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A Study to Assess the Effect of Intensive Uric Acid (UA) Lowering Therapy With RDEA3170, Febuxostat, Dapagliflozin on Urinary Excretion of UA

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ClinicalTrials.gov Identifier: NCT03316131
Recruitment Status : Completed
First Posted : October 20, 2017
Last Update Posted : July 31, 2018
Sponsor:
Collaborators:
Contract Research Organization: USA
PAREXEL Early Phase Clinical Unit Baltimore
PAREXEL Early Phase Clinical Unit-Los Angeles
Clinical Laboratory: USA
Harbor Hospital Laboratory
GenX Laboratories Inc.
Analytical Laboratory (Pharmacokinetic Sample Analysis): USA
Covance Bioanalytical Services, LLC
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
This is a randomized, placebo controlled, double-blind, 2-way crossover study conducted on asymptomatic hyperuricemic patients. The core study consists of screening period, 2 treatment periods (RDEA3170 + febuxostat + dapagliflozin/placebo) and follow-up visit

Condition or disease Intervention/treatment Phase
Asymptomatic Hyperuricemia Drug: RDEA3170 Drug: Febuxostat Drug: Dapagliflozin Other: Dapagliflozin matched placebo Phase 2

Detailed Description:

This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the effect of intensive UA lowering therapy with RDEA3170, febuxostat, and dapagliflozin on urinary excretion of UA, in asymptomatic hyperuricemic patients. Thirty-six asymptomatic hyperuricemic patients aged 18 to 65 years (inclusive) will be enrolled into this study at 2 study centers. Twenty-four patients have been enrolled and completed the study to date. Due to inadequate urine sampling, 12 additional patients were included to ensure an adequate sample size (at least 20 evaluable patients) to evaluate the effects of intensive UA lowering with RDEA3170, febuxostat and dapagliflozin on urinary excretion of UA. With 24 completers available during the interim analysis, this will provide for a total sample size of 36 evaluable patients.

Before any study specific assessments are performed, potential patients must provide informed consent. Each patient will undergo the below mentioned visits:

  • A Screening period of maximum 28 days;
  • Two treatment periods during which patients will be resident in the Clinical Unit from Day -2 to Day 1 and from Day 6 to Day 8; and
  • A Follow-up Visit within 14 to 28 days after the first administration of Investigational Medicinal Product (IMP) in Treatment Period 2.

On Day -2 of Treatment period 1, patient will be randomized (1:1) to 1 of 2 treatment sequences (AB or BA). Each randomized patient will receive orally once daily fixed dose of the below mentioned 2 treatments for 7 consecutive days (1 treatment per treatment period).

  • Treatment A: RDEA3170 + febuxostat + dapagliflozin
  • Treatment B: RDEA3170 + febuxostat + placebo For each treatment period, baseline measurements will be performed. On Day 1, after all dosing and all assessments have been performed, patients will receive instruction to administer the IMP at home once daily in the morning from Day 2 to Day 6 and the IMP will be dispensed for home dosing. Patients will return to the Clinical Unit on Day 6 and will be residential in the Clinical Unit from Day 6 to Day 8.

Treatment Period 1 and Treatment Period 2 will be separated by a washout period of 7 to 21 days.

Patients will return to the Clinical Unit for a Follow-up Visit, 14 to 28 days after Day 1 of Treatment Period 2.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Masking Description: The pharmacokineticist will remain blinded during the study conduct, unless otherwise required based on study findings. The pharmacokineticist will be unblinded to perform the final PK analyses after all patients have completed the study, final bioanalytical results are available and all required study data are considered clean. This may occur before database lock.
Primary Purpose: Treatment
Official Title: Quantifying Uric Acid Excretion With RDEA3170, Febuxostat and Dapagliflozin
Actual Study Start Date : October 25, 2017
Actual Primary Completion Date : July 19, 2018
Actual Study Completion Date : July 19, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment A

Randomized patients will receive orally once daily fixed dose of the following drugs:

RDEA3170 + febuxostat + dapagliflozin;

Drug: RDEA3170
Randomized patients will receive orally once daily fixed dose of RDEA3170 in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: RDEA3170 + febuxostat + dapagliflozin; Treatment B: RDEA3170 + febuxostat + placebo
Other Name: Verinurad

Drug: Febuxostat
Randomized patients will receive orally once daily fixed dose of febuxostat in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: RDEA3170 + febuxostat + dapagliflozin; Treatment B: RDEA3170 + febuxostat + placebo
Other Name: ULORIC

Drug: Dapagliflozin
Randomized patients will receive orally once daily fixed dose of dapagliflozin in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: RDEA3170 + febuxostat + dapagliflozin; Treatment B: RDEA3170 + febuxostat + placebo
Other Name: FARXIGA

Experimental: Treatment B

Randomized patients will receive orally once daily fixed dose of the following drugs:

RDEA3170 + febuxostat + dapagliflozin matched placebo

Drug: RDEA3170
Randomized patients will receive orally once daily fixed dose of RDEA3170 in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: RDEA3170 + febuxostat + dapagliflozin; Treatment B: RDEA3170 + febuxostat + placebo
Other Name: Verinurad

Drug: Febuxostat
Randomized patients will receive orally once daily fixed dose of febuxostat in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: RDEA3170 + febuxostat + dapagliflozin; Treatment B: RDEA3170 + febuxostat + placebo
Other Name: ULORIC

Other: Dapagliflozin matched placebo
Randomized patients will receive orally once daily fixed dose of dapagliflozin matched placebo in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: RDEA3170 + febuxostat + dapagliflozin; Treatment B: RDEA3170 + febuxostat + placebo




Primary Outcome Measures :
  1. Effect of RDEA3170, febuxostat and dapagliflozin on urinary excretion of uric acid (UA) on Day 7 [ Time Frame: On Treatment Period 1 and 2: Day -1 and Day 7 ]

    To assess the difference in within-subject change from baseline in peak UA excretion during the first 8 hours (maximum UA excreted as measured in milligram [mg], in an interval out of the first 8 hours) on Day 7 of treatment (Day 1 is the first day of treatment).

    On Day -1: Hourly baseline collection of urine from -24 to -12 hours followed by a single 12-hour collection from -12 to 0 hours (0 hours is time of dosing on Day 1) On Day 7: Directly after the dose of study treatment, hourly collection of urine is performed every hour from 0 to 12 hours (inclusive) followed by a single pooled collection from 12 to 24 hours.



Secondary Outcome Measures :
  1. Effects of RDEA3170, febuxostat and dapagliflozin on urinary excretion of serum UA (sUA) after 7 days of treatment [ Time Frame: At screening and Treatment Period 1 and 2: Day -1 and Day 7 ]
    To assess the intensive UA lowering effect of RDEA3170, febuxostat and dapagliflozin by evaluating the sUA levels after 7 days of treatment. At screening: One sUA assessment At treatment period: Always in the morning, and after a 10 hour overnight fast.

  2. Area under plasma concentration time curve over a dosing interval (24 hours) (AUCτ) assessment for RDEA3170 and its main metabolites (M1 and M8) febuxostat and dapagliflozin [ Time Frame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose) ]
    To assess AUCτ after administration of single oral fixed dose of RDEA3170 + febuxostat + dapagliflozin/placebo

  3. Maximum observed plasma concentration (Cmax) assessment for RDEA3170 and its main metabolites (M1 and M8) febuxostat and dapagliflozin [ Time Frame: On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose) ]
    To assess Cmax after administration of single oral dose of RDEA3170 + febuxostat + dapagliflozin/placebo

  4. Number of participants with adverse events (AEs) due to RDEA3170, febuxostat and dapagliflozin [ Time Frame: At screening (Day -28), Treatment Period 1 (Day -2), Treatment Periods 1 & 2 (Days -1, 1, 6, 7 and 8) and follow-up visit/early discontinuation visit (EDV) (Day 23) ]
    To assess the renal and general safety and tolerability of intensive UA lowering therapy with RDEA3170, febuxostat and dapagliflozin. AEs will be collected from the start of screening throughout the treatment period up to and including the Follow-up Visit. Serious adverse events will be recorded from the time of informed consent.

  5. Systolic blood pressure [SBP] [ Time Frame: At screening (Day -28), Treatment Period 1 & 2 (Days -1 and 7) and follow-up visit/EDV (Day 23) ]
    To assess SBP as a measure of safety and tolerability.

  6. Diastolic blood pressure [DBP] [ Time Frame: At screening (Day -28), Treatment Period 1 & 2 (Days -1 and 7) and follow-up visit/EDV (Day 23) ]
    To assess DBP as a measure of safety and tolerability.

  7. Pulse rate [ Time Frame: At screening (Day -28), Treatment Period 1 & 2 (Days -1 and 7) and follow-up visit/EDV (Day 23) ]
    To assess pulse as a measure of safety and tolerability.

  8. Laboratory assessments of Hematology [ Time Frame: At screening (day -28), Treatment Period 1 (Days -2, -1 (only FPG) & 7), Treatment Period 2 (Days -1, 1 (only FPG) & 7) and follow-up visit/EDV (Day 23) ]
    To assess the hematology - blood cells count [white blood cell (WBC), red blood cell (RBC), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC)], differential absolute count (neutrophils, lymphocytes, eosinophils, basophils, platelets and reticulocytes), hemoglobin (Hb) count and hemoglobin A1c (HbA1c, at screening Visit only) as a measure of safety and tolerability variables. Fasting samples, collected before breakfast (food) and before dose (when applicable).

  9. Laboratory assessments of Clinical chemistry [ Time Frame: At screening (day -28), Treatment Period 1 (Days -2, -1 (only FPG) & 7), Treatment Period 2 (Days -1, 1 (only FPG) & 7) and follow-up visit/EDV (Day 23) ]
    To assess the clinical chemistry (sodium, potassium, blood urea nitrogen (BUN), creatinine, albumin, calcium, phosphate, UA, liver enzymes, total and unconjugated bilirubin; cystatin-C and estimated glomerular filtration rate (eGFR) (glucose - fasting, done at screening only) as a measure of safety and tolerability.

  10. Laboratory assessments of urinalysis [ Time Frame: At screening (Day -28) and follow-up/EDV (Day 23) ]
    To assess the urinalysis (glucose, protein, blood, UA, sodium, pH, creatinine and cystatin-C) as a measure of safety and tolerability variables. If urinalysis is positive for protein or blood, a microscopy test will be performed to assess RBC, WBC, casts [cellular, granular, hyaline]).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18 to 65 years old
  2. Asymptomatic hyperuricemia (sUA > 6.0 mg/dL)
  3. Body mass index between 18 and 35 kg/m2 inclusive and weight at least 50 kg and no more than 150 kg
  4. Females must be non-pregnant, as well as post-menopausal or willing to use an acceptable method of contraception during the study.

Exclusion Criteria:

  1. History of any clinically significant disease or disorder putting the patient at risk during the study, or influencing study results or ability to participate in the study
  2. eGFR* < 45 mL/minute/1.73 m2 at Screening.
  3. Type 2 diabetes mellitus with HbA1c >8%.
  4. History of diabetic ketoacidosis, hyperosmolar non-ketotic coma, gout, or alcohol or drug abuse.
  5. Ongoing treatment with an SGLT2-inhibitor, a URAT1-inhibitor, and/or a xanthine oxidase inhibitor.
  6. Positive test for hepatitis B, hepatitis C or HIV.
  7. Use of any medications in the 2 weeks preceding first administration of study drug.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03316131


Locations
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United States, California
Research Site
Glendale, California, United States, 91206
United States, Maryland
Research Site
Baltimore, Maryland, United States, 21225
Sponsors and Collaborators
AstraZeneca
Contract Research Organization: USA
PAREXEL Early Phase Clinical Unit Baltimore
PAREXEL Early Phase Clinical Unit-Los Angeles
Clinical Laboratory: USA
Harbor Hospital Laboratory
GenX Laboratories Inc.
Analytical Laboratory (Pharmacokinetic Sample Analysis): USA
Covance Bioanalytical Services, LLC

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03316131     History of Changes
Other Study ID Numbers: D5495C00001
First Posted: October 20, 2017    Key Record Dates
Last Update Posted: July 31, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
Gout
Uric acid
Hyperuricemia
Asymptomatic gout
Febuxostat
Dapagliflozin
Uric acid transporter 1 (URAT1) Inhibitor
Xanthine Oxidase Inhibitor
Sodium-glucose cotransporter 2 (SGLT2) Inhibitor

Additional relevant MeSH terms:
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Febuxostat
Hyperuricemia
Pathologic Processes
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Uric Acid
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs
Gout Suppressants
Antirheumatic Agents
Antioxidants
Protective Agents