A Prospective Study on the Tolerability and Efficacy of the de Novo Use of Myfortic in Liver Transplant Recipients

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00336817

Enrollment

Registered

2006-06-14

Start date

2006-11-30

Completion date

2008-11-30

Last updated

2017-03-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Immunosuppression

Keywords

Liver transplantation, mycophenolate mofetil, gastrointestinal, adverse effects

Brief summary

The objective of this study is to compare the safety and efficacy of Myfortic with CellCept in liver transplant patients. Myfortic and CellCept are both immunosuppressive (anti-rejection) drugs. CellCept is commonly used after liver transplantation but gastrointestinal (GI) side effects are very common, sometimes necessitating in its discontinuation. Myfortic is a new drug similar to CellCept, except it is enteric-coated. Our hypothesis is that Myfortic has less GI side effects than CellCept and also has comparable effectiveness to CellCept.

Detailed description

This is a prospective, randomized, double-blinded, single center, safety and efficacy study comparing Myfortic with CellCept used after liver transplantation. Patients with biopsy-proven acute cellular rejection, renal insufficiency (i.e. acute or chronic renal failure requiring hemodialysis or patients with creatinine clearance \< 50 ml/min), or calcineurin inhibitor-induced neurotoxicity (defined as the presence of neurologic symptoms such as tremors, altered mental status, seizures, etc) will be randomized to start on either Myfortic (720 mg po bid) or CellCept (1 gm po bid). In those patients with calcineurin-induced neurotoxicity or nephrotoxicity, tacrolimus or cyclosporine doses will also be reduced to maintain serum trough levels of 4-8 mg/dl or 100-200 mg/dl, respectively. Comparison: Thirty patients will be enrolled and randomized in this two-armed, double-blinded study- half of the patients will receive Myfortic and the other half, CellCept.

Interventions

DRUGMyfortic

Myfortic 360mg or 720 mg BID for 90 days

DRUGCellCept

CellCept 500mg or 1000mg BID for 90 days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

* ALL patients will be adult liver transplant recipients, males or females, 18-80 years of age. * Patients must be 30 to 180 days (1 to 6 months) post-transplant to be eligible. * Patients currently receiving tacrolimus or cyclosporine with or without corticosteroids as part of their immunosuppressive regimen. * Patients with renal insufficiency (history of renal insufficiency or renal failure in the past, patients on hemodialysis, patients with a rising creatinine post-transplant). * Patients with biopsy-proven acute cellular rejection (mild, moderate, or severe based on Rejection Activity Index (RAI) as graded by pathologists at UPMC) or repeated bouts of rejection (greater than 2 episodes within a 30 day period). * Patients with tacrolimus- or cyclosporine-induced neurotoxicity. * Females of childbearing potential must have a negative serum pregnancy test prior to the inclusion period.

Exclusion criteria

* Multi-organ transplant patients. * HIV positive patients. * Living-related liver transplant recipients * Pregnant patients and nursing mothers. * Patients with a history of extra-hepatic malignancy within the last five years, except excised squamous or basal cell carcinoma of the skin. * Patients with thrombocytopenia (\<50,000/mm3), with an absolute neutrophil count of \<1,000/mm3 and/or leukocytopenia (\<2,000/mm3), and/or hemoglobin \<7.0 g/dL prior to enrollment. * Presence of clinically significant infection requiring continued therapy, severe diarrhea, active peptic ulcer disease, or uncontrolled diabetes mellitus. * Evidence of drug and/or alcohol abuse. * Decisionally impaired subjects who are not medically or mentally capable of providing consent themselves

Design outcomes

Primary

Measure	Time frame	Description
Incidence of Cytomegalovirus Infection or Disease During the Study Period	12 weeks	number of participants
GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil (Reflux Subscale)	screening, 2, 6 and 12 weeks	The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. Reflux subscale range is 2 to 14 with higher scores means worst symptoms
GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil ( Indigestion Subscale)	screening, 2, 6 and 12 weeks	The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The Indigestion subscale range is 4 to 28 with higher scores means worst symptoms
GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil ( Diarrhea Subscale)	screening, 2, 6 and 12 weeks	The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The Diarrhea subscale range is 3 to 21 with higher scores means worst symptoms
GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil ( Constipation Subscale)	screening, 2, 6 and 12 weeks	The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. Constipation subscale range is 3 to 21 with higher scores means worst symptoms
Number of Participants With Bone Marrow Suppression	12 weeks	Number of participants with: Thrombocytopenia (\<50,000 mm3), Leukopenia (\< 2000 mm3), absolute neutrophils count ( \<1000 mm3) or hemoglobin ( \< 7.0 g/dL)
GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil	screening, 2, 6 and 12 weeks	The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The total GSRS range of scores is 15 to 105 with higher scores meaning the worst of symptoms.
GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil (Abdominal Pain Subscale)	screening, 2, 6 and 12 weeks	The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The abdominal Pain subscale range is 3 to 21 with higher scores means worst symptoms

Secondary

Measure	Time frame	Description
Drug Discontinuation Due to Side Effects	12 weeks	Drug discontinuation due to drug side effects regarding Cellcept and Myfortic.
Number of Participants With Clinically Significant Decrease in Serum Creatinine From Baseline Through Week 12	12 weeks	Creatinine levels
Number of Participants With Neurotoxicity	12 weeks	—

Other

Measure	Time frame	Description
Incidence of Biopsy-proven Acute Cellular Rejection During the Study Period	12 weeks	number of patients with ACR
Incidence of Graft Loss or Death During the Study Period	12 weeks	number of patients

Countries

United States

Participant flow

Participants by arm

Arm	Count
Myfortic Group Subjects in the Myfortic arm will receive Myfortic 360mg or 720 mg BID for 90 days Myfortic: Myfortic 360mg or 720 mg BID for 90 days	14
CellCept Group Subjects in the CellCept arm will receive CellCept 500mg or 1000mg BID for 90 days CellCept: CellCept 500mg or 1000mg BID for 90 days	15
Total	29

Baseline characteristics

Characteristic	CellCept Group	Myfortic Group	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	5 Participants	2 Participants	7 Participants
Age, Categorical Between 18 and 65 years	10 Participants	12 Participants	22 Participants
Age, Continuous	58.2 years STANDARD_DEVIATION 8.83338	54.6 years STANDARD_DEVIATION 12.75408	56.4333 years STANDARD_DEVIATION 10.92824
Region of Enrollment United States	15 participants	15 participants	30 participants
Sex: Female, Male Female	8 Participants	2 Participants	10 Participants
Sex: Female, Male Male	7 Participants	12 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 15	0 / 15
serious Total, serious adverse events	0 / 15	0 / 15

Outcome results

Primary

GI Side Effects as Assessed by Gastro Intestinal Symptoms Rating Scale (GSRS) of Enteric-coated Mycophenolate Sodium vs Mycophenolate Mofetil

The GSRS contains 15 items, each rated on a seven-point Likert scale from no discomfort to very severe discomfort. Based on a factor analysis, the 15 GSRS items break down into the following five scale: abdominal pain syndrome ( abdominal pain, hunger pains, and nausea); reflux syndrome (heartburn and acid regurgitation), diarrhea syndrome (diarrhea, loose stools and urgent need for defecation), indigestion syndrome (borborygmus, abdominal distension, eructation and increased flatus) and constipation syndrome (constipation, hard stools, and feeling of incomplete evacuation). The GSRS is a disease-specific instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms. The total GSRS range of scores is 15 to 105 with higher scores meaning the worst of symptoms.