Chronic Kidney Disease
Conditions
Brief summary
To assess the effects of 12 weeks of treatment with lanthanum carbonate compared with placebo on serum intact Fibroblast Growth Factor 23 (FGF23) levels.
Interventions
DRUGLanthanum carbonate
1000 mg in chewable tablets administered three times a day (for a total of 3000 mg/day) for 12 weeks
DRUGPlacebo
Matching placebo chewable tablets administered 3 times a day for 12 weeks
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects meeting all of the criteria listed below may be included in the study: 1. ≥18 years old. 2. Male, or non-pregnant, non-lactating females who agree to comply with any applicable contraceptive requirements of the protocol. 3. Been in the care of a physician for CKD for \>2 months, and are not expected to begin dialysis for at least 6 months. 4. Screening serum c-terminal FGF23 \> 50.0RU/mL. 5. Screening estimated glomerular filtration rate (eGFR) of 30-59mL/min/1.73m2 using the MDRD formula. 6. Normal serum phosphate (0.808-1.55mmol/L). 7. Endogenous 25-hydroxy Vitamin D levels \>20ng/mL. 8. Adequate protein diet (includes 2-3 portions of protein-rich food per day). 9. An understanding, ability, and willingness to fully comply with study procedures and restrictions. 10. Ability to provide written, signed, and dated (personally) informed consent to participate in the study.
Exclusion criteria
1. Vitamin D supplementation required. 2. Compounds containing calcium, phosphate, aluminium or magnesium required. 3. Acute renal failure. 4. Rapidly progressing glomerulonephritis. 5. Vegetarian diet. 6. Known allergy to iodine. 7. Clinically significant uncontrolled concurrent illness, which, in the opinion of the Investigator, would impair subjects' ability to give informed consent or take part in or complete this clinical study. 8. Cirrhosis or other clinically significant liver disease (aspartate transaminase (AST) or alanine transaminase (ALT) \>3 times the upper limit of normal or bilirubin \>2 times the upper limit of normal). 9. Past (treated within the last 5 years) or present GI disorders including uncontrolled peptic ulcer, Crohn's disease (or other conditions where the integrity of the GI tract may be compromised), malignancy, or GI bleed within the last 6 months. 10. Life-threatening malignancy or current multiple myeloma. 11. Known to be Human Immunodeficiency Virus (HIV) positive. 12. History of poor compliance with diet or medication that in the Investigator's opinion may interfere with adherence to the protocol. 13. History of alcohol or other substance abuse within 6 months prior to screening. 14. Subjects must not have used another investigational medicinal product or taken part in a clinical trial within the last 30 days prior to enrolment. 15. Subjects who have previously been enrolled into this study and subsequently withdrawn.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Natural Logarithm Transformed Serum Intact Fibroblast Growth Factor (FGF-23) Levels at Week 12 Last Observation Carried Forward (LOCF) | 12 Weeks | FGF-23 plays an important role in mineral metabolism in chronic kidney disease patients. It is secreted by bone cells in response to hyperphosphatemia. It acts to decrease renal phosphate reabsorption. Administration of a phosphate-binder (i.e. lanthanum carbonate) was expected to produce a reduction in FGF-23 levels. |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in 1,25-Dihydroxy Vitamin D Values at Week 12 (LOCF) | 12 weeks |
| Change From Baseline in Urinary Fractional Excretion of Phosphate Values at Week 12 (LOCF) | 12 weeks |
| Change From Baseline in Serum Intact Parathyroid Hormone (iPTH) Values at Week 12 (LOCF) | 12 Weeks |
| Change From Baseline in Serum Total Calcium Values at Week 12 (LOCF) | 12 weeks |
| Change From Baseline in Calcium-Phosphate Product Values at Week 12 (LOCF) | 12 weeks |
| Change From Baseline in Serum Phosphate Values at Week 12 (LOCF) | 12 weeks |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lanthanum Carbonate 1000 mg in chewable tablets (given as 2 x 500 mg tablets) administered three times a day (for a total of 3000 mg/day) for 12 weeks | 23 |
| Placebo Matching placebo chewable tablets administered 3 times a day for 12 weeks | 12 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Lanthanum Carbonate | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 66.0 years STANDARD_DEVIATION 13.9 | 69.4 years STANDARD_DEVIATION 13.2 | 67.2 years STANDARD_DEVIATION 13.6 |
| Age, Customized >=18 years | 23 Participants | 12 Participants | 35 Participants |
| Region of Enrollment France | 23 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Female | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 13 Participants | 5 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 23 | 0 / 12 |
| serious Total, serious adverse events | 2 / 23 | 0 / 12 |
Outcome results
Primary
Natural Logarithm Transformed Serum Intact Fibroblast Growth Factor (FGF-23) Levels at Week 12 Last Observation Carried Forward (LOCF)
FGF-23 plays an important role in mineral metabolism in chronic kidney disease patients. It is secreted by bone cells in response to hyperphosphatemia. It acts to decrease renal phosphate reabsorption. Administration of a phosphate-binder (i.e. lanthanum carbonate) was expected to produce a reduction in FGF-23 levels.
Time frame: 12 Weeks
Population: Per-protocol (PP) set are subjects who received at least 1 dose of investigational product and who had primary data assessment available from Week 2 or later and who did not have pre-defined major protocol deviations that could have affected the primary variable.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Natural Logarithm Transformed Serum Intact Fibroblast Growth Factor (FGF-23) Levels at Week 12 Last Observation Carried Forward (LOCF) | 4.0089 pg/ml | Standard Error 0.0709 |
| Placebo | Natural Logarithm Transformed Serum Intact Fibroblast Growth Factor (FGF-23) Levels at Week 12 Last Observation Carried Forward (LOCF) | 4.1210 pg/ml | Standard Error 0.0844 |
Comparison: Assuming that the natural logarithm transformed serum intact FGF-23 is normally distributed with a mean of 3.5 and a standard deviation of 0.46, 33 subjects randomised 2:1 (lanthanum carbonate to placebo) will be sufficient to detect with 80% power at the 5% 2-sided significance level a decrease of 0.5 in the mean difference (placebo minus lanthanum carbonate) of the log-transformed data at Week 12.p-value: 0.318695% CI: [-0.3389, 0.1146]ANCOVA
Secondary
Change From Baseline in 1,25-Dihydroxy Vitamin D Values at Week 12 (LOCF)
Time frame: 12 weeks
Population: PP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Change From Baseline in 1,25-Dihydroxy Vitamin D Values at Week 12 (LOCF) | -1.75 pg/ml | Standard Error 3.22 |
| Placebo | Change From Baseline in 1,25-Dihydroxy Vitamin D Values at Week 12 (LOCF) | -6.86 pg/ml | Standard Error 3.85 |
Comparison: The null hypothesis was that there would be no difference between the 2 treatment groups in the mean change from baseline of 1,25-Dihydroxy Vitamin D at Week 12 (LOCF) when utilizing an analysis of covariance (ANCOVA) with treatment as a factor and the baseline 1,25-Dihydroxy Vitamin D as a covariate. The study was not powered for the analysis of this parameter.p-value: 0.325295% CI: [-5.36, 15.57]ANCOVA
Secondary
Change From Baseline in Calcium-Phosphate Product Values at Week 12 (LOCF)
Time frame: 12 weeks
Population: PP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Change From Baseline in Calcium-Phosphate Product Values at Week 12 (LOCF) | 0.0581 mmol^2/L^2 | Standard Error 0.0833 |
| Placebo | Change From Baseline in Calcium-Phosphate Product Values at Week 12 (LOCF) | 0.0710 mmol^2/L^2 | Standard Error 0.0993 |
Comparison: The null hypothesis was that there would be no difference between the 2 treatment groups in the mean change from baseline of Calcium-Phosphate Product at Week 12 (LOCF) in an analysis of covariance (ANCOVA) with treatment as a factor and the baseline Calcium-Phosphate Product as a covariate.p-value: 0.92295% CI: [-0.2811, 0.2553]ANCOVA
Secondary
Change From Baseline in Serum Intact Parathyroid Hormone (iPTH) Values at Week 12 (LOCF)
Time frame: 12 Weeks
Population: PP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Change From Baseline in Serum Intact Parathyroid Hormone (iPTH) Values at Week 12 (LOCF) | 1.67 pg/ml | Standard Error 3.96 |
| Placebo | Change From Baseline in Serum Intact Parathyroid Hormone (iPTH) Values at Week 12 (LOCF) | -4.87 pg/ml | Standard Error 4.72 |
Comparison: The null hypothesis was that there would be no difference between the 2 treatment groups in the mean change from baseline of serum iPTH at Week 12 (LOCF) in an analysis of covariance (ANCOVA) with treatment as a factor and the baseline iPTH as a covariate. The study was not powered for the analysis of this parameter.p-value: 0.299595% CI: [-6.15, 19.23]ANCOVA
Secondary
Change From Baseline in Serum Phosphate Values at Week 12 (LOCF)
Time frame: 12 weeks
Population: PP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Change From Baseline in Serum Phosphate Values at Week 12 (LOCF) | 0.0053 mmol/L | Standard Error 0.0371 |
| Placebo | Change From Baseline in Serum Phosphate Values at Week 12 (LOCF) | 0.0350 mmol/L | Standard Error 0.0443 |
Comparison: The null hypothesis was that there would be no difference between the 2 treatment groups in the mean change from baseline of Serum Phosphate at Week 12 (LOCF) in an analysis of covariance (ANCOVA) with treatment as a factor and the baseline Serum Phosphate as a covariate. The study was not powered for the analysis of this parameterp-value: 0.613495% CI: [-0.1492, 0.0897]ANCOVA
Secondary
Change From Baseline in Serum Total Calcium Values at Week 12 (LOCF)
Time frame: 12 weeks
Population: PP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Change From Baseline in Serum Total Calcium Values at Week 12 (LOCF) | 0.0242 mmol/L | Standard Error 0.0323 |
| Placebo | Change From Baseline in Serum Total Calcium Values at Week 12 (LOCF) | -0.0052 mmol/L | Standard Error 0.0385 |
Comparison: The null hypothesis was that there would be no difference between the 2 treatment groups in the mean change from baseline of Serum Total Calcium at Week 12 (LOCF) in an analysis of covariance (ANCOVA) with treatment as a factor and the baseline Serum Total Calcium as a covariate. The study was not powered for the analysis of this parameter.p-value: 0.563695% CI: [-0.0739, 0.1328]ANCOVA
Secondary
Change From Baseline in Urinary Fractional Excretion of Phosphate Values at Week 12 (LOCF)
Time frame: 12 weeks
Population: PP
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Change From Baseline in Urinary Fractional Excretion of Phosphate Values at Week 12 (LOCF) | -5.9 percentage of excretion of phosphate | Standard Error 1.5 |
| Placebo | Change From Baseline in Urinary Fractional Excretion of Phosphate Values at Week 12 (LOCF) | -2.2 percentage of excretion of phosphate | Standard Error 1.9 |
Comparison: The null hypothesis was that there would be no difference between the 2 treatment groups in the mean change from baseline of Urinary Fractional Excretion of Phosphate at Week 12 (LOCF) when utilizing an analysis of covariance (ANCOVA) with treatment as a factor and the baseline Urinary Fractional Excretion of Phosphate as a covariate. The study was not powered for the analysis of this parameter.p-value: 0.145995% CI: [-8.845, 1.403]ANCOVA