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

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00925704
• Collaborator: (none)
• Enrollment: 41
• Location: 1
• Arms: 3
• Actual Duration (Months): 2
• Patients Per Site Per Month: 20.8

Study Details

Study Description

Brief Summary

To assess the effects of lanthanum carbonate (FOSRENOL) or sevelamer carbonate (RENVELA) on the pharmacokinetics of oral calcitriol (ROCALTROL)

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Calcitriol; Drug: Lanthanum carbonate + Calcitriol; Drug: Sevelamer carbonate + Calcitriol	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase I, Randomized, Open-Label, Three Period Cross-Over Study to Assess the Pharmacokinetics of Oral Calcitriol (ROCALTROL®) in Healthy Volunteers When Administered Alone or When Co-Administered With Lanthanum Carbonate (FOSRENOL®) or Sevelamer Carbonate (RENVELA®)
• Actual Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Jul 31, 2009
• Actual Study Completion Date: Jul 31, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Calcitriol	Drug: Calcitriol; Calcitriol (1.0 microgram) single dose at lunch administered on Day 1 of the study period.; Other Names: Rocaltrol
Experimental: Lanthanum carbonate + calcitriol	Drug: Lanthanum carbonate + Calcitriol; Lanthanum carbonate (1000 mg three times daily with meals for one day) + calcitriol (1.0 microgram) single dose at lunch administered on Day 1 of the study period.; Other Names: Fosrenol + Rocaltrol
Experimental: Sevelamer carbonate + calcitriol	Drug: Sevelamer carbonate + Calcitriol; Sevelamer carbonate (2400 mg three times daily with meals for one day) + calcitriol (1.0 microgram) single dose at lunch administered on Day 1 of the study period.; Other Names: Renvela + Rocaltrol

Outcome Measures

Primary Outcome Measures

1. Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol [pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose]

   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.

Secondary Outcome Measures

1. Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol [pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose]

   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.

2. Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol [pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria

• Healthy volunteers age 19-45 years inclusive at the time of consent.

• Satisfactory medical assessment with no clinically significant or relevant abnormalities in medical history, physical examination, vital signs, electrocardiogram (ECG) and laboratory evaluation (hematology, biochemistry, urinalysis) as assessed by the Investigator.

• No current or recurrent disease (e.g. cardiovascular, renal, liver, gastrointestinal (GI), malignancy or other conditions) that could affect the action, absorption or disposition of the investigational products utilized in this study, or could affect clinical or laboratory assessments.

Exclusion criteria

• Current or recurrent disease (eg, cardiovascular, renal, liver, GI, malignancy or other conditions) 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 of physical or psychiatric illness, any medical disorder that could have required treatment or made the subject unlikely to fully complete the study, or any condition that presented undue risk from the investigational product or study procedures.

• Current use of any medication with the exception of hormonal replacement therapy or hormonal contraceptives within 14 days of first dose of investigational product.

• History of alcohol or other substance abuse within the last year.

• A positive human immunodeficiency virus antibody screen, Hepatitis B surface antigen or Hepatitis C virus antibody screen.

• Use of tobacco in any form

• Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first dose of investigational product.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	West Coast Clinical Trials	Cypress	California	United States	90630

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FDA recall information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00925704
• Other Study ID Numbers: SPD405-129
• First Posted: Jun 22, 2009
• Last Update Posted: Jun 15, 2021
• Last Verified: May 1, 2021

• Additional relevant MeSH terms: Calcitriol; Sevelamer

Study Results

Participant Flow

Pre-assignment Detail	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
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
Period Title: First Intervention
STARTED	6	7	7	6	6	7
COMPLETED	6	7	7	6	6	7
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	6	7	7	6	6	7
COMPLETED	5	7	7	6	5	7
NOT COMPLETED	1	0	0	0	1	0
Period Title: First Intervention
STARTED	5	7	7	6	5	7
COMPLETED	5	7	7	6	5	7
NOT COMPLETED	0	0	0	0	0	0
Period Title: First Intervention
STARTED	5	7	7	6	5	7
COMPLETED	5	7	7	6	5	6
NOT COMPLETED	0	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6	Total
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 Participants	6	7	7	7	7	7	41
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	7 100%	7 100%	7 100%	7 100%	7 100%	41 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	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 (Count of 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 (Count of Participants)
United States	6 100%	7 100%	7 100%	7 100%	7 100%	7 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol
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

Outcome Measure Data

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)
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.
Measure Participants	41	41
Least Squares Mean (95% Confidence Interval) [pg*h/ml]	111	-181

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 (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments
	Method	Mixed Models Analysis
	Comments

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 (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol
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

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Calcitriol (Lanthanum Carbonate)	Calcitriol (Sevelamer Carbonate)
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.
Measure Participants	41	41
Least Squares Mean (95% Confidence Interval) [pg/ml]	-2.74	-9.62

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 (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.313
	Comments
	Method	Mixed Models Analysis
	Comments

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 (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol
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

Outcome Measure Data

Analysis Population Description

PK set

Arm/Group Title	Calcitriol (Lanthanum Carbonate)	Calcitriol (Sevelamer Carbonate)
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.
Measure Participants	41	41
Median (95% Confidence Interval) [hours]	1.27	0.500

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 (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	Wilcoxon (Hodges-Lehmann)
	Comments

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 (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.305
	Comments
	Method	Wilcoxon (Hodges-Lehmann)
	Comments

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
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%)		0/40 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Lanthanum Carbonate + Calcitriol		Sevelamer Carbonate + Calcitriol		Calcitriol Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/38 (13.2%)		2/40 (5%)		3/38 (7.9%)
Musculoskeletal and connective tissue disorders
Back Pain	2/38 (5.3%)	2	0/40 (0%)	2	0/38 (0%)	2
Nervous system disorders
Headache	2/38 (5.3%)	2	2/40 (5%)	2	1/38 (2.6%)	1
Hypoaesthesia	0/38 (0%)		0/40 (0%)		2/38 (5.3%)	2
Psychiatric disorders
Anxiety	2/38 (5.3%)	2	0/40 (0%)	2	0/38 (0%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.