Clinical trial NCT00843349: Fibroblast Growth Factor-23 (FGF23) Reduction in Predialysis Chronic Kidney Disease (CKD)
Official title: Fibroblast Growth Factor-23 Reduction in Predialysis Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Kidney Disease
Keywords: Phosphorus
Fibroblast Growth Factor-23
Kidney Disease
Lead sponsor: University of Miami
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2009-02-13
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: The investigators would like to study the role of phosphorus metabolism in the development of certain hormonal problems in people with chronic kidney disease (CKD). More specifically, the goals of the research are (1) to understand the cause of hyperparathyroidism - a hormone problem that often develops in patients who have kidney disease and (2) to test whether decreasing phosphorus intake could help improve or prevent hyperparathyroidism.

Detailed description: The purposes of this proposal are to (1) develop pilot data of a treatment strategy that manipulates phosphate loading in an effort to ameliorate the development of secondary hyperparathyroidism by increasing endogenous calcitriol levels, which itself, along with decreased phosphate levels, may be potential survival factors; (2) examine the effect of phosphorus restriction/fibroblast growth factor-23 (FGF-23)reduction strategies on insulin resistance and cardiac structure and function in individuals with renal dysfunction. If this proof-of-concept study validates our approach, we will embark on larger trials with extended follow up that would aim to show that the treatment window of phosphate reduction strategies should be expanded to the millions of normophosphatemic patients with early-stage CKD with the ultimate goal being improved survival.

We hypothesize will test the following hypotheses:

1. Decreased dietary phosphorus loading in chronic kidney disease (CKD) patients with normal serum phosphate levels, through dietary restriction, treatment with dietary phosphate binders or a combination of both, will lead to decreased FGF-23 levels, increased calcitriol levels and decreased parathyroid hormone (PTH) levels. In an effort to understand the magnitude and effectiveness of our interventions according to CKD stage, we will test the hypothesis in an equal number of stage 3a (estimated Glomerular Filtration Rate or eGFR 45 - 60 ml/min), stage 3b (eGFR 30 - 45 ml/min) and stage 4 (eGFR 15 - 30 ml/min) CKD patients. This will allow us to define the optimal timing along the spectrum of CKD when our interventions will be most effective which will be critical for planning future longer term outcome studies.
2. Subjects who receive phosphorus reduction strategies will display increased calcitriol levels and decreased insulin resistance from baseline to post-intervention compared to subjects who are randomized to the control arm. The degree of improvement will be modulated such that those who receive both dietary phosphorus restriction and phosphorus binders will display the greatest change.
3. Decreased levels of FGF-23, resulting from phosphorus restriction interventions, will be associated with improved cardiac function, particularly measures of diastolic function as evaluated by pre- and post-intervention echocardiograms.

Overview of Study Design

* Randomized, double-blinded, placebo controlled, physiological, crossover study with a 2 x 2 factorial design of CKD patients
* Written, informed consent will be obtained from all potential subjects at an initial screening visit at the General Clinical Research Center (GCRC), after which they will undergo a brief history and physical, and baseline blood measurements to determine eligibility.
* A certified nutritionist will evaluate subjects' baseline dietary intake during the two week run-in period.
* Eligible subjects will provide two 24-hour urine collections on separate days prior to initiating the protocol to calculate their creatinine clearance and estimate their mean urinary Pi and calcium excretion while eating their usual diets.
* This run-in period will be followed by randomization to binders (Lanthanum Carbonate) vs. placebo and to a phosphorus restricted vs. unrestricted diet
* 25% of subjects will receive binders + restricted diet; 25% binders + unrestricted diet; 25% placebo + restricted diet; and 25% placebo + unrestricted diet (the control group)
* Block randomization will ensure that the 4 intervention groups will include 10 subjects each from CKD stages 3a, 3b and 4 (120 total)
* The nutrition interventions will be managed by a certified nutritionist
* Subjects who are randomized to the unrestricted phosphorus diet arms will be encouraged to maintain their normal eating habits and will not receive any specific dietary counseling from the nutritionist.
* Subjects who are randomized to the phosphorus restriction arms will receive dietary counseling to reduce their phosphorus intake to a target of 900mg/day. If their intake is already estimated to be below that level, they will be encouraged to maintain their current intake. Subjects with lower phosphorus intake at baseline (\<900 mg/d) who are randomized to the unrestricted phosphorus diet will not be encouraged to increase their intake.
* All subjects will take a pill, either the phosphorus binder lanthanum carbonate or a placebo, to ensure subject blinding.
* The nutritionist will meet with all subjects regardless of whether they are consuming a reduced phosphate diet or their normal diet. Since it is difficult to reduce phosphorus intake, subjects who are randomized to phosphorus restriction arms will be aware of their intervention. However, subjects who are randomized to the unrestricted phosphorus diet will not be told of their randomization. The nutritionist will counsel them on healthy eating habits as a form of "placebo".
* Three months of follow up post randomization, during which:

  * Fasting blood and urine measures will be repeated every two weeks after randomization throughout the three month intervention. Data for the study endpoints as well as safety data (see below) will be collected at these time points.
  * A certified nutritionist will counsel subjects randomized to the phosphorus restricted diet on how to substitute foods in their diet that are high in phosphorus with foods of equivalent nutritional value that are lower in phosphorus using counseling techniques employed in routine clinical practice. The nutritionist will not advise subjects that are randomized to an unrestricted phosphorus diet to change their eating habits in any way.
  * The nutritionist will use 3-day food records to evaluate the intake of all study subjects over the 3 month intervention. Subjects will receive their first 3-day food record form at the screening visit (visit 1) and return it on visit 2 to be examined by the study nutritionist in preparation for counseling. After the initial counseling session, subjects will bring their completed 3-day food records to the GCRC at visits 4, 7 and 9.
* All subjects will undergo a limited echocardiogram to measure physiological changes in diastolic function pre- and post-intervention.

Eligibility criteria: Inclusion Criteria:

* We will include stage 3a, 3b and 4 CKD patients, aged 18 years or over with normal serum phosphate levels (≤ 4.6 mg/dl)

Exclusion Criteria:

* Patients with rapidly advancing renal failure who thus might develop hyperphosphatemia or end stage renal disease requiring initiation of dialysis during the study period
* Patients expected to require dialysis initiation within the follow up period
* Patients with hyperphosphatemia \> 4.6 mg/dl
* Patients with any previous or current treatment with phosphate binders or active vitamin D (doxercalciferol or calcitriol)
* Malnutrition, defined as a serum albumin \< 3.0 mg/dl
* Patients with liver disease (ALT or AST \> 100 U/L) or cholestasis (direct bilirubin \> 1.0 mg/dl) because this can limit their ability to absorb fat soluble vitamins such as vitamin D
* Anemia, defined as a hematocrit \< 27% at the screening visit
* Medical conditions impacting Pi metabolism-primary hyper- or hypoparathyroidism; Patients with previous subtotal parathyroidectomy; gastrointestinal malabsorption disorders such as Crohn's Disease, ulcerative colitis, celiac disease, or severe liver dysfunction;
* Patients with outpatient counseling by a renal nutritionist within the previous 6 months
* Hospitalization within the previous 4 weeks
* Pregnancy or breastfeeding mothers
* Patients unable to independently provide written informed consent - prisoners, mentally incompetent, minors

Primary outcomes:
measure: Percentage Changes in Fibroblast Growth Factor-23 (FGF-23) Levels
timeFrame: Week 0 - 12
measure: Percentage Changes in Parathyroid Hormone (PTH) Levels
timeFrame: Week 0 - 12
Secondary outcomes:
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami Hospital
state: Florida
Study officials:
affiliation: University of Miami
name: Myles Wolf, MD, MMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Isakova T, Barchi-Chung A, Enfield G, Smith K, Vargas G, Houston J, Xie H, Wahl P, Schiavenato E, Dosch A, Gutierrez OM, Diego J, Lenz O, Contreras G, Mendez A, Weiner RB, Wolf M. Effects of dietary phosphate restriction and phosphate binders on FGF23 levels in CKD. Clin J Am Soc Nephrol. 2013 Jun;8(6):1009-18. doi: 10.2215/CJN.09250912. Epub 2013 Mar 7.