Clinical trial NCT02303574: Single + Multiple Ascending Dose and Food Effect Study of AZD7986 in Healthy Volunteers, PK, PD and Safety Study
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Safety, Pharmacokinetics, Pharmacodynamics, Food Effect
Keywords: AZD7986, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Food Effect, First-in-human, Single Ascending Dose, Multiple Ascending Dose, Healthy Subjects
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-12-01
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: 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
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD
timeFrame: 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
measure: Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD
timeFrame: 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
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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 outcomes:
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Effect of Food on Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Effect of Food on Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Effect of Food on Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Effect of Food on Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Effect of Food on Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Effect of Food on Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD
timeFrame: 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)
measure: Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2
timeFrame: 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
measure: Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2
timeFrame: At Day 12 (pre-dose, 6 hours and 12 hours)
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: Research Site
Study officials:
affiliation: PAREXEL Early Phase Clinical Unit, Level 7, Northwick Park Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, United Kingdom
name: Annelize Koch, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: AstraZeneca
name: Bengt Larsson
role: STUDY_CHAIR
References: