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The Pharmacokinetics of Rocaltrol When Administered Alone or in Combination With Fosrenol or Renvela in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT00925704
Recruitment Status : Completed
First Posted : June 22, 2009
Results First Posted : May 14, 2010
Last Update Posted : February 11, 2011
Sponsor:
Information provided by:
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label)
Condition Healthy
Interventions Drug: Calcitriol
Drug: Lanthanum carbonate + Calcitriol
Drug: Sevelamer carbonate + Calcitriol
Enrollment 41
Recruitment Details  
Pre-assignment Details Patients were randomly assigned to 1 of 6 treatment sequences which consisted of 3 treatment periods separated by a washout of 7 days. In each of the treatment periods subjects received lanthanum carbonate + calcitriol, sevelamer carbonate + calcitriol or calcitriol alone.
Arm/Group Title Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6
Hide Arm/Group Description Calcitriol (1.0 microgram) single dose at lunch for one day in first intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in third intervention Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in second intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in third intervention Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in third intervention Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in second intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch)for one day in third intervention Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in third intervention Calcitriol (1.0 microgram) single dose at lunch for one day in first intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch)for one day in third intervention
Period Title: First Intervention
Started 6 7 7 7 7 7
Completed 6 7 7 6 6 7
Not Completed 0 0 0 1 1 0
Reason Not Completed
Withdrew consent             0             0             0             1             1             0
Period Title: Washout
Started 6 7 7 6 6 7
Completed 6 7 7 6 6 7
Not Completed 0 0 0 0 0 0
Period Title: Second Intervention
Started 6 7 7 6 6 7
Completed 5 7 7 6 5 7
Not Completed 1 0 0 0 1 0
Reason Not Completed
Withdrawal by Subject             1             0             0             0             1             0
Period Title: Washout
Started 5 7 7 6 5 7
Completed 5 7 7 6 5 7
Not Completed 0 0 0 0 0 0
Period Title: Third Intervention
Started 5 7 7 6 5 7
Completed 5 7 7 6 5 6
Not Completed 0 0 0 0 0 1
Reason Not Completed
Withdrew consent             0             0             0             0             0             1
Arm/Group Title Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6 Total
Hide Arm/Group Description Calcitriol (1.0 microgram) single dose at lunch for one day in first intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in third intervention Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in second intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in third intervention Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in third intervention Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in second intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch)for one day in third intervention Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in third intervention Calcitriol (1.0 microgram) single dose at lunch for one day in first intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch)for one day in third intervention Total of all reporting groups
Overall Number of Baseline Participants 6 7 7 7 7 7 41
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 7 participants 7 participants 7 participants 7 participants 7 participants 41 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
6
 100.0%
7
 100.0%
7
 100.0%
7
 100.0%
7
 100.0%
7
 100.0%
41
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 7 participants 7 participants 7 participants 7 participants 7 participants 41 participants
27.7  (8.94) 30.0  (6.24) 30.9  (5.52) 28.4  (7.28) 31.0  (8.52) 30.4  (10.41) 29.8  (7.55)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 7 participants 7 participants 7 participants 7 participants 7 participants 41 participants
Female
5
  83.3%
3
  42.9%
2
  28.6%
2
  28.6%
4
  57.1%
3
  42.9%
19
  46.3%
Male
1
  16.7%
4
  57.1%
5
  71.4%
5
  71.4%
3
  42.9%
4
  57.1%
22
  53.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 6 participants 7 participants 7 participants 7 participants 7 participants 7 participants 41 participants
6 7 7 7 7 7 41
1.Primary Outcome
Title Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol
Hide Description This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint.
Time Frame pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic set (PK) consists of subjects who received at least 1 dose of investigational product, had evaluable serum concentration-time profiles for calcitriol through 48 hours post-dosing on Day 1 of any treatment period and did not vomit between dosing and 10 hours post-dose on Day 1 of that treatment period.
Arm/Group Title Calcitriol (Lanthanum Carbonate) Calcitriol (Sevelamer Carbonate)
Hide Arm/Group Description:
This group is the least squares mean of AUC 0-48 Lanthanum carbonate + Calcitriol minus least squares mean of AUC 0-48 Calcitriol alone.
This group is the least squares mean of AUC 0-48 Sevelamer carbonate + Calcitriol minus least squares mean of AUC 0-48 Calcitriol alone.
Overall Number of Participants Analyzed 41 41
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg*h/ml
111
(-48.9 to 270)
-181
(-338 to -24.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Calcitriol (Lanthanum Carbonate)
Comments Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.171
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Calcitriol (Sevelamer Carbonate)
Comments Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.024
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
2.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol
Hide Description This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint.
Time Frame pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK set
Arm/Group Title Calcitriol (Lanthanum Carbonate) Calcitriol (Sevelamer Carbonate)
Hide Arm/Group Description:
This group is the least squares mean of Cmax Lanthanum carbonate + Calcitriol minus least squares mean of Cmax Calcitriol alone.
This group is the least squares mean of Cmax Sevelamer carbonate + Calcitriol minus least squares mean of Cmax Calcitriol alone.
Overall Number of Participants Analyzed 41 41
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/ml
-2.74
(-8.12 to 2.63)
-9.62
(-14.9 to -4.34)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Calcitriol (Lanthanum Carbonate)
Comments Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.313
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Calcitriol (Sevelamer Carbonate)
Comments Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
3.Secondary Outcome
Title Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol
Hide Description This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint.
Time Frame pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK set
Arm/Group Title Calcitriol (Lanthanum Carbonate) Calcitriol (Sevelamer Carbonate)
Hide Arm/Group Description:
This group is the median of Tmax Lanthanum carbonate + Calcitriol minus the median of Tmax Calcitriol alone.
This group is the median of Tmax Sevelamer carbonate + Calcitriol minus the median of Tmax Calcitriol alone.
Overall Number of Participants Analyzed 41 41
Median (95% Confidence Interval)
Unit of Measure: hours
1.27
(0.00 to 2.48)
0.500
(0.00 to 1.46)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Calcitriol (Lanthanum Carbonate)
Comments Analysis for Tmax used the Hodges-Lehmann estimate for Wilcoxon's Signed Rank Test.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.039
Comments [Not Specified]
Method Wilcoxon (Hodges-Lehmann)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Calcitriol (Sevelamer Carbonate)
Comments Analysis for Tmax used the Hodges-Lehmann estimate for Wilcoxon's Signed Rank Test.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.305
Comments [Not Specified]
Method Wilcoxon (Hodges-Lehmann)
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description Safety Set consisted of all enrolled subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.
 
Arm/Group Title Lanthanum Carbonate + Calcitriol Sevelamer Carbonate + Calcitriol Calcitriol Alone
Hide Arm/Group Description Lanthanum carbonate (1000 mg three times daily with meals for one day) + Calcitriol (1 microgram single dose at lunch) Sevelamer carbonate (2400 mg three times daily with meals for one day) + Calcitriol (1 microgram single dose at lunch) Calcitriol (1.0 microgram) single dose at lunch
All-Cause Mortality
Lanthanum Carbonate + Calcitriol Sevelamer Carbonate + Calcitriol Calcitriol Alone
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Lanthanum Carbonate + Calcitriol Sevelamer Carbonate + Calcitriol Calcitriol Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/38 (0.00%)      0/40 (0.00%)      0/38 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lanthanum Carbonate + Calcitriol Sevelamer Carbonate + Calcitriol Calcitriol Alone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/38 (13.16%)      2/40 (5.00%)      3/38 (7.89%)    
Musculoskeletal and connective tissue disorders       
Back Pain  2/38 (5.26%)  2 0/40 (0.00%)  0/38 (0.00%) 
Nervous system disorders       
Headache  2/38 (5.26%)  2 2/40 (5.00%)  2 1/38 (2.63%)  1
Hypoaesthesia  0/38 (0.00%)  0/40 (0.00%)  2/38 (5.26%)  2
Psychiatric disorders       
Anxiety  2/38 (5.26%)  2 0/40 (0.00%)  0/38 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
Results Point of Contact
Name/Title: Gerald Tremblay, M.D.
Organization: Shire Pharmaceutical
Responsible Party: Gerald Tremblay, M.D., Shire Pharmaceutical
ClinicalTrials.gov Identifier: NCT00925704     History of Changes
Other Study ID Numbers: SPD405-129
First Submitted: June 19, 2009
First Posted: June 22, 2009
Results First Submitted: March 19, 2010
Results First Posted: May 14, 2010
Last Update Posted: February 11, 2011