Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)

Urine osmolality is a measure of urine concentration, measured by osmometer, which evaluates the freezing point depression of a solution and supplies results as milliosmoles per kilogram of water. Spot urine osmolality was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. All participants were fasting.

Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. Spot urine sample for determination of specific gravity was collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. All participants were fasting.

htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.

Participants were instructed to record all fluid taken and all urine output for the 24-hour period.

Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The units for the data reported are milliliter per minute per 1.73 meter square (mL/min/1.73 m^2). The baseline was the evaluation done at Week 1 in Phase A for this outcome measure.

Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points.

htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.

Urine volume refers to the quantity of urine produced per unit of time.

Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages.

Fluid balance is a term used to describe the balance of the input and output of fluids in the body to allow metabolic processes to function correctly.

Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.

Creatinine is produced from the metabolism of protein, when muscles burn energy. Most creatinine is filtered out of the blood by the kidneys and excreted in urine. The creatinine clearance value is determined by measuring the concentration of endogenous creatinine (that which is produced by the body) in both plasma and urine. Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.

Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.

Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one participant with event are reported.

Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one participant with event are reported.

The growth percentile was based on the assessment of height and weight.

The growth percentile was based on the assessment of height and weight.

Phase A Baseline is the last pre-dose evaluation. The Last Visit is the last available post-baseline evaluation including early term. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)

Phase B Baseline is the last evaluation prior to the first dose in Phase B. The Last Visit is the last available post-baseline evaluation including early term. As prespecified in the protocol, data for safety is reported by the treatment group (Phase B: Prior Tolvaptan and Phase B: Prior Placebo).

Vital sign measurements included measurements of respiratory rate, blood pressure, body temperature and pulse. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).

Laboratory parameters=haematology,chemistry,urinalysis,& LFTs.Criteria for laboratory abnormalities along with their test result grade=Increased creatinine level: Baseline(BSL):Grade 0,>BSL-1.5xBSL:1,>1.5-3xBSL:2,>3-6xBSL:3,>6xBSL:4.Decreased glucose level: <30:-4,30-<40:-3, 40-<55:-2, 55-<65:-1,>=65:0; Increased:<=115:0,>115-160:1,>160-250:2,>250-500:3,>500:4.Decreased potassium level: <2.5:-4,2.5-<3:-3,3-<lower limit of normal(LLN):-1,LLN:0; Increased:upper limit of normal(ULN):0,>ULN-5.5:1,>5.5-6:2,>6-7:3,>7:4.Decreased sodium level: <120:-4,120-124:-3,125-129:-2,130-135:-1,>=136:0; Increased:<=145:0,146-150:1,151-155:2,156-160:3,>160:4. Increased triglyceride level:ULN:0,>ULN-2.5xULN:1,>2.5-5xULN:2,>5-6xULN:3,>6xULN:4. Decreased Neutrophils:<0.5:-4,0.5-<1:-3,1-<1.5:-2,1.5-<LLN:-1,LLN:0. Potentially clinically significant increase or decrease was defined as Baseline grade 0,1,-1 and post-baseline grade >1, <-1 or Baseline grade >1,<-1 and post-baseline grade >or<Baseline grade.

An AE was defined as any untoward medical occurrence in a participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Aquaretic AEs included Medical Dictionary for Regulatory Activities [MedDRA] preferred terms of thirst, polyuria (production of large volumes of dilute urine), nocturia (need to wake up to urinate at night), pollakiuria (abnormally frequent urination), and polydipsia (excessive thirst). As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).