Long-Term Registry of Patients with Urea Cycle Disorders (UCDs)
The main goal of medical management of Urea Cycle Disorder (UCD) patients is to prevent chronic or acute hypperammonemic states leading to central nervous damage- which requires a restriction in dietary protein intake and using nitrogen scavenging agents if diet alone does not help the patients.The objective of this study is to characterize the demographic of the patient population diagnosed with UCD. Another objective is to track growth and neuro-cognitive outcomes for patients with UCDs. Patient participation includes the collection of retrospective and baseline data including ammonia and glutamine levels. Age appropriate questionaires will be given for completion by subject or parent. . Data will be collected on all individuals who are enrolled. The patient population are patients with an established or suspected diagnosis of UCD. The patient or legally acceptable representative must also sign and release an informed consent/HIPPA Authorization and medical records.The study procedures are for each study personnel to be trained for all documentation, baseline visits and enrollment for patients, and retrospective data for ammonia values obtained from the patient will be entered in the registry. The outcome variables will be the control of blood ammonia levels and the frequency of the serious adverse events (SAEs). Blood ammonium levels, and the frequency of hyperammonemic crisis will be observed during this study.The statistical analysis plan (SAP) will show details of all analysis and presentation of study data. Data will be shown to patients who attend the baseline visit, and analysis will be based on all the patients who are enrolled. Post baseline values or change from the baseline outcome variables will be summarized by UCD medication with statistics and graphical presentations.
A Randomized Double-Blind Phase 2 Study Comparing the Efficacy, Safety, and Tolerability of Combination Antivirals (Amantadine, Ribavirin, Oseltamivir Versus Oseltamivir for the Treatment of Influenza in Adults at Risk for Complications
Seasonal influenza is responsible for approximately 226,000 excess hospitalizations annually
and despite effective antivirals causes significant morbidity and mortality (estimated
24,000-50,000 deaths each year in the United States alone). The influenza virus that emerged
in 2009 (A/California/07/2009 H1N1) caused fewer deaths (12,000 flu-related deaths in the
U.S) but in contrast to seasonal flu, nearly 90 percent of the deaths with the 2009 H1N1
occurred among people younger than 65 years of age. The CDC has defined an at-risk
population that is responsible for the majority of hospitalization and morbidity associated
with influenza. This study will evaluate the use of combination antivirals as compared to
oseltamivir alone in the treatment of influenza in an at-risk population.
Subjects who meet the CDC definition for being at-risk and that present with an
influenza-like illness will be screened for the study. Those subjects with a confirmatory
test for influenza (rapid antigen or PCR) will be randomized in a 1:1 manner to receive a
blinded study treatment consisting of either the combination of amantadine, oseltamivir, and
ribavirin or oseltamivir alone for 5 days. Clinical, virologic, and laboratory assessments
on Days 1, 3, 7, 14, and 28 will be used for both safety and efficacy analysis.
Objectives:
- To evaluate the effectiveness of combined treatment with oseltamivir, amantadine, and
ribavirin compared with oseltamivir alone for at-risk individuals with confirmed influenza
infection.
Eligibility:
- Individuals at least 18 years of age who have one or more medical conditions that may
cause complications from influenza, and have developed an influenza-like illness.
Design:
- Participants will be screened with a physical examination and medical history, along
with blood tests and throat swabs to confirm influenza infection.
- Eligible participants will be randomly assigned to take either oseltamivir alone (the
current standard treatment for influenza) or to take oseltamivir, amantadine, and
ribavirin. Participants will have additional blood samples and throat swabs taken at
the start of the study, and will be shown how to complete a study diary at home.
- Participants will receive a study medication kit containing the medication to take at
home twice a day for 5 days.
- Participants will return, with the medication kit, to the clinic on days 1 (the first
day after the start of the study), 3, 7, 14, and 28. The first visit may take 2 to 3
hours, but each subsequent visit should take approximately 1 to 2 hours. Additional
blood samples and throat swabs will be taken at these visits.
CardioMEMSTM HF System Post Approval Study
RATIONALE: Heart failure is a major cause of morbidity and mortality. CardioMEMS HF System is an FDA approved implantable device that wirelessly measures and monitors pulmonary arterial pressure and heart rate. The CHAMPION trial demonstrated that management of heart failure using pulmonary artery pressure information obtained with the CardioMEMS HF System, in addition to traditional signs and symptoms, reduced HF hospitalizations.
INTERVENTION: Patients will be scheduled for follow-up visits at 1 month and every 6 months for 2 years. Following sensor implant and hospital discharge, subjects will take PA pressure measurements on a daily basis, or as directed by the investigator. These measurements will be automatically transmitted to the secure Patient database (CardioMEMS HF website).
OBJECTIVES: The objective of this study is to confirm the post-market safety and effectiveness of the CardioMEMS HF System to premarket.
STUDY POPULATION: Twelve hundred subjects will be enrolled with at least 35% of the enrolled patients being women (420 women out of 1200). Enrollment will be limited to 15% of the total study population at any one site.
STUDY METHODOLOGY: This is a prospective, multi-center, open-label trial conducted in the United States (US). All subjects who sign the informed consent form and satisfy the inclusion/exclusion criteria will be enrolled into the CardioMEMS HF System PAS and will be scheduled for follow-up visits at 1 month and every 6 months for 2 years. Following sensor implant and hospital discharge, subjects will take PA pressure measurements on a daily basis, or as directed by the investigator. These measurements will be automatically transmitted to the secure Patient database (CardioMEMS HF website).
STUDY ENDPOINTS:Primary safety endpoints will be evaluated at 2 years: 1) freedom from device/system related complications and 2) freedom from pressure sensor failure.
STATISTICS: The primary safety hypotheses are that the device / system-related complication-free proportion of subjects will be at least 80% at 24 months (OPC used in the CHAMPION trial) and that the pressure sensor failure-free proportion of subjects will be at least 90% at 24 months (OPC used in the CHAMPION trial). Plotting and analysis of safety endpoints will also be displayed using Kaplan-Meier methods. All safety analyses will be performed on the safety population.
International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA)
BACKGROUND:
Evidence supporting a routine invasive practice paradigm for patients with stable ischemic
heart disease (SIHD) is outdated. In strategy trials conducted in the 1970s, coronary artery
bypass grafting (CABG) improved survival as compared with no CABG in SIHD patients with
high-risk anatomic features. The relevance of these studies today is speculative because
contemporary secondary prevention—aspirin, beta-blockers, statins, ACE inhibitors, and
lifestyle interventions—were used minimally if at all. Subsequent trials have compared
percutaneous coronary intervention (PCI) with medical therapy, as PCI has replaced CABG as
the dominant method of revascularization for SIHD. To date, PCI has not been shown to reduce
death or myocardial infarction (MI) compared with medical therapy in SIHD patients.
COURAGE and BARI 2D, the two largest trials comparing coronary revascularization vs. medical
therapy in SIHD patients, found that among patients selected on the basis of coronary
anatomy after cath, an initial management strategy of coronary revascularization (PCI, PCI
or CABG, respectively) did not reduce the primary endpoints of death or MI (COURAGE), or
death (BARI 2D) compared with OMT alone. These data suggest, but do not prove, that routine
cath--which often leads to ad hoc PCI through the diagnostic-therapeutic cascade--may not be
required in SIHD patients. However, most patients enrolled in COURAGE and BARI 2D who had
ischemia level documented at baseline had only mild or moderate ischemia, leaving open the
question of the appropriate role of cath and revascularization among higher risk patients
with more severe ischemia. Observational data suggest that revascularization of patients
with moderate-to-severe ischemia is associated with a lower mortality than medical therapy
alone, but such data cannot establish a cause and effect relationship. In clinical practice
only about half such patients are referred for cath, indicating equipoise. Furthermore,
analysis of outcomes for 468 COURAGE patients with moderate-to-severe ischemia at baseline
did not reveal a benefit from PCI. This issue cannot be resolved using available data
because all prior SIHD strategy trials enrolled patients after cath, introducing undefined
selection biases (e.g., highest risk patients not enrolled) and making translation of study
results problematic for clinicians managing patients who have not yet had cath.
A clinical trial in SIHD patients uniformly at higher risk (which could not have been
performed before COURAGE and BARI 2D results were available) is needed to inform optimal
management for such patients.
DESIGN NARRATIVE:
The study protocol is final, and was distributed to sites February 2012. Study protocol v2.0
was approved in January 2014.
PARTICIPATING COUNTRIES:
North America
- Canada
- Mexico
- USA (~150 sites)
South America
- Argentina
- Brazil
- Chile
- Peru
Asia
- China
- India
- Japan
- Singapore
- Taiwan
- Thailand
- Russian Federation
Pacifica
- Australia
- New Zealand
Europe
- Austria
- Belgium
- Denmark
- France
- Germany
- Hungary
- Italy
- Lithuania
- Macedonia
- Netherlands
- Poland
- Portugal
- Romania
- Serbia
- Spain
- Sweden
- UK
Middle East
- Israel
- Saudi Arabia
- Turkey
An Open-Label, Multicenter, Historically-Controlled Study to Assess Safety and Efficacy of ELAD in Subjects With Acute Liver Failure (ALF)
VTI-212 is an open-label, multicenter, historically-controlled study of subjects with acute
liver failure (ALF). Approximately 40 subjects who meet the eligibility requirements of the
study will receive ELAD treatment in addition to standard of care treatment for ALF. The
outcomes of these subjects will be compared with matched historical controls drawn from
existing databases.
Subjects will undergo ELAD treatment for a minimum of 3 days (72 hours). It is recommended
ELAD treatment be continued up to 10 days (240 hours).
Following ELAD treatment, subjects will continue standard medical therapy as defined by the
institution and be followed through Study Day 28.
Subjects' diagnosis of ALF will be attributed to one of the following:
1. FHF (acute liver failure with no preexisting liver disease);
2. Primary Graft Non-Function (PNF);
3. Surgically-Induced Liver Failure (including subjects with small for size liver
transplants, living donor liver transplants, and subjects with risk of ALF following
liver cancer surgery.
Screening evaluations and assessments will be completed for subjects and reviewed against
inclusion/exclusion criteria.
Enrollment will define the time of study entry (Hour 0, Study Day 1, study baseline) and
inclusion in the ITT population. Subjects will be evaluated throughout the 28-day study
period.
If standard medical therapy, as defined by the institution and this protocol is consistent
with discharging the subject home, then the subject should be discharged. Prior to
discharge, the subject will be advised to attend all follow-up visits.
An extension of this study, VTI-212E, will provide additional ELAD survival data, as
available, through VTI-212 study termination (after the last surviving enrolled ELAD subject
completes Study Day 28). This registry protocol segment of VTI-212 extends the safety
monitoring period to 5 years to assess survival, incidence and characterization of tumor (in
particular hepatocellular tumor), incidence of liver transplant, and assess quality of life
using a standard, validated questionnaire.
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.
7H-14-1 An Open Label, Randomized Phase 3 Clinical Trial of Nivolumab vs Therapy of Investigator's Choice in Recurrent or Metastatic Platinum-refractory Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Head and neck carcinomas (HNC) describe cancers of the upper digestive tract which include squamous cell cancers (SCCHN) of the mouth, throat, and vocal chords. At present, there is no effective standard of care that provides survival benefits beyond 4 - 6 months in second line treatment of SCCHN that spreads or returns and does not respond to platinum treatment (refractory). Nivolumab is a drug that binds to a tumor cell receptor that blocks the immune system, thus allowing the immune system to attack tumor cells. Nivolumab has demonstrated clinical activity across several tumor types, but there has been no clinical trial so far to study the clinical benefit of nivolumab in SCCHN. Cetuximab, methotrexate, and docetaxel, which appear to be the most active in the platinum refractory setting, have approved indications as single agents for treating SCCHN and will be used as the Investigator's Choice in this study. The objective of this study is to compare progression free survival (PFS) and overall survival (OS) of Nivolumab to Investigators Choice in subjects who have tumor progression within 6 months of last dose of platinum therapy.
Patients who will be enrolled for this study will have laboratory confirmed SCCHN whose disease has spread or returned within 6 months of being treated with a platinum based therapy. Participants will be randomized to receive one of the following: nivolumab, cetuximab, methotrexate, or docetaxel. During the study, participants in all groups will have the study procedures done during each cycle as stated in the protocol. All participants will stop taking study drug(s) if their disease worsens, they have another illness which prevents them from taking the study drug(s), they cannot tolerate the side effects, they withdraw from the study, their study doctor thinks that being on the study is no longer in their best interest, or the sponsor stops the study. All participants will be followed for 35 days and 80 days after stopping the study drug(s), and then every 3 months until death.
Subject characteristics including demographics, baseline performance status, disease
characteristics and baseline laboratory parameters will be summarized by randomized treatment
arm, as well as pooled across randomized treatment arm. A two-sided 0.03 log-rank test will be used to do a formal comparison of PFS across all treatment arms. Median PFS will be estimated via the Kaplan-Meier product limit method. Two-sided 95% confidence intervals (CI) for the median PFS will be computed for each randomized arm. Kaplan-Meier plots of PFS will be presented. Hazard ratios (HR) and corresponding two-sided (1-adjusted )% CI will be estimated using a Cox proportional hazards model, with treatment arm as a single covariate, stratified by the above factor, corresponding to each comparison of PFS. OS will be compared between the treatment arms among all randomized subjects using a two sided, = 0.02 level log-rank test (adjusted for interim analysis), stratified using the same factor as in PFS.
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