Single and Multiple Dosing Study in Hemodialysis Patients With Hyperphosphatemia in Japan

Study Overview
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Brief Summary
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The objective of this study is to assess PK, safety and tolerability of a single oral dose of ASP3325 and to assess PD, PK and safety of repeated oral doses of ASP3325 administered t.i.d. before or just after each meal

Detailed Description
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[Part 1] This part is an open-label, uncontrolled study to evaluate PK and safety with single dosing of ASP3325 in hemodialysis patients. After washout period of therapeutic medication for hyperphosphatemia, six subjects will receive single oral administration of ASP3325 (Tablet A) on a non-dialysis day (Day 1). [Part 2] This part is a 2-arm, open-label, uncontrolled study to evaluate PD, PK and safety with dosing ASP3325 Tablet B t.i.d. before or just after each meal. Eligible subjects at screening will be entered into the washout period for stopping their phosphate-binding treatment. 20 subjects with serum inorganic phosphorus (Pi) level between ≥6.0 and <10.0 mg/dL during the washout period (washout period week 1 or washout period week 2) will be randomized to each treatment group and ASP3325 will be administered for 2 weeks until Day 14.

Official Title
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A Phase 1, Single and Multiple Dosing Study to Evaluate Pharmacokinetics and Pharmacodynamics of ASP3325 in Patients With Chronic Kidney Disease and Hyperphosphatemia Undergoing Hemodialysis

Conditions
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Chronic Kidney Disease, Hyperphosphatemia Undergoing Hemodialysis

Intervention / Treatment
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* Drug: ASP3325


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject who has received maintenance hemodialysis 3 times a week for at least 12 weeks (84 days) prior to the scheduled first day of the washout period. Subject who can receive morning dialysis from the start of the washout period to the end of follow-up period. (Part 2) Subject with pre-dialysis serum Pi level between ≥6.0 and <10.0 mg/dL and be confirmed increase in serum Pi of ≥1.5 mg/dL after the maximum dialysis interval at the washout period week 1 or 2. (Part 2) Subject who did not change the type or dose of any phosphate binder(s), any nutritional supplements or any other drugs with phosphorus reducing action for at least 4 weeks (28 days) prior to the scheduled first day of the washout period. Subject who did not receive calcimimetics (e.g., cinacalcet HCl) for at least 12 weeks (84 days) prior to the scheduled first day of the washout period. Subject taking native or active vitamin D (including vitamin D analogues), calcitonin agents or PTH agents must be on stable dose for at least 4 weeks (28 days) prior to the scheduled first day of the washout period. Exclusion Criteria: Subject who has a history of severe gastrointestinal disorder, major gastrointestinal surgery, malabsorption considered influential on the absorption of the drug and nutrition in the gastrointestinal tract. Subject who has a history of parathyroid intervention (e.g., parathyroidectomy [PTx], percutaneous ethanol injection therapy [PEIT]). Subject whose dry weight loss >5% within 12 weeks (84 days) prior to the scheduled start day of the washout period. Confirmed serum intact PTH >1000 pg/mL at the start of the washout period (only applicable for Part 2). Subject whose last 3 measurement values at the separate day of pre-dialysis systolic/diastolic blood pressure before the scheduled start day of the washout period or during the washout period are all 180 mmHg or higher and 120 mmHg or higher. Subject who has severe congestive heart failure (i.e., NYHA cardiac function classification Class III or severer). Subject who experienced a myocardial infarction or major surgery excluding vascular access surgery within 12 weeks (84 days) prior to the informed consent signing. Subject who has any of liver function tests (ALT, AST, T-Bil) out of range as indicated below at the screening (Part 1) or during the washout period, or patients with a complication of serious hepatic disease (e.g., acute and active chronic hepatitis, liver cirrhosis). AST: >2×ULN, ALT: >2×ULN, T-Bil: >1.25×ULN Subject with history or complication of malignant tumor (considered eligible if recurrence has not been observed for at least 5 years). Subject with history of serious drug hypersensitivity, such as anaphylactic shock.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part1, ASP3325 Tablet A<br>ASP3325 tablets A will be orally administered with 150 mL of water in fasting condition on non-dialysis day in Day 1 | Drug: ASP3325<br>* oral<br>|
| Experimental: Part2, ASP3325 Tablet B group 1<br>ASP3325 tablets B will be orally administered t.i.d. 30 minutes before each meal for 2 weeks | Drug: ASP3325<br>* oral<br>|
| Experimental: Part2, ASP3325 Tablet B group 2<br>ASP3325 tablets B will be orally administered t.i.d. 30 minutes just after each meal for 2 weeks | Drug: ASP3325<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessed by adverse events: Part 1 |  | Up to Day 7 | 
| Safety assessed by adverse events: Part 2 |  | Up to Day 22 | 
| Safety assessed by vital signs: Part 1 | Vital signs include body temperature, blood pressure and pulse rate) | Up to Day 7 | 
| Safety assessed by vital signs: Part 2 | Vital signs include body temperature, blood pressure and pulse rate) | Up to Day 22 | 
| Safety assessed by clinical laboratory test: Part 1 | Clinical laboratory tests include hematology and biochemistry | Up to Day 7 | 
| Safety assessed by clinical laboratory test: Part 2 | Clinical laboratory tests include hematology and biochemistry | Up to Day 22 | 
| Safety assessed by 12-Lead ECG: Part 1 | ECG: electrocardiogram | Up to Day 7 | 
| Safety assessed by 12-Lead ECG: Part 2 | ECG: electrocardiogram | Up to Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of unchanged ASP3325 | Cmax:maximum plasma concentration | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| tmax of unchanged ASP3325 | tmax = time to reach maximum plasma concentration | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| AUClast of ASP3325 | AUClast: Area under the Curve of plasma concentration during observation period in each observational day | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| AUCinf of ASP3325 | AUCinf: Area under the Curve of plasma concentration | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| t1/2 of ASP3325 | t1/2 = apparent terminal elimination half-life | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| Vz/F of ASP3325 | Vz/F = apparent volume of distribution | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| CL/F of ASP3325 | CL/F = oral clearance | Part 1 Before administration, Day 1, 2, 4, 5 and 7 | 
| Ctrough of ASP3325 | Ctrough = observed trough concentration | Part 2 Before administration, Day 3, 5, 8, 10, 12, 15 and 22 | 
| Serum Pi of ASP3325 | Serum Pi: serum phosphate concentration before dialysis | Part 2 Day -21, -14, and -7 in washout period, Day 1, 8, 15 and 22 | 
| Serum Calcium (adjusted for albumin) | Corrected value of Calcium (Ca) (mg/dL) = Observed value of Ca (mg/dL) + [4-albumin (g/dL) | Part 2 Day -21, -14, and -7 in washout period, Day 1, 8, 15 and 22 | 
| Serum concentration of intact PTH before dialysis | PTH = parathyroid hormone | Part 2 Day -21 in washout period, Day 1, 8, 15 and 22 | 
| Serum concentration of FGF23 | FGF23 = fibroblast growth factor 23 | Part 2 Day -21 in washout period, Day 1, 8, 15 and 22 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperphosphatemia, ASP3325, Chronic Kidney Disease, pharmacodynamics, pharmacokinetics