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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
Results First Posted : July 18, 2019
Last Update Posted : August 28, 2019
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

Tracking Information
First Submitted Date  ICMJE October 17, 2017
First Posted Date  ICMJE October 20, 2017
Results First Submitted Date  ICMJE June 27, 2019
Results First Posted Date  ICMJE July 18, 2019
Last Update Posted Date August 28, 2019
Actual Study Start Date  ICMJE October 25, 2017
Actual Primary Completion Date July 19, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7 [ Time Frame: On Day -1 and Day 7 of each treatment period ]
    Change from baseline in peak UA excretion during the first 8 hours on Day 7 of treatment to assess the effects of intensive UA lowering therapy with verinurad, febuxostat and dapagliflozin. Urine sample was collected in hourly intervals, and the highest amount of UA excreted in any interval was designated as peak UA excretion for each patient and treatment period.
  • Change From Baseline in Plasma Concentration (Cmax) on Day 7 [ 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) ]
    Cmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
  • Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 [ 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) ]
    AUClast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
  • Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 [ 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) ]
    AUCτ assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Original Primary Outcome Measures  ICMJE
 (submitted: October 17, 2017)
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 concentration 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2019)
  • Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7 [ Time Frame: At Day -1 and Day 7 ]
    Change from baseline in sUA to assess the intensive UA lowering effect of RDEA3170, febuxostat and dapagliflozin by evaluating the sUA levels after 7 days of treatment.
  • Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 [ 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) ]
    tmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
  • Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 [ 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) ]
    tlast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Original Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2017)
  • Effects of RDEA3170, febuxostat and dapagliflozin on urinary excretion of serum uric acid (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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 weight as a measure of safety and tolerability. 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 criteria of safety and tolerability variables. Fasting samples, collected before breakfast (food) and before dose (when applicable).
  • 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.
  • 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]).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Assess the Effect of Intensive Uric Acid (UA) Lowering Therapy With RDEA3170, Febuxostat, Dapagliflozin on Urinary Excretion of UA
Official Title  ICMJE Quantifying Uric Acid Excretion With RDEA3170, Febuxostat and Dapagliflozin
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 (verinurad + febuxostat + dapagliflozin/placebo) and follow-up visit
Detailed Description

This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the effect of intensive UA lowering therapy with verinurad (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 verinurad, 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: Verinurad + febuxostat + dapagliflozin
  • Treatment B: Verinurad + 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Asymptomatic Hyperuricemia
Intervention  ICMJE
  • Drug: Verinurad
    Randomized patients will receive orally once daily fixed dose of verinurad in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo
    Other Name: RDEA3170
  • 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: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + 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: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo
    Other Name: FARXIGA
  • 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: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo
Study Arms  ICMJE
  • Experimental: Treatment A

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

    verinurad + febuxostat + dapagliflozin;

    Interventions:
    • Drug: Verinurad
    • Drug: Febuxostat
    • Drug: Dapagliflozin
  • Experimental: Treatment B

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

    verinurad + febuxostat + dapagliflozin matched placebo

    Interventions:
    • Drug: Verinurad
    • Drug: Febuxostat
    • Other: Dapagliflozin matched placebo
Publications * Stack AG, Han D, Goldwater R, Johansson S, Dronamraju N, Oscarsson J, Johnsson E, Parkinson J, Erlandsson F. Dapagliflozin Added to Verinurad Plus Febuxostat Further Reduces Serum Uric Acid in Hyperuricemia: The QUARTZ Study. J Clin Endocrinol Metab. 2020 Oct 19. pii: dgaa748. doi: 10.1210/clinem/dgaa748. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 1, 2018)
36
Original Estimated Enrollment  ICMJE
 (submitted: October 17, 2017)
24
Actual Study Completion Date  ICMJE July 19, 2018
Actual Primary Completion Date July 19, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03316131
Other Study ID Numbers  ICMJE D5495C00001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE
  • 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
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP