Chronic Kidney Disease, Hyperphosphatemia
Conditions
Keywords
Chronic Kidney Disease, Pediatric, Sevelamer Carbonate, Hyperphosphatemia
Brief summary
Objective: In hyperphosphatemic pediatric participants with chronic kidney disease (CKD) to * Evaluate the safety and tolerability of sevelamer carbonate * Evaluate the efficacy of sevelamer carbonate on the control of serum phosphorus
Detailed description
The study was divided into 3 periods: a phosphate binder washout Period; a randomized, double-blind, placebo-controlled, Fixed Dose Period; and an open-label, sevelamer carbonate Dose Titration Period.
Interventions
DRUGPlacebo
Placebo for 0.8 g sachets of powder for oral suspension or 800 mg tablets
DRUGSevelamer carbonate
0.8 g sachets of powder for oral suspension or 800 mg tablets
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
* The participant had CKD requiring dialysis or CKD not on dialysis with an estimated glomerular filtration rate (GFR) \<60 mL/min/1.73 m\^2 based on central laboratory results. * The participant had a serum phosphorus level greater than the age appropriate upper limit of normal based on central laboratory results.
Exclusion criteria
* The participant had active dysphagia, swallowing disorders or a predisposition to or current bowel obstruction, ileus or severe gastrointestinal motility disorder(s) including severe constipation, or major gastrointestinal tract surgery. * The participant had a non-renal case of hyperphosphatemia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | Baseline, Week 2 | Full analysis set for fixed dose period (FAS-FDP) participants were analyzed according to their randomized treatment. The change in serum phosphorus (mg/dL) from baseline to week 2 was calculated. |
| Treatment - Emergent Adverse Events (AEs) | Up to 32 weeks (up to 4 weeks washout period, 2 weeks FDP and 26 weeks DTP) | A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. AEs from the time of signing the informed consent through the end of the study for all participants. SAEs occurring during the 15 days following study completion or early termination were also to be collected. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | Baseline, Week 28/Early Termination | Full analysis set for dose titration period (FAS-DTP) participants were analyzed according to their randomized treatment. The change in serum phosphorus (mg/dL) from baseline to Week 28/Early Termination was calculated. |
Countries
France, Germany, Lithuania, Poland, United States
Participant flow
Recruitment details
The study was conducted at 29 centers in 4 countries. A total of 128 participants were screened between 11 May 2012 and 14 November 2014. Of whom, 101 participants were randomized and 27 were screen failures.
Pre-assignment details
Participants were stratified in (1:1) by screening body surface area (BSA) (≥1.2 vs \<1.2 m\^2) & qualifying serum phosphorus (≥7.0 vs \<7.0 mg/dL) to get sevelamer carbonate or placebo in 2 week fixed dose period (FDP). Following FDP, participants entered 26-week dose titration period (DTP) during which all participants received sevelamer carbonate.
Participants by arm
| Arm | Count |
|---|---|
| FDP-Placebo for Sevelamer Carbonate, DTP-Sevelamer Carbonate Participants received placebo for sevelamer carbonate for 2 weeks in FDP and sevelamer carbonate for 26 weeks in DTP. Placebo matched to sevelamer carbonate TID for 2 weeks in FDP: 0.4 g TID for BSA \<0.75 m\^2 or 0.8 g TID for BSA ≥0.75 to \< 1.2 m\^2 POS and 1.6 g TID for BSA ≥1.2 m\^2 as POS/tablets as per participant's preference. If a child ate \<3 meals/snacks per day, dose was given with meals/snacks. In DTP, starting dose of sevelamer carbonate was based on screening BSA & same as prescribed during FDP. Dose was titrated up/down every 2 weeks for 6 weeks & then every 4 weeks to achieve a serum phosphorus level within age appropriate normal values or up to maximum dose as per Investigator's opinion. Dose titrations were based on BSA category: 0.2 g TID for BSA \<0.75 m\^2, 0.4 g TID for BSA ≥0.75 to \< 1.2 m\^2 & 0.8 g TID for BSA ≥1.2 m\^2 (smaller titrations were permitted but could not be \<0.2 g TID with meals/snacks). | 51 |
| FDP-Sevelamer Carbonate, DTP-Sevelamer Carbonate Participants received sevelamer carbonate 0.4 g TID or 0.8 g TID or 1.6 g TID (based on screening BSA category) for 2 weeks in FDP and then continued to receive sevelamer carbonate in DTP. Sevelamer carbonate for 2 weeks in FDP: 0.4 g TID for BSA \<0.75 m\^2 or 0.8 g TID for BSA ≥0.75 to \< 1.2 m\^2 as POS or 1.6 g TID for BSA ≥1.2 m\^2 either as POS or tablets as per participant's preference. If a child ate \<3 meals/snacks per day, dose was given with meals/snacks. In DTP, starting dose of sevelamer carbonate was based on screening BSA & same as dose prescribed during FDP. Dose was titrated up/down every 2 weeks for 6 weeks & then every 4 weeks to achieve a serum phosphorus level within age appropriate normal values or up to maximum dose as per Investigator's opinion. Dose titrations were based on BSA category: by 0.2 g TID for BSA \<0.75 m\^2, 0.4 g TID for BSA ≥0.75 to \<1.2 m\^2 & 0.8 g TID for BSA ≥1.2 m\^2 (smaller titrations were permitted but could not be \<0.2 g TID with meal/snacks). | 50 |
| Total | 101 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Other: Mainly kidney transplant | 8 | 8 |
| Overall Study | Physician Decision | 5 | 3 |
| Overall Study | Randomized but not treated | 0 | 1 |
| Overall Study | Withdrawal by Participant | 2 | 4 |
Baseline characteristics
| Characteristic | FDP-Placebo for Sevelamer Carbonate, DTP-Sevelamer Carbonate | FDP-Sevelamer Carbonate, DTP-Sevelamer Carbonate | Total |
|---|---|---|---|
| Age, Continuous | 14.3 years STANDARD_DEVIATION 3.11 | 13.9 years STANDARD_DEVIATION 2.75 | 14.1 years STANDARD_DEVIATION 2.93 |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 37 Participants |
| Sex: Female, Male Male | 33 Participants | 31 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 51 | 7 / 49 | 57 / 100 |
| serious Total, serious adverse events | 1 / 51 | 4 / 49 | 31 / 100 |
Outcome results
Primary
Change From Baseline (Week 0) to Week 2 in Serum Phosphorus
Full analysis set for fixed dose period (FAS-FDP) participants were analyzed according to their randomized treatment. The change in serum phosphorus (mg/dL) from baseline to week 2 was calculated.
Time frame: Baseline, Week 2
Population: FAS-FDP population included all treated participants with a baseline phosphorus value and at least 1 post-baseline assessment after the first dose of study drug and on or before Week 2. Three participants (1 in sevelamer carbonate group and 2 in placebo group) were excluded from FAS-FDP due to no baseline phosphorus value at week 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FDP-Placebo for Sevelamer Carbonate | Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | At Baseline | 7.2 mg/dL | Standard Deviation 1.841 |
| FDP-Placebo for Sevelamer Carbonate | Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | At Week 2 | 7.24 mg/dL | Standard Deviation 2.029 |
| FDP-Placebo for Sevelamer Carbonate | Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | Change from baseline to Week 2 | 0.04 mg/dL | Standard Deviation 1.478 |
| FDP-Sevelamer Carbonate | Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | At Baseline | 7.2 mg/dL | Standard Deviation 2.09 |
| FDP-Sevelamer Carbonate | Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | At Week 2 | 6.34 mg/dL | Standard Deviation 1.306 |
| FDP-Sevelamer Carbonate | Change From Baseline (Week 0) to Week 2 in Serum Phosphorus | Change from baseline to Week 2 | -0.87 mg/dL | Standard Deviation 1.649 |
Comparison: Primary efficacy endpoint, change from baseline to Week 2 in serum phosphorus, was compared between treatment groups using analysis of covariance (ANCOVA) with baseline phosphorus and screening BSA as covariates and fixed effect for treatment. No center effect was included in the model. The estimate of the treatment difference (Sevelamer Carbonate - Placebo) and its 95% CI were presented. Significance was to be declared if the p-value was ≤0.05.p-value: 0.00195% CI: [-1.44, -0.37]ANCOVA
Primary
Treatment - Emergent Adverse Events (AEs)
A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly/birth defect. AEs from the time of signing the informed consent through the end of the study for all participants. SAEs occurring during the 15 days following study completion or early termination were also to be collected.
Time frame: Up to 32 weeks (up to 4 weeks washout period, 2 weeks FDP and 26 weeks DTP)
Population: Analysis was performed on safety set, which included all enrolled participants who received at least 1 dose of study drug. Participants were analyzed according to actual received treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | SAE related: FDP | 0 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | AE related: DTP | 9 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any SAE: FDP | 1 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any SAE: DTP | 14 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation: FDP | 1 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | SAE related: DTP | 2 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | AE related: FDP | 3 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation: DTP | 0 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE: DTP | 42 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Deaths | 0 participants |
| FDP-Placebo for Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE: FDP | 20 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Deaths | 0 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE: FDP | 19 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | AE related: FDP | 2 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any SAE: FDP | 4 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | SAE related: FDP | 0 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation: FDP | 1 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE: DTP | 35 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | AE related: DTP | 4 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any SAE: DTP | 17 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | SAE related: DTP | 2 participants |
| FDP-Sevelamer Carbonate | Treatment - Emergent Adverse Events (AEs) | Any AE Leading to Study Drug Discontinuation: DTP | 3 participants |
Secondary
Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus
Full analysis set for dose titration period (FAS-DTP) participants were analyzed according to their randomized treatment. The change in serum phosphorus (mg/dL) from baseline to Week 28/Early Termination was calculated.
Time frame: Baseline, Week 28/Early Termination
Population: FAS-DTP population included all treated participants with a baseline phosphorus value and at least 1 post-baseline phosphorus assessment after Week 2. Five participants (3 in sevelamer carbonate group and 2 in the placebo group) were excluded from the FAS-DTP due to no baseline phosphorus value or no phosphorus assessment after Week 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FDP-Placebo for Sevelamer Carbonate | Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | At Baseline (Week 0) | 7.05 mg/dL | Standard Deviation 1.797 |
| FDP-Placebo for Sevelamer Carbonate | Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | At Week 28 / Early Termination | 5.92 mg/dL | Standard Deviation 1.612 |
| FDP-Placebo for Sevelamer Carbonate | Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | Change from Baseline to Week 28/Early Termination | -1.13 mg/dL | Standard Deviation 2.061 |
| FDP-Sevelamer Carbonate | Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | At Baseline (Week 0) | 7.28 mg/dL | Standard Deviation 2.103 |
| FDP-Sevelamer Carbonate | Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | At Week 28 / Early Termination | 6.04 mg/dL | Standard Deviation 1.878 |
| FDP-Sevelamer Carbonate | Change From Baseline (Week 0) to Week 28/Early Termination in Serum Phosphorus | Change from Baseline to Week 28/Early Termination | -1.23 mg/dL | Standard Deviation 2.206 |