Clinical trial NCT03836599: A Study to Assess the Safety and Pharmacokinetics of Verinurad and Allopurinol in Asian and Chinese Subjects
Official title: A Phase I Randomized Double-blind Placebo-controlled Study With 2 Separate Cohorts to Assess the Safety, Tolerability and Pharmacokinetics of Verinurad and Allopurinol in Healthy Asian and Chinese Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Kidney Disease
Keywords: Uric acid transporter 1 (URAT1) Inhibitor
Xantine oxidoreductase inhibitor
Pharmacokinetics
Verinurad
Allopurinol
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2019-02-11
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, placebo controlled, double-blind study with two separate cohorts to assess safety, tolerability and pharmacokinetics of verinurad and allopurinol in healthy subjects.

In cohort 1, twelve Asian subjects will be treated with allopurinol 300mg for 7 days followed by either allopurinol 300mg and verinurad 24mg or matching placebo for 7 days.

In Cohort 2, nine Chinese subjects will be treated with allopurinol 300mg for 7 days followed by allopurinol 300mg and verinurad 12mg administered on 7 out of 8 days.

Detailed description: This is a Phase I study with 2 parallel cohorts which will be performed at a single study center.

Cohort-1 will comprise of 12 healthy Asian participants, and will follow a randomized, double-blind, placebo-controlled design. The number of Chinese participants included in Cohort 1 must be less than 50% of the total number of participants enrolled into the cohort. Nine participants will be randomized to receive 24 mg verinurad and 300 mg allopurinol once daily for 7 days and 3 participants will be randomized to receive matching placebos once daily for 7 days. Cohort 1 participants will undergo a Screening Period of a maximum of 28 days followed by a 7-day Run-in Period during which participants will receive 300 mg allopurinol or matching placebo once daily. Participants will then be randomized before the start of the Run-in Period. The Run-in Period is intended to decrease the risk of skin toxicity of allopurinol. Participants will be admitted to the clinical unit 2-days before the treatment period, during which they will receive once daily doses of 24 mg verinurad and 300 mg allopurinol or matching placebos. Participants will be discharged from the clinical unit on Day 8, but will return for a Follow-up Visit within 7 to 14 days.

Cohort-2 will comprise of 9 healthy Chinese participants and will follow an open-label design. All 9 Chinese participants will receive 12 mg verinurad and 300 mg allopurinol on Day 1 and Day 3 to Day 9. For Cohort-2, participants will undergo a Screening Period of a maximum of 28 days followed by a 7-day Run-in Period during which participants will receive 300 mg allopurinol once daily. Participants will be admitted to the Clinical Unit on Day -2, and will receive a single dose of 12 mg verinurad and 300 mg allopurinol on Day 1. No dosing will be done on Day 2. Participants will continue dosing on Day 3 and will be dosed once daily until Day 9. Participants will be discharged from the Clinical Unit on Day 10, but will return for a Follow-up Visit within 7 to 14 days.

Eligibility criteria: Inclusion Criteria:

* Provision of signed and dated, written informed consent prior to any study specific procedures.
* Applicable only to Cohort 1: Healthy male and female Asian subjects aged 18 to 50 years (inclusive) at the Screening Visit with suitable veins for cannulation or repeated venipuncture. A subject will be considered Asian if the subject and both of the subject's parents are part of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam).
* Applicable only to Cohort 2: Healthy male and female Chinese subjects aged 18 to 50 years (inclusive) at the Screening Visit with suitable veins for cannulation or repeated venipuncture. A subject will be considered Chinese if:

  * Both parents and all grandparents are Chinese, and
  * Subject was born in China, and
  * Subject has not lived outside China for more than 10 years.
* Subject has a sUA acid level \> 4.0 mg/dL at the Screening Visit. The assessment may be repeated once during the Screening Period.
* Females must have a negative pregnancy test at the Screening Visit and Day -7, must not be lactating and must be:

  1. Of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria:

     * Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and Follicle-stimulating hormone (FSH) levels in the post-menopausal range (FSH levels \> 40 IU/mL).
     * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  2. OR if of childbearing potential must be willing to use an acceptable method of contraception to avoid pregnancy for the entire study period.

Exclusion Criteria:

* Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at the Screening Visit as judged by the Investigator including:

  1. Alanine aminotransferase (ALT) \>1.5 x upper limit of normal (ULN);
  2. Aspartate aminotransferase (AST) \>1.5 x ULN;
  3. Bilirubin (total) \> 1.5 x ULN; and
  4. Gamma glutamyl transpeptidase (GGT) \>1.5 x ULN. If any these tests are out-of-range the test can be repeated once at the Screening Visit at the discretion of the Investigator.
* Known carrier of the Human Leukocyte Antigen-B (HLA-B) \*58:01 allele.
* Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody.
* Suspected or known Gilbert's syndrome.
* Current smokers or those who have smoked or used nicotine products (including e-cigarettes within the previous 3 months).
* Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at the Screening Visit or on Day -7.
* Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of investigational product or within 5 half-lives (whichever is longer). The use of hormonal contraception therapy and hormonal replacement therapy for females are permitted.
* Has received another new chemical or biological entity (defined as a compound which has not been approved for marketing in the US) within 30 days or within 5 half-lives (whichever is longer) of the first administration of investigational drug in this study.
* Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.
* Subjects who are vegans or have medical dietary restrictions.

Primary outcomes:
measure: Number of participants with adverse events
timeFrame: From screening up to Follow-up visit/Early discontinuation visit (EDV) (7-14 Days Post-last PK Sample)
measure: Number of participants with abnormal findings in electrocardiography (ECG)
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
measure: Number of participants with abnormal pulse rate
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
measure: Number of participants with abnormal hematology
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
measure: Number of participants with abnormal blood pressure (systolic and diastolic)
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)]
measure: Number of participants with abnormal physical examination
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK sample)]
measure: Number of participants with abnormal electrolytes
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK smaple)]
measure: Number of participants with abnormal hemoglobin (Hb)
timeFrame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
measure: Number of participants with abnormal hematocrit
timeFrame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
measure: Number of participants with abnormal Mean corpuscular volume (MCV)
timeFrame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
measure: Number of participants with abnormal mean corpuscular hemoglobin (MCH)
timeFrame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
measure: Number of participants with abnormal mean corpuscular hemoglobin concentration (MCHC)
timeFrame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
measure: Number of participants with abnormal clinical chemistry
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
measure: Number of participants with abnormal urinalysis.
timeFrame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
Secondary outcomes:
measure: Area under plasma concentration-time curve from zero to infinity (AUC), AUC(0-t), AUC(0-24), and AUCτ
timeFrame: On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2).
measure: Observed concentration and percentage change from baseline in serum uric acid
timeFrame: On Day -1: -24, -21, -18, and -12 hours prior to dosing on Day 1. On Days 1, 7 and 9 (Pre-dose, 3, 6, 12, and 24 hours post-dose).
measure: Observed concentration and percentage change from baseline in urine uric acid
timeFrame: On Day -1: baseline collection of urine: -24 to -22 h, -22 h to -20 h, -18 h to -16 h, -16 h to - 12 h and -12 h to 0 h prior to dosing on Day 1, on Days 1, 7 and 9 (0-2 h, 2-4 h, 4-6 h, 6-8 h, 8-12 h, and 12-24 h post-dose).
measure: Maximum observed plasma concentration (Cmax) and Minimum observed plasma concentration (Cmin)
timeFrame: On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
measure: Time to reach maximum observed plasma concentration (tmax) and Time of last measurable concentration (tlast)
timeFrame: On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2).
measure: Apparent total body clearance of drug from plasma after extravascular administration across the dosing interval (CL/F)
timeFrame: On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
timeFrame: On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
measure: Apparent volume of distribution based on the terminal phase (Vz/F) and Apparent volume of distribution during the terminal phase after extravascular administration (Vss/F)
timeFrame: On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
measure: Mean residence time (MRT)
timeFrame: On Day 1
measure: Accumulation ratio for Cmax and AUCτ
timeFrame: On Day 7 (Cohort 1) or Day 9 (Cohort 2)
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Research Site
state: California
Study officials:
affiliation: Parexel
name: David Han, MD
role: PRINCIPAL_INVESTIGATOR
References: