Efficacy, Safety And Tolerability Of PF-06743649 In Gout Subjects.

Study Overview
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Brief Summary
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The purpose of the study is to assess the effect of PF-06743649 in lowering serum uric acid in subjects suffering from gout following 14 days of dosing, as well as assessing safety and tolerability.

Official Title
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A Randomized, Double Blind, Third Party Open, Placebo Controlled Multi-center Study Of Efficacy, Safety And Tolerability Of Pf-06743649 In Gout Subjects

Conditions
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Gout

Intervention / Treatment
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* Drug: PF-06743649
* Other: Placebo
* Drug: PF-06743649
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject meets the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of acute Arthritis of Primary Gout. Subjects taking urate lowering therapy at the time of screening must be willing to discontinue their prior urate lowering therapy from the time of Screening Visit 1 until completion of the study period Day 16. Subjects taking urate lowering therapy at the time of screening must have a serum urate level of >= 8.0 mg/dL at time of the second screening visit. Subjects NOT taking urate lowering therapy at the time of screening must have a serum urate level of >= 8.0 mg/dL at both screening visits 1 and 2. Exclusion Criteria: Positive medical history or current evidence of medical or psychiatric condition/disease, or ECG or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study. Chronic kidney disease classified as moderate or severe (Clinical Practice Guideline, National Kidney Foundation)12; with GFR < 60 mL/min/1.73m2 calculated by the Cockcroft-Gault equation. Subjects with current tophaceous gout. Gout flare that has not resolved for at least 2 weeks prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06743649 dose level 1 (Cohort 1)<br> | Drug: PF-06743649<br>* Daily dosing (dose level 1) tablet for 14 days<br>|
| Placebo Comparator: Placebo for PF-06743649 (Cohort 1)<br> | Other: Placebo<br>* Daily dosing (tablet) for 14 days<br>|
| Experimental: PF-06743649 dose level 2 (Cohort 2)<br> | Drug: PF-06743649<br>* Daily dosing (dose level 2) tablet(s) for 14 days<br>|
| Placebo Comparator: Placebo for PF-06743649 (Cohort 2)<br> | Other: Placebo<br>* Daily dosing (tablets) for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline of Serum Uric Acid | An elevation in serum uric acid, hyperuricemia, is a prerequisite for the development of gout. | Baseline (pre-dose Day 1) | 
| Percent Change From Baseline in Serum Uric Acid Level at 24 Hours Post Dose on Day 14 |  | Day 14 Hour 24 | 
| Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state AEs included both serious and non-serious events. | Baseline up to 28 days after last study drug administration (Day 42) | 
| Number of Participants With Laboratory Test Abnormalities | Number of participants with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters include hematology (Hemoglobin, Hematocrit, red blood cell [RBC] count, Platelet count, mean corpuscular volume [MCV], mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration [MCHC], white blood cell [WBC] count, Total neutrophils, Eosinophils, Monocytes, Basophils, Lymphocytes), hematocrit (blood urea nitrogen [BUN]/urea and Creatinine, Glucose , Calcium, Sodium, Potassium, Chloride, Total CO2 [Bicarbonate], aspartate transaminase [AST], alanine transaminase [ALT], Total Bilirubin, Alkaline phosphatase, Albumin, Total protein, Thyroid Stimulating Hormone [TSH], free T3 [FT3] and free T4 [FT4] ), urinalysis (pH, Glucose [qual], Protein, Blood, Ketones, Nitrites, Leukocyte esterase, Urobilinogen, Urine bilirubin, Microscopy [including crystals]) and other (follicle-stimulating hormone [FSH], Urine drug screen). | Baseline up to follow up visit (Day 25-29) | 
| Number of Participants With Potentially Clinically Significant Vital Signs Findings | Criteria for potential clinically important change in vital signs included: Systolic blood pressure (BP) less than (<) 90 millimeters of mercury (mmHg) or more than or equal to (>=)30 mmHg change from baseline, diastolic BP of <50 mmHg or >=20 mmHg change from baseline, Supine pulse rate of <40 or more than (>)120 beats per minute (bpm). | Baseline up to follow up visit (Day 25-29) | 
| Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | Criteria for potential clinically important changes in ECG (12-lead) were defined as: the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval) >=300 milliseconds (msec) or increase from baseline >=25% when baseline >200 msec or increase from baseline >=50% when baseline less than or equal to (<=) 200 msec; time from the beginning of the electrocardiogram Q wave to the end of the S wave corresponding to ventricular depolarization (QRS) interval >=140 msec or >=50% increase from baseline; the beginning of the Q wave to the end of the T wave corresponding to electrical systole (QT) interval corrected using the Fridericia formula (QTcF) of 450 to < 480 msec, 480 to <500 msec and >=500 msec, or an increase of 30 to <60 msec or >=60 msec from baseline. | Baseline up to Day 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Serum Uric Acid Levels at Day 1, Day 3, Day 7, Day 11, Day 14 and Follow-up |  | Day 1, Day 3, Day 7, Day 11, Day 14 and follow-up visit (Day 25-29) | 
| Number of Participants Reaching Serum Uric Acid Levels <6, <5 and <4 mg/dL at 24 Hours Post Dose on Day 7 and Day 14 | Number of participants reaching serum uric acid levels <6, <5 and <4 mg/dL at 7 and 14 days after initiation. | 24 hours post dose on Day 7 and Day 14 | 
| Incidence and Severity of Gout Flare Attacks |  | Baseline up to Day 42 | 
| Duration of Gout Flare Attacks | Duration of gout flare attacks with participants who developed gout flare attacks. | Baseline up to Day 42 | 
| Plasma Levels of PF-06743649 After Initiation of Dosing at Day 1, Day 7, and Day 14 | Data has been calculated by setting concentration values below the lower limit of quantification to zero. The lower limit of quantification was 10.0 nanograms per milliliter (ng/mL). | 0, 1, 2, 4, 8, 12 and 24 hours at Day 1, Day 7, and Day 14 | 
| Plasma Levels of PF-06743648 After Initiation of Dosing at Day 1, Day 7, and Day 14 | PF-06743648 is an active metabolite of PF-06743649. Data has been calculated by setting concentration values below the lower limit of quantification to zero. The lower limit of quantification was 2.00 nanograms per milliliter (ng/mL). | Day 1, Day 7, and Day 14 | 
| Change From Baseline in Plasma Levels of Xanthine at Day 1, Day 7, Day 14, and at Follow-up | Change in plasma levels of xanthine from baseline at time points 0 (prior to dosing except on Day 1), 1, 2, 4, 8, 12 and 24 hours following dosing with PF-06743649 or placebo on days 1, 7 and 14 as well prior to dosing on days 3 and 11 and at follow-up of treatment with PF-06743649 or placebo. | Baseline, Day 1, Day 7, Day 14, and at follow-up visit (Day 25-29) | 
| Change From Baseline in Plasma Levels of Hypoxanthine at Day 1, Day 7, Day 14, and at Follow-up |  | Day 1, Day 7, Day 14, and at follow-up visit (Day 25-29) | 
| Change From Baseline in Urinary Uric Acid Levels at Day 1, Day 7, and Day 14 | Change from baseline in urinary uric acid cumulative amounts. | Baseline, Day 1, Day 7 and Day 14 | 
| Change From Baseline in Urinary Xanthine Levels at Day 1, Day 7, and Day 14 | Change from baseline in urinary xanthine cumulative amounts. | Baseline, Day 1, Day 7 and Day 14 | 
| Change From Baseline in Urinary Hypoxanthine Levels at Day 1, Day 7, and Day 14 | Change from baseline in urinary hypoxanthine cumulative amounts at Day 1, Day 7 and Day 14 | Baseline, Day 1, Day 7 and Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperuricemia, gout, serum uric acid