To demonstrate the effect of salt and/or protein intake on aquaresis in patients with ADPKD who are treated with a vasopressin V2 receptor antagonist as measured by 24-hour urine volume.
ID
Source
Brief title
Condition
- Renal and urinary tract disorders congenital
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome variable will be change in 24-hour urine volume as a
percentage, comparing with the mean of the two 24-hour urine volumes collected
at baseline versus the mean of the two volumes collected at the end of the
two-week treatment periods with low salt, low protein and placebo.
Secondary outcome
Secondary outcomes of this study will be changes in serum copeptin levels (the
stable precursor of vasopressin), changes in mGFR (iohexol clearance), changes
in blood pressure and quality of life using a questionnaire. Adverse events
will be monitored, serum electrolytes will be checked.
Background summary
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the
formation of numerous cysts in both kidneys and progressive renal function
decline leading to renal replacement therapy (RRT) at a median age of 58 years.
The first (and at the moment only) drug to slow down renal function decline, is
a vasopressin V2 receptor antagonist (V2RA). This medicament slows renal
function decline by 26 to 34%. V2RA also causes aquaresis associated
side-effects such as polyuria of >6 liter per day in the majority of patients.
These side-effects limit wide spread use among ADPKD-patients. Therefore, there
is a need to improve its tolerability. Currently, an METc-approved study is
performed in which the influence of hydrochlorothiazide and metformin on urine
volume while treated with a V2RA is investigated (METc 2017.662). While using a
V2RA, urine concentrating ability is strongly diminished. Therefore, urine
volume is largely determined by total osmolar excretion. This is a well-known
fact in nephrogenic diabetes insipidus, a disease with clear pathophysiological
similarities to treatment with a vasopressin V2 receptor antagonist (a defect
receptor versus pharmacological blockade). In a recent study we found osmolar
excretion to be associated with urinary volume during V2RA treatment. Whether a
change in osmolar load changes polyuria during V2RA has not yet been
investigated. Furthermore, it is not known whether change in sodium or protein
influence the aquaresis to the same amount.
Study objective
To demonstrate the effect of salt and/or protein intake on aquaresis in
patients with ADPKD who are treated with a vasopressin V2 receptor antagonist
as measured by 24-hour urine volume.
Study design
After screening, subjects enter a first run-in period in which compliance to
the recommended diet is assessed. When subjects comply to the salt- and protein
recommendations, they enter a second run-in period with addition of 6 grams of
salt and 40 grams of protein. After run-in, four treatment periods start.
During the four treatment periods, subjects will receive:
1. Sodium chloride capsules of 750 mg 2dd4 (= 6 gram extra) or matching placebo.
2. Protein beverage with 40 grams of protein per day or matching placebo.
Intervention
After screening, subjects enter a first run-in period in which compliance to
the recommended diet is assessed. When subjects comply to the salt- and protein
recommendations, they enter a second run-in period with addition of 6 grams of
salt and 40 grams of protein. After run-in, four treatment periods start.
During the four treatment periods, subjects will receive:
• Salt continuation - protein continuation
• Salt continuation - protein restriction (placebo)
• Salt restriction (placebo) - protein continuation
• Salt and protein restriction (placebo, placebo)
Study burden and risks
Patients who are using tolvaptan as part of regular clinical care will be
included. These patients have frequent visits and there is a need to control
laboratory values every month during the first 18 months of treatment.
Participating in this study entails a minimum of 2-4 extra visits within 8
weeks of treatment plus the run-in period (6 study visits versus 2-4 in regular
care). Run-in period can be extended unlimited times until the subject complies
to the recommended diet. Extending the run-in period will be discussed with the
subject and will be scheduled after the subject gives oral approval.
Patients have to comply to a diet which is low in salt (6 g/day) and protein
intake (0,8 g/kg ideal body weight), which is in accordance with the advices
for healthy food in the national guidelines for treatment of chronic kidney
disease.
Other study procedures are:
- Minimum of 6 times 2x24-hours urine collections;
- 6 times venous blood samples;
- 6 times collecting spot urine;
- 5 times GFR measurement (iohexol method)
- 6 times 3-day diet diary
Possible discomfort/risks associated with intervention
- Increased aquaretic side-effects during high-salt and high-protein
intervention such as polyuria, thirst, polydipsia and nocturia;
- The high salt diet may lead to a modest increase in mean arterial pressure,
however these effects are only temporarily (maximal 6 weeks) and reversible
after returning to the reduced salt intake and pose no danger. Moreover, for
most patients, this is normal salt intake.
Potential benefit of participation
There are no expected direct benefits to participation. However, participants
will receive dietary advice from a dietician and have to comply to a diet which
is low in salt and protein intake for at least 12 weeks. This diet is in
accordance with the guideline chronic kidney disease, so participating in this
study gives subjects the opportunity to implement this diet to their regular
life style. Furthermore, the study will gain insight in dietary factors
influencing urine volume and lead to advices the patient can use during the
rest of the V2RA treatment.
Hanzeplein 1
Groningen 9700RB
NL
Hanzeplein 1
Groningen 9700RB
NL
Listed location countries
Age
Inclusion criteria
1. Diagnosis of ADPKD, based upon modified Ravine criteria, or documented by
their nephrologist or internist.
2. Prescribed tolvaptan as part of routine clinical care in the highest dose
tolerable (preferably 120 mg daily)
3. Age >= 18 years.
4. eGFR >30 ml/min/1.73m2.
5. Providing informed consent.
6. Compliance to the recommended diet (<9 grams of salt per day, < 1,2 grams of
protein per kg ideal bodyweight per day) at two consecutive times.
Exclusion criteria
1. Patients who, in the opinion of the investigator may present a safety risk.
2. Patients who are unlikely to adequately comply to the trial*s procedures
(due for instance to medical conditions likely to require interruption or
discontinuation, history of substance abuse or non-compliance).
3. a. Patients taking medication likely to confound endpoint assessments
(lithium, systemic corticosteroids, diuretics).
3. b. Patients having concomitant illnesses likely to confound endpoint
assessments (e.g. diabetes mellitus for which medication is needed or diabetes
insipidus).
4. Women who are pregnant or breastfeeding.
5. Patients with limited access to water.
6. Patients with an abnormal sense of thirst.
Design
Recruitment
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 |
|---|---|
| CCMO | NL71622.042.19 |
| Other | Volgt, protocol is onder beoordeling van www.clinicaltrials.gov |