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Myfortic or CellCept Gastrointestinal Effects in African American Kidney Recipients

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ClinicalTrials.gov Identifier: NCT00522548
Recruitment Status : Terminated (enrollment halted in order to have all patients complete follow-up by Jan 2011)
First Posted : August 29, 2007
Results First Posted : January 23, 2018
Last Update Posted : January 23, 2018
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Roy D. Bloom, MD, University of Pennsylvania

Brief Summary:
Myfortic (enteric-coated mycophenolate sodium) has been shown to have similar effectiveness to CellCept (mycophenolate mofetil) in preventing rejection in kidney transplant recipients. However, enteric coated mycophenolate sodium has been thought to possibly be associated with fewer gastrointestinal side effects. Mycophenolate mofetil and enteric coated mycophenolate sodium pharmacokinetics (how the drug is absorbed and broken down) have not been well-studied in African American kidney transplant recipients. The investigators are interested in studying enteric coated mycophenolate sodium and mycophenolate mofetil pharmacokinetics and gastrointestinal side effects in African American kidney transplant recipients.

Condition or disease Intervention/treatment Phase
Transplants and Implants Drug: Enteric coated mycophenolate sodium Drug: Mycophenolate mofetil Phase 4

Detailed Description:

African American patients often experience more gastrointestinal (GI) complications after kidney transplant than Caucasian patients. In addition, African American kidney transplant recipients also experience a higher incidence of acute rejection and have worse outcomes compared with all other ethnic groups. Reasons accounting for these differences are not well understood.

In light of the increased risk of GI complications in African American patients, we will compare in a pilot study, different regimens (described below) that we commonly use in our clinical practice in this population. As part of this study, patients will also fill out a GSRS survey at specified time points to help describe gastrointestinal side effects after transplant.

Pharmacokinetic studies (studies looking at how the drugs are absorbed and broken down) for mycophenolate mofetil or enteric coated mycophenolate sodium have largely been performed in Caucasian populations. There is little information available in African-American patients. This is particularly concerning in the face of the worst clinical outcomes observed after transplantation in African American kidney transplant recipients.

Comparisons: Patients will be randomized to one of two groups

  • Group 1: Myfortic (enteric-coated mycophenolate sodium) in combination with Prograf (tacrolimus) or its generic equivalent and corticosteroids
  • Group 2: CellCept (mycophenolate mofetil) or its generic equivalent manufactured by Sandoz in combination with Prograf (tacrolimus) or its generic equivalent and corticosteroids

Since toxicity of mycophenolate mofetil and enteric coated mycophenolate sodium may be influenced by pharmacokinetics (studies that look at how the drugs are absorbed and broken down) of these respective drugs, we will compare the pharmacokinetics of enteric coated mycophenolate sodium and mycophenolate mofetil in a subset of patients. This pharmacokinetic data may have the additional valuable benefit of helping to optimize dosing parameters for mycophenolate mofetil and enteric coated mycophenolate sodium in African American kidney transplant patients in the future.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study consisted of 2 parallel active comparator arms.
Masking: None (Open Label)
Masking Description: Masking description is not applicable since no masking was used in this study.
Primary Purpose: Treatment
Official Title: Gastrointestinal Adverse Effect Outcomes of De Novo African American Kidney Transplant Recipients Treated With Tacrolimus, Corticosteroids and Mycophenolate Mofetil or Enteric Coated Mycophenolate Sodium
Study Start Date : March 2007
Actual Primary Completion Date : January 2011
Actual Study Completion Date : January 2011


Arm Intervention/treatment
Active Comparator: Enteric coated mycophenolate sodium
Patients in this group will receive Myfortic (enteric-coated mycophenolate sodium) at a target dose of 720 mg orally twice daily for 6 months after transplant.
Drug: Enteric coated mycophenolate sodium
Patients in this group will receive Myfortic (enteric-coated mycophenolate sodium) in combination with Thymoglobulin (rabbit Anti-thymocyte globulin) induction immunosuppression, Prograf (tacrolimus) or its generic equivalent, and corticosteroid immunosuppression.
Other Name: Myfortic
Active Comparator: Mycophenolate mofetil
Patients in this group will receive CellCept (mycophenolate mofetil) or its generic equivalent manufactured by Sandoz, at a target dose of 1000 mg orally twice daily for 6 months after transplant.
Drug: Mycophenolate mofetil
Patients in this group will receive CellCept (mycophenolate mofetil) or its generic equivalent formulation manufactured by Sandoz, in combination with Thymoglobulin (rabbit Anti-thymocyte globulin) induction immunosuppression, Prograf (tacrolimus) or its generic equivalent, and corticosteroid immunosuppression.
Other Name: CellCept



Primary Outcome Measures :
  1. Gastrointestinal Toxicity Due to Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Formulation Manufactured by Sandoz [ Time Frame: 6 months ]
    At 24 weeks, we assessed the number of patients at this timepoint who required permanent dose decrease or discontinuation of either enteric coated mycophenolate sodium or mycophenolate mofetil or its generic equivalent formulation manufactured by Sandoz related to gastrointestinal toxicity.


Secondary Outcome Measures :
  1. The Incidence of the Requirement of Full Dose Proton Pump Inhibitors in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz [ Time Frame: 6 months ]
    If patients were not on any medications from a medication class known as H-2 antagonists, they were started on ranitidine 150 mg orally twice daily after transplant (with dose adjusted for renal function). Patients were excluded if they were on proton pump inhibitor at time of study screening, however some patients required addition of proton pump inhibitor post-study enrollment. If a patient had upper gastrointestinal side effects such as acid reflux unreleived on ranitidine therapy or nausea, they were switched to a proton pump inhibitor.

  2. The Incidence of Intolerance (Defined as Transient Dose Reduction or Transient Discontinuation of Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz [ Time Frame: 6 months ]
    The incidence of intolerance was defined as transient dose reduction or transient discontinuation of enteric coated mycophenolate sodium or mycophenolate mofetil or its generic equivalent manufactured by Sandoz meaning doses could subsequently be resumed or increased back to original starting dose, once intolerance resolved.

  3. Gastrointestinal Symptom Rating Scale (GSRS) Score Changes From Baseline to 24 Weeks After Transplant in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz [ Time Frame: baseline (pre-transplant to two days after transplant) and at 6 months after transplant. ]
    The Gastrointestinal Symptom Rating Scale (GSRS) is a 15-item self-administered questionnaire to assess symptoms associated with common gastrointestinal (GI) disorders, and has been validated in renal transplant recipients. It uses a seven-graded Likert scale, where 1 represents the most positive option and 7 the most negative one and the patient grades symptoms based on the past 7 days. A score of ≥ 2 indicates the presence of GI symptoms. Higher values indicate more unfavorable conditions. The questionairre is divided into 5 sub-scales: diarrhea, indigestion, constipation, abdominal pain, and reflux and a mean score is calculated for each dimension. The lowest mean score possible for each dimension is 1 and the highest is 7. Patients completed a GSRS survey at baseline (pre-transplant to two days after transplant), and at weeks 1,4,12 and 24 after transplant.

  4. The Incidence of the Occurrence of Upper Gastrointestinal Symptoms Per GSRS Scale Ratings in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Formulation Manufactured by Sandoz [ Time Frame: 6 months ]
    The Gastrointestinal Symptom Rating Scale (GSRS) is a 15-item self-administered questionnaire to assess symptoms associated with common gastrointestinal (GI) disorders, and has been validated in renal transplant recipients. It uses a seven-graded Likert scale, where 1 represents the most positive option and 7 the most negative one and the patient grades symptoms based on the past 7 days. A score of ≥ 2 indicates the presence of GI symptoms. Higher values indicate more unfavorable conditions. The questionairre is divided into 5 sub-scales: diarrhea, constipation, abdominal pain, indigestion and reflux and a mean score is calculated for each dimension. The lowest mean score possible for each dimension is 1 and the highest is 7. Patients completed a GSRS survey at baseline (pre-transplant to two days after transplant), and at weeks 1,4,12 and 24 post-transplant.

  5. The Incidence of the Occurrence of Lower Gastrointestinal Symptoms Per GSRS Scale Ratings in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz [ Time Frame: 6 months ]
    The Gastrointestinal Symptom Rating Scale (GSRS) is a 15-item self-administered questionnaire to assess symptoms associated with common gastrointestinal (GI) disorders, and has been validated in renal transplant recipients. It uses a seven-graded Likert scale, where 1 represents the most positive option and 7 the most negative one and the patient grades symptoms based on the past 7 days. A score of ≥ 2 indicates the presence of GI symptoms. Higher values indicate more unfavorable conditions. The questionairre is divided into 5 sub-scales: diarrhea, constipation, abdominal pain, indigestion and reflux and a mean score is calculated for each dimension. The lowest mean score possible for each dimension is 1 and the highest is 7. Patients completed a GSRS survey at baseline (pre-transplant to two days after transplant), and at weeks 1,4,12 and 24 post-transplant. Patients who withdrew from the study only had data included up to the point of withdraw. No values were carried forward.

  6. The Incidence of Rejection in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz. [ Time Frame: 6 months ]
    All rejection episodes of the kidney transplant were proven by kidney transplant biopsy and were measured at 24 weeks for all patients still participating in the study at that timepoint.

  7. Serum Creatinine in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz [ Time Frame: 6 months ]
    Serum creatinine lab values were used as part of a measure of renal function at 24 weeks for any patient that was still participating in the study at this time-point.

  8. Modification of Diet and Renal Disease (MDRD) Measured Glomerular Filtration Rates in Patients on Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz [ Time Frame: 6 months ]
    Modification of Diet and Renal Disease (MDRD) Measured Glomerular Filtration Rates were used as part of a measure of renal function and measured at 24 weeks in patients who were still participating in the study at that point.

  9. Pharmacokinetics (Mycophenolic Acid Trough Levels) of Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz in a Sub-set of Patients [ Time Frame: 1 and 6 months ]
    Pharmacokinetics is the study of how a drug is absorbed and broken down in the body. Pharmacokinetics of enteric coated mycophenolate sodium and mycophenolate mofetil are measured by a level called mycophenolic acid level. Mycophenolic acid levels in this pharmacokinetic study were drawn starting in the morning at time zero (immediately prior to morning dose, also known as trough), then at 0.5, 1,1.5, 2, 2.5, 3,3.5,4,6, 8 and 12 hours post dose. Data was also dose-normalized (concentration was divided by dose).

  10. Pharmacokinetics (Mycophenolic Acid Maximum Concentration) of Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz in a Sub-set of Patients [ Time Frame: 1 and 6 months ]
    Pharmacokinetics is the study of how a drug is absorbed and broken down in the body. Pharmacokinetics of Enteric-Coated Mycophenolate Sodium or Mycophenolate Mofetil are measured by a level called mycophenolic acid level. Mycophenolic acid levels in this pharmacokinetic study were drawn starting in the morning at time zero (immediately prior to morning dose, also known as trough), then at 0.5, 1,1.5, 2, 2.5, 3,3.5,4,6, 8 and 12 hours post dose. Data was also dose-normalized (concentration was divided by dose).A mycophenolic acid drawn at the peak level is called C Max or maximum concentration.

  11. Pharmacokinetics (Mycophenolic Acid Area Under the Curve) of Enteric Coated Mycophenolate Sodium or Mycophenolate Mofetil or Its Generic Equivalent Manufactured by Sandoz in a Sub-set of Patients [ Time Frame: 1 and 6 months ]
    Pharmacokinetics is the study of how a drug is absorbed and broken down in the body. Pharmacokinetics of Enteric-Coated Mycophenolate Sodium or Mycophenolate Mofetil are measured by a level called mycophenolic acid level. Mycophenolic acid levels in this pharmacokinetic study were drawn starting in the morning at time zero (immediately prior to morning dose, also known as trough), then at 0.5, 1,1.5, 2, 2.5, 3,3.5,4,6, 8 and 12 hours post dose. Data was also dose-normalized (concentration was divided by dose). A mycophenolic acid area under the curve value, also known as AUC represents drug exposure.



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recipients of a deceased donor or living donor kidney transplant
  • Recipients of age greater than 18 years but less than 76 years
  • African Americans (self-reported patients of Black African descent who live in the United States)
  • Willingness to participate in a randomized, clinical trial, as indicated by signed informed consent
  • Patients with a history of gastrointestinal complications including any of the following: a history of diarrhea, constipation, acid reflux, or abdominal pain as reported by the patient
  • For women of childbearing age, effective contraception must be used before beginning CellCept or Myfortic, during therapy and 6 weeks after therapy has been discontinued (childbearing women should have a negative serum or urine pregnancy test within 1 week prior to starting CellCept or Myfortic therapy)

Exclusion Criteria:

  • Recipients with any prior solid organ transplant (including kidney)
  • Recipients receiving a concurrent solid organ (heart, liver, pancreas) or cell (islet, bone marrow, stem cell) transplant
  • Recipient age is less than 18 years old or greater than 75 years old
  • Recipients who are not African American (self-reported patients of Black African descent who live in the United States)
  • Recipients on proton pump inhibitor therapy at the time of initial screening (pre-transplant to 2 days post-transplant)
  • Recipients with a gastrointestinal bleed within the past three months
  • Recipients who are pregnant or breast feeding
  • Recipients with known human immunodeficiency virus (HIV) infection
  • Allergy to any of the immunosuppressant medications
  • Concurrent investigational medication
  • Any medical or psychosocial condition, which, in the opinion of the investigators, would hinder compliance with the study requirements
  • Inability or unwillingness of patient to provide informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00522548


Locations
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104-4322
Sponsors and Collaborators
University of Pennsylvania
Novartis Pharmaceuticals
Investigators
Principal Investigator: Roy Bloom, MD University of Pennsylvania-Renal Electrolyte and Hypertension Division

Responsible Party: Roy D. Bloom, MD, Medical Director, Penn Kidney/Pancreas Transplant Program, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT00522548     History of Changes
Other Study ID Numbers: CERL080A-US49
First Posted: August 29, 2007    Key Record Dates
Results First Posted: January 23, 2018
Last Update Posted: January 23, 2018
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Roy D. Bloom, MD, University of Pennsylvania:
African American
Kidney Transplant

Additional relevant MeSH terms:
Tacrolimus
Antilymphocyte Serum
Thymoglobulin
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents