Comparison of tacrolimus and cyclosporin therapy in heart transplantation.

• Register: EUCTR
• Last refreshed on: 10 July 2015
• Main ID: EUCTR2015-001041-83-Outside-EU/EEA
• Date of registration: 13/04/2015
• Prospective Registration: Yes
• Primary sponsor: Astellas Pharma Canada Inc.
• Public title: Comparison of tacrolimus and cyclosporin therapy in heart transplantation.
• Scientific 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 Mycophenolic Acid Therapeutic Drug Monitoring
• Target sample size: 100
• Recruitment status: NA
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001041-83
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Canada

Contacts

• Name: Service Desk
• Affiliation: Astellas Pharma Europe BV

• Name: Service Desk
• Affiliation: Astellas Pharma Europe BV

Key inclusion & exclusion criteria

Inclusion criteria:
1. 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.
2. Patients (or their legal guardians) who have signed and dated the Informed Consent Form and are willing and able to follow the study protocol.
3. Patients who are primary cadaveric heart transplant recipients.
4. Males or females from birth.
5. 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.
6. 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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 10
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 90
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1

Exclusion criteria:
1. Previous organ transplant recipients.
2. Multi-organ transplant recipients.
3. Recipients of a heart from a donor with incompatible ABO blood type.
4. Patients with significant graft dysfunction and/or significant de novo infection(s) at time of randomization (i.e. within 10 days of transplantation).
5. Patients with known hypersensitivity to tacrolimus, cyclosporine, mycophenolate mofetil, daclizumab, prednisone, cremophor, polysorbate 80 and/or HCO-60.
6. Patients who are pregnant or lactating or planning to become pregnant prior to completion of the study.
7. Patients who have consumed an investigational (i.e. unmarketed) product in the 30 days prior to transplantation or at any time during posttransplantation follow-up.
8. Patients receiving cholestyramine or colestipol.
9. Patients having any one of the following at enrolment:
a. History of malignancy which is not currently chart-documented as cured or active malignancy (with exception of eradicable nonmetastatic in-situ basal cell or squamous cell carcinoma of the skin).
b. Leukopenia (white cell count < 2500/cu mm).
c. Anemia (hemoglobin < 80 g/L).
d. Positive test for Hepatitis B surface antigen and/or Hepatitis C.
e. Historical positive test for Human Immunodeficiency Virus (HIV).
f. Serum creatinine > 230 µmol/l.
g. Continual elevation of AST and/or ALT to = 3X the upper limit of normal.
h. Body mass index (weight in kg / height in m2) > 30.
10.Undiagnosed diabetes mellitus as determined by 2h 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.
11.Blood glucose = 11.1 mmol/L at pre-operative assessment.
12.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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cardiac transplant recipients
MedDRA version: 17.1 Level: LLT Classification code 10050432 Term: Prophylaxis against heart transplant rejection System Organ Class: 100000004865

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Trade Name: Prograf
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Prograf
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Prograf
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: TACROLIMUS
CAS Number: 104987-11-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Trade Name: Neoral
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: CICLOSPORIN
CAS Number: 59865-13-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Trade Name: Neoral
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: CICLOSPORIN
CAS Number: 59865-13-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Trade Name: Neoral
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: CICLOSPORIN
CAS Number: 59865-13-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Neoral
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: CICLOSPORIN
CAS Number: 59865-13-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Neoral
Pharmaceutical Form: Oral solution
INN or Proposed INN: CICLOSPORIN
CAS Number: 59865-13-3
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 100-

Trade Name: Sandimmune i.v.
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CICLOSPORIN
CAS Number: 59865-13-3
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Secondary Objective: 1. to investigate changes in circulating markers of inflammation and oxidation concomitantly with the changes in the subcellular markers outlined above and with the magnitude of acute cellular rejection in the 2 treatment groups.
2. to evaluate efficacy with respect to graft survival, acute rejection (AR) episodes (frequency, severity, time to event and resolution), treatment for AR, and successful steroid taper in the treatment groups.
3. to assess safety with respect to adverse events in the treatment groups:
dyslipidemia, hypertension, diabetes mellitus, nephrotoxicity, clinical chemistry and hematology findings.
4. to measure treatment failure and crossover for treatment failure in the treatment groups.
5. to measure cardiovascular risk status using the Framingham assessment. (NA for pediatric patients)
6. to measure Quality of Life and general well-being using patient health surveys.
7. to measure impact of treatment choice on healthcare resource use.

Timepoint(s) of evaluation of this end point: Week 2 to 1 year post-implant

Main Objective: To investigate changes in subcellular markers of growth, apoptosis, differentiation, survival, inflammation and oxidative stress, in relationship with cellular acute rejection, in de novo cardiac transplant recipients receiving either tacrolimus or cyclosporine as primary immunosuppressant.

Primary end point(s): The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies. ERK 1/2, JNK, and p38 MAPK have been selected as the principal primary endpoint parameters.
Additional primary endpoint parameters are MEK 1/2, MEK 3/6, cSrc, ERK 5, AKT, Bax/Bcl-2, and nitrotyrosine.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 2 to 1 year post-implant

Secondary end point(s): Systemic markers
1. Changes in circulating markers of inflammation and oxidation (adhesion molecules and other markers of inflammation MCP-1, s-ICAM, E-selectin, homocysteine, hsCRP; and markers of redox state F2 isoprostanes, T-bars, nitrotyrosine, GSH/GSSG) and circulating markers of myocardial damage (troponin t and BNP).
Efficacy
2. ISHLT acute rejection profiles and time to first acute rejection episode following de novo cardiac transplant.
3. Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection.
4. Number of acute rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise.
5. Mean cases of acute rejection (MCAR) per patient.
6. Incidence of successful steroid taper or withdrawal at 26 and 52 weeks.
7. Incidence of treatment failure and crossover for treatment failure.
8. Exploratory evaluation of patients’ general well being using the following patient questionnaires:
? SF-12v2™ Health Survey (32, Appendix 9). (NA for pediatric patients)
? Heart Transplant Recipient Opinions of Immunosuppressive Medications (Appendix 10). (NA for pediatric patients)
? For pediatric patients, the following will be used:
o Functional Status IIR
o PedsQL™ Pediatric Quality of Life Inventory, Version 4.0
o SF-10 for Children™
o Impact on family Scale
Safety
9. Effects on glucose metabolism (fasting glucose, HbA1c, 2-hour oral glucose tolerance test) and incidence of post-transplant diabetes mellitus.
10.Incidence of dyslipidemia defined as lipid profiles not satisfying the Canadian recommendations for high-risk patients
11.Incidence of post-transplant hypertension (JNC-VI).
12.Impairment in renal function as defined by magnitude of change in estimates of glomerular filtration rate, protein excretion rate, and serum cystatin C levels.
13.Framingham assessment for cardiovascular risk status (31, Appendix 8).
14.Adverse events.
Health Resource Use required related to immunosuppression and its treatment
15.Hospital days and visits to emergency room
16.Visits to a physician or other health care professional
17.Days in residential care or visits by community supportive services

Secondary ID(s)

FKC-009

Source(s) of Monetary Support

Astellas Pharma Canada Inc.