Primary objective:* Evaluate long-term effect of tolvaptan in ADPKD through rate of renal volume change(%) for tolvaptan-treated compared to placebo-treated subjects.Secondary objectives:* Evaluate long-term efficacy of tolvaptan in ADPKD through a…
ID
Source
Brief title
Condition
- Renal and urinary tract disorders congenital
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Rate of renal volume (total, both kidneys) change (normalized as percentage)
for tolvaptan (combining all doses) relative to placebo
Secondary outcome
Composite endpoint
Time to multiple ADPKD clinical progression events (ie, onset or progression
hypertension, severe renal pain (requiring medical intervention), worsening
albuminuria, worsening renal function for tolvaptan (combining all doses)
relative to placebo while on treatment.
Non-composite endpoints
For tolvaptan compared to placebo:
1. Rate of GFR change from postdose baseline (End of titration) to last on-drug
trial visit (using l/serumcreatinine as primary measure while Cockcroft-Gault
results will be exploratory).
2. For subjects who are non-hypertensive at baseline, change from baseline for
resting mean arterial pressure (MAP) at scheduled clinic visits up to point of
exposure to anti-hypertensive therapy for any reason.
3. For subjects who are non-hypertensive at baseline, time to progress to a)
high-pre-hypertension (sBP > 129 and/or dBP > 84) or b) hypertension (sBP > 139
and/or dBP > 89 mm Hg) or c) requiring anti-hypertensive therapy
4. For subjects who are taking anti-hypertensive therapy at baseline,
percentage with clinically sustained decrease of BP leading to a sustained
reduction in anti-hypertensive therapy compared to baseline (while taking
investigational product) at visit Months 12, 24 and 36 for hypertensive
subjects.
5. Change from baseline in kidney pain as assessed by 1-10 pain scale as
average AUC between baseline and last trial visit prior to initiating medical
(eg, narcotic or tricyclic) or surgical therapy for pain.
Background summary
Tolvaptan as a specific AVP V2 receptor antagonist, has shown to produce a
dose-related, transient, aquaresis. ADPKD patients have shown a high AVP plasma
concentration.
Animal trials show that treatment with vasopressine antagonist inhibits cyst
growth and in some cases regresses cyst growth.
Three previous studies have shown that ADPKD patients on tolvaptan responded
with potent vasopressine inhibition leading to a delay in the development of
kidney cysts.
Preliminary results from an open-label trial with tolvaptan in ADPKD confirm
that effectivity improves with each higher dose of tolvaptan but also that
higher doses were less tolerated by the patients. As a large degree of
variability in subject response was seen, this trial will implement a titration
strategy. Subjects will start at the relatively low daily dose of 45/15 mg mg
and will progress in three weeks to the highest tolerated dose of 90/30 mg.
Throughout the trial, subjects will have the option to up and down titrate, as
circumstances warrant.
Study objective
Primary objective:
* Evaluate long-term effect of tolvaptan in ADPKD through rate of renal volume
change(%) for tolvaptan-treated compared to placebo-treated subjects.
Secondary objectives:
* Evaluate long-term efficacy of tolvaptan in ADPKD through a composite of
ADPKD progression clinical markers (ie, hypertension, renal pain, albuminuria
and renal function)
* Evaluate long-term efficacy of tolvaptan in ADPKD using single clinical
markers of ADPKD progression
* Evaluate long-term safety of tolvaptan through standard clinical measures
Evaluate pharmacokinetic (PK), pharmacodynamic (PD) and exploratory parameters
for tolvaptan in ADPKD
Study design
This is a multi-centre, double-blind, placebo-controlled, parallel-arm trial in
adult subjects with ADPKD
* After determining eligibility, and monitoring of the available data from
screening subjects for baseline event rates, tolvaptan or placebo will be
titrated from lowest to highest tolerated levels when given in split dose
regimens of 45/15, 60/30 or 90/30 mg PO, given BID, on awakening and
approximately 9 hours later for up to 36 months.
Intervention
Tolvaptan (using 15 or 30 mg strengths) or matching placebo (randomized in 2:1
ratio) will be self-administered for 36 months, as oral tablets given in
split-dose separated by approximately 9 hours, first dose being given on
awakening.
Regimens include 45/15, 60/30 and 90/30 mg of the standard tolvaptan
formulation and will be titrated to tolerability.
Treatment duration on this trial is 3 years.
Study burden and risks
Possible side effect of tolvaptan, see also page 27-28 of the protocol and page
7-9 of the patient information form version 3.0.
The most commonly reported side effects with tolvaptan were thirst, dry mouth,
frequent urination and non-specific headache.
Some people feel uncomfortable in the MRI machine.
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Age
Inclusion criteria
*GFR estimated at >= 60mL/min
*Expected rapidly progressive kidney growth (total volume >=750cc) by Magnetic Resonance Imaging (MRI) at randomization
Exclusion criteria
* Safety contraindications including: non-compliance with therapies, insufficient or no reproductive precautions, unawareness of thirst, severe allergic reactions to compounds with similar chemical structure
* Contraindications to or interference with MRI assessments
* Concurrent conditions or taking therapies likely to confound endpoint assessments or prevent completion of the trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-002768-24-NL |
| ClinicalTrials.gov | NCT00428948 |
| CCMO | NL13875.042.06 |