| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018627 |
| E.1.2 | Term | Gout |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the percent reduction from baseline in serum urate (sUA) levels following 4 weeks of continuous treatment of RDEA594 in combination with allopurinol to allopurinol alone in subjects with documented inadequate hypouricemic response with standard doses of allopurinol. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the proportion of subjects whose sUA levels are < 6.0 mg/dL, <5.0 mg/dL and <4.0 mg/dL at each study visit by treatment group in all subjects and in subjects who have an sUA greater than or equal to 6 mg/dL at the baseline visit.
•To evaluate the absolute and percent reduction from baseline in sUA levels at each visit.
•To evaluate the percentage change in 24-hour urine urate level (excretion) from baseline to Day 28.
•To evaluate the incidence of gout flares.
•To evaluate the safety and tolerability of RDEA594 in combination with allopurinol in subjects with gout.
•To compare the multiple-dose pharmacokinetics (PK) of allopurinol and oxypurinol in the absence versus presence of RDEA594 co-administration.
•To evaluate the proportion of subjects whose sUA level decreases to or is maintained at <6.0 mg/dL and <5.0 mg/dL in the double-blind and Open-Label Extension Periods. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacokinetic sub-study within the main study to compare multiple-dose pharmacokinetics (PK) of allopurinol and oxypurinol in the absence versus presence of RDEA594 co-administration. |
|
| E.3 | Principal inclusion criteria |
1.Subject is male or a post-menopausal or surgically sterile female. (Post-menopausal is generally defined as a period of twelve (12) consecutive months of amenorrhoea. In women under 55 years of age whose menopausal status is in question, a follicle-stimulating hormone (FSH) level of >40 mIU/ml or an oestrogen deficiency of < 30 pg/m or a negative oestrogen test can confirm they are post-menopausal.)
2.Subject is 18 - 80 years of age.
3.Subject has been taking allopurinol as the sole urate lowering therapy for hyperuricemia for at least 6 weeks at a dose between 200 mg - 600 mg per day without an adequate response (i.e., sUA level not less than 6.0 mg/dL on at least 2 occasions at least approximately 2 weeks apart, which can include the screening visit).
4.Subject has a sUA level ≥ 6 mg/dL at screening.
5.Subject meets criteria for the diagnosis of gout as per the American Rheumatism Association (ARA) Criteria for the Classification of Acute Arthritis of Primary Gout.
6.Subject is willing and able to give informed consent and adhere to visit/protocol schedules (informed consent must be given before the first study procedure is performed).
7. Subjects entering the optional Double-Blind Extension Period must have completed 28 days of dosing (+/- 3 days) in the Double-Blind Treatment Period and the Day 42 Visit in the Follow-up Period within 4 months and must not have experienced any serious adverse events considered possibly related to study drug.
8. Subjects entering the optional Open-Label Extension Period must continue to be
compliant with the protocol through Week 44 of the Double-Blind Extension Period
and must not have experienced any serious adverse events considered possibly related to study drug. |
|
| E.4 | Principal exclusion criteria |
1.Subject who consumes more than 14 drinks of alcohol per week (e.g., 1 drink = 5 oz [150 ml] of wine, 12 oz [360 ml] of beer, or 1.5 oz [45 ml] of hard liquor).
2.Subject with a history or suspicion of drug abuse.
3.Subject with a history of documented or suspected kidney stones.
4.Subject has rheumatoid arthritis or other autoimmune disease requiring treatment.
5.Subject with documented or suspicion of HIV infection.
6.Subject with a positive serology to HCV antibodies (Abs), and/or hepatitis B surface antigen (HBsAg).
7.Subject with a history of malignancy within 5 years prior to the first dose of study medication, other than non-melanomatous skin cancer or cervical dysplasia.
8.Subject with a history of cardiac abnormalities, including abnormal and clinically
relevant ECG changes such as bradycardia (sinus rate <45 bpm), complete left bundle branch block (LBBB), second or third degree heart block, intraventricular conduction delay with QRS duration >120 msec, symptomatic or asymptomatic arrhythmias with the exception of sinus arrhythmia, evidence of ventricular pre-excitation, frequent palpitations or syncopal episodes, heart failure, hypokalemia, family history of Long QT Syndrome, and/or family history of sudden death in otherwise healthy individual between the ages of 1 and 30 years.
9.Subject with any condition predisposing to QT prolongation including pathological Q-wave (defined as Q-wave >40 msec or depth > 0.4-0.5 mV).
10.Subject with any use of concomitant medications that prolong the QT/QTc interval within the 14 days prior to Baseline (Day 1).
11.Subject with a QT interval corrected for heart rate according to Fridericia (QTcF) > 450 msec at Screening or pre-dose at Baseline (Day 1).
12.Subject with uncontrolled hypertension (above 150/95).
13.Subject with inadequate renal function [serum creatinine >1.5 mg/dL or creatinine clearance < 60 mL/min (by Cockroft-Gault formula)].
14.Subject with a hemoglobin < 10 g/dL (males) or < 9 g/dL (females).
15.Subject with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 2.5 x upper limit of normal (ULN).
16.Subject with a gamma glutamyl transferase (GGT) > 3 x ULN.
17.Subject with active peptic ulcer disease requiring treatment.
18.Subject with a history of xanthinuria, active liver disease, or hepatic dysfunction.
19.Subject requires therapy with any other urate-lowering medication, other than the study medications.
20.Subject requires long-term use of salicylates above 100 mg per day; thiazide diuretics (except low-dose hydrochlorothiazide); losartan; azathioprine; mercaptopurine; theophylline; intravenous colchicine; cyclosporine; cyclophosphamide; pyrazinamide; sulfamethoxazole; or trimethoprim.
21.Subject taking medications known as enzyme inducers.
22.Subject reports receiving a strong or moderate inhibitor of CYP3A4 or a P-gp inhibitor within 1 month prior to study drug dosing, due to potential interactions with colchicine.
23.Subject with an acute gout flare (exclusive of chronic synovitis/ arthritis) during the Screening-Period that has not resolved one week prior to the Baseline Visit (Day 0).
24.Subject is pregnant or breast feeding.
25.Subject who has received an investigational medication within 4 weeks prior to the screening visit for this study.
26.Subject who previously participated in a clinical study involving RDEA806 or RDEA594.
27.Subject with known hypersensitivity or allergy to RDEA594, allopurinol or colchicine or any components in their formulations.
28.Subject with a body mass index (BMI) >48 kg/m2.
29.Subject who is taking greater than 1000 mg/day of Vitamin C.
30.Subject with any other medical or psychological condition, which in the opinion of the Investigator and/or Medical Monitor, might create undue risk to the subject or interfere with the subject’s ability to comply with the protocol requirements, or to complete the study.
31.Subjects with inadequate renal function [serum creatinine >1.5 mg/dL or creatinine clearance < 60 mL/min (by Cockroft-Gault formula)] after completing the Double-Blind Treatment period prior to entering Extension Period.
32. Subjects requiring treatment with prohibited medications noted in exclusion criteria numbers 20-23 after completing the Double-Blind Treatment Period prior to entering the Extension Period.
33. Subjects who have had a clinically relevant medical event as determined by the investigator in consultation with medical monitor prior to entering the Extension Period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To compare the percent reduction from baseline in serum urate (sUA) levels following 4 weeks of continuous treatment of RDEA594 in combination with allopurinol to allopurinol alone in subjects with documented inadequate hypouricemic response with standard doses of allopurinol. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-To evaluate the proportion of subjects whose sUA levels are < 6.0 mg/dL, < 5.0
mg/dL and < 4.0 mg/dL at each study visit by treatment group in all subjects and in
subjects who have an sUA ≥ 6 mg/dL at the baseline visit.
-To evaluate the absolute and percent reduction from baseline in sUA levels at each
visit.
-To evaluate the percentage change in 24-hour urine urate level (excretion) from
baseline to Day 28.
-To evaluate the incidence of gout flares.
-To evaluate the safety and tolerability of RDEA594 in combination with allopurinol
in subjects with gout.
-To compare the multiple-dose pharmacokinetics (PK) of allopurinol and oxypurinol
in the absence versus presence of RDEA594 co-administration.
-To evaluate the proportion of subjects whose sUA level decreases to or is maintained
at < 6.0 mg/dL and < 5.0 mg/dL in the Double-Blind and Open-Label Extension
Periods. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 28 days and through extension |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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