Study to Assess the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of AZD0284 in Healthy Subjects

NCT02976831 | Completed Phase 1 DMC

• 1 other identifier: D7800C00001
• Study Type: interventional
• Target: 83
• Locations: 1 country
• Sites: 1

Brief Summary

Plaque psoriasis vulgaris is a chronic inflammatory skin disorder, affecting 1-3% of the population in Europe and the United States of America (USA) and represents one of the most prevalent immune inflammatory diseases. AZD0284 is a potent selective inverse agonist of RORg, which is being developed for the management of psoriasis. The current Phase 1 study investigates the safety, tolerability, food effect, pharmacokinetic (PK) and pharmacodynamic (PD) properties of single and repeated doses of AZD0284. The study will be conducted in healthy subjects. The study will be divided into 2 parts: Part 1 (SAD) and Part 2 (MAD), with Part 1 being split into 2 sub-parts: 1A (fasting) and 1B (fed). The results from this study will form the basis for decisions on future studies. The study will help to identify appropriate, well-tolerated doses that can be administered in subsequent studies in patients with psoriasis.

Conditions

Plaque Psoriasis Vulgaris

Keywords

Plaque psoriasis vulgaris

Outcome Measures

Primary Outcomes (6)

• Safety and tolerability of AZD0284 following single dosing (Part 1) and multiple ascending oral dosing (Part 2) assessed by recording the number of adverse events.

  Standard adverse event collection. An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.

  From Screening till Visit 3 (5 to 7 days post final dose)

• Safety and tolerability of AZD0284 following single dosing (Part 1) and multiple ascending oral dosing (Part 2) assessed by recording the supine vital signs (BP [supine and standing], pulse and oral body temperature).

  The following variables will be collected after the subject has rested in the supine position for at least 5 minutes: * Systolic BP (mmHg) * Diastolic BP (mmHg) * Pulse (beats per minute \[bpm\]) * Oral body temperature

  From Screening till Visit 3 (5 to 7 days post final dose)

• Safety and tolerability of AZD0284 following single dosing (Part 1) and multiple ascending oral dosing (Part 2) assessed by electrocardiogram (ECG).

  A 12-lead ECG will be obtained after the subject rested in the supine position for at least 10 minutes (using the sites own ECG machines when not performing dECGs and using the same machine as the dECGs when time points coincide).

  From Screening till Visit 3 (5 to 7 days post final dose)

• Safety and tolerability of AZD0284 following single dosing (Part 1) and multiple ascending oral dosing (Part 2) assessed by digital ECG (dECG)

  From Screening till Visit 3 (5 to 7 days post final dose)

• Safety and tolerability of AZD0284 following single dosing (Part 1) and multiple ascending oral dosing (Part 2) assessed by telemetry

  From Screening till Visit 3 (5 to 7 days post final dose)

• Safety and tolerability of AZD0284 following single dosing (Part 1) and multiple ascending oral dosing (Part 2) by physical examination and laboratory assessments (hematology, clinical chemistry and urinalysis).

  The complete physical examinations will include an assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.

  From Screening till Visit 3 (5 to 7 days post final dose)

Secondary Outcomes (31)

• Pharmacokinetics: Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD0284.

  Part 1A and Part 1B: From Day 1 to Day 4 ( at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose).

• Effect of food on the bioavailability of AZD0284.

  From Day 1 till Follow up Visit (5 to 7 days post final dose)

• Presence and extent of renal clearance of AZD0284.

  Days 1,2, and 3

• Confirmation of Proof of Mechanism (PoM) of AZD0284.

  Screening, Day 1, Day 2 and Day 3

• Pharmacokinetics: Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD0284.

  Part 1A and Part 1B: From Day 1 to Day 4 ( at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose).

Study Arms (2)

AZD0284

EXPERIMENTAL

Part 1A: Following an overnight fast of at least 10 hours, each subject will receive a single dose of AZD0284 or matching placebo in the form of an oral solution with water. The total volume that the subject will receive (IMP and water) will be 240 mL. Part 1B (food cohort): Subjects, will receive a single dose of AZD0284 at a dose level in the range of or slightly above the dose level anticipated to yield therapeutic exposure, currently predicted to be achieved with 28 mg AZD0284 at twice daily dosing. The total volume that the subject will receive (IMP and water) will be 240 mL. Part 2: In Part 2, subjects will receive 1 dose level of AZD0284 (once or twice daily) with water from Day 1 to between (including) Day 7 and Day 14. The total volume that the subject will receive (IMP with water) will be 240 mL. Subjects may be dosed in either the fasted or fed state depending on emerging data from Part 1.

Drug: AZD0284

Placebo

ACTIVE COMPARATOR

Part 1A: Following an overnight fast of at least 10 hours, each subject will receive a single dose of placebo in the form of an oral solution with water. The first cohort will receive 4.0 mg AZD0284 or placebo on Day 1. The actual dose for subsequent cohorts will be determined after review of all available safety or other pertinent data from the previous dose by the SRC Part 1B (food cohort): In Part 1B, subjects, will receive a single dose of placebo at a dose level in the range of or slightly above the dose level anticipated to yield therapeutic exposure, currently predicted to be achieved with 28 mg AZD0284 at twice daily dosing. Part 2: In Part 2, each subject will receive 1 dose level of placebo (once or twice daily) with water from Day 1 to between (including) Day 7 and Day 14. The total volume that the subject will receive (placebo with water) will be 240 mL. Subjects may be dosed in either the fasted or fed state depending on emerging data from Part 1.

Drug: Placebo

Interventions

AZD0284 DRUG

Oral solution, concentration: 2 mg/mL and 15 mg/mL

AZD0284

Placebo DRUG

Placebo matching AZD0284 in the form of an oral solution with water.

Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and/or female subjects aged 18 to 50 years (inclusive) with suitable veins for cannulation or repeated venipuncture.
• 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 one of the following criteria.
• Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the post-menopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
• Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
• Hormone replacement therapy is not allowed for females to exclude any drug-drug interaction between the hormone replacement therapy and AZD0284

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the PI, 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 (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant illness, infection, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the PI.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
• Abnormal vital signs, after 10 minutes supine rest, defined as any of the following:
• Systolic BP (SBP) \< 90 mmHg or ≥ 140 mmHg
• Diastolic BP (DBP) \< 50 mmHg or ≥ 90 mmHg
• Pulse \< 45 or \> 85 beats per minute (bpm)
• Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12 Lead ECG as considered by the PI that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy. 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.
• PR(PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation)
• PR (PQ) interval prolongation (\> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
• 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
• Known or suspected history of drug abuse, as judged by the PI
• Current smokers or those who have smoked or used nicotine products within the previous 3 months.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

London, HA1 3UJ, United Kingdom

Location

MeSH Terms

Interventions

AZD-0284

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2016
• First Posted: November 29, 2016
• Study Start: December 9, 2016
• Primary Completion: May 30, 2017
• Study Completion: May 30, 2017
• Last Updated: June 14, 2017

Record last verified: 2017-06

Locations

GB (1)