Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04665830 |
| Other study ID # |
2018/789 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2018 |
| Est. completion date |
May 1, 2020 |
Study information
| Verified date |
December 2020 |
| Source |
Hamid Al-Essa Organ Transplant Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
From this randomized controlled study, we aim to:
A.Do do cardiovascular risk stratification of renal transplant recipients who are followed up
in Hamed Al-Essa organ transplant center of Kuwait.
B. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy
vs. maximum tolerated statin therapy alone in the reduction of major cardiovascular events
among renal transplant recipients with cardiovascular disease.
C. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy
vs. maximum tolerated statin therapy alone in terms of LDL-C-lowering, muscle symptoms, and
quality of life.
D. To compare patient adherence to the different treatment protocols.
Description:
Background:
Low-density lipoprotein (LDL) cholesterol is a well-established and modifiable risk factor
for cardiovascular disease. Monoclonal antibodies that inhibit proprotein convertase
subtilisin-kexin type 9 (PCSK9) have emerged as a new class of drugs that effectively lower
LDL cholesterol levels.1 Approximately 735,000 Americans have a myocardial infarction each
year (2), and about 800,000 have a stroke. (3) Many patients remain at increased
cardiovascular risk despite maximum tolerated statin therapy and could benefit from further
LDL-C reduction. Most patients are treated with HMG-CoA reductase inhibitors, commonly known
as statins. Millions of patients are eligible for cholesterol-lowering medication, according
to current guidelines.4 High-intensity statin therapy reduces LDL-C and cardiovascular events
more than moderate intensity statin therapy. 5 However, the response to statins is variable,
and in some patients it is not tolerable (between 7 percent and 29 percent of patients taking
statins report having muscle symptoms) 6, which represent a principal reason for
nonadherence. Moreover, high-intensity statin therapy may have less benefit in low-risk
primary prevention patients with a modest increase in the incidence of diabetes in such cases
5, 7. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are currently
indicated for some patients at high risk, including those with familial hypercholesterolemia
or pre-existing cardiovascular disease. PCSK9 inhibitors are a new class of medications that
have been found to be very effective in reducing LDL-C, either as monotherapy or when added
to background statin therapy. Normally, PCSK9 binds to low-density lipoprotein cholesterol
(LDL-C) receptors, reducing the activity of the LDL-C receptors. PCSK9 inhibitors prevent
PCSK9 from binding to the LDL receptor, thereby increasing the activity of the receptors and
enhancing removal of LDL-C from circulation. 8 Current guidelines recommend that patients
whose 10-year risk of major cardiovascular events is 10 percent or greater take statins. 9
Two PCSK9 inhibitors are currently available and approved by FDA for use in the United
States: evolocumab and alirocumab. These drugs are monoclonal antibodies (mAbs) administered
by Proposed Clinical Trial Protocol on Use of PCSK9 Inhibitors for Primary Prevention of
Cardiovascular Disease 3 subcutaneous injection bi-weekly or monthly and are currently
approved for patients with familial hypercholesterolemia or clinical atherosclerotic
cardiovascular disease who require additional lowering of LDL-C. Two recent reports on the
effects of evolocumab and alirocumab have raised expectations that these drugs will
dramatically reduce cardiovascular events.10,11 the rate of major cardiovascular events was
lower with alirocumab than with placebo (1.7 percent versus 3.3 percent; hazard ratio 0.52;
95 percent confidence interval 0.31 to 0.90; P=0.02). 11 Notably, the annual cost for a
single patient in the United States for PCSK9 inhibitors is approximately $14,000.9 The
prevalence of cardiovascular diseases (CVD) has increased in kidney transplant recipients.
CVD remains a leading cause of mortality among recipients with functioning grafts. The
pathophysiology of CVD recipients is a complex interplay between preexisting risk factors,
metabolic sequelae of immunosuppressive agents, infection, and rejection.17
Aim of the study:
A. Cardiovascular risk stratification of renal transplant recipients who are followed up in
Hamed Al-Essa organ transplant center of Kuwait.
B. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy
vs. maximum tolerated statin therapy alone in the reduction of major cardiovascular events
among renal transplant recipients with cardiovascular disease.
C. To compare the effectiveness of a PCSK9 inhibitor plus maximum tolerated statin therapy
vs. maximum tolerated statin therapy alone in terms of LDL-C-lowering, muscle symptoms, and
quality of life.
D. To compare patient adherence to the different treatments protocols.
Patient and methods:
Patients eligible for participation in this study are renal transplant recipients aged
between 30 and 80 years and have clinically evident atherosclerotic cardiovascular disease,
defined as a history of myocardial infarction, non-hemorrhagic stroke, or symptomatic
peripheral artery disease, as well as additional characteristics that placed them at higher
cardiovascular risk.
This group of patients will be selected after screening of all renal transplant recipients
who are followed up in Hamed Al-Essa organ transplant center of Kuwait along 6 months
duration. Cardio-vascular risk score will be estimated using Framingham score. Patients with
score higher than 20 will be randomized in this prospective controlled study to receive
either the evolocumab (group 1, n=100 patients) or the conventional group (group 2, n=100
patients).
The selection criteria:
1. Signed informed consent, 2. Male or female Kuwaiti older than 30 and younger than ≤ 80
years of age at signing of informed consent 3. History of clinically evident cardiovascular
disease(diagnosis of myocardial infarction ; non-hemorrhagic stroke or symptomatic peripheral
arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index
(ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to
atherosclerotic disease, 4. At least 1 major risk factor or at least 2 minor risk factors
below: Major Risk Factors (1 Required): o diabetes (type 1 or type 2) o age ≥ 65 years at
randomization (and ≤ 85 years at time of informed consent) o MI or non-hemorrhagic stroke
within 6 months of screening o additional diagnosis of myocardial infarction or
non-hemorrhagic stroke excluding qualifying MI or non-hemorrhagic stroke o current daily
cigarette smoking o history of symptomatic PAD (as mentioned before) if eligible by MI or
stroke history; Minor Risk Factors (2 Required): o history of non-MI related coronary
revascularization o residual coronary artery disease with ≥ 40% stenosis in ≥ 2 large vessels
o Most recent HDL-C <1.0 mmol/L for men and <1.3 mmol/L for women by central laboratory
before randomization o Most recent CRP > 2.0 mg/L by central laboratory before randomization
o Most recent LDL-C ≥ 3.4 mmol/L or non-HDL-C ≥ 4.1 mmol/L by central laboratory before
randomization o metabolic syndrome.
Exclusion Criteria:
1. Recent MI or stroke 2. NYHA class III or IV, or last known left ventricular ejection
fraction < 30% 3. Known hemorrhagic stroke at any time 4. Uncontrolled or recurrent
ventricular tachycardia 5. Planned or expected cardiac surgery or revascularization within 3
months after randomization 6. Uncontrolled hypertension (sitting systolic blood pressure
(SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg), 7. Prior use of PCSK9 inhibition
treatment other than evolocumab or use of evolocumab < 12 weeks prior to final lipid
screening 8. Untreated or inadequately treated hyperthyroidism or hypothyroidism (thyroid
stimulating hormone (TSH) < lower limit of normal or > 1.5 times the upper limit of normal
and free thyroxine (T4) levels that are outside normal range at final screening. ,9. Severe
renal graft dysfunction(estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 at
final screening, 10. Active liver disease or hepatic dysfunction, defined as aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by
central laboratory analysis at final screening. 11. Personal or family history of hereditary
muscular disorders. 12. Malignancy or HIV patients, 13. Known major active infection or major
hematologic, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the
investigator, 13. Female subject who has either (1) not used acceptable method(s) of birth
control for at least 1 month prior to screening or (2) is not willing to use such a method
during treatment with IP and for an additional 15 weeks after the end of treatment with IP,
unless the subject is sterilized or postmenopausal; 23. Known sensitivity to any of the
active substances or their excipients to be administered during dosing.
Methods:
The baseline characteristics of the patients in the two groups will be collected with special
stress on demographic data, history of myocardial infarction, history of previous
non-hemorrhagic stroke, and symptomatic peripheral artery disease. At baseline, all patients
will be on statin therapy (defined in accordance with American College of Cardiology and
American Heart Association joint guidelines12) and or ezetimibe. All antihypertensive
medications, antiplatelet and diuretic therapy will be recorded. The duration of follow-up
will be 12 months.
Randomization:
Eligible patients will be randomly assigned in a 1:1 ratio to receive subcutaneous injections
of evolocumab (either 140 mg every 2 weeks) or matching placebo. Randomization will be
performed in a double-blinded manner with the use of a central computerized system, with
stratification according to the final screening LDL cholesterol level (<2.2 or ≥2.2 mmol per
liter) and region.
Follow up:
All patients will be followed up in Hamed Al-Essa organ transplant center clinics at least
every 2 months or according the local follow up protocol. Patients who have a fasting LDL
cholesterol level of 1.8 mmol per liter or higher or a non-high-density lipoprotein (HDL)
cholesterol level of 2.6 mmol per liter or higher while they were taking an optimized regimen
of lipid-lowering therapy, which was defined as preferably a high intensity statin but must
have been at least atorvastatin at a dose of 20 mg daily with or without ezetimibe.
Our immunosuppression protocol consists of 5 doses of antithymocyte globulin (Sanofi US,
Bridgewater, NJ, USA) for high risk patients (as re-transplants, prior pregnancy, blood
transfusion, HLA-antibody positive and or more than 4 HLA mismatches)or 2 doses of IL-2
receptor blocker (basiliximab; Novartis, Inc., Switzerland) for low risk patients.
Maintenance therapy consists of prednisolone, MMF and a calcineurin inhibitor (CNI). The dose
of CNI will be gradually decreasing till the lowest dose by the end of the 1st year guided by
12-hour trough level. We keep the cyclosporine A level between 200 to 250 ng/ml during 1st
month then between 150-200 ng/ml for a couple of months then between 125-150 ng/ml for 2
months and from 75-125 ng/ml till the end of the 1st year. Similarly, we keep tacrolimus
trough levels between 8 to 10 ng/ml during 1st 3 months then from 5-8 ng/ml thereafter.
Maintenance immunosuppression with sirolimus based regimen will be used to rejection free
patients with low immunological risk after 3 months of transplantation.
Acute cellular rejection (ACR) will be treated with intravenous methylprednisolone sodium
succinate (solumedrol 1 gram daily for 3 days) and or thymoglobulin (1 mg /kg for 7 -10 days)
for steroid resistant rejection. Antibody mediated rejection (AAMR) will be treated with
plasma exchange, IVIG (2gm/kg) and rituximab. Patients, who will receive thymoglobulin as
antirejection, will be managed by secondary prophylaxis for 1 month. Patients will be
monitored daily during hospital stay then at each outpatient visit with complete blood
picture, serum creatinine, creatinine clearance, liver function tests (bilirubin, liver
enzymes and albumin) and drug levels.
Lipid Data:
The LDL cholesterol level will be checked in the central laboratory for all patients in both
groups at baseline (according to routine laboratory analysis) and every third month using
desktop Mission CE0123 cholesterol monitoring machine, till the end of the study.
End Points:
The primary efficacy end point will be any major cardiovascular events, defined as the
cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or
coronary revascularization. The key secondary efficacy end point will be cardiovascular
death, myocardial infarction, or stroke. Safety was assessed through collection of data on
adverse events and central laboratory testing in Ibn Sina laboratory, Sabah area of Kuwait.
Statistics and sample size calculation:
Statistical analysis of data will be evaluated on computer using SPSS (Statistical Package
for Social Science for Windows) 11.0 package software (SPSS Inc., Chicago, IL, USA). In order
to analyze the identifying and disease related characteristics of patients, matched t-test
will be used to compare means and standard deviations of numerical variables of the two
groups and to test whether there will be a difference between pre-education and
post-education score averages. Categorical data will be compared using the chi square test.
Values for P less than .05 were considered significant.
Confidentiality and consent :
To maintain confidentiality, all research data, blood and/urine specimens, Consent Forms,
Data Collection Forms, reports, and other records that leave the site will be identified only
by a Code Number-participant identification number (Participant ID). All records will be kept
in a locked file cabinet. All computer entry and networking programs will be done using PIDs
only. Participants' identifiable private information will not be released to a third party
without written permission of the participants.
Detailed information will be delivered to each patient about the study including the aim and
benefits. Before starting the enrolment of each patient, the investigator will get signed
informed consent which will be kept in patient file. Moreover, a copy of this consent will be
given to the patient.
- We will exclude participants with diminished capacity, such as minors and mentally
retarded, who cannot consent for themselves from this study.
- The original copy of the consent will be kept in the investigators' records, a copy will
be given to each participant, and this will be documented in the participant's record.
- The primary investigator and co-primary investigators will be responsible for
implementing the consenting process and obtaining the Informed Consent of Participants.
