A Study of Mycophenolate Mofetil (CellCept) in Lung Transplant Recipients

Study Overview
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Brief Summary
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This open-label, single center study will assess the pharmacokinetics, efficacy and safety of mycophenolate mofetil in lung allograft recipients. Participants will be split into 2 groups according to the original disease: Group A (cystic fibrosis) and Group B (chronic obstructive pulmonary disease [COPD], emphysema, idiopathic pulmonary fibrosis, alpha-1 antitrypsin deficiency [A1AD]). All participants will receive mycophenolate mofetil orally, 1.5 grams (g) twice daily (BID) from Day 2 to 30 post transplantation, and 1 g BID from Day 31 to 90 post transplantation. Anticipated time on study treatment is 90 days, and target sample size is 50-100 individuals.

Official Title
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Pharmacokinetics of Mycophenolate Mofetil in de Novo Lung Allograft Recipients

Conditions
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Lung Transplantation

Intervention / Treatment
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* Drug: mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: primary single or bilateral lung allograft original disease cystic fibrosis, COPD, emphysema, idiopathic pulmonary fibrosis or A1AD Exclusion Criteria: lung allograft retransplantation multiple organ transplantation severe gastrointestinal disorder malignancies or history of malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate Mofetil; Cystic Fibrosis<br>Participants with cystic fibrosis will receive mycophenolate mofetil 1.5 g, orally (PO), BID from Days 2 through 30 post-transplantation, and 1 g, PO, BID from Days 31 through 90 post-transplantation. | Drug: mycophenolate mofetil<br>* 1.5 g PO BID from Days 2 to 30 post-transplantation, 1 g PO BID Days 31 to 90 post-transplantation<br>* Other names: CellCept;|
| Experimental: Mycophenolate Mofetil; Other<br>Participants with COPD, emphysema, idiopathic pulmonary fibrosis, or A1AD will receive mycophenolate mofetil 1.5 g, PO, BID, from Days 2 through 30 post-transplantation, and 1 g, PO, BID from Days 31 through 90 post-transplantation. | Drug: mycophenolate mofetil<br>* 1.5 g PO BID from Days 2 to 30 post-transplantation, 1 g PO BID Days 31 to 90 post-transplantation<br>* Other names: CellCept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) of Mycophenolic Acid (MPA), Mycophenolic Acid Glucuronide (MPAG) and Acyl Glucuronide Metabolite of Mycophenolic Acid (AcMPAG) at Day 4 | Cmax was expressed in milligrams per liter (mg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 after transplantation | 
| Cmax of MPA, MPAG and AcMPAG at Day 8 | Cmax was expressed in mg/L. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Cmax of MPA, MPAG and AcMPAG at Day 20 | Cmax was expressed in mg/L. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Cmax of MPA, MPAG and AcMPAG at Day 90 | Cmax was expressed in mg/L. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Cmax of Free MPA at Day 4 | Cmax was expressed in micrograms per liter (mcg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| Cmax of Free MPA at Day 8 | Cmax was expressed in mcg/L. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Cmax of Free MPA at Day 20 | Cmax was expressed in mcg/L. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Cmax of Free MPA at Day 90 | Cmax was expressed in mcg/L. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Dose-Normalized Cmax of MPA, MPAG, AcMPAG and Free MPA at Day 4 | Dose-normalized Cmax was determined (in 1 per liter [1/L]) by dividing the Cmax by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| Dose-Normalized Cmax of MPA, MPAG, AcMPAG and Free MPA at Day 8 | Dose-normalized Cmax was determined (in 1/L) by dividing the Cmax by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Dose-Normalized Cmax of MPA, MPAG, AcMPAG and Free MPA at Day 20 | Dose-normalized Cmax was determined (in 1/L) by dividing the Cmax by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Dose-Normalized Cmax of MPA, MPAG, AcMPAG and Free MPA at Day 90 | Dose-normalized Cmax was determined (in 1/L) by dividing the Cmax by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Time to Maximum Concentration (Tmax) of MPA, MPAG, AcMPAG and Free MPA at Day 4 |  | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| Tmax of MPA, MPAG, AcMPAG and Free MPA at Day 8 |  | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Tmax of MPA, MPAG, AcMPAG and Free MPA at Day 20 |  | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Tmax of MPA, MPAG, AcMPAG and Free MPA at Day 90 |  | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Minimum Concentration (Cmin) of MPA, MPAG and AcMPAG at Day 4 | Cmin was expressed in mg/L. | Predose (0 hour) on Day 4 post-transplantation | 
| Cmin of MPA, MPAG and AcMPAG at Day 8 | Cmin was expressed in mg/L. | Predose (0 hour) on Day 8 post-transplantation | 
| Cmin of MPA, MPAG and AcMPAG at Day 20 | Cmin was expressed in mg/L. | Predose (0 hour) on Day 20 post-transplantation | 
| Cmin of MPA, MPAG and AcMPAG at Day 90 | Cmin was expressed in mg/L. | Predose (0 hour) on Day 90 post-transplantation | 
| Cmin of Free MPA at Day 4 | Cmin was expressed in mcg/L. | Predose (0 hour) on Day 4 post-transplantation | 
| Cmin of Free MPA at Day 8 | Cmin was expressed in mcg/L. | Predose (0 hour) on Day 8 post-transplantation | 
| Cmin of Free MPA at Day 20 | Cmin was expressed in mcg/L. | Predose (0 hour) on Day 20 post-transplantation | 
| Cmin of Free MPA at Day 90 | Cmin was expressed in mcg/L. | Predose (0 hour) on Day 90 post-transplantation | 
| Volume of Distribution (Vz) of MPA, MPAG and AcMPAG at Day 4 | Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| Vz of MPA, MPAG and AcMPAG at Day 8 | Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Vz of MPA, MPAG and AcMPAG at Day 20 | Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Vz of MPA, MPAG and AcMPAG at Day 90 | Vz is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Clearance (CL) of MPA, MPAG and AcMPAG at Day 4 | CL is a quantitative measure of the rate at which a drug substance is removed from the body and expressed in liters per hour (L/hour). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| CL of MPA, MPAG and AcMPAG at Day 8 | CL is a quantitative measure of the rate at which a drug substance is removed from the body and expressed in L/hour. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| CL of MPA, MPAG and AcMPAG at Day 20 | CL is a quantitative measure of the rate at which a drug substance is removed from the body and expressed in L/hour. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| CL of MPA, MPAG and AcMPAG at Day 90 | CL is a quantitative measure of the rate at which a drug substance is removed from the body and expressed in L/hour. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Area Under the Curve From Time 0 to 12 Hours (AUC0-12) of MPA, MPAG and AcMPAG at Day 4 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours time milligrams per liter (hours*[mg/L]). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| AUC0-12 of MPA, MPAG and AcMPAG at Day 8 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours*(mg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| AUC0-12 of MPA, MPAG and AcMPAG at Day 20 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours*(mg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| AUC0-12 of MPA, MPAG and AcMPAG at Day 90 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours*(mg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| AUC0-12 of Free MPA at Day 4 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours times micrograms per liter (hours*[mcg/L]). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| AUC0-12 of Free MPA at Day 8 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours*(mcg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| AUC0-12 of Free MPA at Day 20 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours*(mcg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| AUC0-12 of Free MPA at Day 90 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours and expressed in hours*(mcg/L). | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Dose-Normalized AUC0-12 of MPA, MPAG, AcMPAG and Free MPA at Day 4 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours. Dose-normalized AUC0-12 was determined (in hours/L) by dividing the AUC0-12 by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| Dose-Normalized AUC0-12 of MPA, MPAG, AcMPAG and Free MPA at Day 8 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours. Dose-normalized AUC0-12 was determined (in hours/L) by dividing the AUC0-12 by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Dose-Normalized AUC0-12 of MPA, MPAG, AcMPAG and Free MPA at Day 20 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours. Dose-normalized AUC0-12 was determined (in hours/L) by dividing the AUC0-12 by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Dose-Normalized AUC0-12 of MPA, MPAG, AcMPAG and Free MPA at Day 90 | AUC0-12 is a measure of the serum concentration of the drug from time 0 to 12 hours. Dose-normalized AUC0-12 was determined (in hours/L) by dividing the AUC0-12 by the actual dose taken. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 
| Free Fraction of Free MPA at Day 4 | MPA Free fraction (in percent [%]) was calculated by dividing free MPA AUC0-12 by total MPA AUC0-12 times 100%. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 4 post-transplantation | 
| Free Fraction of Free MPA at Day 8 | MPA Free fraction (in %) was calculated by dividing free MPA AUC0-12 by total MPA AUC0-12 times 100%. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 8 post-transplantation | 
| Free Fraction of Free MPA at Day 20 | MPA Free fraction (in %) was calculated by dividing free MPA AUC0-12 by total MPA AUC0-12 times 100%. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 20 post-transplantation | 
| Free Fraction of Free MPA at Day 90 | MPA Free fraction (in %) was calculated by dividing free MPA AUC0-12 by total MPA AUC0-12 times 100%. | Predose (0 hour), 0.5, 1, 1.5, 2, 4, 8, 10, and 12 hours post-dose on Day 90 post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in 1 Second (FEV1) at Day 90 Post-Transplantation | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. | Day 90 post-transplantation | 
| Percent of Predicted FEV1 at Day 90 Post-Transplantation | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Percent predicted FEV1 [%] = (FEV1 [L] / Predicted normal value FEV1 [L]) * 100% | Day 90 post-transplantation | 
| Forced Vital Capacity (FVC) at Day 90 Post-Transplantation | FVC at Day 90 post-transplantation is reported. | Day 90 post-transplantation | 
| Change From Baseline in Intracellular Adenosine-Tri-Phosphate (iATP) Levels | iATP was expressed in ng/mL. | Baseline, Days 4, 8, 20 and 90 post-transplantation | 
| Change From Baseline in T-Cell Phenotype | Reported values are change in the T-cell phenotype status from baseline to Day 20 and 90 for cluster of differentiation (CD) 3, CD19, CD4, CD4CD25, CD28, CD45RA, CD45RO, CD69, CD127, and CD152. | Baseline, Days 20 and 90 post-transplantation | 
| Percentage of Participants With Opportunistic Infections | Opportunistic infections included all infections which occurred due to aspergillus, candida, pneumocystis, cryptococcus, listeria, herpes zoster, herpes simplex, cytomegalovirus pathogens. | Up to Day 90 |