TICTAC: Safety Outcomes of Lower Immunosuppression Versus Traditional Immunosuppression in Heart Transplant Recipients

• Sponsor: Newark Beth Israel Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00299221
• Collaborator: Astellas Pharma Inc (Industry)
• Enrollment: 150
• Locations: 2
• Arms: 2
• Duration (Months): 68
• Patients Per Site: 75
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This was a study to compare less intense immunosuppression with a more traditional approach. The hypothesis was that less immunosuppression will provide similar protection against rejection than typical 2-3 drug therapy.

Condition or Disease	Intervention/Treatment	Phase
Immunosuppression	Drug: Tacrolimus; Drug: combination therapy	Phase 4

Detailed Description

This was a prospective, randomized, controlled (open-label) trial of 2 different strategies of immunosuppression in de novo post-heart transplant patients. The hypothesis was that immunosuppression with tacrolimus and mycophenolate mofetil, coupled with rapid steroid weaning would provide similar anti-rejection efficacy as tacrolimus with only a 2 week course of mycophenolate mofetil but including the same rapid steroid wean.

The primary endpoint was the mean International Society for Heart and Lung Transplantation (ISHLT) biopsy score over the first 6 months post-transplant. Secondary endpoints included the incidence of adverse events over the first year post-transplant, as well as all-cause mortality, 12 month ISHLT biopsy score (mean), along with the incidence of proven cytomegalovirus disease. In addition, the incidence of allograft vasculopathy as assessed by angiography or intravascular ultrasound was compared between groups.

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Tacrolimus In Combination, Tacrolimus Alone Compared (TICTAC Trial): A Prospective Randomized Trial Of Minimized Immunosuppression In Adult Heart Transplant Recipients
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Monotherapy Tacrolimus alone	Drug: Tacrolimus; tacrolimus; Other Names: Prograf
Active Comparator: Combination therapy tacrolimus with mycophenolate mofetil	Drug: Tacrolimus; tacrolimus; Other Names: Prograf ; Drug: combination therapy; MMF; Other Names: mycophenolate mofetil / CellCept

Outcome Measures

Primary Outcome Measures

1. Mean International Society for Heart and Lung Transplantation Biopsy Score Over the First 6 Months Post-transplantation [6 months]

   Mean ISHLT biopsy score Biopsies of the heart may be various grades and each is assigned a numerical score. Grade 0 is 0 points, 1A = 1, 1B = 2, grade 2 = 3, grade 3A = 4, Grade 3B = 5, and grade 4 = 6 units. The mean biopsy score is the numeric average of the biopsy scores for the first 6 post-transplant months. Best value is 0, worst score is 6.

Secondary Outcome Measures

1. Percent of Patients Alive at One Year Post-transplant [1 year]

   Percent of patients alive at one year post-transplant. In other words, all cause mortality over time

2. Number of Patients With Cytomegalovirus (CMV) at One Year Post-transplant [1 year]

   Number of patients developing cytomegalovirus disease by 1 year post-transplant

3. Number of Patients With Allograft Vasculopathy (CAD) at One Year Post Transplant [1 year]

   Number of patients diagnosed with allograft vasculopathy / coronary artery disease (CAD) at one year post transplant

4. Mean ISHLT Biopsy Score Over First Year Post-transplant [1 year]

   Mean ISHLT biopsy score Biopsies of the heart may be various grades and each is assigned a numerical score. Grade 0 is 0 points, 1A = 1, 1B = 2, grade 2 = 3, grade 3A = 4, Grade 3B = 5, and grade 4 = 6 units. The mean biopsy score is the numeric average of the biopsy scores for the first 6 post-transplant months. Best value is 0, worst score is 6.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult (at least 18 years old)

• Undergoing a first heart transplant (no heart/kidney transplants), who receive their transplant at one of the study sites

• Specifically INCLUDED are patients on ventricular assist devices, and allosensitized recipients

Exclusion Criteria:

• Age less than 18

• Inability to provide proper informed consent

• Combined organ transplantation

• Re-Transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
2	Mt. Sinai Cardiovascular Institute	New York	New York	United States	10029

Sponsors and Collaborators

• Newark Beth Israel Medical Center
• Astellas Pharma Inc

Investigators

• Principal Investigator: David A Baran, MD, Newark Beth Israel Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David A. Baran, MD, Director, Heart Failure and Transplant Research, Newark Beth Israel Medical Center
• ClinicalTrials.gov Identifier: NCT00299221
• Other Study ID Numbers: TICTAC
• First Posted: Mar 6, 2006
• Last Update Posted: May 28, 2015
• Last Verified: May 1, 2015

• Keywords provided by David A. Baran, MD, Director, Heart Failure and Transplant Research, Newark Beth Israel Medical Center: immunosuppression; steroid withdrawal; rejection; coronary disease; cytomegalovirus infection
• Additional relevant MeSH terms: Mycophenolic Acid; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Pts recruited from April 2004-Aug 2008
Pre-assignment Detail	Consent often obtained after transplant

Arm/Group Title	Monotherapy	Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
Period Title: Overall Study
STARTED	79	71
COMPLETED	79	71
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Monotherapy	Combination Therapy	Total
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.	Total of all reporting groups
Overall Participants	79	71	150
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	64 81%	57 80.3%	121 80.7%
>=65 years	15 19%	14 19.7%	29 19.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (10.7)	54.6 (11.6)	54.65 (10)
Sex: Female, Male (Count of Participants)
Female	17 21.5%	11 15.5%	28 18.7%
Male	62 78.5%	60 84.5%	122 81.3%
Region of Enrollment (participants) [Number]
United States	79 100%	71 100%	150 100%

Outcome Measures

1. Primary Outcome

Title	Mean International Society for Heart and Lung Transplantation Biopsy Score Over the First 6 Months Post-transplantation
Description	Mean ISHLT biopsy score Biopsies of the heart may be various grades and each is assigned a numerical score. Grade 0 is 0 points, 1A = 1, 1B = 2, grade 2 = 3, grade 3A = 4, Grade 3B = 5, and grade 4 = 6 units. The mean biopsy score is the numeric average of the biopsy scores for the first 6 post-transplant months. Best value is 0, worst score is 6.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

all pts, intention to treat

Arm/Group Title	Monotherapy	Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
Measure Participants	79	71
Mean (Standard Deviation) [units on a scale]	0.7 (0.44)	0.65 (0.4)

2. Secondary Outcome

Title	Percent of Patients Alive at One Year Post-transplant
Description	Percent of patients alive at one year post-transplant. In other words, all cause mortality over time
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

all pts, intention to treat

Arm/Group Title	Monotherapy	Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
Measure Participants	79	71
Number [percent of participants]	98 124.1%	98 138%

3. Secondary Outcome

Title	Number of Patients With Cytomegalovirus (CMV) at One Year Post-transplant
Description	Number of patients developing cytomegalovirus disease by 1 year post-transplant
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

all patients

Arm/Group Title	Monotherapy	Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
Measure Participants	79	71
Number [participants]	2 2.5%	2 2.8%

4. Secondary Outcome

Title	Number of Patients With Allograft Vasculopathy (CAD) at One Year Post Transplant
Description	Number of patients diagnosed with allograft vasculopathy / coronary artery disease (CAD) at one year post transplant
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Percent of patients with allograft CAD at one year post-transplant

Arm/Group Title	Monotherapy	Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
Measure Participants	79	71
Number [patients]	0	0

5. Secondary Outcome

Title	Mean ISHLT Biopsy Score Over First Year Post-transplant
Description	Mean ISHLT biopsy score Biopsies of the heart may be various grades and each is assigned a numerical score. Grade 0 is 0 points, 1A = 1, 1B = 2, grade 2 = 3, grade 3A = 4, Grade 3B = 5, and grade 4 = 6 units. The mean biopsy score is the numeric average of the biopsy scores for the first 6 post-transplant months. Best value is 0, worst score is 6.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

all pts, Intention to treat

Arm/Group Title	Monotherapy	Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
Measure Participants	79	71
Mean (Standard Deviation) [units on a scale]	0.67 (0.39)	0.62 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Monotherapy, Combination Therapy
	Comments	comparing ISHLT biopsy score between groups at 1 year
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	.2
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Deviation; Value: .4
	Estimation Comments

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Cytomegalovirus (CMV) disease
Arm/Group Title	Monotherapy		Combination Therapy
Arm/Group Description	These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be discontinued in this group at 14 days post-transplant		These patients will receive tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, followed by a rapid 8 week wean of steroids to discontinuation. MMF will be maintained in this group, unless intolerance develops.
All Cause Mortality
	Monotherapy		Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Monotherapy		Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/79 (2.5%)		1/71 (1.4%)
General disorders
death	2/79 (2.5%)	2	1/71 (1.4%)	1
Other (Not Including Serious) Adverse Events
	Monotherapy		Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/79 (0%)		0/71 (0%)

Limitations/Caveats

This trial enrolled 150 patients, but cannot be used to generalize care to other patients without careful consideration of risks and benefits. All patients had corticosteorids weaned so this trial doesn't assess the risk of steroid weaning.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.