Kidney Failure, Chronic
Conditions
Brief summary
The purpose of this study is to compare the absorption of dietary phosphorus following a single dose with lanthanum carbonate (1000mg) and a single dose of sevelamer carbonate (2400mg).
Interventions
DRUGLanthanum Carbonate
1 x 1000mg tablet
DRUGSevelamer
3 x 800mg tablets
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Ability to provide informed consent to participate in the study. * Healthy volunteers, age 19-45 inclusive. * Subject must be willing to comply with applicable contraceptive requirements of the protocol * Female subjects must have a negative pregnancy test * Satisfactory medical assessment with no clinically significant or relevant abnormalities in medical history, physical examination, vital signs, ECG and laboratory evaluation. * Body Mass Index (BMI) between 20.0 and 29.9kg/m² inclusive. * Serum 1.25 dihydroxy vitamin D3 \>30pg/mL. * Ability to chew or swallow a dose of the investigational products and mannitol solution as prescribed in the protocol. * Ability and willingness to fast for up to 24 hours.
Exclusion criteria
* Current or recurrent disease that could affect the action, absorption or disposition of the investigational products utilized in this study, or could affect clinical or laboratory assessments. * 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. * Significant illness within 2 weeks of the first dose of investigational product. * Current use of any medication with the exception of hormonal replacement therapy or hormonal contraceptives within 14 days of first dose of investigational product. * Known or suspected intolerance or hypersensitivity to the investigational product(s) or mannitol solution, closely related compounds or any of the stated ingredients. * History of alcohol or other substance abuse within the last year. * 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. * 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 30 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. * 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. * An inability to follow a standardized diet and/or meal schedule, as required during the study. * Substantial changes in eating habits within 30 days prior to receiving the first dose of investigational product, as assessed by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Net Phosphorous Absorption | 10 hours post-dose | Net phosphorous absorption (Lanthanum carbonate period) = phosphorous ingested in meal minus (Rectal effluent phosphorous after Lanthanum carbonate + meal minus Rectal effluent phosphorous after fasting). Net phosphorous absorption (Sevelamer Carbonate period) = Phosphorous ingested in meal minus (Rectal effluent phosphorous after Sevelamer carbonate + meal minus Rectal effluent phosphorous after fasting). Net phosphorous absorption (Meal only period) = Phosphorous ingested in meal minus (Rectal effluent phosphorous after meal only minus Rectal effluent phosphorous after fasting). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Net Phosphorous Binding | 10 hours post-dose | Net Phosphorous Binding (Lanthanum carbonate period) = Rectal effluent phosphorous after Lanthanum carbonate + meal minus Rectal effluent phosphorous after meal only. Net Phosphorous Binding (Sevelamer carbonate period) = Rectal effluent phosphorous after Sevelamer carbonate + meal minus Rectal effluent phosphorous after meal only. |
| Net Calcium Absorption | 10 hours post-dose | Net Calcium Absorption (Lanthanum carbonate period) = Calcium ingested in meal minus (Rectal effluent calcium after Lanthanum carbonate + meal minus Rectal effluent calcium after fasting). Net Calcium Absorption (Sevelamer Carbonate period) = Calcium ingested in meal minus (Rectal effluent calcium after Sevelamer carbonate + meal minus Rectal effluent calcium after fasting). Net Calcium Absorption (Meal only period) = Calcium ingested in meal minus (Rectal effluent calcium after meal only minus Rectal effluent calcium after fasting). |
Countries
United States
Participant flow
Pre-assignment details
Patients were randomized to one of 6 treatment sequences each of which consisted of four treatment periods separated by a 7-14 day washout period. In each of the first three treatment periods subjects received lanthanum carbonate 100mg +meal, sevelamer carbonate 2400mg+meal or meal. Subjects fasted in the fourth treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Lanthanum carbonate (1000 mg) + meal in first intervention period, washout, Sevelamer carbonate (2400 mg) + meal in second intervention period, washout, Meal only in third intervention period, washout, Fasting in fourth intervention period | 3 |
| Sequence 2 Sevelamer carbonate (2400 mg) + meal in first intervention period, washout, Meal only in second intervention period, washout, Lanthanum carbonate (1000 mg) + meal in third intervention period, washout, Fasting in fourth intervention period | 5 |
| Sequence 3 Meal only in first intervention period, washout, Lanthanum carbonate (1000 mg) + meal in second intervention period, washout, Sevelamer carbonate (2400 mg) + meal in third intervention period, washout, Fasting in fourth intervention period | 5 |
| Sequence 4 Lanthanum carbonate (1000 mg) + meal in first intervention period, washout, Meal only in second intervention period, washout, Sevelamer carbonate (2400 mg) + meal in third intervention period, washout, Fasting in fourth intervention period | 5 |
| Sequence 5 Sevelamer carbonate (2400 mg) + meal in first intervention period, washout, Lanthanum carbonate (1000 mg) + meal in second intervention period, washout, Meal only in third intervention period, washout, Fasting in fourth intervention period | 5 |
| Sequence 6 Meal only in first intervention period, washout, Sevelamer carbonate (2400 mg) + meal in second intervention period, washout, Lanthanum carbonate (1000 mg) + meal in third intervention period, washout, Fasting in fourth intervention period | 5 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Intervention | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| First Intervention | Intolerance to nasogastric tube | 0 | 0 | 0 | 0 | 1 | 0 |
| First Intervention | Problems collecting rectal effluent | 1 | 0 | 0 | 0 | 0 | 0 |
| First Intervention | Withdrawal by Subject | 1 | 0 | 1 | 0 | 0 | 0 |
| Fourth Intervention | Inability to comply with fasting | 0 | 0 | 0 | 0 | 0 | 1 |
| Second Intervention | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Third Intervention | Adverse Event | 0 | 1 | 1 | 0 | 0 | 0 |
| Washout | Problem collecting rectal effluent | 0 | 0 | 1 | 0 | 0 | 0 |
| Washout | Problems collecting rectal effluent | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence 2 | Sequence 3 | Sequence 4 | Sequence 1 | Sequence 5 | Sequence 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 5 Participants | 3 Participants | 5 Participants | 5 Participants | 28 Participants |
| Age, Continuous | 23.6 years STANDARD_DEVIATION 2.07 | 24.4 years STANDARD_DEVIATION 3.85 | 27.4 years STANDARD_DEVIATION 9.71 | 26.0 years STANDARD_DEVIATION 9.54 | 25.8 years STANDARD_DEVIATION 5.45 | 28.2 years STANDARD_DEVIATION 6.38 | 25.9 years STANDARD_DEVIATION 6.06 |
| Region of Enrollment United States | 5 Participants | 5 Participants | 5 Participants | 3 Participants | 5 Participants | 5 Participants | 28 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 24 | 3 / 26 | 3 / 20 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 26 | 0 / 20 |
Outcome results
Primary
Net Phosphorous Absorption
Net phosphorous absorption (Lanthanum carbonate period) = phosphorous ingested in meal minus (Rectal effluent phosphorous after Lanthanum carbonate + meal minus Rectal effluent phosphorous after fasting). Net phosphorous absorption (Sevelamer Carbonate period) = Phosphorous ingested in meal minus (Rectal effluent phosphorous after Sevelamer carbonate + meal minus Rectal effluent phosphorous after fasting). Net phosphorous absorption (Meal only period) = Phosphorous ingested in meal minus (Rectal effluent phosphorous after meal only minus Rectal effluent phosphorous after fasting).
Time frame: 10 hours post-dose
Population: Pharmacodynamic Set (PD) consists of subjects who provided all rectal effluent collections and completed all treatment periods. Subjects who vomited during any of the treatment periods were excluded from the PD set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Net Phosphorous Absorption | 156.03 mg | Standard Error 14.161 |
| Sevelamer Carbonate | Net Phosphorous Absorption | 221.78 mg | Standard Error 14.112 |
| Meal Only | Net Phosphorous Absorption | 281.68 mg | Standard Error 14.112 |
Comparison: Net phosphorus absorption was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: <0.00195% CI: [-96.01, -35.49]Mixed Models Analysis
Comparison: Net phosphorus absorption was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: <0.00195% CI: [-155.91, -95.39]Mixed Models Analysis
Comparison: Net phosphorus absorption was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: <0.00195% CI: [-89.87, -29.93]Mixed Models Analysis
Secondary
Net Calcium Absorption
Net Calcium Absorption (Lanthanum carbonate period) = Calcium ingested in meal minus (Rectal effluent calcium after Lanthanum carbonate + meal minus Rectal effluent calcium after fasting). Net Calcium Absorption (Sevelamer Carbonate period) = Calcium ingested in meal minus (Rectal effluent calcium after Sevelamer carbonate + meal minus Rectal effluent calcium after fasting). Net Calcium Absorption (Meal only period) = Calcium ingested in meal minus (Rectal effluent calcium after meal only minus Rectal effluent calcium after fasting).
Time frame: 10 hours post-dose
Population: PD set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Net Calcium Absorption | 49.46 mg | Standard Error 10.48 |
| Sevelamer Carbonate | Net Calcium Absorption | 70.13 mg | Standard Error 10.45 |
| Meal Only | Net Calcium Absorption | 65.02 mg | Standard Error 10.45 |
Comparison: Net calcium absorption was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: 0.04995% CI: [-41.22, -0.13]Mixed Models Analysis
Comparison: Net calcium absorption was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: 0.13395% CI: [-36.11, 4.99]Mixed Models Analysis
Comparison: Net calcium absorption was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: 0.61295% CI: [-15.24, 25.47]Mixed Models Analysis
Secondary
Net Phosphorous Binding
Net Phosphorous Binding (Lanthanum carbonate period) = Rectal effluent phosphorous after Lanthanum carbonate + meal minus Rectal effluent phosphorous after meal only. Net Phosphorous Binding (Sevelamer carbonate period) = Rectal effluent phosphorous after Sevelamer carbonate + meal minus Rectal effluent phosphorous after meal only.
Time frame: 10 hours post-dose
Population: PD set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanthanum Carbonate | Net Phosphorous Binding | 135.05 mg | Standard Error 12.348 |
| Sevelamer Carbonate | Net Phosphorous Binding | 63.15 mg | Standard Error 12.348 |
Comparison: Phosphorus binding was analysed using a mixed linear effect model with fixed effects for sequence group, period and treatment group. Subject within sequence effect was included as a random effect.p-value: <0.00195% CI: [40.03, 103.77]Mixed Models Analysis