Asymptomatic Hyperuricemia
Conditions
Keywords
Gout, Uric acid, Hyperuricemia, Asymptomatic gout, Febuxostat, Dapagliflozin, Uric acid transporter 1 (URAT1) Inhibitor, Xanthine Oxidase Inhibitor, Sodium-glucose cotransporter 2 (SGLT2) Inhibitor
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.
Interventions
DRUGVerinurad
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
DRUGFebuxostat
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
DRUGDapagliflozin
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
OTHERDapagliflozin 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
Sponsors
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
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7 | 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 | 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 | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | 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 | 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 |
| Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7 | 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. |
Countries
United States
Participant flow
Recruitment details
The trial was conducted at two study centres: Baltimore and Los Angeles. The date of the first subject visit was 25 Oct 2017 and the date of the last subject last visit was 19 Jul 2018. A total of 36 adults asymptomatic hyperuricemic patients were included into this study.
Pre-assignment details
Patients who provided informed consent underwent screening procedures within the 28 days. Patients returned to the Clinical Unit on Day -2 of Treatment Period 1 and were randomized (1:1) to two treatment sequences ( treatment AB or BA).
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin/placebo. Each patient randomized to treatment A in period 1 received Treatment B in period 2 and each patient randomized to treatment B in period 1 received Treatment A in period 2 | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 2 | Protocol deviation | 1 | 0 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 12.01 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 36 |
| other Total, other adverse events | 7 / 35 | 5 / 36 |
| serious Total, serious adverse events | 0 / 35 | 0 / 36 |
Outcome results
Primary
Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7
AUClast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without 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)
Population: Pharmacokinetic Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | Verinurad | 149.1 h∙ng/mL | Geometric Coefficient of Variation 37.79 |
| Treatment Sequence A+B | Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | M1 | 212.7 h∙ng/mL | Geometric Coefficient of Variation 42.74 |
| Treatment Sequence A+B | Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | M8 | 174.2 h∙ng/mL | Geometric Coefficient of Variation 34.57 |
| Treatment Sequence B+A | Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | Verinurad | 141.0 h∙ng/mL | Geometric Coefficient of Variation 44.9 |
| Treatment Sequence B+A | Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | M1 | 221.3 h∙ng/mL | Geometric Coefficient of Variation 49.13 |
| Treatment Sequence B+A | Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | M8 | 176.5 h∙ng/mL | Geometric Coefficient of Variation 36.85 |
Comparison: Treatment A/Treatment B, for Verinurad90% CI: [1, 1.13]
Comparison: Treatment A/Treatment B, for M190% CI: [0.9, 1.02]
Comparison: Treatment A/Treatment B, for M890% CI: [0.94, 1.04]
Primary
Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7
AUCτ assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without 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)
Population: Pharmacokinetic Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | Verinurad | 149.0 h∙ng/mL | Geometric Coefficient of Variation 37.84 |
| Treatment Sequence A+B | Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | M1 | 212.6 h∙ng/mL | Geometric Coefficient of Variation 42.78 |
| Treatment Sequence A+B | Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | M8 | 174.1 h∙ng/mL | Geometric Coefficient of Variation 34.59 |
| Treatment Sequence B+A | Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | Verinurad | 140.9 h∙ng/mL | Geometric Coefficient of Variation 44.9 |
| Treatment Sequence B+A | Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | M1 | 221.1 h∙ng/mL | Geometric Coefficient of Variation 49.13 |
| Treatment Sequence B+A | Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | M8 | 176.3 h∙ng/mL | Geometric Coefficient of Variation 36.81 |
Comparison: Treatment A/Treatment B, for Verinurad90% CI: [1, 1.13]
Comparison: Treatment A/Treatment B, for M190% CI: [0.9, 1.02]
Comparison: Treatment A/Treatment B, for M890% CI: [0.94, 1.04]
Primary
Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7
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.
Time frame: On Day -1 and Day 7 of each treatment period
Population: Protocol Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7 | -12.87 milligrams (mg) |
| Treatment Sequence B+A | Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7 | -13.15 milligrams (mg) |
95% CI: [-8.67, 9.22]
Primary
Change From Baseline in Plasma Concentration (Cmax) on Day 7
Cmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without 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)
Population: Pharmacokinetic Analysis Set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Plasma Concentration (Cmax) on Day 7 | Verinurad | 17.52 ng/mL | Geometric Coefficient of Variation 45.87 |
| Treatment Sequence A+B | Change From Baseline in Plasma Concentration (Cmax) on Day 7 | M1 | 25.28 ng/mL | Geometric Coefficient of Variation 41.55 |
| Treatment Sequence A+B | Change From Baseline in Plasma Concentration (Cmax) on Day 7 | M8 | 18.45 ng/mL | Geometric Coefficient of Variation 35.45 |
| Treatment Sequence B+A | Change From Baseline in Plasma Concentration (Cmax) on Day 7 | Verinurad | 15.26 ng/mL | Geometric Coefficient of Variation 52.48 |
| Treatment Sequence B+A | Change From Baseline in Plasma Concentration (Cmax) on Day 7 | M1 | 25.61 ng/mL | Geometric Coefficient of Variation 57.24 |
| Treatment Sequence B+A | Change From Baseline in Plasma Concentration (Cmax) on Day 7 | M8 | 18.42 ng/mL | Geometric Coefficient of Variation 44.36 |
Comparison: Treatment A/Treatment B, for Verinurad90% CI: [1.03, 1.25]
Comparison: Treatment A/Treatment B, for M190% CI: [0.88, 1.07]
Comparison: Treatment A/Treatment B, for M890% CI: [0.91, 1.08]
Secondary
Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7
tlast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without 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)
Population: Pharmacokinetic Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | Verinurad | 24.00 hour |
| Treatment Sequence A+B | Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | M8 | 24.00 hour |
| Treatment Sequence A+B | Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | M1 | 24.00 hour |
| Treatment Sequence B+A | Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | M1 | 24.00 hour |
| Treatment Sequence B+A | Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | M8 | 24.00 hour |
| Treatment Sequence B+A | Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | Verinurad | 24.00 hour |
Secondary
Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7
tmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without 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)
Population: Pharmacokinetic Analysis Set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | M8 | 4.00 hour |
| Treatment Sequence A+B | Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | M1 | 4.00 hour |
| Treatment Sequence A+B | Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | Verinurad | 4.00 hour |
| Treatment Sequence B+A | Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | M8 | 4.00 hour |
| Treatment Sequence B+A | Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | M1 | 4.00 hour |
| Treatment Sequence B+A | Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | Verinurad | 4.00 hour |
Secondary
Change From Baseline in Urinary Excretion of Serum UA (sUA) on 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.
Time frame: At Day -1 and Day 7
Population: Pharmacodynamic Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Treatment Sequence A+B | Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7 | -327.161 umol/L |
| Treatment Sequence B+A | Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7 | -264.851 umol/L |