 100%

Outcome Measures

1. Primary Outcome

Title	Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax).
Description	To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Geometric Mean (Geometric Coefficient of Variation) [nmol/L]	385.8 (27.4)	591.9 (27.1)	234.1 (39.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD7986, AZD7986 + Verapamil
	Comments	The study was designed based on a test for bioequivalence. Using an estimated standard deviation for Cmax of AZD7986 of less than or equal to 0.202, 12 evaluable subjects were deemed needed to achieve a power of 90%, at an assumed ratio of 0.95, to show that a two-sided 90% confidence interval for the ratio of Cmax between 2 treatments (AZD7986 and AZD7986+ Verapamil/Itraconazole) would be contained within the (0.8;1.25) equivalence limit. 3 extra subjects were added to compensate for dropout.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Geometric mean ratio of Cmax for AZD7986 administered with verapamil over Cmax for AZD7986 administered alone. Presented as a percentage.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Geometric Mean Ratio
	Estimated Value	153.40
	Confidence Interval	(2-Sided) 90%; 136.16 to 172.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AZD7986, AZD7986 + Itraconazole
	Comments	The study was designed based on a test for bioequivalence. Using an estimated standard deviation for Cmax of AZD7986 of less than or equal to 0.202, 12 evaluable subjects were deemed needed to achieve a power of 90%, at an assumed ratio of 0.95, to show that a two-sided 90% confidence interval for the ratio of Cmax between 2 treatments (AZD7986 and AZD7986+ Verapamil/Itraconazole) would be contained within the (0.8;1.25) equivalence limit. 3 extra subjects were added to compensate for dropout.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Geometric mean ratio of Cmax for AZD7986 administered with itraconazole over Cmax for AZD7986 administered alone. Presented as a percentage.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Geometric Mean Ratio
	Estimated Value	60.66
	Confidence Interval	(2-Sided) 90%; 53.84 to 68.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Effect of Verapamil and the Effect of Itraconazole on the PK of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC).
Description	To assess the effect of verapamil and itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L]	6697 (44.8)	8857 (43.3)	7615 (35.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD7986, AZD7986 + Verapamil
	Comments	The study was sized for Cmax primarily and not AUC. A two-sided 90% confidence interval for the ratio of AUC between the two treatments groups was used to determine equivalence.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Geometric mean ratio of AUC for AZD7986 administered with verapamil over AUC for AZD7986 administered alone. Presented as a percentage.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Geometric Mean Ratio
	Estimated Value	132.25
	Confidence Interval	(2-Sided) 90%; 121.78 to 143.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AZD7986, AZD7986 + Itraconazole
	Comments	The study was sized for Cmax primarily and not AUC. A two-sided 90% confidence interval for the ratio of AUC between the two treatments groups was used to determine equivalence.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Geometric mean ratio of AUC for AZD7986 administered with itraconazole over AUC for AZD7986 administered alone. Presented as a percentage.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Geometric Mean Ratio
	Estimated Value	113.70
	Confidence Interval	(2-Sided) 90%; 104.69 to 123.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Pharmacokinetics (PK) of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC [0-t]).
Description	To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L]	6545 (44.8)	8739 (43.5)	7361 (34.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AZD7986, AZD7986 + Verapamil
	Comments	The study was sized for Cmax primarily and not AUC (0-t). A two-sided 90% confidence interval for the ratio of AUC (0-t) between the two treatments groups was used to determine equivalence.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Geometric mean ratio of AUC (0-t) for AZD7986 administered with verapamil over AUC (0-t) for AZD7986 administered alone. Presented as a percentage.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Geometric Mean Ratio
	Estimated Value	133.51
	Confidence Interval	(2-Sided) 90%; 122.70 to 145.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	AZD7986, AZD7986 + Itraconazole
	Comments	The study was sized for Cmax primarily and not AUC (0-t). A two-sided 90% confidence interval for the ratio of AUC (0-t) between the two treatments groups was used to determine equivalence.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Geometric mean ratio of AUC (0-t) for AZD7986 administered with itraconazole over AUC (0-t) for AZD7986 administered alone. Presented as a percentage.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Geometric Mean Ratio
	Estimated Value	112.45
	Confidence Interval	(2-Sided) 90%; 103.34 to 122.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Pharmacokinetics (PK) of AZD7986 by Assessment of Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz).
Description	To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Mean (Standard Deviation) [hours]	23.35 (5.731)	20.36 (4.812)	27.89 (5.407)

5. Primary Outcome

Title	Pharmacokinetics (PK) of AZD7986 by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax)
Description	To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Median (Full Range) [hours]	0.75	1.50	1.50

6. Primary Outcome

Title	Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F).
Description	To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Mean (Standard Deviation) [L/h]	9.807 (5.267)	7.359 (3.765)	8.308 (3.452)

7. Primary Outcome

Title	Pharmacokinetics (PK) of AZD7986 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F).
Description	To assess the effect of Verapamil and Itraconazole on the PK of AZD7986.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	AZD7986	AZD7986 + Verapamil	AZD7986 + Itraconazole
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Mean (Standard Deviation) [Litres]	297.1 (83.48)	194.6 (41.68)	317.8 (89.06)

8. Primary Outcome

Title	Assessment of the Area Under the Plasma Concentration-curve Over the Dosing Interval (AUC [0 - τ]) of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole.
Description	To assess the area under the plasma concentration-time curve from time over the dosing interval tau (24 hours) of Verapamil, itraconazole and OH-itraconazole (a metabolite of Itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	Verapamil	Itraconazole	OH-itraconazole (a Metabolite of Itraconazole)
Arm/Group Description	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Geometric Mean (Geometric Coefficient of Variation) [h*nmol/L]	2178 (44.7)	18090 (22.6)	31390 (19.8)

9. Primary Outcome

Title	Assessment of the Tmax of Verapamil, Itraconazole and OH-itraconazole Following Co-administration of AZD7986 With Verapamil or Itraconazole.
Description	To assess the time to reach maximum observed concentration of Verapamil, Itraconazole and OH-itraconazole (a metabolite of itraconazole) following co-administration of AZD7986 with Verapamil or Itraconazole.
Time Frame	Period 1,2&3: Day1 (AZD7986),Day5 (AZD7986+Verapamil) & Day6 (AZD7986): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12,24,48,72,96,120 & 144 hours post-dose; Period 3: Day6 (Itraconazole): pre-dose,0.25,0.5,0.75,1,1.5,2,3,4,5,8,9,12 & 24 hours post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and for whom at least 1 of the primary PK parameters for AZD7986 could be calculated for at least 1 treatment period, and who had no major protocol deviations thought to impact on the analysis of the PK data.

Arm/Group Title	Verapamil	Itraconazole	OH-itraconazole (a Metabolite of Itraconazole)
Arm/Group Description	Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).	Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).
Measure Participants	15	15	15
Median (Full Range) [hours]	4.00	1.50	5.00

Adverse Events

Time Frame	Treatment Period 1: Day -1 up to 96 hours post-dose; Treatment Period 2: Day -1 up to morning of Day 9,; Treatment Period 3: Day -1 up to Day 10 (itraconazole).
Adverse Event Reporting Description	An AE is 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. AEs which met the "Definitions of Serious Adverse Event" defined in the clinical study protocol were regarded as SAEs.
Arm/Group Title	AZD7986		AZD7986 + Verapamil		AZD7986 + Itraconazole		Verapamil		Itraconazole		All Subjects
Arm/Group Description	Participants received a single dose of AZD7986 (25 mg) administration on Day 1 (1 hour before food).		Participants received Verapamil (240 mg; extended release formulation) administered daily (1 hour before food) on Days 1 to 10 plus administration of a single dose of AZD7986 (25 mg) on Day 5 (1 hour before food).		Participants received Itraconazole (200 mg; oral solution formulation 10 mg/mL) administered twice on Day 1 and then daily on Days 2 to 11 (1 hour before food) plus administration of AZD7986 (25 mg) as a single dose on Day 6 (1 hour before food).		Participants received Verapamil		Participants received Itraconazole.		Overall number of participants in the study.
All Cause Mortality
	AZD7986		AZD7986 + Verapamil		AZD7986 + Itraconazole		Verapamil		Itraconazole		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	AZD7986		AZD7986 + Verapamil		AZD7986 + Itraconazole		Verapamil		Itraconazole		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	AZD7986		AZD7986 + Verapamil		AZD7986 + Itraconazole		Verapamil		Itraconazole		All Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/15 (33.3%)		7/15 (46.7%)		5/15 (33.3%)		3/15 (20%)		6/15 (40%)		11/15 (73.3%)
Blood and lymphatic system disorders
Lymphadenopathy	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1
Ear and labyrinth disorders
Ear discomfort	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1
Gastrointestinal disorders
Abdominal pain	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1	3/15 (20%)	3
Diarrhoea	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	3/15 (20%)	3	3/15 (20%)	3
Abdominal discomfort	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1	3/15 (20%)	3
Constipation	0/15 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Gingival bleeding	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Mouth ulceration	1/15 (6.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	2/15 (13.3%)	2
Nausea	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Sensitivity of teeth	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
General disorders
Influenza like illness	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	2/15 (13.3%)	2
Fatigue	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Injection site pain	0/15 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Infections and infestations
Nasopharyngitis	0/15 (0%)	0	2/15 (13.3%)	2	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1	4/15 (26.7%)	4
Oral herpes	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Pharyngitis	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/15 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Myalgia	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1
Nervous system disorders
Headache	0/15 (0%)	0	5/15 (33.3%)	5	1/15 (6.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0	7/15 (46.7%)	7
Somnolence	0/15 (0%)	0	2/15 (13.3%)	2	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	2/15 (13.3%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1	3/15 (20%)	3
Oropharyngeal pain	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1	1/15 (6.7%)	1	3/15 (20%)	3
Throat irritation	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Dry skin	2/15 (13.3%)	2	3/15 (20%)	3	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1	7/15 (46.7%)	7
Dermatitis contact	0/15 (0%)	0	1/15 (6.7%)	1	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	2/15 (13.3%)	2
Hyperhidrosis	1/15 (6.7%)	1	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Hot flush	0/15 (0%)	0	0/15 (0%)	0	0/15 (0%)	0	1/15 (6.7%)	1	0/15 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

All of the study information and data collected during the study were considered confidential and the property of AstraZeneca. After completion of the study, the investigator should prepare a joint publication with AstraZeneca. The investigator must undertake not to submit any part of the individual data from this clinical study protocol for publication without prior consent of AstraZeneca at a mutually agreed time.