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This is a 2-part, 2 periods per part, open-label study with spironolactone oral suspension in pediatric patients with edema due to HF or hepatic cirrhosis. Both study parts will evaluate the safety, PK and PD of multiple doses of spironolactone in patients aged from birth to ≤17 years of age.
This is a 2-part, 2 periods per part, open-label study with spironolactone oral suspension in pediatric patients with edema due to heart failure or hepatic cirrhosis. Both study parts will evaluate the safety, PK and PD of multiple doses of spironolactone. In Part 1 of the study, a single dose of spironolactone oral suspension will be administered. In Part 2 of the study, a low and a high dose of spironolactone oral suspension will be selected based on the results of Part 1, and will be administered to patients.
Part 1 During a 14-day screening period, 18 patients will be enrolled in parallel to 1 of 3 groups, with 6 patients in each group (Group 1: adolescents: ≥12 to ≤17 years of age; Group 2: children: ≥6 to <12 years of age; and Group 3: children: ≥2 to <6 years of age). For these patients the study will begin with a multiple-dose period, where patients will be administered a once-daily (QD) 1.5 mg/kg dose of spironolactone oral suspension for a total of 10 days. There will then be a 30-day follow-up period. Following the conclusion of Groups 1 though 3 in the multiple-dose period of Part 1 of the study, a Safety Review Committee will review all data from Groups 1 though 3 and determine whether and how the study should proceed. If the study proceeds as planned, 6 patients aged from birth to <2 years of age will be enrolled into Group 4 during a 14-day screening period. These patients will begin the study with a single-dose period, during which they will be administered a single dose of spironolactone oral suspension at a dose determined by the Safety Review Committee. They will be followed for 7 days. They will proceed into the multiple-dose period, and will be administered a QD dose (at the same level received in the single-dose period), for a total of 10 days. There will then be a 30-day follow-up period.
Part 2 After reviewing data from Part 1 of the study, the Safety Review Committee will make the decision whether to open enrollment in Part 2 of the study, whether to open enrollment to all age groups, and the low and high doses of spironolactone oral suspension to be used. If the study proceeds as planned, 54 patients will be enrolled in parallel to either Group 1, 2, or 3, with 18 patients in each. Nine patients in each group will be assigned a low dose of spironolactone oral suspension, and 9 patients will be assigned to a high dose. These patients will proceed as described in Part 1, with a multiple-dose period where spironolactone oral suspension is administered QD at either a low or high dose for a total of 10 days, followed by a 30-day follow-up period. Following the conclusion of Groups 1 through 3 in the multiple-dose period of Part 2, eighteen patients aged from birth to <2 years of age will be enrolled into Group 4. Nine patients will be assigned to a low dose of spironolactone oral suspension, and 9 patients will be assigned to a high dose. As described for Part 1, these patients will begin the study with a single-dose period during which they will be administered a single dose (low or high) of spironolactone oral suspension and then followed for 7 days before being administered a QD dose (at the same level received in the single-dose period), for a total of 10 days. There will then be a 30-day follow-up period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1: multiple doses spironolactone oral suspension (Group 1) | Experimental | Patients aged ≥12 to ≤17 years of age in Part 1 of the study, administered spironolactone oral suspension QD for 10 days |
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| Part 1: multiple doses spironolactone oral suspension (Group 2) | Experimental | Patients aged ≥6 to <12 years of age in Part 1 of the study, administered spironolactone oral suspension QD for 10 days |
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| Part 1: multiple doses spironolactone oral suspension (Group 3) | Experimental | Patients aged ≥2 to <6 years of age in Part 1 of the study, administered spironolactone oral suspension QD for 10 days |
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| Part 1: single and multiple doses spironolactone oral suspension (Group 4) | Experimental | Patients aged from birth to <2 years of age in Part 1 of the study, administered spironolactone oral suspension as a single dose, and then QD for 10 days |
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| Part 2: multiple doses spironolactone oral suspension (Group 1) | Experimental | Patients aged ≥12 to ≤17 years of age in Part 2 of the study, administered low or high dose spironolactone oral suspension QD for 10 days |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Spironolactone Oral Suspension | Drug | Spironolactone will be dosed on a mg/kg basis, with actual weight on Day 1 (pre-dose) determining the spironolactone suspension volume administered. Therefore, for a given patient, the dose administered on Day 1, based on the weight measured on Day 1, will be administered throughout their participation in the study. Spironolactone will be administered as a single dose in the single-dose periods (Group 4, Parts 1 and 2), and as QD dosing in the multiple-dose periods (Groups 1 to 4, Parts 1 and 2). The low and high doses to be administered during Part 2 of the study will be determined by the Safety Review Committee following their review of Part 1 data. |
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Absorption rate constant (Ka) of spironolactone (time^-1) in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 2: Absorption rate constant (Ka) of spironolactone (time^-1) in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 1: Total clearance from plasma after oral administration (CL/F) of spironolactone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. |
| Measure | Description | Time Frame |
|---|---|---|
| Parts 1 and 2: Incidence of adverse events, serious adverse events, and adverse events leading to discontinuation during the single-dose periods (Group 4 only) | Day 1 to Day 8 | |
| Parts 1 and 2: Number of patients with clinically significant findings from clinical laboratory tests, vital signs, and physical examinations during the single-dose periods (Group 4 only) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Paul Sudhakar, M.Pharm | Contact | 816-507-8249 | pauls@ptspharma.com |
| Name | Affiliation | Role |
|---|---|---|
| Gerald Sakowski | CMP Pharma | Study Director |
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| Part 2: multiple doses spironolactone oral suspension (Group 2) | Experimental | Patients aged ≥6 to ≤12 years of age in Part 2 of the study, administered low of high dose spironolactone oral suspension QD for 10 days |
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| Part 2: multiple doses spironolactone oral suspension (Group 3) | Experimental | Patients aged ≥2 to ≤6 years of age in Part 2 of the study, administered low or high dose spironolactone oral suspension QD for 10 days |
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| Part 2: single and multiple doses spironolactone oral suspension (Group 4) | Experimental | Patients aged from birth to <2 years of age in Part 2 of the study, administered low or high dose spironolactone oral suspension as a single dose, and then QD for 10 days |
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| Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 2: Total clearance from plasma after oral administration (CL/F) of spironolactone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 1: Volume of distribution after oral administration (V/F) of spironolactone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 2: Volume of distribution after oral administration (V/F) of spironolactone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 1: Total clearance from plasma after oral administration (CL/F) of canrenone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 2: Total clearance from plasma after oral administration (CL/F) of canrenone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 1: Volume of distribution after oral administration (V/F) of canrenone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 2: Volume of distribution after oral administration (V/F) of canrenone in the multiple-dose period | Patients will be assigned to a pharmacokinetic sampling schedule as follows: Group 1, Subgroup 1 - Day 1: pre-dose; Day 10; 0.08-0.5 hours, 1-1.5 hours, 2-3 hours, 4-6 hours, 10-13 hours post-dose; Day 11: 22-26 hours post-dose Group 1, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.5-1 hour, 1.5-2 hours, 3-4 hours, 6-8 hours post-dose; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 1 - Day 1: pre-dose; Day 10: 0.08-0.75 hours, 1.5-2.5 hours, 3.5-6 hours, 10-13 hours; Day 11: 22-26 hours post-dose Groups 2 and 3, Subgroup 2 - Day 1: pre-dose; Day 10: pre-dose, 0.75-1.5 hours, 2.5-3.5 hours, 6-8 hours, 10-13 hours post-dose Group 4: the pharmacokinetic sampling schedule during the multiple-dose period for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3. | Pre-dose (Day 1) to 22-26 hours post-dose (Day 11) |
| Part 1: Change from baseline in body weight (kg) (Groups 1 through 3) | Body weight should be measured using the same scale each time and will be reported at: Screening; Day 1: pre-dose (baseline) and anytime between 6 and 8 hours post-dose; Day 5: pre-dose; Day 10: pre-dose and 6 to 8 hours post-dose; Day 11: 22 to 26 hours post-dose; Day 18: during visit. | Day 1 to Day 18 |
| Part 1: Change from baseline in body weight (kg) (Group 4) | Body weight should be measured using the same scale each time and will be reported at: Screening; Day 1: pre-dose (baseline), and anytime between 6 and 8 hours post-dose; Day 3: anytime between 46 and 50 hours post-dose; Day 8: 166 to 170 hours post-dose; Day 8: 166 to 170 hours post-dose; Day 9: pre-dose and anytime between 6 and 8 hours post-dose; Day 13: pre-dose; Day 18: pre-dose and 6 to 8 hours post-dose; Day 19: 22 to 26 hours post-dose; Day 26: during visit. | Day 1 to Day 26 |
| Part 2: Change from baseline in body weight (kg) (Groups 1 through 3) | Body weight should be measured using the same scale each time and will be reported at: Screening; Day 1: pre-dose (baseline) and anytime between 6 and 8 hours post-dose; Day 5: pre-dose; Day 10: pre-dose and 6 to 8 hours post-dose; Day 11: 22 to 26 hours post-dose; Day 18: during visit. | Day 1 to Day 18 |
| Part 2: Change from baseline in body weight (kg) (Group 4) | Body weight should be measured using the same scale each time and will be reported at: Screening; Day 1: pre-dose (baseline), and anytime between 6 and 8 hours post-dose; Day 3: anytime between 46 and 50 hours post-dose; Day 8: 166 to 170 hours post-dose; Day 8: 166 to 170 hours post-dose; Day 9: pre-dose and anytime between 6 and 8 hours post-dose; Day 13: pre-dose; Day 18: pre-dose and 6 to 8 hours post-dose; Day 19: 22 to 26 hours post-dose; Day 26: during visit. | Day 1 to Day 26 |
| Part 1: Change from baseline in sodium/potassium (Na/K) ratio (Groups 1 through 3) | The Na/K ratio (mmol/mmol) will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints in all groups: Day -1: late afternoon/prior to dinner and last void prior to bedtime; Day 1: first morning void; Day 10: late afternoon/prior to dinner and last void prior to bedtime; Day 11: first morning void. 24-hour urine will be collected for analysis of electrolytes in Groups 1 and 2 only. Urine collection begins on Day -1 AFTER the first morning void and ends AFTER the first morning void on Day 1. Urine collection should start AFTER the first morning void on Day 10 and end AFTER the first morning void on Day 11. | Day -1 to Day 11 |
| Part 1: Change from baseline in sodium/potassium (Na/K) ratio (Group 4) | The Na/K ratio (mmol/mmol) will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints: Day 8: late afternoon/prior to dinner and last void prior to bedtime; Day 9: first morning void; Day 18: late afternoon/prior to dinner and last void prior to bedtime; Day 19: first morning void. | Day 8 to Day 19 |
| Part 2: Change from baseline in sodium/potassium (Na/K) ratio (Groups 1 through 3) | The Na/K ratio (mmol/mmol) will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints in all groups: Day -1: late afternoon/prior to dinner and last void prior to bedtime; Day 1: first morning void; Day 10: late afternoon/prior to dinner and last void prior to bedtime; Day 11: first morning void. 24-hour urine will be collected for analysis of electrolytes in Groups 1 and 2 only. Urine collection begins on Day -1 AFTER the first morning void and ends AFTER the first morning void on Day 1. Urine collection should start AFTER the first morning void on Day 10 and end AFTER the first morning void on Day 11. | Day -1 to Day 11 |
| Part 2: Change from baseline in sodium/potassium (Na/K) ratio (Group 4) | The Na/K ratio (mmol/mmol) will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints: Day 8: late afternoon/prior to dinner and last void prior to bedtime; Day 9: first morning void; Day 18: late afternoon/prior to dinner and last void prior to bedtime; Day 19: first morning void. | Day 8 to Day 19 |
| Part 1: Change from baseline in fractional excretion of sodium (FENa; %) (Groups 1 through 3) | FENa will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints in all groups: Day -1: late afternoon/prior to dinner and last void prior to bedtime; Day 1: first morning void; Day 10: late afternoon/prior to dinner and last void prior to bedtime; Day 11: first morning void. 24-hour urine will be collected for analysis of electrolytes in Groups 1 and 2 only. Urine collection begins on Day -1 AFTER the first morning void and ends AFTER the first morning void on Day 1. Urine collection should start AFTER the first morning void on Day 10 and end AFTER the first morning void on Day 11. FENa will be calculated as follows: [(urine sodium × plasma creatinine)/plasma sodium × urine creatinine) × 100] | Day -1 to Day 11 |
| Part 1: Change from baseline in fractional excretion of sodium (FENa; %) (Group 4) | FENa will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints: Day 8: late afternoon/prior to dinner and last void prior to bedtime; Day 9: first morning void; Day 18: late afternoon/prior to dinner and last void prior to bedtime; Day 19: first morning void. FENa will be calculated as follows: [(urine sodium × plasma creatinine)/plasma sodium × urine creatinine) × 100] | Day 8 to Day 19 |
| Part 2: Change from baseline in fractional excretion of sodium (FENa; %) (Groups 1 through 3) | FENa will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints in all groups: Day -1: late afternoon/prior to dinner and last void prior to bedtime; Day 1: first morning void; Day 10: late afternoon/prior to dinner and last void prior to bedtime; Day 11: first morning void. 24-hour urine will be collected for analysis of electrolytes in Groups 1 and 2 only. Urine collection begins on Day -1 AFTER the first morning void and ends AFTER the first morning void on Day 1. Urine collection should start AFTER the first morning void on Day 10 and end AFTER the first morning void on Day 11. FENa will be calculated as follows: [(urine sodium × plasma creatinine)/plasma sodium × urine creatinine) × 100] | Day -1 to Day 11 |
| Part 2: Change from baseline in fractional excretion of sodium (FENa; %) (Group 4) | FENa will be calculated using data from spot urine (all groups) and 24-hour urine chemistry (Groups 1 and 2) collection. Spot urine will be collected for analysis of electrolytes at the following timepoints: Day 8: late afternoon/prior to dinner and last void prior to bedtime; Day 9: first morning void; Day 18: late afternoon/prior to dinner and last void prior to bedtime; Day 19: first morning void. FENa will be calculated as follows: [(urine sodium × plasma creatinine)/plasma sodium × urine creatinine) × 100] | Day 8 to Day 19 |
| Day 1 to Day 8 |
| Parts 1 and 2: Absorption rate constant (Ka) of spironolactone (time^-1) in the single-dose period (Group 4 only) | The pharmacokinetic sampling schedule for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3, but samples will likely be collected on Days 1, 3, and 8. The number of PK samples collected may be reduced from this preliminary schedule based on review of PK concentration-time data from Groups 1 to 3 and will not exceed allowable limits for blood volume collection in neonates and infants in 1 day and within 30 days. | Day 1 to Day 8 |
| Parts 1 and 2: Total clearance from plasma after oral administration (CL/F) of spironolactone in the single-dose period (Group 4 only) | The pharmacokinetic sampling schedule for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3, but samples will likely be collected on Days 1, 3, and 8. The number of PK samples collected may be reduced from this preliminary schedule based on review of PK concentration-time data from Groups 1 to 3 and will not exceed allowable limits for blood volume collection in neonates and infants in 1 day and within 30 days. | Day 1 to Day 8 |
| Parts 1 and 2: Volume of distribution after oral administration (V/F) of spironolactone in the single-dose period (Group 4 only) | The pharmacokinetic sampling schedule for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3, but samples will likely be collected on Days 1, 3, and 8. The number of PK samples collected may be reduced from this preliminary schedule based on review of PK concentration-time data from Groups 1 to 3 and will not exceed allowable limits for blood volume collection in neonates and infants in 1 day and within 30 days. | Day 1 to Day 8 |
| Parts 1 and 2: Total clearance from plasma after oral administration (CL/F) of canrenone in the single-dose period (Group 4 only) | The pharmacokinetic sampling schedule for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3, but samples will likely be collected on Days 1, 3, and 8. The number of PK samples collected may be reduced from this preliminary schedule based on review of PK concentration-time data from Groups 1 to 3 and will not exceed allowable limits for blood volume collection in neonates and infants in 1 day and within 30 days. | Day 1 to Day 8 |
| Parts 1 and 2: Volume of distribution after oral administration (V/F) of canrenone in the single-dose period (Group 4 only) | The pharmacokinetic sampling schedule for Group 4 will be determined following Safety Review Committee of data from Groups 1 through 3, but samples will likely be collected on Days 1, 3, and 8. The number of PK samples collected may be reduced from this preliminary schedule based on review of PK concentration-time data from Groups 1 to 3 and will not exceed allowable limits for blood volume collection in neonates and infants in 1 day and within 30 days. | Day 1 to Day 8 |
| Part 1: Incidence of adverse events, serious adverse events, and adverse events leading to discontinuation during the multiple-dose period (Groups 1 through 3) | Day 1 to Day 41 |
| Part 1: Incidence of adverse events, serious adverse events, and adverse events leading to discontinuation during the multiple-dose period (Group 4 only) | Day 9 to Day 49 |
| Part 2: Incidence of adverse events, serious adverse events, and adverse events leading to discontinuation during the multiple-dose period (Groups 1 through 3) | Day 1 to Day 41 |
| Part 2: Incidence of adverse events, serious adverse events, and adverse events leading to discontinuation during the multiple-dose period (Group 4 only) | Day 9 to Day 49 |
| Part 1: Number of patients with clinically significant findings from clinical laboratory tests, vital signs, and physical examinations during the multiple-dose period (Groups 1 through 3) | Day 1 to Day 41 |
| Part 1: Number of patients with clinically significant findings from clinical laboratory tests, vital signs, and physical examinations during the multiple-dose period (Group 4 only) | Day 9 to Day 49 |
| Part 2: Number of patients with clinically significant findings from clinical laboratory tests, vital signs, and physical examinations during the multiple-dose period (Groups 1 through 3) | Day 1 to Day 41 |
| Part 2: Number of patients with clinically significant findings from clinical laboratory tests, vital signs, and physical examinations during the multiple-dose period (Group 4 only) | Day 9 to Day 49 |
| Part 1: Change from baseline in abdominal girth (cm) (Groups 1 through 3) | Abdominal girth is the measurement of the distance around the abdomen at a specific point, usually the level of the navel, and will be measured on Day 1: pre-dose; Day 5: pre-dose; and Day 10: pre-dose. | Day 1 to Day 10 |
| Part 1: Change from baseline in abdominal girth (cm) (Group 4) | Abdominal girth is the measurement of the distance around the abdomen at a specific point, usually the level of the navel, and will be measured on Day 8: 166 to 170 h post-dose; Day 9: pre-dose; Day 13: pre-dose; Day 18: pre-dose. | Day 8 to Day 18 |
| Part 2: Change from baseline in abdominal girth (cm) (Groups 1 through 3) | Abdominal girth is the measurement of the distance around the abdomen at a specific point, usually the level of the navel, and will be measured on Day 1: pre-dose; Day 5: pre-dose; and Day 10: pre-dose. | Day 1 to Day 10 |
| Part 2: Change from baseline in abdominal girth (cm) (Group 4) | Abdominal girth is the measurement of the distance around the abdomen at a specific point, usually the level of the navel, and will be measured on Day 8: 166 to 170 h post-dose; Day 9: pre-dose; Day 13: pre-dose; Day 18: pre-dose. | Day 8 to Day 18 |
| Part 1: Number of patients with clinically significant findings from electrolytes and other laboratory results (Groups 1 through 3) | Laboratory test results will include serum sodium, potassium, magnesium, blood urea nitrogen, serum creatinine, glycemia, albumin, total proteins, estimated glomerular filtration rate, urinary sodium and potassium, creatinine, and osmolality. | Day 1 to Day 18 |
| Part 1: Number of patients with clinically significant findings from electrolytes and other laboratory results (Group 4) | Laboratory test results will include serum sodium, potassium, magnesium, blood urea nitrogen, serum creatinine, glycemia, albumin, total proteins, estimated glomerular filtration rate, urinary sodium and potassium, creatinine, and osmolality. | Day 9 to Day 26 |
| Part 2: Number of patients with clinically significant findings from electrolytes and other laboratory results (Groups 1 through 3) | Laboratory test results will include serum sodium, potassium, magnesium, blood urea nitrogen, serum creatinine, glycemia, albumin, total proteins, estimated glomerular filtration rate, urinary sodium and potassium, creatinine, and osmolality. | Day 1 to Day 18 |
| Part 2: Number of patients with clinically significant findings from electrolytes and other laboratory results (Group 4) | Laboratory test results will include serum sodium, potassium, magnesium, blood urea nitrogen, serum creatinine, glycemia, albumin, total proteins, estimated glomerular filtration rate, urinary sodium and potassium, creatinine, and osmolality. | Day 9 to Day 26 |
| Part 1: Levels of N-terminal pro B-type natriuretic peptide (pg/mL) in Groups 1 to 3 | Day 11 |
| Part 1: Levels of N-terminal pro B-type natriuretic peptide (pg/mL) in Group 4 | Day 19 |
| Part 2: Levels of N-terminal pro B-type natriuretic peptide (pg/mL) in Groups 1 to 3 | Day 11 |
| Part 2: Levels of N-terminal pro B-type natriuretic peptide (pg/mL) in Group 4 | Day 19 |
| Part 1: Levels of cystatin C (mg/L) in Groups 1 to 3 | Day 11 |
| Part 1: Levels of cystatin C (mg/L) in Group 4 | Day 19 |
| Part 2: Levels of cystatin C (mg/L) in Groups 1 to 3 | Day 11 |
| Part 2: Levels of cystatin C (mg/L) in Group 4 | Day 19 |
| ID | Term |
|---|---|
| D005355 | Fibrosis |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| D002191 | Canrenoic Acid |
| ID | Term |
|---|---|
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
Not provided
Not provided