The Medtronic CoreValve Evolut R US Clinical Study
Transcatheter aortic valve implantation (TAVI) has become a routine treatment option at specialized heart centers treating patients with severe aortic stenosis who are at high risk for surgical aortic valve replacement (SAVR). Medtronic has developed modifications to the Medtronic CoreValve System Transcatheter Aortic Valve frame and delivery catheter system to enable recapture of the device before it is fully released from the delivery system. These modifications are incorporated in the CoreValve Evolut R System.
The purpose of the study is to evaluate the safety and efficacy of the CoreValve Evolut R System in patients with severe symptomatic aortic stenosis who are considered at high through extreme risk for surgical aortic valve replacement.
This is a prospective, single arm, historical controlled, multi-center study. This study will involve no more than 250 subjects in up to 25 sites. The study population includes males and females with severe symptomatic aortic stenosis who are considered at high through extreme risk for surgical aortic valve replacement. Subjects will be followed up to 5 years following implantation.
Study endpoints are safety endpoints and efficacy endpoints. Safety endpoints are: All-cause mortality rate, stroke (disabling) rate, incidence of permanent pacemaker implant rate at 30 days. Efficacy endpoints are: Device success rate, Resheath and recapture success rate, percent of subjects with mild prosthetic regurgitation at early post-implant, hemodynamic performance metrics at 30 days.
Statistics/analysis: Subjects who are taken to the procedure room for implantation will comprise the study population evaluated for the study objectives and associated endpoints. An initial analysis will be performed when both of the following conditions are met:
1. The first 150 consecutive implanted subjects have completed their 30 day follow-up.
2. A total of 25 resheath or recapture attempts inclusive of all valve sizes, have been performed.
The final analysis will be performed after a minimum of 150 subjects but no greater than 250 subjects are implanted with the study device and followed for 5 years.
All endpoints are descriptive and no statistical hypothesis test will be performed.
Portico Resheathable Transcatheter Aortic Valve System US IDE Trial
Rationale: To potentially offer a SJM transcatheter Portico valve that is safe and effective for subjects with symptomatic severe aortic valve stenosis who are considered at high or extreme risk for conventional surgical aortic valve replacement. Purpose: The Portico Transcatheter Heart Valve is indicated for patients with symptomatic severe native aortic stenosis, who are considered high surgical or extreme surgical risk. Study population: High-Risk:Subjects must have comorbidities such that the surgeon and cardiologist CoPIs concur that the predicted risk of operative mortality is 15% and/or a minimum STS score of 8, and has symptomatic aortic stenosis. Extreme Risk: The subject, after formal consults by a cardiologist and two cardiovascular surgeons agree that medical factors preclude operation, based on a conclusion that the probability of death or serious, irreversible morbidity exceeds the probability of meaningful improvement, and has symptomatic aortic stenosis. Specifically the predicted risk of operative mortality should exceed 50%. Study Methodology: The PORTICO clinical trial is a prospective, multicenter, randomized, controlled clinical study, designed to evaluate the safety and effectiveness of the SJM Portico Transcatheter Heart Valve and Delivery Systems (Portico) via the transfemoral and alternative delivery methods, in high and extreme risk cohorts. If the participant takes part in the study, their treatment will be determined in a way similar to flipping a coin, called randomization. Prior to randomization, patients will be classified as high or extreme risk and stratified by vascular access within each risk group. Depending on their valve size they will be randomized into one of two study groups which will determine the device they are implanted with: Test Group: Portico Transcatheter Heart Valve / Control Group: FDAapproved Transcatheter Valve. There are also 2 registries in this study and they may be placed in a registry which will not require randomization. All registry patients will receive a TAVI and will have follow up as a research participant. The first registry is called a rollin registry. They may be considered for this registry based on their order of enrollment in the study. If they are one of the first three patients to enroll in the trial they will not be randomized but will receive a Portico valve. The second registry is for patients who already have a prosthetic aortic valve in place and are in need of replacing the prosthetic valve. If they qualify for this registry, a Portico valve will be implanted inside their existing prosthetic valve. The PORTICO trial will include a maximum of 908 subjects at up to 70 investigational sites. Study endpoints: A non-hierarchical composite of all-cause mortality, disabling stroke, or moderate or greater aortic insufficiency/regurgitation at one year for high and extreme risk cohort. Follow-up: 30 day, 6 month, One year and annually thereafter through year 5. Statistics: Basic descriptive statistics and P values will be reported.Analysis: The primary analysis will be based on the intent to treat (ITT) population. The ITT population is defined at the time that randomization treatment is assigned to the subject. For the primary analysis in this study, subjects will be analyzed according to their ITT arm, and the randomization day will be considered Day 0 when referring to a specific number of days.
Cardiovascular Inflammation Reduction Trial (CIRT):
A randomized, double-blind, placebo-controlled, event-driven trial of weekly
low-dose methotrexate (LDM) in the prevention of cardiovascular events among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome
RATIONALE: Because there has been a great deal of evidence that inflammation plays a major role in atherothrombotic events, we would like to test whether low doses of methotrexate (an antimetabolite that reduces inflammatory biomarkers) will decrease myocardial infarction, stroke, or cardiovascular dealth among patients with a recent history of coronary artery disease and either type 2 diabetes or metabolic syndome. INTERVENTION: First, all consented subjects will be given study drug, low-dose methotrexate (LDM), for a maximum of 8 weeks to see if they can safely tolerate the drug. Second, the subjects will be randomized into either study target dose of 15 to 20 mg po weekly or placebo. Safety and efficacy outcomes will be assessed.PRIMARY AIM: To determine in a randomized, double-blind, placebo-controlled setting whether LDM given at a target dose of 15 to 20 mg po weekly will reduce rates of myocardial infarction, stroke, or cardiovascular death among patients with a prior history of coronary artery disease and either type 2 diabetes or metabolic syndrome.STUDY POPULATION: CIRT will randomize 7,000 men and women, age 18 years and over, who have any past history of myocardial infarction or have multivessel coronary artery disease defined by angiography, have completed any planned coronary revascularization procedures associated with the qualifying event, have been on a stable secondary prevention regimen for a minimum of 60 days, and have either a clinical diagnosis of type 2 diabetes or metabolic syndrome.METHODOLOGY: CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have either suffered documented myocardial infarction or have angiographically demonstrated multivessel coronary artery disease will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. STATISTICS: The randomized design and large sample size of CIRT should provide balanced distributions of baseline characteristics between the two treatment groups; Initial analyses will form part of the routine monitoring of the trial and will be regularly reported to the DSMB. For continuous and ordinal variables, including age and baseline levels of risk factors including lipid levels, blood pressure, and body mass index, comparisons will use the Wilcoxon rank-sum test.
Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial
Carotid revascularization for asymptomatic carotid stenosis by carotid endarterectomy (CEA) or carotid artery stenting (CAS) is common and costly. The rationale for incurring large national costs for revascularization of asymptomatic patients is based on the results of the previous studies all of which were done without comparison to modern intensive medical management.
CREST-2 is two parallel multi-center randomized, observer-blinded endpoint clinical trials. The study is assessing: 1) the treatment differences between MEDICAL management compared with CEA, and 2) the treatment differences between MEDICAL management compared to CAS. Each is a two-arm, randomized trial of approximately 1,240 asymptomatic patients with high-grade stenosis randomized to receive revascularization plus intensive medical management (CAS or CEA) versus intensive medical management alone (MEDICAL).
The study population is people aged >35 years old who have high-grade cervical carotid artery stenosis and who are confirmed to be asymptomatic. It is anticipated that approximately 2480 adult men and women will be enrolled.
The primary outcome is the composite of stroke plus death (S+D) within 44 days after randomization and ipsilateral ischemic stroke thereafter up to 4 years, and this composite endpoint will be estimated using Kaplan-Meier survival approaches. Statistical testing will employ superiority testing, with the null hypothesis that MEDICAL is equivalent to CAS or CEA versus the alternative that MEDICAL differs from CAS or CEA.
Secondary outcomes are: 1) the assessment if MEDICAL differs from CAS, and differs from CEA, to maintain the level of cognitive function at the 4-year assessment, 2) if there are treatment differences in the incidence of major stroke, minor stroke, disabling stroke, non-disabling stroke, and tissue-based stroke at 4-years, and 3) potential effect modification of the CAS or CEA versus MEDICAL differences, based on patient age, sex, severity of carotid stenosis, restenosis, risk factor level, and duration of asymptomatic period.
Medtronic CoreValve SURTAVI Trial -Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI)
SURTAVI Clinical Investigation Protocol:
Background:Purpose:The purpose of this study is to investigate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk by randomizing patients to either Surgical Aortic Valve Replacement (SAVR) or TAVI with the Medtronic CoreValve System or Medtronic EVOLUT-R system.Objectives:The primary objective of this trial is to evaluate in a prospective randomized fashion whether TAVI is non-inferior to SAVR with respect to composite endpoint of all-cause mortality and disabling stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate surgical risk.The secondary objective of this trial is to assess differences in quality of life, clinical benefit (efficacy endpoints) and health economics in patients with symptomatic severe aortic stenosis and at intermediate risk treated with either Transcatheter Aortic Valve Implantation (TAVI) or Surgical Aortic Valve Replacement (SAVR).Study population:Patients who have symptomatic severe Aortic Stenosis at intermediate surgical risk defined by a Society of Thoracic Surgeons (STS) mortality risk of 4% and 10% will be presented to the Heart Team for inclusion in the trial.Methodology/study arms:This study is designed as a prospective, multi-center, multi-national, randomized, interventional trial to investigate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk. Approximately 1600 subjects will be recruited in up to 115 investigational centers located in the United States, Canada and Europe. The study may be expanded to include additional geographies based on enrollment rates and identification of qualified centers. Subjects will be randomized on a 1:1 basis to either transcatheter aortic valve implant (TAVI) with one of two approved valves, Medtronic CoreValve System (MCS)/EVOLUT R System or to surgical aortic valve replacement (SAVR).Primary Endpoint:All-cause mortality or disabling stroke at 24 months Follow-up: Subjects will be followed through 5 years with assessments at 30 days, 3 months, 6 months, 12 months, 18 months, 24 months, and 3, 4, and 5 years post MCS TAVI or post SAVR.Statistics/Analysis:The statistical analysis will be performed by the statistics department of Medtronic. As primary analysis all randomized subjects will be analyzed following the modified intention to treat (mITT) approach; i.e. analyses will be conducted on the cohort of subjects who undergo an attempted study treatment, analyzed according to the randomized assignment. A secondary analysis of key objectives will be performed according to the therapy actually received.
SURTAVI Single-Arm, Non-Randomized Phase (Addendum Version 1.0):
Background: The Medtronic CoreValve SURTAVI Trial is a prospective, randomized, multicenter investigational trial. The purpose of this trial is to investigate the safety and effectiveness of transcatheter aortic valve implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk by randomizing patients to either Surgical Aortic Valve Replacement (SAVR) or TAVI. The purpose of this addendum to the Medtronic CoreValve SURTAVI Trial protocol is to conclude the randomized phase and initiate the single-arm, non-randomized, TAVI only phase of the trial.
Objectives: The primary objective of this trial is to evaluate the safety and effectiveness of the Medtronic CoreValve System and CoreValve Evolut R System, as measured by a composite endpoint of all-cause mortality or disabling stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate surgical risk.
Patient Population: Patients who have symptomatic severe Aortic Stenosis who are determined by the Heart Team to be at intermediate surgical risk.
Design: The single-arm phase is designed as a prospective, multi-center in the United States, non-randomized, interventional trial to evaluate the safety and effectiveness of transcatheter aortic valve implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk.
All enrolled subjects will be assigned to transcatheter aortic valve implant (TAVI).
Follow-Up: All enrolled subjects will undergo in-clinic follow-up evaluations at the following time points post implant, 30 days, 6 months, 12 months, 24 months and annually thereafter through 5 years. In the single-arm phase of this trial, the 3 months and 18 months follow-up visits are no longer required like in the primary SURTAVI Trial Clinical Investigation Protocol (CIP).
Statistical Analysis: There are three analysis populations defined for this study. The primary analysis for the primary objective and most secondary objectives will use the attempted implant population. The echocardiographic assessment of valve performance data will be analyzed based on the implanted population. (1)All enrolled population all subjects who are enrolled in the trial (2) Attempted implant population - all subjects in whom a procedure is attempted. A procedure attempt is defined as when the subject is brought into the procedure room and any of the following have occurred: anesthesia administered, vascular line placed, TEE placed or any monitoring line placed. (3) Implanted population All attempted implant subjects who are actually implanted with the investigational TAVI device.
COAST: COILING OF ANEURYSMS SMALLER THAN 5 MM WITH
Rationale and Intervention:This is a prospective, single-arm, multi-center post-marketing data collection study to determine the safety and effectiveness of HyperSoft and HydroFrame/HydroSoft coils in the treatment of small intracranial aneurysms. HyperSoft Helical, HyperSoft 3 D and HydroFram/HydroSoft are newly designed coils where the shape and softness of these coils are designed for small aneurysms. There are 2 phases in this study. In Phase 1, participants will be enrolled if they will be treated with HyperSoft 3D and HyperSoft helical coils. When the sponsor adds phase 2, patients will be enrolled into Phase 2 if their aneurysm will be framed with HydroFrame HydroSoft 3D and finished with HyperSoft 3D and /or Hyper Soft helical coils. Objectives:The primary objective of this study is to assess clinical and imaging outcomes in the endovascular treatment of small ( 4.9 mm) intracranial aneurysms utilizing the HyperSoft 3D and HyperSoft helical coils specifically designed for the treatment of small aneurysms.Study Population: 300 participants who have been diagnosed with small ( 4.9 mm) intracranial aneurysms and who were treated with the coils from 16 centers. Study Methodology:Endovascular coiling of the aneurysm is performed per each institutions standard procedure.Data from each participant will be collected up to 12 months post procedure. There are up to five data points which include baseline (pre- procedure), procedure/post procedure through discharge and follow-up at 6 or 12 months. Data from imaging (2-D DSA, diagnostic) of aneurysm, clinical assessment (mRS, Hunt & Hess,NIHSS), aneurysm occlusion grading (Raymond-Roy grading scale /RRGS), retreatment and adverse events/safety will be collected per protocol at various time points. Study Endpoints or Outcomes:Efficacy: Raymond-Roy grading scale (RRGS) of 2 or better occlusion on follow-up angiography performed >150 days post embolization, not requiring retreatment.Safety: Freedom from new post-procedural bleeding and ischemic stroke associated with a 4-point worsening neurologically within 48 hours of aneurysm treatment or any new aneurysmal bleeding secondary to treated aneurysm. Follow up:All Study subjects will undergo follow-up angiographic (DSA or MRA) evaluations at 6 months and/or 12 months following the procedure or if an unscheduled visit is required.Statistics and Plans for Analysis:Two-sided 95% confidence intervals will be calculated about the estimated post EVT occlusion rates using the exact binomial distribution. Secondary analyses will include any neurological and mortality, bleeding rate of target aneurysms at one year (includes rebleeding of target ruptured aneurysms), recurrence rate/recanalization (at time of >150 day angiographic follow up), and retreatment rate (at one year). All clinical outcome analyses will be performed on the per protocol and ITT populations.
Global Observational Study to Evaluate the Correlation Between Coronary and Carotid Atherosclerotic Disease (CAD) and Links with Clinical Outcomes
Observational study to collect F/U imaging & clinical endpoint data from pts. who successfully completed baseline coronary IVUS (intravascular ultrasound) imaging in the dal-PLAQUE 2 (DP2) study to determine the correlation & clinical relevance of such imaging as related to coronary artery disease (CAD). Pts. who have had baseline angiography/IVUS, with or w/o baseline carotid ultrasound but NOT undergone follow-up angiography/IVUS as part of DP2 will have F/U angiogram/IVUS within 18-27 mos. of baseline imaging. Pts. who have had baseline carotid ultrasound but NOT undergone a F/U carotid ultrasound as part of DP2 will have follow-up carotid ultrasound within 18-27 mos. of baseline imaging. Main objectives is to compare: extent of atherosclerosis in coronary arteries with the extent of atherosclerosis in carotid arteries at a single point in time. Pts. who have successfully undergone baseline IVUS imaging, with or w/o baseline carotid ultrasound, in DP2 will be included. Pts., who successfully completed baseline angiography/IVUS in DP2, with or w/o baseline carotid ultrasound, will be scheduled for final F/U angiography/IVUS any time between 18-27 mos. after DP2 baseline imaging. Pts. who successfully completed baseline carotid ultrasound in DP2 will be scheduled for F/U carotid ultrasound any time between 18 -27 mos. after DP2 baseline imaging. Endpoints: death, death from coronary heart disease, resuscitated cardiac arrest, non-fatal MI, stroke, hospitalization for documented acute coronary syndrome, coronary revascularization procedure & carotid artery surgery or angioplasty. Pts. will have annual phone contact for 3 yrs. to check for the occurrence of cardiovascular & cerebrovascular clinical endpoints. Imaging parameters from this study will be combined with the imaging data from DP2 to compare coronary & carotid atherosclerosis extent at baseline & rate of progression up to 2 yrs.
Medtronic CoreValve® U.S. Expanded Use Study
The primary objective of the study is to evaluate the safety and effectiveness of the
Medtronic CoreValve® System (MCS) in a subset of subjects excluded from the U.S. Extreme
Risk Pivotal Trial population due to one or more additional co-morbidities, as measured by a
composite of all-cause death or major stroke at 12 months, in the treatment of symptomatic
severe aortic stenosis in subjects necessitating aortic valve replacement. Subjects enrolled
in this study have a predicted operative mortality or serious, irreversible morbidity risk
of ≥50% at 30 days associated with surgical aortic valve replacement.
Medically Ill Patient Assessment of Rivaroxaban Versus Placebo IN Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER)
RATIONALE: The risk of developing venous thromboembolism is a major cause of morbidity in the hospitalized population. Current therapies such as heparin often have a narrow therapeutic index meaning if you don't give exactly the right doses in the therapeutic range, the patient is at risk of severe bleeding and possible mortality. Rivaroxaban is an oral, direct acting Factor Xa inihibitor anticoagulant that posseses a wider therapeutic index which reduces the risk of adverse bleeding. The rationale of this study is to compare the efficacy and safety of rivaroxaban in preventing venous thromboembolism and related deaths compared to placebo group after discharge in the high-risk medically ill population. INTERVENTION: Experiment group will receive rivaroxaban for 45 days and standard therapy. The placebo group will receive standard therapy only. OBJECTIVES: The primary objective is to assess the efficacy and safety of rivaroxaban, compared with placebo in the prevention of symptomatic VTE and VTE-related death posthospitaldischarge in high-risk, medically ill patients.STUDY POPULATION: Approximately 8000 subjects worldwide who are 40 years of age or older and hospitalized for at least 3 days with diagnoses of one of the following: congestive heart failure, acute respiratory insufficiency, acute exacerbation of chronic obstructive pulmonary disease, acute ischemic stroke, acute infectious disease, or inflammatory disease including rheumatic disease.STUDY METHODOLOGY: This is a multicenter, prospective, randomized, double-blind, placebo-controlled, event-driven study designed to evaluate rivaroxaban, compared with placebo, in the prevention of symptomatic VTE events and VTE-related deaths for a period of 45 days posthospital discharge. Study drug will start at randomization (Day 1), and will continue until Day 45 (inclusive).STUDY ENDPOINTS:The primary efficacy outcome is the composite of all symptomatic VTE events (lower extremity DVT, non-fatal PE) and VTE-related deathSTATISTICS: Key Analysis Set and Analysis Phase Intention-to-Treat (ITT): This analysis set consists of all randomized subjects who have a signed valid informed consent. Up-to-Day-45: This analysis phase includes all data from randomization to Day 45 (inclusive).