A Phase IV, Two-part, Open-label Study Assessing the Pharmacokinetics, Safety and Pharmacodynamics of Spironolactone Oral Suspension in Pediatric Patients

A Phase IV, Two-part, Open-label Study Assessing the Pharmacokinetics, Safety and Pharmacodynamics of Single and Multiple Doses of Spironolactone Oral Suspension in Pediatric Patients With Edema Due to Heart Failure or Cirrhosis

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.

Inclusion Criteria:

• Patient or patient's parent or legal guardian (if applicable) provides written consent to participate in the study and provides written informed consent prior to any study procedures being performed.
• Female patients of childbearing potential may be enrolled if they are practicing abstinence and have a negative urine pregnancy test at Screening and/or Day 1, or using 2 forms of highly effective contraception.
• Male patients with female partners of childbearing potential may be enrolled if they are practicing abstinence or using 2 forms of highly effective contraception.
• Patients must agree to stay in clinic or the supervised care unit on specified days.
• Patients must have past diagnosis of edema (includes peripheral and/or pulmonary edema) due to heart failure or hepatic cirrhosis requiring, or expected to require, treatment with spironolactone in the investigator's judgment.
• Stable therapy for chronic comorbidities (unrelated to HF or cirrhosis, and as approved by the Investigator and Medical Monitor) is allowed, with no changes to these medications in the 72 hours prior to administration of study drug on Day 1 and for the duration of the study.
• Loop diuretics (such as furosemide), if taken, must be stable for 72 hours prior to dosing of spironolactone on Day 1 and to the extent possible for the remainder of the study.

Exclusion Criteria:

• Prematurity, defined as babies not born out of full-term pregnancy (Group 4 only) (˂38 weeks of gestation).
• Have received spironolactone or eplerenone in the past 14 days before Screening.
• Current acute renal injury (as determined by the Investigator).
• Chronic renal insufficiency: estimated glomerular filtration rate calculated using the modified Schwartz formula <30% of expected for age and size.
• Electrocardiogram corrected QT interval of >460 msec.
• Patients who have received blood transfusions within 2 weeks prior to Screening, and for the duration of treatment.
• Electrolyte disturbances (at Screening):
• Has poorly controlled diabetes (HbA1c >8.5%).
• Requires circulatory assistance device.
• Any prior solid organ transplant.
• Major surgery (as determined in the Investigator's judgement) within 1 month of dosing unless approved by the investigator and medical monitor.
• Has known history of hypersensitivity or intolerance to spironolactone or other ingredients in the study drug formulation.
• Has known contraindication to treatment with spironolactone.
• Requires treatment with a medication known to affect spironolactone exposure as indicated in the contraindications and drug interaction recommendations listed in the label.
• Is pregnant or lactating.
• Participation in a drug study or exposure to any other investigational drug or placebo within 2 months of study drug administration in the current study.
• Use of thiazide diuretics, K-sparing diuretics, any hormonal contraceptive agent, or consumption of any nutrients known to modulate the activity of CYP450 enzymes outside of the permitted use.
• Concomitant prescription medications outside the stable standard of care regimen for edematous conditions and other chronic comorbidities administered within 2 weeks prior to study drug administration.
• Patients who have smoked or used smoking-cessation or nicotine-containing products within 3 months of the first dose of the study drug until last/End of Study Visit.
• Consumption of caffeine, energy drinks, alcohol, or recreational drugs (including marijuana) within 72 hours prior to administration of study drug on Day 1 and for the duration of the study.
• Uncontrolled (with treatment), active bacterial, fungal, or viral infections within 72 hours prior to Screening.
• Screening laboratory tests positive for HIV, hepatitis B, and hepatitis C.