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

A Phase 3b, Two-part, Multicenter, One Year Randomized, Double-blind, Placebo-controlled Trial of the Safety, Pharmacokinetics, Tolerability, and Efficacy of Tolvaptan Followed by a Two Year Open-label Extension in Children and Adolescent Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02964273

Enrollment

Registered

2016-11-16

Start date

2016-09-23

Completion date

2021-11-17

Last updated

2023-01-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Keywords

Autosomal Dominant Polycystic Kidney Disease, ADPKD, Tolvaptan, Renal cysts, Chronic Kidney Disease, Genetic Kidney Disease

Brief summary

The primary objective of the study is to assess the long term safety of treatment with tolvaptan in children and adolescents with autosomal dominant polycystic kidney disease (ADPKD). The secondary objective is to assess the pharmacodynamics, pharmacokinetics, and efficacy of tolvaptan in the same participant population.

Detailed description

Tolvaptan has been demonstrated to delay the decline of kidney function in adults with rapidly progressing ADPKD (chronic kidney disease \[CKD\] stages 1 to 3) as measured by estimated glomerular filtration rate (eGFR) and Total Kidney Volume (TKV). This trial will be the first trial of tolvaptan in children and adolescents with ADPKD. Participants in this study will be randomly assigned to one of two groups in Phase A; tolvaptan or placebo. Participants will have an equal chance of being assigned to either treatment group and will be stratified by age and gender into the following cohorts: * Female participant ages 12 to 14 years, inclusive * Female participant ages 15 to 17 years, inclusive * Male participant ages 12 to 14 years, inclusive * Male participant ages 15 to 17 years, inclusive Phase (A) of this study will last 12 months. After that time, all participants who qualify will be assigned tolvaptan and will be treated with tolvaptan for 24 months (Phase B). A qualified participant is defined as one who has completed Phase A on investigational medicinal product (IMP), is willing to continue in the trial, and who does not have any adverse events (AEs), which would require IMP discontinuation. Participants in this study will be required to make monthly visits to the study clinic and will be closely monitored over the course of the study.

Interventions

DRUGTolvaptan

Tolvaptan spray-dried, immediate release tablets

DRUGTolvaptan Matching-placebo

Tolvaptan matching-placebo tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

4 Years to 17 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * Male and female participants aged 4 to 17 years (inclusive) with a diagnosis of ADPKD as defined by the presence of family history and/or genetic criteria AND who have at least 10 renal cysts, each of which measure at least 0.5 cm, confirmed upon magnetic resonance imaging (MRI) inspection; participants under the age of 12 years must have at least 4 cysts that are at least 1 cm in size, confirmed by ultrasound. * Weight ≥20 kg. * Participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m\^2 within 31 days prior to randomization (using the Schwartz formula, eGFR = 0.413 × height \[cm\]/serum creatinine milligrams per deciliter \[mg/dL\]). * Independent in toileting. * Ability to swallow a tablet. Key

Exclusion criteria

* Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT) \> 1.5 × the upper limit of normal (ULN). * Nocturnal enuresis. * Need for chronic diuretic use. * Participants with advanced diabetes (e.g., glycosylated hemoglobin \>7.5, and/or glycosuria by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal disease(s) (i.e., currently active glomerular nephritides), renal cancer, single kidney, or recent (within 6 months of screening) renal surgery or acute kidney injury. * Participants having disorders in thirst recognition or inability to access fluids. * Participants with critical electrolyte imbalances, as determined by the investigator. * Participants with, or at risk of, significant hypovolemia as determined by investigator. * Participants with clinically significant anemia, as determined by investigator. * Participants 12 years of age and older having contraindications to, or interference with MRI assessments (e.g., ferro-magnetic prostheses, aneurysm clips, severe claustrophobia). * Participants with a history of taking a vasopressin agonist/antagonist. * Participants taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (i.e., marketed) therapies for the purpose of affecting polycystic kidney disease (PKD) cysts such as tolvaptan, vasopressin antagonists, anti-sense ribonucleic acid (RNA) therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (i.e., octreotide, sandostatin). * Participants who have had cyst reduction surgery within 6 weeks of the screening visit.

Design outcomes

Primary

Measure	Time frame	Description
Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)	Baseline, and Week 1 of Phase A	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.
Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)	Baseline, and Week 1 of Phase A	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.

Secondary

Measure	Time frame	Description
Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A	Phase A Baseline, Months 1, 6, and 12	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.
Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B	Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24	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.
Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24	Phase B Baseline, Months 12 and 24	htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
Phase A: 24-hour Urine Volume	24 hours post dose after Month 1 on study medication in Phase A	Urine volume refers to the quantity of urine produced per unit of time.
Phase A: 24-hour Fluid Intake	24 hours post dose after Month 1 on study medication in Phase A	Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages.
Phase A: 24-hour Fluid Balance	24 hours post dose after Month 1 on study medication in Phase A	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.
Phase A: 24-hour Sodium Clearance	24 hours post dose after Month 1 on study medication in Phase A	Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Phase A: 24-hour Creatinine Clearance	24 hours post dose after Month 1 on study medication in Phase A	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.
Phase A: 24-hour Free Water Clearance	24 hours post dose after Month 1 on study medication in Phase A	Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)	Baseline, and Month 12 of Phase A	htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations	At Baseline, Months 6, 12, 18, and 24 of Phase B	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.
Phase A: Change From Baseline in Growth Percentile by Gender and Age	At Baseline, Months 6 and 12 of Phase A	The growth percentile was based on the assessment of height and weight.
Phase B: Change From Baseline in Growth Percentile by Gender and Age	At Baseline, Months 6, 12, 18, and 24 of Phase B	The growth percentile was based on the assessment of height and weight.
Phase A: Change From Baseline in Creatinine Value	Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, Follow Up Day 7, End of Treatment, and Last Visit	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: Change From Baseline in Creatinine Value	Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Follow Up Day 7, End of Treatment, and Last Visit	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).
Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs	From first dose of study drug up to 14 days post last dose (up to approximately 37 months)	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).
Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)	From first dose of study drug up to 14 days post last dose (up to approximately 37 months)	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.
Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs)	From first dose of study drug up to 14 days post last dose (up to approximately 37 months)	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).
Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations	At Baseline, Months 6 and 12 of Phase A	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.
Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1	Prior to Week 1 in Phase A and B	Participants were instructed to record all fluid taken and all urine output for the 24-hour period.

Countries

Belgium, Germany, Italy, United Kingdom

Participant flow

Recruitment details

Participants took part in the study at 18 sites in Belgium, Germany, Italy, and the United Kingdom from 23 September 2016 to 17 November 2021.

Pre-assignment details

A total of 91 participants with autosomal dominant polycystic kidney disease (ADPKD) were randomized into 2 groups in a 1:1 ratio to receive tolvaptan or matching placebo.

Participants by arm

Arm	Count
Phase A: Tolvaptan Participants received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 12 months. Doses may be titrated down dependent upon participant tolerability.	48
Phase A: Placebo Participants received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 12 months. Doses may be titrated down dependent upon participant tolerability.	43
Total	91

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Phase A: Double-blind Period (12 Months)	Adverse Events	1	0	0	0
Phase A: Double-blind Period (12 Months)	Physician Decision	0	2	0	0
Phase A: Double-blind Period (12 Months)	Withdrawal by Subject	3	1	0	0
Phase B: Open-label Period (24 Months)	Adverse Events	0	0	0	2
Phase B: Open-label Period (24 Months)	Reason Not Specified	0	0	2	1
Phase B: Open-label Period (24 Months)	Withdrawal by Subject	0	0	4	3

Baseline characteristics

Characteristic	Phase A: Placebo	Total	Phase A: Tolvaptan
Age, Continuous	12.8 years STANDARD_DEVIATION 2.8	12.9 years STANDARD_DEVIATION 3	12.9 years STANDARD_DEVIATION 3.2
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	2 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	42 Participants	89 Participants	47 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	2 Participants	2 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	42 Participants	88 Participants	46 Participants
Sex: Female, Male Female	23 Participants	44 Participants	21 Participants
Sex: Female, Male Male	20 Participants	47 Participants	27 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 48	0 / 43	0 / 42	0 / 39
other Total, other adverse events	45 / 48	42 / 43	38 / 42	39 / 39
serious Total, serious adverse events	1 / 48	6 / 43	7 / 42	8 / 39

Outcome results

Primary

Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)

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.

Time frame: Baseline, and Week 1 of Phase A

Population: The FAS included all participants who were randomized to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm	Measure	Group	Value (MEAN)	Dispersion
Phase A: Tolvaptan	Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)	Baseline	1.017 ratio	Standard Deviation 0.006
Phase A: Tolvaptan	Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)	Change From Baseline at Week 1, Phase A	-0.009 ratio	Standard Deviation 0.007
Phase A: Placebo	Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)	Baseline	1.017 ratio	Standard Deviation 0.006
Phase A: Placebo	Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)	Change From Baseline at Week 1, Phase A	-0.002 ratio	Standard Deviation 0.008

Primary

Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)

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.

Time frame: Baseline, and Week 1 of Phase A

Population: The Full Analysis Set (FAS) included all participants who were randomized to a treatment group, received at least 1 dose of the investigational medicinal product (IMP), and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. Number analyzed is the number of participants with data available for analysis at the given time point.

Arm	Measure	Group	Value (MEAN)	Dispersion
Phase A: Tolvaptan	Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)	Baseline	635 milliosmoles per kilogram (mOsm/kg)	Standard Deviation 252
Phase A: Tolvaptan	Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)	Change From Baseline at Week 1, Phase A	-386 milliosmoles per kilogram (mOsm/kg)	Standard Deviation 284
Phase A: Placebo	Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)	Baseline	646 milliosmoles per kilogram (mOsm/kg)	Standard Deviation 250
Phase A: Placebo	Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)	Change From Baseline at Week 1, Phase A	-93 milliosmoles per kilogram (mOsm/kg)	Standard Deviation 332

Secondary

Phase A: 24-hour Creatinine Clearance

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.