End Stage Renal Disease
Conditions
Keywords
End stage Renal disease
Brief summary
This study is being conducted to assess any potential differences in the absorption and excretion between two lanthanum carbonate formulations. This study is also being done to assess the safety and tolerability of the two lanthanum carbonate formulations.
Interventions
DRUGLanthanum carbonate Granule Formulation
3x's per day for 3 days, 1 dose in the am for day 4. (A single dose equals 1000mg of lanthanum carbonate granule formulation. Dose is administered immediately after each meal.)
DRUGLanthanum carbonate Chewable Tablets (Fosrenol)
3x's per day for 3 days, 1 dose on day 4. (A single dose equals a 1000mg tablet of lanthanum carbonate. Dose is administered immediately after each meal.)
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Ability to provide informed consent to participate in the study. * Healthy volunteers, age 18-55 inclusive. * Subject must be willing to comply with applicable contraceptive requirements of the protocol * Female subjects must have a negative pregnancy test * Ability to chew and or swallow doses of the investigational products as prescribed in the protocol. * Ability to fully comply with all study procedures and restrictions, including consumption of all food provided while a resident in the CRC.
Exclusion criteria
* Current or relevant previous history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or study procedures. * Clinically significant abnormal serum phosphate levels, outside of normal limits. * Current use of any medication with the exception of hormonal replacement therapy or hormonal contraceptives within 7 days of first dose of investigational product. * A known history of lactose intolerance or allergy to milk or other foods. * Clinically significant or multiple allergies as determined by an Investigator. * History of alcohol or other substance abuse within the last 6 months. * A positive screen for alcohol or drugs of abuse. * Male subjects who consume more than 21 units of alcohol per week or three units per day. Female subjects who consume more than 14 units of alcohol per week or two units per day. * A positive human immunodeficiency virus (HIV) antibody screen, Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV) antibody screen. * Female subjects who are pregnant (positive pregnancy test), lactating, or less than 90 days post-partum. * Subjects that have previously been randomized in this study. * Use of tobacco in any form or other nicotine-containing products in any form. Ex-users must report that they have stopped using tobacco for at least 60 days prior to receiving the first dose of investigational product. * Routine consumption of more than two units of caffeine per day or subjects who experience caffeine withdrawal headaches. * Donation of blood or blood products within 60 days prior to receiving the first dose of investigational product. * Plasma donation within 28 days prior to the first dose of the investigational product. * Use of another investigational product within 30 days prior to receiving the first dose of investigational product or active enrolment in another drug or vaccine clinical study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Urinary Phosphate Excretion 3-Day Average | Continuous collection over 3 days |
Secondary
| Measure | Time frame |
|---|---|
| Urinary Phosphate Excretion on Day 4 | Continuous collection on Day 4 |
| Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Lanthanum Carbonate | 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose on Day 4 |
| Maximum Plasma Concentration (Cmax) of Lanthanum Carbonate | 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose on Day 4 |
| Time of Maximum Plasma Concentration (Tmax) of Lanthanum Carbonate | 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose on Day 4 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lanthanum Carbonate Granules First Granule formulation first at 1000 mg three times a day for 3 days and a single 1000 mg dose after breakfast on Day 4, a washout period, then chewable tablet formulation at 1000 mg three times a day for 3 days and a single 1000 mg dose after breakfast on Day 4. | 39 |
| Lanthanum Carbonate Chewable Tablet First Chewable tablet formulation first at 1000 mg three times a day for 3 days and a single 1000 mg dose after breakfast on Day 4, a washout period, then granule formulation at 1000 mg three times a day for 3 days and a single 1000 mg dose after breakfast on Day 4. | 33 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Adverse Event | 1 | 0 |
| First Intervention | Lost to Follow-up | 2 | 0 |
| First Intervention | Non-compliance with meals | 0 | 1 |
| First Intervention | Unable to collect urine | 4 | 0 |
| First Intervention | Withdrawal by Subject | 2 | 0 |
| Second Intervention | Protocol Violation | 1 | 0 |
| Second Intervention | Unable to collect urine | 1 | 0 |
| Second Intervention | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Lanthanum Carbonate Granules First | Lanthanum Carbonate Chewable Tablet First | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 33 Participants | 72 Participants |
| Age, Continuous | 31.5 years STANDARD_DEVIATION 8.7 | 31.3 years STANDARD_DEVIATION 7.83 | 31.4 years STANDARD_DEVIATION 8.26 |
| Region of Enrollment United States | 39 Participants | 33 Participants | 72 Participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Male | 28 Participants | 24 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 71 | 6 / 61 |
| serious Total, serious adverse events | 0 / 71 | 0 / 61 |
Outcome results
Primary
Urinary Phosphate Excretion 3-Day Average
Time frame: Continuous collection over 3 days
Population: Pharmacodynamic Set (PD) includes all subjects who completed all urine collections and consumed at least 95% of food in all treatment periods. Subjects who vomited from days -2 to 4 of any treatment period were excluded from the set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate Granules | Urinary Phosphate Excretion 3-Day Average | 16.01 mmol | Standard Error 0.485 |
| Lanthanum Carbonate Chewable Tablet | Urinary Phosphate Excretion 3-Day Average | 17.35 mmol | Standard Error 0.484 |
90% CI: [-2.18, -0.51]Mixed Models Analysis
Secondary
Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Lanthanum Carbonate
Time frame: 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose on Day 4
Population: Pharmacokinetic set (PK) includes all subjects who had sufficient post-dose blood samples taken to estimate Cmax and AUC 0-48 hours after dosing on Day 4 in all treatment periods. Subjects who vomited between dosing and 10 hours post-dose on Day 4 of any treatment period were excluded from the PK set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate Granules | Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Lanthanum Carbonate | 14.2 ng*h/ml | Standard Deviation 6.02 |
| Lanthanum Carbonate Chewable Tablet | Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Lanthanum Carbonate | 10.3 ng*h/ml | Standard Deviation 3.5 |
Comparison: The LS means and associated SEs for granules and tablets as well as the difference between granules and tablets were determined. From the LS mean and SE of the difference, a 90% CI was constructed for the difference of the logs of granules and tablets. An exponential transformation was applied to the lower and upper limits of the CI. This created a point estimate and 90% CI for the ratio of LS means for granules to tablets.90% CI: [1.26, 1.42]Mixed Models Analysis
Secondary
Maximum Plasma Concentration (Cmax) of Lanthanum Carbonate
Time frame: 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose on Day 4
Population: PK set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate Granules | Maximum Plasma Concentration (Cmax) of Lanthanum Carbonate | 0.638 ng/ml | Standard Deviation 0.241 |
| Lanthanum Carbonate Chewable Tablet | Maximum Plasma Concentration (Cmax) of Lanthanum Carbonate | 0.504 ng/ml | Standard Deviation 0.181 |
Comparison: The LS means and associated SEs for granules and tablets as well as the difference between granules and tablets were determined. From the LS mean and SE of the difference, a 90% CI was constructed for the difference of the logs of granules and tablets. An exponential transformation was applied to the lower and upper limits of the CI. This created a point estimate and 90% CI for the ratio of LS means for granules to tablets.90% CI: [1.2, 1.33]Mixed Models Analysis
Secondary
Time of Maximum Plasma Concentration (Tmax) of Lanthanum Carbonate
Time frame: 3, 4, 5, 6, 8, 12, 18, 24, 36 and 48 hours post-dose on Day 4
Population: PK set
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate Granules | Time of Maximum Plasma Concentration (Tmax) of Lanthanum Carbonate | 4.00 hours | Full Range 0 |
| Lanthanum Carbonate Chewable Tablet | Time of Maximum Plasma Concentration (Tmax) of Lanthanum Carbonate | 4.00 hours | Full Range 0 |
90% CI: [0, 0.5]Wilcoxon (Hodges-Lehmann)
Secondary
Urinary Phosphate Excretion on Day 4
Time frame: Continuous collection on Day 4
Population: PD set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate Granules | Urinary Phosphate Excretion on Day 4 | 15.03 mmol | Standard Error 0.569 |
| Lanthanum Carbonate Chewable Tablet | Urinary Phosphate Excretion on Day 4 | 17.01 mmol | Standard Error 0.569 |
90% CI: [-3.17, -0.8]Mixed Models Analysis