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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Outcomes Assessor);   Primary Purpose: Treatment
Condition Asymptomatic Hyperuricemia
Interventions Drug: Verinurad
Drug: Febuxostat
Drug: Dapagliflozin
Other: Dapagliflozin matched placebo
Enrollment 36
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).
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Period Title: Treatment Period 1
Started 18 18
Completed 18 18
Not Completed 0 0
Period Title: Treatment Period 2
Started 18 18
Completed 17 18
Not Completed 1 0
Reason Not Completed
Protocol deviation             1             0
Arm/Group Title All Subjects
Hide Arm/Group Description 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
Overall Number of Baseline Participants 36
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants
42.3  (12.01)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants
Female
1
   2.8%
Male
35
  97.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 36 participants
American Indian or Alaska Native
0
   0.0%
Asian
2
   5.6%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
17
  47.2%
White
14
  38.9%
More than one race
3
   8.3%
Unknown or Not Reported
0
   0.0%
1.Primary Outcome
Title Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Protocol Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Least Squares Mean (95% Confidence Interval)
Unit of Measure: milligrams (mg)
-12.87
(-21.03 to -4.70)
-13.15
(-21.31 to -4.98)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.28
Confidence Interval (2-Sided) 95%
-8.67 to 9.22
Estimation Comments [Not Specified]
2.Primary Outcome
Title Change From Baseline in Plasma Concentration (Cmax) on Day 7
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Verinurad Number Analyzed 35 participants 36 participants
17.52
(45.87%)
15.26
(52.48%)
M1 Number Analyzed 35 participants 36 participants
25.28
(41.55%)
25.61
(57.24%)
M8 Number Analyzed 35 participants 36 participants
18.45
(35.45%)
18.42
(44.36%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for Verinurad
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.14
Confidence Interval (2-Sided) 90%
1.03 to 1.25
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for M1
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.97
Confidence Interval (2-Sided) 90%
0.88 to 1.07
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for M8
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 90%
0.91 to 1.08
Estimation Comments [Not Specified]
3.Primary Outcome
Title Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h∙ng/mL
Verinurad Number Analyzed 35 participants 36 participants
149.1
(37.79%)
141.0
(44.90%)
M1 Number Analyzed 35 participants 36 participants
212.7
(42.74%)
221.3
(49.13%)
M8 Number Analyzed 35 participants 36 participants
174.2
(34.57%)
176.5
(36.85%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for Verinurad
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.06
Confidence Interval (2-Sided) 90%
1.00 to 1.13
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for M1
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.96
Confidence Interval (2-Sided) 90%
0.90 to 1.02
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for M8
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 90%
0.94 to 1.04
Estimation Comments [Not Specified]
4.Primary Outcome
Title Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: h∙ng/mL
Verinurad Number Analyzed 35 participants 36 participants
149.0
(37.84%)
140.9
(44.90%)
M1 Number Analyzed 35 participants 36 participants
212.6
(42.78%)
221.1
(49.13%)
M8 Number Analyzed 35 participants 36 participants
174.1
(34.59%)
176.3
(36.81%)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for Verinurad
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 1.06
Confidence Interval (2-Sided) 90%
1.00 to 1.13
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for M1
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.96
Confidence Interval 90%
0.90 to 1.02
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Treatment Sequence A+B, Treatment Sequence B+A
Comments Treatment A/Treatment B, for M8
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Geometric mean ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 90%
0.94 to 1.04
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamic Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Least Squares Mean (95% Confidence Interval)
Unit of Measure: umol/L
-327.161
(-352.559 to -301.762)
-264.851
(-290.060 to -239.643)
6.Secondary Outcome
Title Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Median (Full Range)
Unit of Measure: hour
Verinurad Number Analyzed 35 participants 36 participants
4.00
(2.00 to 8.00)
4.00
(3.00 to 8.08)
M1 Number Analyzed 35 participants 36 participants
4.00
(2.00 to 8.00)
4.00
(3.00 to 4.03)
M8 Number Analyzed 35 participants 36 participants
4.00
(3.00 to 8.02)
4.00
(3.00 to 8.08)
7.Secondary Outcome
Title Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description:
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study
Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Overall Number of Participants Analyzed 36 36
Median (Full Range)
Unit of Measure: hour
Verinurad Number Analyzed 35 participants 36 participants
24.00
(23.85 to 24.47)
24.00
(23.22 to 24.40)
M1 Number Analyzed 35 participants 36 participants
24.00
(23.85 to 24.47)
24.00
(23.22 to 24.40)
M8 Number Analyzed 35 participants 36 participants
24.00
(23.85 to 24.47)
24.00
(23.22 to 24.40)
Time Frame Adverse events were collected from the start of randomization throughout the treatment period up to and including the Follow-up Visit. Serious adverse events were recorded from the time of informed consent.
Adverse Event Reporting Description From screening (Day -28) to follow-up (Day 23)
 
Arm/Group Title Treatment Sequence A+B Treatment Sequence B+A
Hide Arm/Group Description Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
All-Cause Mortality
Treatment Sequence A+B Treatment Sequence B+A
Affected / at Risk (%) Affected / at Risk (%)
Total   0/35 (0.00%)   0/36 (0.00%) 
Hide Serious Adverse Events
Treatment Sequence A+B Treatment Sequence B+A
Affected / at Risk (%) Affected / at Risk (%)
Total   0/35 (0.00%)   0/36 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Treatment Sequence A+B Treatment Sequence B+A
Affected / at Risk (%) Affected / at Risk (%)
Total   7/35 (20.00%)   5/36 (13.89%) 
Gastrointestinal disorders     
Diarrhoea * 1  1/35 (2.86%)  1/36 (2.78%) 
Flatulence * 1  1/35 (2.86%)  1/36 (2.78%) 
Nausea * 1  0/35 (0.00%)  1/36 (2.78%) 
General disorders     
Catheter Site Pain * 1  0/35 (0.00%)  1/36 (2.78%) 
Influenza Like Illness * 1  1/35 (2.86%)  0/36 (0.00%) 
Vessel Puncture Site Haematoma * 1  1/35 (2.86%)  1/36 (2.78%) 
Infections and infestations     
Upper Respiratory Tract Infection * 1  0/35 (0.00%)  1/36 (2.78%) 
Injury, poisoning and procedural complications     
Eyelid Injury * 1  1/35 (2.86%)  0/36 (0.00%) 
Skin Abrasion * 1  0/35 (0.00%)  1/36 (2.78%) 
Nervous system disorders     
Headache * 1  1/35 (2.86%)  1/36 (2.78%) 
Psychiatric disorders     
Insomnia * 1  1/35 (2.86%)  0/36 (0.00%) 
Skin and subcutaneous tissue disorders     
Dry Skin * 1  0/35 (0.00%)  1/36 (2.78%) 
1
Term from vocabulary, MedDRA 20.1
*
Indicates events were collected by non-systematic assessment
The initial plan was to recruit 24 patients, but due to difficulties in determining the peak urinary uric acid excretion in 11 patients, it was decided to include 12 additional patients to ensure adequate sample size.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Fredrik Erlandsson
Organization: AstraZeneca RD, Gothenburg
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03316131    
Other Study ID Numbers: D5495C00001
First Submitted: October 17, 2017
First Posted: October 20, 2017
Results First Submitted: June 27, 2019
Results First Posted: July 18, 2019
Last Update Posted: August 28, 2019