A medical research study is evaluating an investigational novel drug (medication 1) as compared with standard therapy (medication 2) in patients presenting to the emergency department with myocardial infarction (MI). The study enrolled a total of 3,000 subjects, 1,500 in each study arm. Follow-up was conducted at 45 days post-MI. The following are the results of the trial:
Endpoints Medication 1 Medication 2 P-Value
Primary: death from cardiac causes 134 210 0.03
Secondary: hyperkalemia 57 70 0.4
What is the relative risk of death from a cardiac cause, expressed as a percentage? (Round to the nearest whole number.)
Q22
A researcher is trying to determine whether a newly discovered substance X can be useful in promoting wound healing after surgery. She conducts this study by enrolling the next 100 patients that will be undergoing this surgery and separating them into 2 groups. She decides which patient will be in which group by using a random number generator. Subsequently, she prepares 1 set of syringes with the novel substance X and 1 set of syringes with a saline control. Both of these sets of syringes are unlabeled and the substances inside cannot be distinguished. She gives the surgeon performing the surgery 1 of the syringes and does not inform him nor the patient which syringe was used. After the study is complete, she analyzes all the data that was collected and performs statistical analysis. This study most likely provides which level of evidence for use of substance X?
Q23
A pharmaceutical company conducts a randomized clinical trial in an attempt to show that their new anticoagulant drug prevents more thrombotic events following total knee arthroplasty than the current standard of care. However, a significant number of patients are lost to follow-up or fail to complete treatment according to the study arm to which they were assigned. Several patients in the novel drug arm are also switched at a later time to a novel anticoagulant or warfarin per their primary care physician. All patients enrolled in the study are subsequently analyzed based on the initial group they were assigned to and there is a significant improvement in outcome of the new drug. What analysis most appropriately describes this trial?
Q24
A pharmaceutical company conducts a randomized clinical trial to demonstrate that their new anticoagulant drug, Aclotsaban, prevents more thrombotic events following total knee arthroplasty than the current standard of care. A significant number of patients are lost to follow-up, and many fail to complete treatment according to the study arm to which they were assigned. Despite these protocol deviations, the results for the patients who completed the course of Aclotsaban are encouraging. Which of the following analytical approaches is most appropriate for the primary analysis to establish the efficacy of Aclotsaban?
Q25
A group of investigators have conducted a randomized clinical trial to evaluate the efficacy of adding a novel adenosine A1 receptor agonist to the standard anti-epileptic treatment in reducing the frequency of focal seizures. It was found that patients taking the combination regimen (n = 200) had a lower seizure frequency compared to patients taking the standard treatment alone (n = 200; p < 0.01). However, several participants taking the novel drug reported severe drowsiness. The investigators administered a survey to both the combination treatment group and standard treatment group to evaluate whether the drowsiness interfered with daily functioning using a yes or no questionnaire. Results are shown:
Interference with daily functioning Yes (number of patients) No (number of patients)
Combination treatment group 115 85
Standard treatment group 78 122
Which of the following statistical methods would be most appropriate for assessing the statistical significance of these results?
Q26
A group of investigators conducted a randomized controlled trial to compare the effectiveness of rivaroxaban to warfarin for ischemic stroke prevention in patients with atrial fibrillation. A total of 14,000 participants were enrolled and one half was assigned to each of the cohorts. The patients were followed prospectively for 3 years. At the conclusion of the trial, the incidence of ischemic stroke in participants taking rivaroxaban was 1.7% compared to 2.2% in participants taking warfarin. The hazard ratio is calculated as 0.79 and the 95% confidence interval is reported as 0.64 to 0.97. If the study was conducted with a total of 7,000 participants, which of the following changes would most be expected?
RCTs US Medical PG Practice Questions and MCQs
Question 21: A medical research study is evaluating an investigational novel drug (medication 1) as compared with standard therapy (medication 2) in patients presenting to the emergency department with myocardial infarction (MI). The study enrolled a total of 3,000 subjects, 1,500 in each study arm. Follow-up was conducted at 45 days post-MI. The following are the results of the trial:
Endpoints Medication 1 Medication 2 P-Value
Primary: death from cardiac causes 134 210 0.03
Secondary: hyperkalemia 57 70 0.4
What is the relative risk of death from a cardiac cause, expressed as a percentage? (Round to the nearest whole number.)
A. 64% (Correct Answer)
B. 42%
C. 72%
D. 36%
E. 57%
Explanation: ***64%***
- The **relative risk (RR)** is calculated as the event rate in the exposed group divided by the event rate in the unexposed (control) group.
- For cardiac death, the event rate for Medication 1 is 134/1500 = 0.0893, and for Medication 2 is 210/1500 = 0.14. Therefore, RR = 0.0893 / 0.14 = 0.6378.
- Expressing as a percentage: 0.6378 × 100 = 63.78%, which rounds to **64%**.
- This indicates that Medication 1 has 64% of the risk of cardiac death compared to Medication 2, representing a **36% relative risk reduction**.
*42%*
- This option is incorrect as it does not reflect the accurate calculation of **relative risk** using the provided event rates.
- A calculation error or conceptual misunderstanding of the relative risk formula would lead to this value.
*72%*
- This percentage is higher than the calculated relative risk, suggesting an incorrect application of the formula or a misinterpretation of the event rates.
- It does not represent the ratio of risk between the two medication groups for cardiac death.
*36%*
- This value represents the **relative risk reduction** (100% - 64% = 36%), not the relative risk itself.
- This is a common error where students confuse relative risk with relative risk reduction.
*57%*
- While closer to the correct answer, this value is not the precise result when rounding to the nearest whole number.
- Small calculation discrepancies or rounding at intermediate steps could lead to this slightly different percentage.
Question 22: A researcher is trying to determine whether a newly discovered substance X can be useful in promoting wound healing after surgery. She conducts this study by enrolling the next 100 patients that will be undergoing this surgery and separating them into 2 groups. She decides which patient will be in which group by using a random number generator. Subsequently, she prepares 1 set of syringes with the novel substance X and 1 set of syringes with a saline control. Both of these sets of syringes are unlabeled and the substances inside cannot be distinguished. She gives the surgeon performing the surgery 1 of the syringes and does not inform him nor the patient which syringe was used. After the study is complete, she analyzes all the data that was collected and performs statistical analysis. This study most likely provides which level of evidence for use of substance X?
A. Level 3
B. Level 1 (Correct Answer)
C. Level 4
D. Level 5
E. Level 2
Explanation: ***Level 1***
- The study design described is a **randomized controlled trial (RCT)**, which is considered the **highest level of evidence (Level 1)** in the hierarchy of medical evidence.
- Key features like **randomization**, **control group**, and **blinding (double-blind)** help minimize bias and strengthen the validity of the findings.
*Level 2*
- Level 2 evidence typically comprises **well-designed controlled trials without randomization** (non-randomized controlled trials) or **high-quality cohort studies**.
- While strong, they do not possess the same level of internal validity as randomized controlled trials.
*Level 3*
- Level 3 evidence typically includes **case-control studies** or **cohort studies**, which are observational designs and carry a higher risk of bias compared to RCTs.
- These studies generally do not involve randomization or intervention assignment by the researchers.
*Level 4*
- Level 4 evidence is usually derived from **case series** or **poor quality cohort and case-control studies**.
- These studies provide descriptive information or investigate associations without strong control for confounding factors.
*Level 5*
- Level 5 evidence is the **lowest level of evidence**, consisting of **expert opinion** or **animal research/bench research**.
- This level lacks human clinical data or systematic investigative rigor needed for higher evidence levels.
Question 23: A pharmaceutical company conducts a randomized clinical trial in an attempt to show that their new anticoagulant drug prevents more thrombotic events following total knee arthroplasty than the current standard of care. However, a significant number of patients are lost to follow-up or fail to complete treatment according to the study arm to which they were assigned. Several patients in the novel drug arm are also switched at a later time to a novel anticoagulant or warfarin per their primary care physician. All patients enrolled in the study are subsequently analyzed based on the initial group they were assigned to and there is a significant improvement in outcome of the new drug. What analysis most appropriately describes this trial?
A. Per protocol
B. As treated
C. Non-inferiority
D. Intention to treat (Correct Answer)
E. Modified intention to treat
Explanation: ***Intention to treat***
- **Intention-to-treat (ITT)** analysis includes all participants randomized to a treatment arm, regardless of whether they completed the intervention or switched treatments, reflecting a real-world scenario and preserving randomization benefits.
- This approach minimizes bias from **loss to follow-up** or **treatment crossovers** and provides a more conservative estimate of treatment effect.
*Per protocol*
- **Per-protocol analysis** only includes participants who completed the study exactly as planned without any deviations.
- This method is susceptible to **selection bias** because it excludes patients who may have experienced adverse events or treatment failures, potentially overestimating treatment efficacy.
*As treated*
- **As-treated analysis** analyzes patients based on the actual treatment received, rather than the treatment to which they were randomized.
- This approach can introduce **confounding** and selection bias, as patients who switch treatments may do so for reasons related to their prognosis or treatment response.
*Non-inferiority*
- A **non-inferiority trial** design aims to show that a new treatment is not appreciably worse than an active control, rather than proving superiority.
- This describes a **type of study design** or hypothesis, not an analysis method for handling patient data after randomization with non-adherence.
*Modified intention to treat*
- A **modified intention-to-treat (mITT)** analysis typically excludes a small, predefined group of patients from the ITT population, such as those who never received any study drug or were found to be ineligible after randomization.
- While similar to ITT, it involves specific exclusions that are not described in this scenario, where all randomized patients were analyzed **based on initial assignment**.
Question 24: A pharmaceutical company conducts a randomized clinical trial to demonstrate that their new anticoagulant drug, Aclotsaban, prevents more thrombotic events following total knee arthroplasty than the current standard of care. A significant number of patients are lost to follow-up, and many fail to complete treatment according to the study arm to which they were assigned. Despite these protocol deviations, the results for the patients who completed the course of Aclotsaban are encouraging. Which of the following analytical approaches is most appropriate for the primary analysis to establish the efficacy of Aclotsaban?
A. Intention-to-treat analysis (Correct Answer)
B. Sub-group analysis
C. Per-protocol analysis
D. As-treated analysis
E. Non-inferiority analysis
Explanation: ***Intention-to-treat analysis***
- **Intention-to-treat (ITT) analysis** is the gold standard for the **primary analysis in superiority trials** and includes all patients in the groups to which they were originally randomized, regardless of protocol deviations, loss to follow-up, or treatment discontinuation.
- ITT preserves **randomization balance**, prevents bias from selective dropout (patients may drop out due to adverse effects or lack of efficacy), and provides a **conservative, realistic estimate** of treatment effect in actual clinical practice.
- For **regulatory approval and establishing efficacy**, ITT is the most appropriate primary analysis method even when dropout rates are high, as it maintains the integrity of the randomized comparison.
*Per-protocol analysis*
- **Per-protocol analysis** includes only patients who completed the study exactly as planned without protocol deviations.
- While the encouraging results in completers are noted, per-protocol analysis can **introduce significant bias** by excluding patients who dropped out due to adverse events or lack of efficacy, potentially **overestimating treatment benefit**.
- Per-protocol is typically used as a **secondary/supportive analysis**, not the primary method for establishing superiority.
*As-treated analysis*
- **As-treated analysis** categorizes patients according to the treatment they actually received rather than their randomized assignment.
- This violates the principle of randomization and can introduce **confounding bias**, as actual treatment received may be influenced by prognostic factors.
*Sub-group analysis*
- **Sub-group analysis** evaluates treatment effects within specific patient subsets.
- This is **hypothesis-generating** rather than confirmatory and increases the risk of false-positive findings (multiple comparisons problem) unless pre-specified in the protocol.
*Non-inferiority analysis*
- **Non-inferiority analysis** tests whether a new treatment is not worse than control by more than a pre-specified margin.
- The goal here is to demonstrate **superiority** (better than standard care), not non-inferiority, making this approach inappropriate.
Question 25: A group of investigators have conducted a randomized clinical trial to evaluate the efficacy of adding a novel adenosine A1 receptor agonist to the standard anti-epileptic treatment in reducing the frequency of focal seizures. It was found that patients taking the combination regimen (n = 200) had a lower seizure frequency compared to patients taking the standard treatment alone (n = 200; p < 0.01). However, several participants taking the novel drug reported severe drowsiness. The investigators administered a survey to both the combination treatment group and standard treatment group to evaluate whether the drowsiness interfered with daily functioning using a yes or no questionnaire. Results are shown:
Interference with daily functioning Yes (number of patients) No (number of patients)
Combination treatment group 115 85
Standard treatment group 78 122
Which of the following statistical methods would be most appropriate for assessing the statistical significance of these results?
A. Paired t-test
B. Unpaired t-test
C. Chi-square test (Correct Answer)
D. Analysis of variance
E. Multiple linear regression
Explanation: ***Chi-square test***
- The **chi-square test** is appropriate for comparing **categorical data** (yes/no responses) between two or more independent groups.
- The data presented (number of patients endorsing "yes" or "no" for interference with daily functioning in two different treatment groups) perfectly fits this scenario.
*Paired t-test*
- A **paired t-test** is used to compare means of two related (or dependent) samples, such as measurements taken on the same subjects before and after an intervention.
- This scenario involves two independent groups, not repeated measures on the same subjects.
*Unpaired t-test*
- An **unpaired t-test** (also known as an independent samples t-test) is used to compare the means of two independent groups for a **continuous outcome variable**.
- Here, the outcome variable ("interference with daily functioning") is categorical (yes/no), not continuous.
*Analysis of variance*
- **ANOVA** is used to compare the means of **three or more independent groups** for a **continuous outcome variable**.
- This study involves only two groups and a categorical outcome, making ANOVA unsuitable.
*Multiple linear regression*
- **Multiple linear regression** is used to model the relationship between a **continuous dependent variable** and two or more independent variables (either continuous or categorical).
- The outcome variable in this case is categorical, not continuous, making linear regression inappropriate.
Question 26: A group of investigators conducted a randomized controlled trial to compare the effectiveness of rivaroxaban to warfarin for ischemic stroke prevention in patients with atrial fibrillation. A total of 14,000 participants were enrolled and one half was assigned to each of the cohorts. The patients were followed prospectively for 3 years. At the conclusion of the trial, the incidence of ischemic stroke in participants taking rivaroxaban was 1.7% compared to 2.2% in participants taking warfarin. The hazard ratio is calculated as 0.79 and the 95% confidence interval is reported as 0.64 to 0.97. If the study was conducted with a total of 7,000 participants, which of the following changes would most be expected?
A. Increased risk of selection bias
B. Decreased type I error rate
C. Decreased hazard ratio
D. Increased confidence interval range (Correct Answer)
E. Increased risk of confounding bias
Explanation: ***Increased confidence interval range***
- A smaller sample size (7,000 instead of 14,000) reduces the **precision** of the study's estimates, leading to a wider **confidence interval (CI)**.
- A wider CI reflects greater **uncertainty** around the true effect size of the intervention.
*Increased risk of selection bias*
- **Randomized controlled trials (RCTs)** inherently minimize selection bias by randomly assigning participants to treatment groups, regardless of sample size.
- The risk of selection bias is primarily addressed by the study design, not directly by the sample size if randomization is maintained.
*Decreased type I error rate*
- The **Type I error rate (alpha level)**, typically set at 0.05, is an a priori decision made by investigators and does not change based on sample size.
- A smaller sample size would likely **increase the Type II error rate** (failing to detect a true difference) due to reduced power.
*Decreased hazard ratio*
- The **hazard ratio (HR)** is a measure of the relative effect of the intervention on an outcome and is an estimate derived from the observed data.
- While a smaller sample size can lead to more variability in the HR estimate, it does not inherently mean the hazard ratio itself would decrease.
*Increased risk of confounding bias*
- **Randomization** in a well-conducted RCT helps to distribute known and unknown confounders evenly between study groups, regardless of sample size.
- The primary method to control for confounding is the study design (randomization), not the number of participants.
