Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder of the kidney [8, 18]. Dysregulation of the primary cilium on renal epithelial cells causes localized and unregulated expansion of the nephronic epithelium, resulting in the formation of fluid-filled cysts that grow and ultimately obstruct nephrons, blood vessels, and lymphatics [10]. In general, disease progression is inexorable, with an estimated 45–70% of patients developing end-stage kidney disease (ESKD) by age 65 years [11]. ADPKD is the fourth most common cause of ESKD, after diabetes, hypertension, and glomerulonephritis, accounting for 10% of patients receiving dialysis or kidney transplantation in Europe [17].

Tolvaptan, an oral selective antagonist of the vasopressin V2 receptor, is the only medication for ADPKD that has demonstrated beneficial disease-modifying properties in adults. Phase 3 clinical trials demonstrated the efficacy of tolvaptan in slowing the decline of kidney function in adults with relatively early-stage ADPKD and high likelihood of rapid disease progression (the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 [TEMPO 3:4] trial) and those with more advanced disease (the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial) [19, 21].

The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) established that kidney enlargement is a continuous process in ADPKD, with cysts expanding in young patients years or even decades before renal damage becomes apparent [1, 9, 14]. Cysts steadily develop and grow in children with ADPKD while kidney function remains normal, even as these patients manifest early symptoms such as nocturnal hypertension [12]. It is therefore reasonable to hypothesize that treatment with a disease-modifying agent like tolvaptan prior to adulthood might have beneficial effects on long-term outcomes. Of relevance, a recent case study found that treatment with tolvaptan resolved hyponatremia and prevented kidney enlargement in a female infant with confirmed ADPKD [7]. To further address the potential role of tolvaptan in pediatric disease, the current report describes the rationale and design of the first study to assess the pharmacodynamics (PD), pharmacokinetics (PK), safety, and efficacy of tolvaptan in children and adolescents with ADPKD. The study design was developed, in discussions with regulatory authorities, to provide initial data on the use of tolvaptan in children with ADPKD at high risk of progression, with focus on safety of use, appropriate dosing, and pharmacodynamic activity.

Methods

Subjects

The target population will consist of at least 60 male and female subjects aged 12–17 years who have a diagnosis of ADPKD, as defined by the presence of renal cysts, ADPKD family history, and/or genetic criteria. To be eligible, subjects must have ≥ 10 renal cysts, each measuring ≥ 0.5 cm on magnetic resonance imaging (MRI) inspection. Prospective subjects who are MRI naive should have an ultrasound to confirm the presence of ≥ 4 cysts, each ≥ 1 cm in size, prior to receiving a trial-specific MRI inspection. Subjects aged 4–11 years will also be allowed to enter the study during the recruitment period for the target population, provided they meet entry criteria. For the younger group, MRI assessment is not performed; accordingly, the detection of ≥ 4 renal cysts on ultrasound, each ≥ 1 cm in size, suffices to confirm cyst presence. (Full inclusion/exclusion criteria in Table 1) While the required enrollment is 60 subjects aged 12–17 years, it is expected that the trial may also enroll approximately 40 subjects aged 4–11 years, for a total sample size of approximately 100 subjects.

Table 1 Eligibility requirements
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Study design

This is an ongoing, phase 3b, two-part study (EudraCT number: 2016-000187-42; ClinicalTrials.gov identifier: NCT02964273) [3, 5]. Enrollment started in September 2016, and the estimated primary completion date is December 2019, with study completion anticipated in December 2021 [3]. Twenty study sites located in Belgium, Germany, Italy, and the UK are participating. The trial is being conducted in compliance with FDA regulations, International Conference on Harmonization Good Clinical Practice Guideline (E6), international ethical principles derived from the Declaration of Helsinki, Council for International Organizations of Medical Science guidelines, and applicable local laws and regulations. Age-appropriate assent documents were created.

Phase A

Phase A is a 1-year, randomized, double-blind, placebo-controlled, multicenter trial (Fig. 1). The target population consists of four cohorts (n = 15 per cohort), stratified by gender and age: males and females 15–17 years and males and females 12–14 years. Following double-blind 1:1 randomization, eligible subjects will receive either tolvaptan, administered as 7.5-, 15-, and 30-mg immediate-release tablets, or matching placebo tablets for up to 12 months. Tolvaptan and placebo will be administered every day as split-dose regimens, with the first dose taken upon waking and the second taken 8–9 h later. Each dose will be administered with a recommended 240 mL of water consumed within a 1-h period. Subjects are additionally encouraged to drink plain water per thirst throughout the day and one to two glasses of water before bedtime to help maintain proper hydration status.

Starting doses are based on weight. After 1 week, subjects who tolerate their initial dose will up-titrate once, as noted in Table 2. Subjects may down-titrate at any time in order to determine the range of tolerated doses.

Table 2 Tolvaptan weight-based dosing
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Phase B

Phase B is a 2-year, open-label extension in up to 100 subjects aged 4–17 years who completed phase A on treatment, are willing to continue in the study, and do not have any adverse events (AEs) requiring study drug discontinuation (Fig. 2).

Fig. 1
figure 1

Overall study design of phase A (randomized, double-blind). aSubjects between the ages of 4 and 11 are eligible for the trial but are not included in the age cohorts. ADPKD, autosomal dominant polycystic kidney disease

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Fig. 2
figure 2

Overall study design of phase B (open-label extension)

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Efficacy and pharmacodynamic assessments

Phase A

In phase A, spot urine osmolality and spot urine specific gravity (co-primary endpoints) will be assessed at baseline, week 1, and month 1. Serum creatinine will be assessed at all visits, and serum sodium will be assessed at all visits until month 11. The number of daytime and nighttime voids will be recorded at week 1, month 1, month 6, and month 12, and 24-h fluid balance will be evaluated at week 1.

Subjects 12–17 years of age will have their kidneys scanned by MRI according to published standards [19] at screening and month 12. All subjects will have renal pelvic measurements by ultrasound at screening, month 1, and month 12. Subsequent measurement of kidney dimensions and evaluation of height-adjusted TKV will be performed at a central laboratory by individuals blinded to treatment assignment. As treatment effects on TKV or kidney function may be difficult to discern in a pediatric population with early-stage disease, pharmacodynamic parameters were considered the most appropriate co-primary endpoints for this study. Percent change from baseline to month 12 in height-adjusted TKV was designated as the key secondary endpoint. All primary, secondary, and exploratory endpoints of the trial, for both the 12–17- and the 4–11-year-old age groups, are listed in Table 3.

Table 3 Endpoints of the study
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Phase B

In phase B, serum creatinine and serum sodium assessments will occur at all visits until month 24. Twenty-four-hour fluid balance will be evaluated at week 1. MRI scans of the kidney will occur at month 12 and month 24. Renal pelvic measurements by ultrasound will occur at month 1 and month 12.

Pharmacokinetic assessments

During phase A only, sparse PK blood samples will be collected from all subjects at week 1, month 1, month 6, and month 12 for determination of steady-state concentrations of plasma tolvaptan and metabolites.

In addition, after at least 1 month on treatment during phase A, a subset of 20 consenting subjects in the 12–17-year-old age group (10 on tolvaptan and 10 on placebo) will undergo dense PK and PD sampling for 24 h following the schedule and procedures described by Shoaf et al. [16]. The blind in phase A will be maintained in this dense PK subpopulation via an Interactive Response System [13].

Subject-reported outcome assessments

Subject-reported outcomes are assessed using generic pediatric quality-of-life questionnaires and information relevant to the medical, social, and economic consequences of new and ongoing ADPKD-related morbidities.

Safety assessments

Safety is assessed throughout the study by AE assessments, clinical laboratory results, physical examination, vital signs, and 12-lead electrocardiogram. At each study visit, the investigator elicits AEs with a nonleading question, and all AEs reported by a subject must be recorded. Subjects in this study will be tested for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (BT) at screening/baseline and for ALT and AST at week 1 and every month for the duration of the study. The appearance of any suspicious symptom or sign in the investigator’s clinical judgment (a liver function test 2 × upper limit of normal [ULN] is generally accepted as a clinically significant occurrence across various medical disciplines) will trigger prompt re-testing, i.e., within 48–72 h. If significant abnormalities in transaminases and/or bilirubin are confirmed, other testing to fully evaluate the likely proximate cause will be undertaken, with the option of consulting local hepatic experts for interpretation and guidance. In addition, a hepatic adjudication committee has been convened for the purpose of oversight of hepatic events.

Liver transaminase or bilirubin levels reaching or exceeding 2 × ULN that have an uncertain or rapidly increasing trajectory will prompt at least temporary interruption of tolvaptan. Following interruption, tolvaptan will not be resumed until monitoring indicates abnormalities have resolved, are stable, or are not rapidly increasing, and then only with an increased frequency of monitoring (e.g., once weekly until returning to monthly monitoring at the discretion of the investigator) and if deemed appropriate in the clinical judgment of the investigator. A subject will be discontinued from the study on confirmation of any of the following criteria: ALT or AST ≥ 8 × ULN; ALT or AST ≥ 5 × ULN for more than 2 weeks; ALT or AST ≥ 3 × ULN and either BT ≥ 2 × ULN or international normalized ratio > 5; and ALT or AST ≥ 3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) and signs of jaundice.

Statistics

Phase A will have two co-primary endpoints: change from baseline in spot urine osmolality and specific gravity (premorning dose) after 1 week of daily dosing. For the primary endpoint analysis, a sample size of at least 60 subjects aged 12–17 years inclusive is expected. Since data will be summarized using descriptive statistics and are aimed at testing safety and tolerability, no formal power calculations were undertaken.

Efficacy assessments will be conducted on the full analysis set, defined as subjects who have been randomized to a treatment group, have received at least one dose of study drug, and have both a phase A baseline and at least one post-baseline efficacy evaluation. Subgroup analyses of the primary and key secondary endpoints will be performed to examine differences in treatment response based on phase A baseline status (e.g., gender, age stratum). For all secondary endpoints, descriptive statistics by visit will be presented.

Safety analyses will be conducted on all subjects who received one dose of study drug. Summary statistics of changes from phase A and phase B baseline will be provided for safety variables based on all available data.

Discussion

The purpose of the study described here is to assess the safety, tolerability, PD, PK, and efficacy of tolvaptan in children with ADPKD. As this will be the first study to assess tolvaptan in pediatric subjects with ADPKD, a number of features associated with the study population have been considered and addressed. For example, it is expected that very few, if any, of the screened participants will present with disease-specific symptoms, and formal diagnostic criteria for ADPKD so early in disease progression have yet to be developed. To circumvent this issue, an advisory panel of experts was convened to develop screening standards. The consensus opinion was that family history/genetics, cyst number as assessed by MRI (or ultrasound in younger subjects), and progression of disease that would warrant treatment are together the most reasonable approach to diagnose early disease. Therefore, to be eligible for enrollment, subjects must have a family history and/or genetic criteria for ADPKD and ≥ 10 renal cysts, each measuring ≥ 0.5 cm on MRI; subjects under the age of 12 years must have ≥ 4 cysts, each measuring ≥ 1 cm on ultrasound.

The early stage of polycystic kidney disease in the pediatric study population also complicates efficacy assessments. Post hoc analyses of TEMPO 3:4 showed that the beneficial treatment effects of tolvaptan on TKV and eGFR were similar across chronic kidney disease (CKD) stages, including among subjects early in disease progression (CKD 1) [20]. Although clinically significant, the absolute changes in TKV growth and eGFR decline versus placebo were nonetheless relatively small across CKD stages and could be particularly difficult to detect in pediatric subjects. Given that a large sample size and long follow-up would likely be necessary to discern treatment effects on TKV growth and eGFR decline in a pediatric population, the study steering committee and regulatory authorities agreed that pharmacodynamic effects would be more practicable and informative primary study endpoints in a first trial of tolvaptan for the treatment of pediatric ADPKD. Accordingly, the co-primary endpoints are change from baseline in spot urine osmolality and in urine specific gravity. These endpoints will assess whether tolvaptan acts in the same way in children/adolescents as it does in adults, which has not been examined before. Results from these analyses should inform the choice of assessments in future pediatric trials.

In adults, optimal ADPKD treatment requires constant 24-h inhibition of the V2 receptor, and patients are thus typically encouraged to take maximally tolerated doses. Adults receive a split-dosing regimen to maintain suppression of vasopressin action across 24 h, consisting of a higher dose early in the day, followed by a lower dose approximately 8–9 h later. The primary tolerability concern with tolvaptan dosing is excretion of solute-free water, or aquaresis, which manifests as polyuria (production of large volumes of dilute urine), polydipsia (excess thirst and drinking), nocturia (need to wake up to urinate at night), and pollakiuria (abnormally frequent urination) [19]. Post hoc analyses of the TEMPO 3:4 study population showed that aquaretic AEs resulting in tolvaptan discontinuation were more likely in subjects with higher baseline renal function [4]. Furthermore, sensitivity to aquaretic effects appeared to be highest during initial titration of the drug [4].

Combined, the adult data on aquaresis suggest that the current study’s pediatric ADPKD population, with its high renal clearance capacity and younger age demographic, could be especially sensitive to aquaretic AEs, particularly early during titration. Subjects within each cohort will therefore initiate treatment at a weight-adjusted split starting dose that is no greater than 67% of the maximal weight-adjusted starting dose for the adult subjects in TEMPO 3:4. This low starting dose will be administered for 1 week to allow acclimation to the excess diuresis commonly associated with tolvaptan and, hopefully, to avoid potential problems with aquaretic AEs early in titration. Only after 1 week at the starting dose, if tolerated, will the dosage be up-titrated once to the weight-adjusted starting dose used in TEMPO 3:4. As is the case with adult dosing, participants will receive a higher dose early in the day, followed by a lower dose administered approximately 8–9 h later, which produces maximal inhibition on waking and a gradual fall-off of effect during the night, when frequent urination would lead to interruption of sleep.

The most notable safety issue with tolvaptan in adult ADPKD studies was the potential for idiosyncratic hepatic toxicity [22]. To mitigate this risk, the frequency of liver function testing was increased from once every 4 months in TEMPO 3:4 to once monthly in REPRISE [22]. Accordingly, subjects in the current pediatric study will be tested for ALT/AST, ALP, and BT during screening and for ALT/AST at week 1 and monthly during the entire trial. Evidence of liver damage will be assessed by the local physician, an independent hepatic adjudication committee, and an independent data monitoring committee. In addition, stringent drug interruption rules will be employed to ensure rapid response to any potential hepatic signals.

The current study has some potential limitations resulting from its design. First, the dramatic difference in aquaretic effect between tolvaptan and placebo may lead the subject and/or investigator to perceive treatment assignment. The prescription of additional fluids to subjects during study drug administration may serve to confound this effect, and it should be noted that the pharmacodynamic and efficacy endpoints are objective and unlikely to be affected by the participant’s perceptions. Second, the study inclusion criteria relating to ADPKD diagnosis and cyst burden are largely opinion-based, and their predictive value for early disease progression remains unknown. The criteria are justifiable, however, given study data indicating that cyst burden correlates with the presence of hypertension in pediatric ADPKD patients, and that hypertension is predictive of rapid disease progression in this population [2, 6, 12]. Finally, tolerability of tolvaptan in a population that still has good renal function may be dose limiting or could cause early tolvaptan discontinuation. Nonetheless, the current study is expected to provide valuable information on the safety, tolerability, PD, PK, and efficacy of tolvaptan in pediatric patients with ADPKD and potentially inform the design of trials intended to assess therapeutic efficacy in this population.