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Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation

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ClinicalTrials.gov Identifier: NCT00629122
Recruitment Status : Completed
First Posted : March 5, 2008
Results First Posted : December 11, 2017
Last Update Posted : December 11, 2017
Sponsor:
Information provided by (Responsible Party):
Meredith Aull, Weill Medical College of Cornell University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Health Services Research
Condition Kidney Failure, Chronic
Interventions Drug: Tacrolimus (Arm B)
Drug: Clotrimazole Troche
Drug: Tacrolimus (Arm A)
Drug: Nystatin Suspension
Enrollment 5
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description

Sublingual (SL) tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral (PO) tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).

Study day 1: Initiate SL tacrolimus and nystatin suspension x 5 doses. Study day 3: Collection of pharmacokinetic parameters around 5th SL tacrolimus dose.

Study day 3: Start washout period, no drug administration (tacrolimus, nystatin).

Study day 5: End washout period. Study day 6: Initiate PO tacrolimus and nystatin suspension x 5 doses. Study day 8: Collection of pharmacokinetic parameters around the 5th PO tacrolimus dose.

Study day 15: Participants will be contacted by telephone to assess for any adverse effects.

Sublingual (SL) tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral (PO) tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).

Study day 1: Initiate SL tacrolimus and clotrimazole troche x 5 doses. Study day 3: Collection of pharmacokinetic parameters around the 5th SL tacrolimus dose.

Study day 3: Start washout period, no drug administration (tacrolimus, clotrimazole).

Study day 5: End washout period.

Study day 6: Initiate PO tacrolimus and clotrimazole troche x 5 doses. Study day 8: Collection of pharmacokinetic parameters around the 5th PO tacrolimus dose.

Study day 15: Participants will be contacted by telephone to assess for any adverse effects.

Period Title: First Period: Day 1- 3 (Sublingual)
Started 2 3
Completed 2 3
Not Completed 0 0
Period Title: Second Period: Day 3-5 (Washout)
Started 2 3
Completed 2 3
Not Completed 0 0
Period Title: Third Period: Day 6-8 (Oral)
Started 2 3
Completed 2 3
Not Completed 0 0
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole) Total
Hide Arm/Group Description Sublingual (SL) tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral (PO) tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8). Sublingual (SL) tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral (PO) tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8). Total of all reporting groups
Overall Number of Baseline Participants 2 3 5
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 3 participants 5 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
1
  50.0%
1
  33.3%
2
  40.0%
>=65 years
1
  50.0%
2
  66.7%
3
  60.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 3 participants 5 participants
Female
1
  50.0%
1
  33.3%
2
  40.0%
Male
1
  50.0%
2
  66.7%
3
  60.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 2 participants 3 participants 5 participants
2 3 5
1.Primary Outcome
Title C0 (ng/mL)
Hide Description Trough concentration
Time Frame Day 3 and Day 8, time 0 (before tacrolimus dose)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description:
Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).
Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
Overall Number of Participants Analyzed 2 3
Median (Full Range)
Unit of Measure: ng/mL
Day 3 (Sublingual)
1.45
(0.1 to 2.8)
6.2
(3.0 to 8.3)
Day 8 (Oral)
1.25
(0.2 to 2.3)
6.5
(3.2 to 11.2)
2.Primary Outcome
Title Cmax
Hide Description Maximum concentration (ng/mL)
Time Frame Day 3 and Day 8, at time of maximum concentration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description:
Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).
Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
Overall Number of Participants Analyzed 2 3
Median (Full Range)
Unit of Measure: ng/mL
Day 3 (Sublingual)
9.6
(2.0 to 17.2)
14.0
(6.5 to 22.5)
Day 8 (Oral)
4.6
(3.2 to 6.0)
19.5
(10.1 to 19.8)
3.Primary Outcome
Title Tmax
Hide Description Time to Maximum concentration (hours)
Time Frame Day 3 and Day 8, time of maximum concentration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description:
Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).
Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
Overall Number of Participants Analyzed 2 3
Median (Full Range)
Unit of Measure: hours
Day 3 (Sublingual)
1.75
(1.5 to 2.0)
3.0
(1.5 to 4.0)
Day 8 (Oral)
0.875
(0.75 to 1.0)
2.0
(2.0 to 4.0)
4.Primary Outcome
Title Estimated AUC 0-6
Hide Description Area Under the Concentration-Time Curve from 0-6 hours (mg-hr/L)
Time Frame Day 3 and Day 8, calculated based on concentrations measured between hours 0 and 6
Hide Outcome Measure Data
Hide Analysis Population Description
Where "0" is entered, the patient did not receive that combination (ie. was in other arm)
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description:
Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).
Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
Overall Number of Participants Analyzed 2 3
Measure Type: Number
Unit of Measure: mg-hr/L
Patient 1 Sublingual (day 3) 9.3 0
Patient 1 Oral (day 8) 4.9 0
Patient 2 Sublingual (day 3) 0 27.2
Patient 2 Oral (day 8) 0 32.4
Patient 3 Sublingual (day 3) 0 66
Patient 3 Oral (day 8) 0 76
Patient 4 Sublingual (day 3) 0 63.7
Patient 4 Oral (day 8) 0 52.5
Patient 5 Sublingual (day 3) 63.0 0
Patient 5 Oral (day 8) 23.2 0
5.Primary Outcome
Title Tacrolimus Powder Dissolution Time
Hide Description Tacrolimus Powder Dissolution Time during Sublingual Administration (minutes)
Time Frame Day 3, minutes to powder dissolution
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description:
Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).
Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
Overall Number of Participants Analyzed 2 3
Median (Full Range)
Unit of Measure: minutes
2.25
(2.0 to 2.5)
2.0
(1.5 to 3.0)
6.Secondary Outcome
Title Drug Interactions and Genotypes
Time Frame 2 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
We were unable to assess genotype polymorphisms due to the small number of subjects enrolled in the study.
Arm/Group Title Arm A (Tacrolimus and Nystatin) Arm B (Tacrolimus and Clotrimazole)
Hide Arm/Group Description:
Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8).
Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Arm A (Tacrolimus + Nystatin) Arm B (Tacrolimus + Clotrimazole)
Hide Arm/Group Description Sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8). Sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8).
All-Cause Mortality
Arm A (Tacrolimus + Nystatin) Arm B (Tacrolimus + Clotrimazole)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Arm A (Tacrolimus + Nystatin) Arm B (Tacrolimus + Clotrimazole)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/2 (0.00%)      0/3 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Arm A (Tacrolimus + Nystatin) Arm B (Tacrolimus + Clotrimazole)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/2 (100.00%)      3/3 (100.00%)    
Gastrointestinal disorders     
Bitter taste in mouth * [1]  2/2 (100.00%)  2 3/3 (100.00%)  3
*
Indicates events were collected by non-systematic assessment
[1]
Bitter taste of the tacrolimus powder for sublingual administration.
Small sample size; variable absorption profile; poor vascular access in some subjects; possible enteral absorption of sublingual drug; unable to assess genotype polymorphisms due to the small number of subjects.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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.
Results Point of Contact
Name/Title: Meredith J. Aull, Pharm.D.
Organization: Weill Cornell Medical College
Phone: (212) 746-8720
Responsible Party: Meredith Aull, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT00629122     History of Changes
Other Study ID Numbers: 0710009492
First Submitted: February 12, 2008
First Posted: March 5, 2008
Results First Submitted: July 9, 2015
Results First Posted: December 11, 2017
Last Update Posted: December 11, 2017