Single + Multiple Ascending Dose and Food Effect Study of AZD7986 in Healthy Volunteers, PK, PD and Safety Study

A PHASE I, RANDOMISED, SINGLE-BLIND, PLACEBO-CONTROLLED, 2-PART STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS AND FOOD EFFECT OF SINGLE AND MULTIPLE ORAL DOSES OF AZD7986 IN HEALTHY VOLUNTEERS.

This is a phase I, randomised, single-blind placebo-controlled, 2-part study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of single and multiple oral doses of AZD7986 in healthy volunteers

Study Overview

• Status: Completed
• Conditions: Safety, Pharmacokinetics, Pharmacodynamics, Food Effect
• Intervention / Treatment: Drug: AZD7986, oral solution, 1 to 50 mg/mL; Drug: Placebo, oral solution

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Harrow, United Kingdom, HA1 3UJ
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of signed and dated written informed consent prior to any study specific procedures.
2. Healthy male or female subjects aged 18 to 50 years (inclusive) at screening with suitable veins for cannulation or repeated venepuncture.

3. Females must be of non-child-bearing potential, confirmed at screening by fulfilling one of the following criteria:

   • Post-menopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in the post menopausal range.
   • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

4. Male subjects must be non fertile, i.e., surgically sterilised with documentation of azoospermia or must practice an effective contraceptive method to prevent pregnancies. Effective contraceptive methods are:

   • Sexual abstinence from before the first administration of the IMP until 3 months after final administration of the IMP, only if this is in line with the preferred and usual lifestyle of the subject.
   • Use of a condom plus spermicide agent in addition to having their partner use another acceptable method (oral or injectable hormonal contraceptives, contraceptive patch, intrauterine devices, vaginal hormonal rings, vaginal diaphragm or cervical caps) from before the first administration of the IMP until 3 months after final administration of the IMP.
   • Subject's sexual partner is of non childbearing potential, i.e., post menopausal or surgically sterilised (e.g., tubal ligation, hysterectomy in medical history).
5. Have a body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive at screening.

Exclusion Criteria:

• 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.
• History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.

• 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
  • 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.
  • Volunteers with active malignancy or neoplastic disease in the previous 5 years other than superficial basal cell carcinoma.
  • Disease history suggesting abnormal immune function.
  • Volunteers 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.

• Some subjects lacking functional dipeptidyl peptidase 1 (DPP1) enzyme have been described to have periodontitis and palmoplantar hyperkeratosis:

  • For Part 1a and Part 1b: Subjects with signs of current gingivitis/periodontitis. Gingival evaluation (by inspection) will be performed by a dental hygienist or trained study physician.
  • For Part 2: Subjects with a history of recurring gingivitis/periodontitis or signs of current gingivitis/periodontitis. Gingival evaluation will be performed by a dental hygienist or trained study physician. Evaluation of bleeding propensity due to gingivitis will be performed by using dental hygienist instrumentation. Exact measurement of gum pockets is not needed.
  • Subjects with a history of hyperkeratosis or erythema in palms or soles.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AZD7986, single and mulltiple doses; In Part 1 up to 8 cohorts with single doses starting with 5 mg AZD7986 as oral solution. In Part 2 up to 5 cohorts with multiple doses of AZD7986 as oral solution	Drug: AZD7986, oral solution, 1 to 50 mg/mL; Starting dose in single ascending dose part: 5 mg
PLACEBO_COMPARATOR: Placebo, single and multiple doses; In Part 1 up to 8 cohorts and in Part 2 up to 5 cohorts with matching placebo to AZD7986 as oral solution	Drug: Placebo, oral solution; Matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2)	To investigate the safety and tolerability of AZD7986 by assessment of AEs (non-serious and serious) following administration of oral solution in SAD (Part 1a - fasted state and 1b - fed state) and MAD (Part 2)	Part 1a and 1b: Day -1, Day 1 to Day 3 (spontaneous, at pre-dose, 3, 12, 24, 48 and 72 hours [h] post-dose), Day 4, Day 5 and follow-up (7-10 days after dosing [not for participants included in Part 1b]); Part 2: Day -1, Day 1 to Day 21/28 and follow-up
Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD	To assess the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) for Part 1a (fasted state) and 1b (fed state) - SAD	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD	To assess the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD	To assess the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) for Part 1a (fasted state) and 1b (fed state) - SAD. AUC was estimated by AUC(0 last) + Clast/λz where Clast was the last observed quantifiable concentration.	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD	To assess the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. Note: Day 1 data calculated over a 24 hour period and was therefore not comparable with the Day 21 and Day 28 data	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD	To assess area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCτ) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. AUCτ: AUC from time zero to 24 hours post-dose presented on Day1	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD	To assess the observed maximum plasma concentration (Cmax) for Part 1a (fasted state) and 1b (fed state) - SAD. Cmax was taken directly from the individual concentration-time curve	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD	To assessthe observed maximum plasma concentration (Cmax) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. Cmax was taken directly from the individual concentration-time curve	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD	To assess the time to reach maximum observed concentration (tmax) for Part 1a (fasted state) and 1b (fed state) - SAD; tmax was taken directly from the individual concentration-time curve	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD	To assess the time to reach maximum observed concentration (tmax) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; tmax was taken directly from the individual concentration-time curve	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD	To assess the half life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½.λz) for Part 1a (fasted state) and 1b (fed state) - SAD	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD	To assess the apparent terminal elimination half-life (t½.λz) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; tmax was taken directly from the individual concentration-time curve. Note: Day 1 data were calculated over a 24 hour period and was therefore not comparable with the Day 21 and Day 28 data	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD	To assess the mean residence time (MRT) for Part 1a (fasted state) and 1b (fed state) - SAD	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD	To assess the mean residence time (MRT) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD	To assess the apparent clearance (CL/F) for Part 1a (fasted state) and 1b (fed state) - SAD; CL/F for parent drug was estimated as dose divided by AUC	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD	To assess the apparent clearance (CL/F) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; CL/F for parent drug was estimated as dose divided by AUC	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD	To assess the apparent volume of distribution (Vz/F) for Part 1a (fasted state) and 1b (fed state) - SAD; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD	To assess the the apparent volume of distribution (Vz/F) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD	To assess the accumulation ratio for (Rac(AUC(0-τ)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as AUC(0-τ) Day 21/AUC(0-24) Day 1	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD	To assess the accumulation ratio for Cmax (Rac(Cmax)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as Cmax Day 21/Cmax Day 1	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD	To assess the temporal change parameter (TCP) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as AUC(0-τ) Day 21/AUC Day 1, if extrapolated part was less than 20%	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD	To assess cumulative amount of analyte excreted from 0 to 48 hours (CumAe0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state)	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD	To assess percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state)	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD	To assess renal clearance from 0 to 48 hours (CLR0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state)	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD	To assess cumulative amount of analyte excreted from 0 to 24 hours (CumAe0-24) for Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD	To assess percentage of dose excreted unchanged into the urine from 0 to 24 hours (Cumfe0 24) for Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD	To assess renal clearance from 0 to 24 hours (CLR0-24) for Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD	To assess Cumulative amount of analyte excreted from 0 to 48 hours (CumAe0-48)) for Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD	To assess Percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0 48) for Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD	To assess Percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0 48) for Part 2	Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Food on Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) for Part 1a (fasted state) and 1b (fed state) - SAD	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) for Part 1a (fasted state) and 1b (fed state) - SAD. AUC was estimated by AUC(0 last) + Clast/λz where Clast was the last observed quantifiable concentration.	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the observed maximum plasma concentration (Cmax) for Part 1a (fasted state) and 1b (fed state) - SAD. Cmax was taken directly from the individual concentration-time curve	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the time to reach maximum observed concentration (tmax) for Part 1a (fasted state) and 1b (fed state) - SAD; tmax was taken directly from the individual concentration-time curve	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the half life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½.λz) for Part 1a (fasted state) and 1b (fed state) - SAD	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the mean residence time (MRT) for Part 1a (fasted state) and 1b (fed state) - SAD	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the apparent clearance (CL/F) for Part 1a (fasted state) and 1b (fed state) - SAD; CL/F for parent drug was estimated as dose divided by AUC	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Effect of Food on Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD	To assess the effect of food by evaluating the apparent volume of distribution (Vz/F) for Part 1a (fasted state) and 1b (fed state) - SAD; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz	At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2	Absolute neutrophil count (ANC) was evaluated as part of the safety laboratory assessments and to evaluate the pharmacodynamics (PD) marker	At Day 16, 21 ((last dosing day in Cohort 1), 25, 28 (last sampling day in Cohort 1 and last dosing day in Cohorts 2 and 3), 32, 38, 41 and 52
Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2	Absolute neutrophil count (ANC) was evaluated as part of the safety laboratory assessments and to evaluate the pharmacodynamics (PD) marker	At Day 12 (pre-dose, 6 hours and 12 hours)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Annelize Koch, Dr, PAREXEL Early Phase Clinical Unit, Level 7, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, United Kingdom; Study Chair: Bengt Larsson, AstraZeneca

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 3, 2014
• Primary Completion (ACTUAL): August 3, 2016
• Study Completion (ACTUAL): August 3, 2016

Study Registration Dates

• First Submitted: November 3, 2014
• First Submitted That Met QC Criteria: November 25, 2014
• First Posted (ESTIMATE): December 1, 2014

Study Record Updates

• Last Update Posted (ACTUAL): December 11, 2018
• Last Update Submitted That Met QC Criteria: December 10, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: AZD7986, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Food Effect, First-in-human, Single Ascending Dose, Multiple Ascending Dose, Healthy Subjects
• Additional Relevant MeSH Terms: Pharmaceutical Solutions
• Other Study ID Numbers: D6190C00001; 2014-004043-13 (EUDRACT_NUMBER)