Impact of Evolocumab (Repatha) in Cardiac Transplant Patients With Coronary Allograft Vasculopathy
Phase: PHASE2
Conditions: Heart Transplant
Sponsor: University of Nebraska

 
ClinicalTrials.gov Cover Page 
 
 
 
Title: Impact of Evolocumab (Repatha) in Cardiac Transplant Patients with Coronary 
Allograft Vasculopathy (CAV) 
 
ID: NCT03944577 
 
Document date: 01.01.2022 
 
Document: Study Protocol and Statistical Analysis Plan 
 
 
 
 

Eligibility Criteria 
 
Inclusion criteria 
• Heart transplant patients 19-80 years of age 
• Coronary allograft vasculopathy documented by left heart cardiac catheterization 
• Able to provide signed informed consent 
 
Note: Evolocumab will be given as add-on therapy to heart transplant patients with 
CAV.  Patients already on statin or other lipid lowering therapy are eligible for 
enrollment. 
 
Exclusion criteria 
• Rejection requiring IV therapy in the prior 3 months 
• Infection requiring IV therapy in the prior 3 months 
• Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) > 3 times the upper limit of normal 
• Current or recent use of a PCSK9 inhibitor within the past 12 weeks 
• Dual organ transplant recipient other than heart/kidney 
• Renal dysfunction defined as GFR < 20 ml/min 
• Known allergy to evolocumab or its components 
 
 
Randomization/Registration Procedure 
 
Heart transplant patients will be recruited for participation solely from the University of 
Nebraska Heart Transplant clinic.  Our program provides care for approximately 330 
heart transplant patients in total, and currently performs 40-50 heart transplants per 
year.  Of these, over 40 patients already have a known diagnosis of CAV with more 
expected to be diagnosed in the coming year. 
 
Heart transplant patients with CAV will be identified by the primary investigator and the 
transplant cardiology team.  Eligible individuals will then be invited to participate (by 
phone call or during a clinical appointment) by the transplant cardiology research team.  
Interested patients will then be referred to trained personnel for informed consent, 
screening and study enrollment.  Coordination is expected between study enrollment 
and a standard post-transplant clinic appointment to facilitate participation. 
 
This study will be an open label, single cohort study.  No randomization of patients or 
treatment blinding will occur.  Enrollment is expected to take one year, with an 
additional one year of follow-up resulting in a total study duration of two years. 
 
 
 
 

Research Study Design 
 
Standard post-transplant care 
 
Heart transplant patients with CAV who primary transplant followup care at the 
University of Nebraska will serve as the study cohort.  Given the complexity of heart 
transplant patients, care is highly- protocolized and organized according to graft age.  
Care is most intensive in the first year following transplant wherein patients are initially 
evaluated on a weekly basis for the first month with reduced frequency (biweekly  
monthly  quarterly) based on clinical progress over the first year.  During year 2 post 
transplant, stable post-transplant patients are typically seen quarterly and this extends 
to biannual evaluations during year 3.  After 3 years, stable post-transplant patients can 
often be seen on an annual basis.  Thorough evaluations are completed annually 
including comprehensive labwork (complete blood count, complete metabolic panel, 
fasting lipid panel, thyroid function tests, hemoglobin A1c, creatinine kinase, urine 
protein analysis), assessment for donor specific antibodies, and imaging/testing.  
Imaging/testing includes an annual echocardiogram and chest x-ray as well as other 
imaging (DEXA scan, carotid and abdominal ultrasounds) at frequencies determined by 
comorbidities.  Immunosuppression is maintained with calcineurin inhibitors (primarily 
tacrolimus) and DNA synthesis inhibitors (mycophenolate mofetil, mycophenolic acid or 
azathioprine).  Patients are switched to mTOR inhibitors (primarily sirolimus) if 
significant renal dysfunction develops or CAV is diagnosed.  High dose steroids are 
started at the time of transplant and typically weaned off during the first year.  
Calcineurin inhibitors and mTOR inhibitors are dosed according to trough serum levels, 
and thus monitored at least every three months indefinitely. 
 
CAV is diagnosed by angiography.  Patients undergo a left heart cardiac catheterization 
annually for the first five years per standardized protocol.  Beyond five years, cardiac 
catheterization can be alternated with a dobutamine stress echocardiogram.  If the 
dobutamine stress test is abnormal (wall motion changes), a cardiac catheterization is 
completed to assess for CAV.  Once patients are diagnosed with CAV, annual cardiac 
catheterizations are completed.  Severity of CAV, once present, is based on 
angiographic findings as outlined in Table 3 below[1].  Of note, intravascular ultrasound 
can also identify CAV but is currently not used to guide management beyond changing 
immunosuppression regimen due to less outcome data (compared to cardiac 
catheterization). 
 
Transplant patients are closely monitored for graft rejection.  In general, rejection risk 
declines with increasing donor graft age.  Surveillance endomyocardial biopsies are 
completed during the first year post-transplant (selected patients can undergo serum 
gene expression testing in lieu of endomyocardial biopsy).  Donor specific antibodies 
are monitored on annually.  Beyond one year post-transplant, rejection is detected 
primarily by symptoms (new onset CHF symptoms, arrhythmias or increasing fatigue) or 
systolic dysfunction on echocardiogram which prompts an endomyocardial biopsy. 
 
 

Table 3 – ISHLT CAV nomenclature[1] 
Classification 
Severity 
Definition 
CAV-0 
Nonsignificant No detectable angiographic lesion 
CAV-1 
Mild 
Angiographic left main <50%   or 
Primary vessel lesion <70%     or 
Branch stenosis <70% 
CAV-2 
Moderate 
Angiographic left main <50%   or 
Primary vessel lesion ≥70%     or 
Isolated branch stenosis in 2 systems ≥70% 
CAV-3 
Severe 
Angiographic left main ≥50%   or 
≥2 primary vessels with lesion ≥70%     or 
Isolated branch stenosis in all 3 systems ≥70%    or 
Any CAV grade with EF ≤45% or restrictive physiology 
 
 
Research study design – patient enrollment and evolocumab administration 
 
Heart transplant patients with CAV will be eligible for enrollment per inclusion and 
exclusion criteria listed in Section 3.  The majority of heart transplant patient are on 
statin therapy (pravastatin is most common).  Evolocumab will be given either as add-on 
therapy for heart transplant patients with CAV currently prescribed statin or other LDL 
lowering therapy, as well as those unable to tolerate lipid-lowering medications. 
 
Study participation is expected to coordinate with the standard care of heart transplant 
patients.  As most patients with CAV are more than 2 years post-transplant, enrollment 
will likely occur around the patient’s annual clinical evaluation.  Female patients of 
childbearing potential will undergo pregnancy testing prior to or during the 
screening/enrollment visit before study drug administration.  Informed consent and 
baseline documentation will be completed by research personnel at the patient’s annual 
evaluation when feasible.   
 
Enrolled study participants will be treated with evolocumab (Repatha) 140 mg injected 
subcutaneously every 2 weeks for 52 weeks.  All study participants will receive 
instruction on correct self-administration by research pharmacists.  Study drug will be 
distributed to patients via courier or Fed Ex temperature-controlled coolers by the 
research pharmacy.  The evolocumab dose (140 mg every 2 weeks) will remain 
constant for the duration of the study.  Side effects will be assessed on a quarterly 
basis.  Serious adverse events considered related to treatment, death, and pregnancy 
will all result in immediate discontinuation of the study drug. 
 
Primary endpoint – LDL percentage change after 12 weeks of evolocumab therapy. 
 
The primary objective of this study is to measure the impact of PCSK9 inhibition via 
evolocumab on serum LDL in heart transplant patients with CAV after 12 weeks.  
Similar to prior phase 2 trials investigating evolocumab, LDL change will serve as the 
primary endpoint providing a direct benchmark for comparison of heart transplant 

patients.  Baseline LDL will be obtained at study enrollment, likely with the patient’s 
annual clinical evaluation.  After 12 weeks of therapy, a fasting serum lipid profile will be 
obtained for measurement of LDL and assessment of the primary endpoint.  Statistical 
analysis is detailed in Section 8 below. 
 
Secondary endpoints 
 
Assess the effect of evolocumab on CAV progression.  All patients enrolled will have 
CAV documented by cardiac angiography.  Standard post-transplant care includes 
annual angiograms in patients diagnosed with CAV to monitor for disease progression.  
CAV progression will be defined as an increase of one CAV grade (CAV-1  CAV-2 or 
CAV-2CAV-3).  The number of patients with CAV progression of at least one grade 
while on evolocumab will be compared to historical controls for our transplant program.  
Percentage diameter stenosis for each vessel with visible CAV also will be determined 
by quantitative coronary angiography (QCA) using Philips Xcelera software package in 
a blinded fashion by an experience interventional cardiologist for patients angiograms 
completed one year prior to study entry, at study entry, and study conclusion.  
Angiographic change while on evolocumab therapy will be compared to the preceding 
year. 
 
Assess the effect of evolocumab on immunosuppression regimens and graft rejection.  
Transplant patient are maintained on lifelong immunosuppression.  These agents are 
prone to significant drug-drug interactions which can limit therapies.  Serum levels of 
immunosuppression are monitored every three months per standard protocol.  
Measured serum levels at 3, 6, 9, and 12 months, as well as the number of dose 
adjustments while on evolocumab therapy while on evolocumab therapy will be 
compared to the preceding year.  Statistical adjustment for confounding factors such as 
changes in renal function or other drugs known to alter immunosuppression levels (i.e. 
diltiazem, certain antimicrobial drugs) will be completed.  In addition, the incidence of 
transplant rejection will be documented while on evolocumab therapy and compared to 
the prior year.  Transplant rejection will be defined as symptoms requiring therapeutic 
intervention or endomyocardial biopsy findings of ≥grade 2 or positive C4d staining or 
new donor specific antibodies. 
 
Measure the effect of evolocumab on serum lipids including HDL and triglycerides after 
1 year of therapy.  Fasting lipid profiles (total cholesterol, LDL, HDL and triglycerides) 
after 52 weeks of evolocumab therapy will be compared to baseline levels.  Fasting lipid 
profiles are assessed annually as part of routine post-transplant care.  The percentage 
change of LDL, HDL and triglyceride from baseline will be calculated after 1 year of 
evolocumab therapy. 
 
Statistical analysis is detailed in Section 8 below. 
 
 
 

 
Regulatory oversight 
 
The study will be conducted under the oversight of the University of Nebraska IRB.  An 
independent University of Nebraska Medical Center Data Safety and Monitoring Board 
(DSMB) will be established to monitor participant safety, data quality and evaluate the 
progress of the study. 
 
 
Drug Formulation and Procurement 
 
Study drug (evolocumab) will be provided by Amgen Inc.   While evolocumab is 
commercially available and FDA approved for patient use, storage and distribution in 
this study will be managed by research pharmacy staff at the University of Nebraska.  
Study drug will be stored by research pharmacy staff who will distribute it to patients.  
Study participants receive study drug quarterly directly from research pharmacy staff or 
via courier in temperature-controlled KoolTempGTS coolers (Cold Chain Technologies, 
Franklin, Massachusetts).  Drug accountability will be managed by research 
pharmacists as well. 
 
 
Toxicity and Adverse Event Reporting Guidelines 
 
Evolocumab is currently FDA-approved and commercially available for patient use in 
the United States.  Currently used in patients for the secondary prevention of 
cardiovascular disease and treatment of primary hyperlipidemias, adverse event data is 
available from greater than 27,000 patients enrolled in clinical trials.  Clinical experience 
has shown evolocumab to be well-tolerated with minimal adverse events (see Tables 4 
and 5 below).   
 
Adverse events will be assessed by research personnel at week 2, 4, 12, 26, 38 and 
study conclusion (52).  Events will be obtained either by phone survey or during a 
standard-of-care clinic visit.  Data will be stored and managed using the Forte Electronic 
Data Capture (EDC) software system.  Adverse events will be collected using the 
Common Terminology Criteria for Adverse Event (CTCAE) version 5.0 forms.  Adverse 
events will be quantified and presented by organ system.  Reported events will be 
cataloged and reported to the University of Nebraska IRB and Amgen annually and at 
the conclusion of the study by research personnel.  Reported events will be 
independently reviewed by a cardiology faculty member with significant experience 
prescribing PCSK9 inhibitors.   
 
All suspected unexpected serious adverse reactions (SUSARs) related or possibly 
related to evolocumab and their follow-up reports will be reported to Amgen within 24 
hours of submission to the regulatory agency or IRB.  Amgen will be informed of any 
pregnancy occurring and/or existing during exposure to the investigational medicinal 

product and pregnancies occurring in the partner of a patient participating in the study 
and potential infant exposure within ten (10) calendar days of sponsor awareness. 
 
 
Section 8. Statistical Analysis Plan 
 
Statistical analysis will be completed with the direct assistance of faculty from the 
University of Nebraska biostatistics department. Sample size (n=40) is chosen based on 
the size of the heart transplant clinic (the number of heart transplant patients with CAV 
expected to be eligible for study participation). 
 
The primary outcome is percentage change from the baseline in LDL levels after 12 
weeks of evolocumab therapy.  Prior trials have demonstrated that evolocumab lowers 
LDL cholesterol at week 12 by greater than 50% from baseline[2, 3]. The sample size of 
n=40 is expected to yield greater than 99% power to detect 50% reduction of LDL 
cholesterol from baseline after 12 weeks of evolocumab therapy at a significance level 
of 0.05 using a two-sided Wilcoxon signed-rank test, assuming the estimated standard 
deviation of reduction of 0.17.  
 
Descriptive statistics will be presented as frequencies and percentages for categorical 
variables, and mean ± standard deviation, or median with range for continuous 
variables, unless otherwise indicated. Paired t-tests or Nonparametric Wilcoxon signed-
rank tests will be completed where appropriate to compare the primary endpoint before 
and after 12 weeks of evolocumab therapy, and compare continuous secondary 
endpoints after 1 year of evolocumab therapy to baseline. A linear mixed model analysis 
will be conducted to analyze immunosuppression serum levels measured at baseline, 3 
months, 6 months, 9 months, and 1 year of evolocumab therapy. The binary secondary 
endpoint of CAV progression will be assessed after 1 year of evolocumab therapy using 
McNemar tests. Safety data will be reported with frequencies and percentages. All tests 
will be two-tailed. A p-value <0.05 will be considered significant. Analysis will be 
performed using SAS version 9.4 (SAS Institute, Cary, NC). 
 
Given the limited statistical power due to the small cohort, conclusions from secondary 
endpoints are expected to by primarily hypothesis-generating with data providing 
support for potential future studies.