B P1 C4 Clinical Trials in Cardiovascular Medicine Flashcards
_____ studies can assess the natural history of disease, demonstrate relationships between risk factors and outcomes, and generate hypotheses for more definitive experimental testing.
Yet observational studies are almost always biased and limited when it comes to assessing the merits of new therapies
Observational
This single-greatest inherent problem with attempting to infer effects of therapies from observational studies is termed “_____” and refers to biases, known or unknown, that influence which therapies are used for which patients and which conditions.
Confounding by indication
These biases can be overcome to some extent by taking account of, or adjusting for, all the other factors that might have influenced the decision to use that medication and the outcomes in those patient
_____ are prospective human experiments in which an **intervention (which could be a pharmacologic or device therapy or an interventional strategy) are compared with a control and in which randomization is used to eliminate the potential biases related to administration of a therapy
Randomized clinical trials
In a large enough study, _____ ensures that patients in both the experimental group and the control group are similar in every respect excepting the randomly allocated therapy.
Randomization
Phase _____ studies assess the safety and tolerability in the first human experience of a novel therapy typically using healthy volunteers.
Phase I
These studies can be open label and even single arm and collect information that can be helpful in identifying a maximally tolerated dose (dose escalation studies).
Phase _____ studies are designed to confirm the biologic activity of the experimental therapy in patients with the disease of interest and, in some cases, to determine the likely optimal dose for both efficacy and tolerability
Phase II
Safety and tolerability are also assessed along with other secondary and exploratory measures of efficacy that might inform further development. Phase II trials often use surrogate endpoints rather than clinical endpoints
Phase ______, are designed to provide enough information on efficacy and safety for regulatory evaluation and hopefully approval. Pivotal trials require assessment of “approvable” endpoints— that is, endpoints that have been previously agreed upon by regulatory authorities such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA)
Phase III, or pivotal studies
Phase _____ trials, sometimes referred to as post-marketing trials, are designed to add mechanistic or other support for an indication, to extend a previous indication to a new population, or to meet a regulatory requirement such as providing additional safety information, perhaps in a specific patient population.
Phase IV
The EVALUATE trial,6 for example, was a phase IV trial examining the effect of sacubitril/valsartan compared with enalapril on aortic stiffness and ventricular remodeling to provide mechanistic support for the findings in PARADIGM-HF, a positive phase III outcomes trial.
Clinical trial designs vary, and each have distinct advantages and disadvantages.
The most commonly used is a _____ design in which patients are randomized to two or more groups and endpoints are compared between groups.
These trials can be placebo controlled or active controlled and can have multiple arms (e.g., a placebo, active comparator and study drug, or multiple doses of a study drug).
In this design, patients are randomized to receive one of these therapies for the duration of the trial.This type of design can be used for either clinical outcomes trials or phase II trials in which the primary endpoint is a surrogate (e.g.,cholesterol or a natriuretic peptide).
Parallel group design
In contrast, in __________ trials, patients receive one therapy for a period of time and then are “crossed over” to receive placebo or another therapy.
In this design, individual patients act as their own control, and these designs are typically used for phase II studies in which the endpoint is a measured surrogate such as a biomarker.
Crossover trials
The advantage of crossover trials is that fewer patients are needed because each patient serves as his or her own control, reducing variability.
The disadvantage is that effects of a therapy from the first phase can carry over and contaminate the second phase. This issue is typically mitigated with a washout period, a time between therapies during which the effect of the first phase would be expected to wear off. Crossover designs are not suitable for long-acting therapies or to outcomes trials (where a clinical outcome, such as a death or hospitalization, might influence whether the patient would join the second phase).
_____ trials are essentially parallel group studies in which there are two consecutive randomizations within the same patient population so that an individual patient would be randomized to treatment A versus B,and also to C versus D,leaving four distinct treatment groups (A+C, A+D, B+C, B+D).
In a factorial design trial, each randomization is essentially treated as its own trial. Factorial trials are best when the therapies are distinct enough that there will be no “interaction” between therapies.
Assuming there is no or minimal interaction between therapies, factorial designs can be executed with a modest increase in the sample size required for a single intervention
Factorial design trials
Examples of factorial design trials include the ISIS-2 trial, which randomized patients to both streptokinase or placebo and additionally randomized the same patients to aspirin or placebo, and the DREAM trial, which compared the effects of ramipril versus placebo, and rosiglitazone versus placebo on the incidence of diabetes.
_____ trials test whether therapy A is superior to therapy B, which can be either an active comparator or placebo.
Superiority trials aim to _____ the null hypothesis that there is no difference between the therapies
Superiority trials
Reject the null hypothesis
_____ trials are designed to determine whether one therapy is noninferior to (loosely translated to not worse than) another therapy.
In the case of noninferiority trials, rejecting the null hypothesis requires that therapy A be not inferior to therapy B within a certain margin of error; this requires setting a prespecified noninferiority margin and requiring an upper 95% confidence interval to be within that margin.
Noninferiority trials
Noninferiority trials are typically used when it is necessary to show only that a novel therapy is “as good as” an established therapy, which may be clinically important if the novel therapy has a better side effect profile, is less expensive, or may be easier to administer
in smaller trials randomizing by a simple coin-toss (or random number) method can lead to imbalances at any time during the trial. For example, in a 100-patient trial, there would be a 5% risk of 60% of participants being allocated to one therapy.
The commonly used ______ randomization scheme mitigates this risk by ensuring equal number of participants assigned to each randomized group within each block of x, ensuring that the maximum imbalance at any given time is essentially the size of the permuted block.
Blocked or permuted block
______ randomization is a design in which groups of individuals, rather than actual individuals, are randomized.
For example, trials testing specific strategies might randomly allocate clinics to one approach or another, as was done in the HOOPS trial, which randomly allocated 174 practices to pharmacist intervention or usual care to optimize use of guideline-directed therapy in patients with left ventricular dysfunction. This avoids the risk of investigators applying the new strategy under investigation to “control” patients in the same clinic or practice because all patients in each practice or clinic receive one or other strategy.
Cluster randomization
