Pharmacokinetics of LCP-Tacro in Stable Kidney Transplant Patients

• Sponsor: Veloxis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00496483
• Collaborator: CTI Clinical Trial and Consulting Services (Other)
• Enrollment: 60
• Locations: 2
• Arm: 1
• Duration (Months): 8
• Patients Per Site: 30
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

A three sequence, open-label, multi-center, prospective, study in stable kidney transplant patients to assess and compare the pharmacokinetics (Cmax, C24, and AUC), and safety of LCP-Tacro (tacrolimus) tablets versus Prograf (tacrolimus) capsules.

Condition or Disease	Intervention/Treatment	Phase
Renal Failure	Drug: LCP Tacro (tacrolimus); Drug: Prograf	Phase 2

Detailed Description

A three sequence, open-label, multi-center, prospective, study in stable kidney transplant patients to assess and compare the pharmacokinetics (Cmax, C24, and AUC), and safety of LCP-Tacro (tacrolimus) tablets versus Prograf (tacrolimus) capsules.

Stable kidney transplant patients who fulfill all I/E criteria will be enrolled and kept on Prograf for 7 days. Following a 24-hour PK study on Day 7 to determine pharmacokinetics for Prograf, all patients will be converted to once daily LCP-Tacro for 7 days with no dose changes allowed. On Day 14 and Day 21 a 24-hour LCP-Tacro PK study will be performed. On Day 22 patients will be converted back to their original twice daily dose of Prograf for a safety follow-up period of 30 days ending with a safety assessment on day 53.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-Label, Multi-Center Prospective, Conversion Study in Stable Kidney Transplant Patients to Compare the Pharmacokinetics of LCP-Tacro Tablets Once-A-Day to Prograf® Capsules Twice-A-Day
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Active Comparator: LCP-Tacro (tacrolimus) Experimental: LCP Tacro; investigational product LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.

Drug: LCP Tacro (tacrolimus); Prograf will be administrated twice a day, per product labeling, with an interval of 12 ± 1 hours between the morning and evening doses. Patients will continue on the same dose on Day0 through Day 7 to maintain target trough levels of 7-12 ng/mL. On the morning of Day 8, following the final blood draw for the PK assessment, patient will be converted to LCP-Tacro using the conversion Ratio 0.66-0.8. LCP-Tacro tablets will be administered orally once daily in the morning, with an interval of 24 ± 1 hours between doses. Other Names: Tacrolimus modified-release LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.; Other Names: tacrolimus ; Drug: Prograf; Prograf will be administrated twice a day, per product labeling, with an interval of 12 ± 1 hours between the morning and evening doses. Patients will continue on the same dose on Day0 through Day 7 to maintain target trough levels of 7-12 ng/mL. On the morning of Day 8, following the final blood draw for the PK assessment, patient will be converted to LCP-Tacro using the conversion Ratio 0.66-0.8. LCP-Tacro tablets will be administered orally once daily in the morning, with an interval of 24 ± 1 hours between doses. Other Names: Tacrolimus modified-release LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.; Other Names: Tacrolimus

Outcome Measures

Primary Outcome Measures

1. Evaluation of Steady State Tacrolimus Trough Levels (C24). [7 days]

   Patients had a baseline trough level (C24) measured at day 7 before conversion to LCP-Tacro.

2. Evaluation of Steady State Tacrolimus Exposure (AUC 0-24). [7 days]

   Patients had a baseline AUC measured (0 to 24 hours) at day 7 before conversion to LCP-Tacro.

3. Evaluation of Steady State Tacrolimus Exposure Trough Levels (C24). [21 days]

   Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, a trough level (C24) was measured.

4. Evaluation of Steady State Tacrolimus Exposure (AUC 0-24). [21 days]

   Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, AUC was measured (0 to 24 hours).

Secondary Outcome Measures

1. Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 21. [21 days]

   Cmax and Cavg was measured at day 21 (Cmin was measured as part of the primary outcome).

2. Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 21. [21 days]

   Tmax was measured at day 21 (Cmin was measured as part of the primary outcome).

3. Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 21. [21 days]

   Degree og fluctuation and degree of swing was measured at day 21 (Cmin was measured as part of the primary outcome).

4. Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 7. [7 days]

   Cmax and Cavg was measured at baseline day 7 (Cmin was measured as part of the primary outcome).

5. Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 7. [7 days]

   Tmax was measured at baseline day 7 (Cmin was measured as part of the primary outcome).

6. Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 7. [7 days]

   Degree og fluctuation and degree of swing was measured as baseline at day 7 (Cmin was measured as part of the primary outcome).

7. Safety Evaluation [52 days]

   A combination of deaths, graft failure and biopsy proven acute rejections (BPAR) was used to evaluate the safety.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women 18-65 years of age who are recipients of a renal transplant at least 6 months prior to enrollment

• Patients on oral Prograf therapy as part of their maintenance immunosuppression therapy, with stable doses and trough levels of tacrolimus of 7-12 ng/mL for at least two weeks prior to enrollment.

• Patients maintained on concurrent immunosuppression with mycophenolate mofetil (MMF, CellCept) or mycophenolic acid delayed-release tablets (Myfortic), with stable doses for at least two weeks prior to enrollment

• Patients with serum creatinine < 2.0mg/dL prior to enrollment

• Able to swallow study medication

• Patients capable of understanding the purposes and risks of the study, who can give written informed consent and who are willing to participate in and comply with the study

• Women of childbearing potential must have a negative serum pregnancy test within seven days prior to receiving study medication

• Patients who successfully pass a drug screen

Exclusion Criteria:

• Recipients of any transplanted organ other than a kidney

• White blood cell count < 2.8 x 10^9 /L

• Patients who are receiving a total dose of Prograf for 24 hours < 3mg

• Patients unable or unwilling to provide informed consent

• Pregnant or nursing women

• Patients with reproductive potential who are unwilling/unable to use a double barrier method of contraception

• Administration of other investigational agent in the three months prior to enrollment

• Patient receiving any drug interfering with tacrolimus metabolism

• Patients who have taken sirolimus within the past three months prior to screening

• Patient with an episode of acute cellular requiring antibody therapy within the 6 months prior to enrollment

• Patient treated for acute cellular rejection within the 30 days prior to enrollment

• Patient who is HCV negative and has received an HCV positive (HCV RNA by PCR or HCV antibody) donor kidney

• Patient has a current malignancy or a history of malignancy (within the past 5 years), except basal or non-metastatic squamous cell carcinoma of the skin that has been treated successfully

• Patient has uncontrolled concomitant infection, a systemic infection requiring treatment, or any other unstable medical condition that could interfere with the study objectives

• Patient has severe diarrhea, vomiting, active peptic ulcer or gastrointestinal disorder that may affect the absorption of tacrolimus

• Patient will require therapy with any immunosuppressive agent other than those prescribed in the study

• Patient has a known hypersensitivity to corticosteroids, mycophenolate mofetil, mycophenolic acid or tacrolimus

• Patient has any form of current substance abuse, psychiatric disorder or a condition that, in the opinion of the Investigator, may invalidate communication with the Investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Cincinnati	Cincinnati	Ohio	United States	45267
2	Methodist Hospital Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

• Veloxis Pharmaceuticals
• CTI Clinical Trial and Consulting Services

Investigators

• Study Director: Alan Glicklich, MD, Veloxis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Veloxis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00496483
• Other Study ID Numbers: LCP-Tacro 2011
• First Posted: Jul 4, 2007
• Last Update Posted: Jul 23, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Veloxis Pharmaceuticals: Tacrolimus; Pharmacokinetics; Kidney Transplantation
• Additional relevant MeSH terms: Renal Insufficiency; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	LCP-Tacro
Arm/Group Description	All Patients received Prograf for 7 days, then all patients were converted to once daily LCP-Tacro for 14 days. One dose adjustment up or down 25% was permitted on Day 15. On Day 22 patients were converted back to their original twice daily dose of Prograf for a safety follow-up period of 30 days. LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Period Title: Overall Study
STARTED	60
Dosed	51
COMPLETED	48
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Overall Participants	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.6 (12.08)
Sex: Female, Male (Count of Participants)
Female	19 31.7%
Male	41 68.3%
Region of Enrollment (participants) [Number]
United States	60 100%

Outcome Measures

1. Secondary Outcome

Title	Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 21.
Description	Cmax and Cavg was measured at day 21 (Cmin was measured as part of the primary outcome).
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit. The arithmetic mean and standard deviation is given.

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	46
Cmax	13.94 (5.84)
Cavg	9.08 (2.84)

2. Secondary Outcome

Title	Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 21.
Description	Tmax was measured at day 21 (Cmin was measured as part of the primary outcome).
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	46
Mean (Full Range) [hour]	6.00

3. Secondary Outcome

Title	Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 21.
Description	Degree og fluctuation and degree of swing was measured at day 21 (Cmin was measured as part of the primary outcome).
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit. Arithmetic mean and standard deviation is given below.

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	46
Fluctuation	77.04 (50.59)
Swing	110.07 (89.23)

4. Primary Outcome

Title	Evaluation of Steady State Tacrolimus Trough Levels (C24).
Description	Patients had a baseline trough level (C24) measured at day 7 before conversion to LCP-Tacro.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. The arithmetic mean and standard deviation is given.

Arm/Group Title	Prograf
Arm/Group Description	Prograf 0.5 mg, 1 mg and 5 mg capsules administered orally twice daily, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	47
Mean (Standard Deviation) [ng/mL]	7.00 (1.54)

5. Primary Outcome

Title	Evaluation of Steady State Tacrolimus Exposure (AUC 0-24).
Description	Patients had a baseline AUC measured (0 to 24 hours) at day 7 before conversion to LCP-Tacro.
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. The arithmetic mean and standard deviation is given.

Arm/Group Title	Prograf
Arm/Group Description	Prograf 0.5 mg, 1 mg and 5 mg capsules administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	47
Mean (Standard Deviation) [ng*hr/mL]	218.82 (55.99)

6. Primary Outcome

Title	Evaluation of Steady State Tacrolimus Exposure Trough Levels (C24).
Description	Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, a trough level (C24) was measured.
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit. The arithmetic mean and standard deviation is given.

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	46
Mean (Standard Deviation) [ng/mL]	6.94 (2.20)

7. Primary Outcome

Title	Evaluation of Steady State Tacrolimus Exposure (AUC 0-24).
Description	Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, AUC was measured (0 to 24 hours).
Time Frame	21 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit. The arithmetic mean and standard deviation is given.

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	46
Mean (Standard Deviation) [ng*hr/mL]	218.03 (68.23)

8. Secondary Outcome

Title	Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 7.
Description	Cmax and Cavg was measured at baseline day 7 (Cmin was measured as part of the primary outcome).
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. The arithmetic mean and standard deviation is given.

Arm/Group Title	Prograf
Arm/Group Description	Prograf 0.5 mg, 1 mg and 5 mg capsules administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	47
Cmax	19.14 (8.15)
Cavg	9.12 (2.33)

9. Secondary Outcome

Title	Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 7.
Description	Tmax was measured at baseline day 7 (Cmin was measured as part of the primary outcome).
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.

Arm/Group Title	Prograf
Arm/Group Description	Prograf 0.5 mg, 1 mg and 5 mg capsules administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	46
Mean (Full Range) [hour]	1.82

10. Secondary Outcome

Title	Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 7.
Description	Degree og fluctuation and degree of swing was measured as baseline at day 7 (Cmin was measured as part of the primary outcome).
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Arithmetic mean and standard deviation is given below.

Arm/Group Title	Prograf
Arm/Group Description	Prograf 0.5 mg, 1 mg and 5 mg capsules administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	47
Fluctuation	127.41 (57.28)
Swing	174.55 (93.72)

11. Secondary Outcome

Title	Safety Evaluation
Description	A combination of deaths, graft failure and biopsy proven acute rejections (BPAR) was used to evaluate the safety.
Time Frame	52 days

Outcome Measure Data

Analysis Population Description

All enrolled patients are included in the safety population.

Arm/Group Title	LCP-Tacro
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL.
Measure Participants	60
Death	0 0%
Graft failure	0 0%
BPAR	0 0%

Adverse Events

Arm/Group Title	LCP-Tacro		Prograf
Arm/Group Description	LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL. 60 patients were enrolled into the study, but only 51 were dosed with LCP-Tacro.		Prograf 0.5 mg, 1 mg and 5 mg capsules administered orally twice daily, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL. 60 patients were entrolled into the study and one withdrew consent right after screening. Therefore 59 patients are inlcuded in the ITT safety set.
All Cause Mortality
	LCP-Tacro		Prograf
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LCP-Tacro		Prograf
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/51 (3.9%)		0/59 (0%)
Cardiac disorders
Angina Pectoris	1/51 (2%)	1	0/59 (0%)	0
General disorders
Pyrexia	1/51 (2%)	1	0/59 (0%)	0
Other (Not Including Serious) Adverse Events
	LCP-Tacro		Prograf
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/51 (68.6%)		19/59 (32.2%)
Blood and lymphatic system disorders
Leukopenia	1/51 (2%)	1	0/59 (0%)	0
Anaemia	0/51 (0%)	0	1/59 (1.7%)	1
Leukocytosis	1/51 (2%)	1	0/59 (0%)	0
Cardiac disorders
Angina pectoris	2/51 (3.9%)	2	0/59 (0%)	0
Eye disorders
Conjunctuvitis	1/51 (2%)	1	0/59 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/51 (0%)	0	2/59 (3.4%)	2
Nausea	2/51 (3.9%)	2	0/59 (0%)	0
Constipation	1/51 (2%)	1	0/59 (0%)	0
Abdominal pain	1/51 (2%)	1	0/59 (0%)	0
Small intestinal obstruction	0/51 (0%)	0	1/59 (1.7%)	1
General disorders
Chills	2/51 (3.9%)	2	0/59 (0%)	0
Pain	1/51 (2%)	1	1/59 (1.7%)	1
Application site irritation	1/51 (2%)	1	0/59 (0%)	0
Pyrexia	0/51 (0%)	0	1/59 (1.7%)	1
Oedema peripheral	0/51 (0%)	0	1/59 (1.7%)	1
Infections and infestations
Upper respiratory infection	0/51 (0%)	0	1/59 (1.7%)	1
Gatroenteritis	1/51 (2%)	1	0/59 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/51 (0%)	0	1/59 (1.7%)	1
Muscle strain	0/51 (0%)	0	1/59 (1.7%)	1
Investigations
Urinary casts	0/51 (0%)	0	1/59 (1.7%)	1
Heart rate increased	1/51 (2%)	1	0/59 (0%)	0
Cardiac murmur	1/51 (2%)	1	0/59 (0%)	0
Blood pressure increased	0/51 (0%)	0	1/59 (1.7%)	1
Immunosuppressant drug level increased	0/51 (0%)	0	1/59 (1.7%)	1
Metabolism and nutrition disorders
Diabetes Mellitus	1/51 (2%)	1	0/59 (0%)	0
Hypoglycemia	1/51 (2%)	1	0/59 (0%)	0
Hypoalbuminaemia	0/51 (0%)	0	1/59 (1.7%)	1
Hypokalaemia	1/51 (2%)	1	0/59 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle spasms	1/51 (2%)	1	0/59 (0%)	0
Joint swelling	1/51 (2%)	1	0/59 (0%)	0
Back pain	1/51 (2%)	1	0/59 (0%)	0
Nervous system disorders
Headache	3/51 (5.9%)	3	0/59 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	1/51 (2%)	1	0/59 (0%)	0
Nasal congestion	1/51 (2%)	1	1/59 (1.7%)	1
Pharyngolaryngeal pain	1/51 (2%)	1	1/59 (1.7%)	1
Paranasal sinus hypersecretion	0/51 (0%)	0	1/59 (1.7%)	1
Dsypnoea	2/51 (3.9%)	2	0/59 (0%)	0
Cough	0/51 (0%)	0	1/59 (1.7%)	1
Throat irritation	1/51 (2%)	1	0/59 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/51 (0%)	0	1/59 (1.7%)	1
Vascular disorders
Phlebitis	2/51 (3.9%)	2	0/59 (0%)	0
Poor venous access	1/51 (2%)	1	0/59 (0%)	0
Hypertension	1/51 (2%)	1	0/59 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The study is a multicenter collaborative investigation and the clinical trial results are to be published as a collaborative manuscript. Authorship will reflect varying levels of individual contribution to the study by the individual PI's.