Canadian Cardiology de Novo Study: A Comparison Between Tacrolimus- and Cyclosporine- Based Immunoprophylactic Regimens

Heart Diseases Clinical Trial

Official title:

Clinical and Laboratory Evaluation of Acute Rejection, Myocyte Growth, Repair, and Oxidative Stress Following de Novo Cardiac Transplant: A Comparison Between Tacrolimus- and Cyclosporine- Based Immunoprophylactic Regimens With MPA TDM

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00157014
• Other study ID #: FKC-009
• Status: Completed
• Phase: Phase 3
• First received: September 8, 2005
• Last updated: May 4, 2017
• Start date: May 10, 2004
• Est. completion date: July 18, 2008

Study information

• Verified date: April 2017
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety and efficacy of tacrolimus in de novo heart transplantation.

Description:

Subcellular markers will be assessed in relationship to cellular acute rejection in de novo cardiac transplant recipients receiving either tacrolimus or cyclosporine as their primary immunosuppressant

Two parallel active arms.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 111
• Est. completion date: July 18, 2008
• Est. primary completion date: July 18, 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• Patients (or their legal guardians) who are capable of understanding, and who have been fully informed of the purpose of the study and the risks of participation.

• Patients (or their legal guardians) who have signed and dated the Informed Consent form and are willing and able to follow the study protocol.

• Patients who are primary cadaveric heart transplant recipients.

• Males or females from birth.

• Female patients of child-bearing potential who have a current negative pregnancy test and agree to practice effective birth control, as judged by the investigator, while participating in the study. Prepubescent pediatric patients will not require pregnancy testing.

• Patients able to tolerate oral medication and who do not have a gastrointestinal condition likely to affect the absorption kinetics or metabolism of the oral study medications.

Exclusion Criteria:

• Previous organ transplant recipients.

• Multi-organ transplant recipients.

• Recipients of a heart from a donor with incompatible ABO blood type.

• Patients with significant graft dysfunction and/or significant de novo infection(s) at time of randomization

• Patients with known hypersensitivity to tacrolimus, cyclosporine, mycophenolate mofetil (MMF), daclizumab, prednisone, cremophor, polysorbate 80 and/or polyoxyl 60 hydrogenated castor oil (HCO-60).

• Patients who are pregnant or lactating or planning to become pregnant prior to completion of the study.

• Patients who have consumed an investigational product in the 30 days prior to transplantation or at any time during post-transplantation follow-up.

• Patients receiving cholestyramine or colestipol.

• Patients having any one of the following at enrolment:

1. History of malignancy, not chart-documented as cured or active malignancy (with exception of eradicable non-metastatic in-situ basal cell or squamous cell carcinoma).

2. Leukopenia (white cell count < 2500/cu mm).

3. Anemia (hemoglobin < 80 g/L).

4. Positive test for hepatitis B surface antigen and/or hepatitis C.

5. Historical positive test for human immunodeficiency virus (HIV).

6. Serum creatinine > 230 umol/l.

7. Continual elevation of AST and/or ALT to >= 3X the upper limit of normal.

8. Body mass index (weight in kg/height in m2) > 30.

• Undiagnosed diabetes mellitus as determined by 2 hour (2h) oral glucose tolerance test (OGTT) or fasting glucose test or uncontrolled diabetes mellitus at screening. In either case, the patient may be declared as no longer excluded by this criterion upon establishment of control of the diabetes through appropriate medical management.

• Blood glucose >= 11.1 mmol/L at pre-operative assessment.

• Patients having a significant disease, substance dependency, or disability that may prevent adherence to, or understanding of, the protocol and/or the investigator's instructions.

Related Conditions & MeSH terms

• Heart Diseases
• Heart Transplantation

Intervention

Drug:
• Tacrolimus
Oral
• Cyclosporine
Oral
• Mycophenolate mofetil
Intravenous and Oral
• Methylprednisolone
Intravenous
• Prednisone
Oral

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Astellas Pharma Inc	Astellas Pharma Canada, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies	The markers assessed were p-ERK ½ (phosphorylated extracellular signal-regulated kinase), p-JNK (phosphorylated jun N-terminal kinase) and p-p38 MAPK (phosphorylated mitogen-activated protein kinase).; The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).; Change is defined as Week 52 assessment- Week 2 assessment.	2 Weeks and 52 Weeks
Primary	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)	The markers assessed were p-ERK ½, p-JNK and p-p38 MAPK.; The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).; Change is defined as Week 52 assessment- Week 2 assessment.	2 Weeks and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: MCP-1	Change is defined as Week 52 assessment - Pre-Transplant assessment.; MCP-1= monocyte chemoattractant protein-1	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: s-ICAM	Change is defined as Week 52 assessment - Pre-Transplant assessment.; s-ICAM= soluble-intracellular adhesion molecule	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: E-selectin	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Homocysteine	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: hsCRP	Change is defined as Week 52 assessment - Pre-Transplant assessment.; hsCRP= high-sensitivity C Reactive Protein	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: F2 Isoprostanes	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: T-bars	Change is defined as Week 52 assessment - Pre-Transplant assessment.; T-bars = thiobarbituric acid reactive substances	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Nitrotyrosine	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: GSH/GSSG	Change is defined as Week 52 assessment - Pre-Transplant assessment.; GSH/GSSG= ratio of reduced to oxidised glutathione	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: BNP	Change is defined as Week 52 assessment - Pre-Transplant assessment.; BNP= Brain Natriuretic Peptide	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Troponin T	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Osteopontin	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Fibrinogen	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-6	Change is defined as Week 52 assessment - Pre-Transplant assessment.; IL= Interleukin	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-18	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Cystatin-C	Change is defined as Week 52 assessment - Pre-Transplant assessment.	Pre-Transplant and 52 Weeks
Secondary	Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria	Acute rejection was defined as a rejection with ISHLT Grade =3A or by the presence of hemodynamic compromise.; ISHLT Grades =3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.; Patients may report more than one acute rejection.	52 Weeks
Secondary	Time to First Acute Rejection Episode Following de Novo Cardiac Transplant	Acute Rejection was defined as a rejection with ISHLT Grade =3A or by the presence of hemodynamic compromise.; ISHLT Grades =3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.; Time to first acute rejection is defined as: date of onset - date of transplant.	52 Weeks
Secondary	Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection	Severe Acute Rejection is defined as rejection with ISHLT Grade 4.	52 Weeks
Secondary	Number of Cardiac Rejection Episodes Requiring Treatment	The number of rejection episodes requiring treatment (medications started/ stopped, non-medication treatment, or both) regardless of biopsy grade or presence of hemodynamic compromise.	52 Weeks
Secondary	Mean Cases of Acute Rejection (MCAR) Per Patient	MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies.; Acute rejection was defined as a rejection with ISHLT Grade =3A or by the presence of hemodynamic compromise.; ISHLT Grades =3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.	52 Weeks
Secondary	Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52	A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.	26 Weeks and 52 Weeks
Secondary	Number of Patients With Treatment Failure and Crossover for Treatment Failure	Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first.; Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.	52 Weeks
Secondary	Changes in Circulating Markers of Inflammation and Oxidation: F2 Isoprostanes (Pediatric Population)	Change is defined as Week 52 assessment - Pre-Transplant assessment	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation and Oxidation: Nitrotyrosine (Pediatric Population)	Change is defined as Week 52 assessment - Pre-Transplant assessment	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation and Oxidation: hsCRP (Pediatric Population)	Change is defined as Week 52 assessment - Pre-Transplant assessment	Pre-Transplant and 52 Weeks
Secondary	Changes in Circulating Markers of Inflammation and Oxidation: Cystatin-C (Pediatric Population)	Change is defined as Week 52 assessment - Pre-Transplant assessment	Pre-Transplant and 52 Weeks
Secondary	Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)	Acute rejection was defined as a rejection with ISHLT Grade =3A or by the presence of hemodynamic compromise.; ISHLT Grades =3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.; Patients may report more than one rejection episode.	52 Weeks
Secondary	Time to First Acute Rejection Episode Following de Novo Cardiac Transplant (Pediatric Population)	Acute Rejection was defined as a rejection with ISHLT Grade =3A or by the presence of hemodynamic compromise.; ISHLT Grades =3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.; Time to first acute rejection is defined as: date of onset - date of transplant.	52 Weeks
Secondary	Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection (Pediatric Population)	Severe Acute Rejection was defined as rejection with ISHLT Grade 4.	52 Weeks
Secondary	Number of Cardiac Rejection Episodes Requiring Treatment (Pediatric Population)	A summary of rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise.	52 Weeks
Secondary	Mean Cases of Acute Rejection (MCAR) Per Patient (Pediatric Population)	MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies.; Acute rejection was defined as a rejection with ISHLT Grade =3A or by the presence of hemodynamic compromise.; ISHLT Grades =3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection.	52 Weeks
Secondary	Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 (Pediatric Population)	A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.	26 Weeks and 52 Weeks
Secondary	Number of Patients With Treatment Failure and Crossover for Treatment Failure (Pediatric Population)	Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first.; Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.	52 Weeks

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