Md2 Block1 Exam Prep Q Research

Front 1

The trial was inadequately designed because it was conducted only on children.

Back 1

This statement is false. Although the trial was conducted only on children, as long as the inferences are made about the effects of ciprofloxacin suspension on children, and no conclusions are drawn about another population (eg adults), there is no reason to describe the trial as having an inadequate design.

Hint 1

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 2

The trial was potentially biased because there was no control treatment.

Back 2

This statement is false. Ciprofloxacin suspension, the novel treatment under investigation, was compared to pivmecillinam tablets which may be regarded as the control treatment. A control group does not have to be a negative control (one receiving no active treatment). Hence this was a controlled trial.

Hint 2

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 3

The main outcome variable was the total number of stools for each patient in the study period.
Wrong answer.

Back 3

This statement is false. The main outcomes of interest were percentages of children exhibiting clinical or bacteriological success. The total number of stools was a secondary outcome.

Hint 3

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 4

The main effects of interest were the differences between the two treatments in the percentages of children who were judged clinically successful (15%) and biologically successful (10%).

Back 4

Right answer.
This statement is true.

Hint 4

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 5

As neither standard errors nor standard deviations has been quoted, there is no specification of the precision of the main effect of interest.

Back 5

Wrong answer.
This statement is false. Confidence intervals, which are derived using standard errors, provide information about the precision of the main effects of interest, namely the differences in the percentages of children who were clinically and bacteriologically successful. Thus some measurement of the precision of the main effect has been provided.

Hint 5

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 6

Since the difference between the two treatments in the percentages of children who were judged clinically successful was greater than that of the percentages judged biologically successful (15% compared to 10%), ciprofloxacin suspension would be preferred to pivmecillinam if the main concern was for clinical success.

Back 6

Wrong answer.
This statement is false. The results show that the percentage of children with clinical success who received ciprofloxacin was not significantly different from the percentage in those who received pivmecillinam (difference in percentages = 15.0%, P=0.10). However, the difference in terms of bacteriological success between the treatments (10.0%) was statistically significant (P=0.03). Thus, although the differences in the percentages was greater for clinical success, the only difference which was statistically significant was that which related to bacteriological success.

Hint 6

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 7

The only result quoted that achieved statistical significance at the 5% level was the comparison of the percentages of children who were bacteriologically successful.

Back 7

Right answer.
This statement is true.

Hint 7

Number needed to treat

Consider the following summary of the methods and findings of a study in a paper by Abdus Salam et al in the Lancet (1998; 352: 522-526).

Background Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. A randomized double-blind study was undertaken to test the effects of ciprofloxacin treatment in children with shigella dysentry.

Methods The efficacy and toxic effects of ciprofloxacin suspension (10mg/kg) every 12 h for 5 days, maximum individual dose 500mg) were compared with those of pivmecillinam tablets (15-20 mg/kg every 8h for 5 days, maximum individual dose 300mg). 143 children aged 2-15 years with dysentry of 72h or less duration were enrolled in the study. Patients stayed in hospital for 6 days, and were followed up 7, 30 and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentry on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful. Secondary endpoints of interest were duration of fever, duration of abdominal pain, and the total number of stools for each patient in the study period.

Statistical analysis Differences in proportions were tested with the Chi-squared test with continuity correction or Fisher's Exact test if the predicted size of any cell was five or less. Differences in continuous variables were assessed with Student's t-test or the Mann-Whitney U test otherwise. All tests of significance were two-tailed.

Findings 13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 of 60 patients who received ciprofloxacin and in 39 of 60 patients who received pivmecillinam (difference in percentages = 15.0%, 95% CI for difference = -0.7% to 30.8%, P=0.10). Treatment was bacteriologically successful in all of the patients who received ciprofloxacin, and in 54 of the patients who received pivmecillinam (difference in percentages = 10.0%, 95% for difference = 2.4% to 17.6%, P=0.03). Joint pain began in 18% of patients who received ciprofloxacin and 22% of patients who received pivmecillinam (P>0.2), and no patient had signs of arthritis. The median number of stools during the study was 35 in the ciprofloxacin group and 36 in the pivmecillinam group (P>0.2).

Interpretation Ciprofloxacin suspension and pivmecillinam had the same clinical efficacy in this trial. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. It can be concluded that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Front 8

he number-needed-to-treat for effectiveness is calculated as 1/(0.85-0.41).

Back 8

Right answer.
This statement is true. The NNT is calculated as 1/(0.85-0.41) = 1/(0.59-0.15)=2.27. So at least three patients will have to be treated in order that one extra person will respond, i.e. will improve by 50%.

Hint 8

Chapter 40, Question 2.
Number-needed-to-treat

In a randomized, placebo-controlled study of riboflavin for the prevention of migraine (Schoenen J et al. Neurology 1998; 50: 466-470), the authors reported that the proportion of patients who had 'responded' (improved by at least 50%) was 15% for placebo and 59% for riboflavin (P=0.002). The number-needed-to-treat for effectiveness was 2.3. Select all of the following statements which you believe to be true.

Front 9

The number-needed-to-treat for effectiveness is calculated as the reciprocal of the difference in the proportions of the two positive outcomes.

Back 9

Right answer.
This statement is true.

Hint 9

Chapter 40, Question 2.
Number-needed-to-treat

In a randomized, placebo-controlled study of riboflavin for the prevention of migraine (Schoenen J et al. Neurology 1998; 50: 466-470), the authors reported that the proportion of patients who had 'responded' (improved by at least 50%) was 15% for placebo and 59% for riboflavin (P=0.002). The number-needed-to-treat for effectiveness was 2.3. Select all of the following statements which you believe to be true.

Front 10

At least 2 patients need to be treated to prevent one person from getting a migraine.

Back 10

Wrong answer.
This statement is false. As the NNT=2.3, at least three patients are required in order that one extra person will improve by 50%.

Hint 10

Chapter 40, Question 2.
Number-needed-to-treat

In a randomized, placebo-controlled study of riboflavin for the prevention of migraine (Schoenen J et al. Neurology 1998; 50: 466-470), the authors reported that the proportion of patients who had 'responded' (improved by at least 50%) was 15% for placebo and 59% for riboflavin (P=0.002). The number-needed-to-treat for effectiveness was 2.3. Select all of the following statements which you believe to be true.

Front 11

At least 3 patients need to be treated to ensure that one extra person will be a responder.

Back 11

Right answer.
This statement is true.

Hint 11

Chapter 40, Question 2.
Number-needed-to-treat

In a randomized, placebo-controlled study of riboflavin for the prevention of migraine (Schoenen J et al. Neurology 1998; 50: 466-470), the authors reported that the proportion of patients who had 'responded' (improved by at least 50%) was 15% for placebo and 59% for riboflavin (P=0.002). The number-needed-to-treat for effectiveness was 2.3. Select all of the following statements which you believe to be true.

Front 12

he number-needed-to-treat is a measure of the statistical significance of the results of the trial.

Back 12

Wrong answer.
This statement is false. NNT is a measure of the clinical usefulness of the results of a trial, whereas the P-value is a measure of its statistical significance.

Hint 12

Chapter 40, Question 2.
Number-needed-to-treat

In a randomized, placebo-controlled study of riboflavin for the prevention of migraine (Schoenen J et al. Neurology 1998; 50: 466-470), the authors reported that the proportion of patients who had 'responded' (improved by at least 50%) was 15% for placebo and 59% for riboflavin (P=0.002). The number-needed-to-treat for effectiveness was 2.3. Select all of the following statements which you believe to be true.

Front 13

3
The main outcome variable was measured on a continuous scale.

Back 13

Wrong answer.
This statement is false. The main outcome variable was the proportion of individuals who had died by 28 days, which is measured on a categorical scale.

Hint 13

The summary of a double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock (Abraham E et al. Lancet 1998; 351: 929-933) is shown below.

Background: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock.

Methods: In a randomized, multicentre, double-blind placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.

Findings: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, P=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy, but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, P<0.001; day 28, P=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group.

Interpretation: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

Front 14

3
The main effect of interest was large.

Back 14

Wrong answer.
This statement is false. The effect of interest is the difference between the two groups in the percentages of individuals who had died by 28 days. It is not quoted but can be calculated as 42.8%-40.3%=2.5% Thus an additional 2.5% of the treated group remain alive at 28 days compared to the placebo group. This is not a large difference.

Hint 14

The summary of a double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock (Abraham E et al. Lancet 1998; 351: 929-933) is shown below.

Background: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock.

Methods: In a randomized, multicentre, double-blind placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.

Findings: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, P=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy, but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, P<0.001; day 28, P=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group.

Interpretation: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

Front 15

3
The main effect of interest was precise.

Back 15

Right answer.
This statement is true. Because of the large sample size, the standard error of the difference in the percentages dying is quite small and so the confidence interval for the difference in death rates between the two groups is quite narrow. The 95% CI is -2% to 7%, i.e. the improvement in survival rates could have been

Hint 15

The summary of a double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock (Abraham E et al. Lancet 1998; 351: 929-933) is shown below.

Background: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock.

Methods: In a randomized, multicentre, double-blind placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.

Findings: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, P=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy, but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, P<0.001; day 28, P=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group.

Interpretation: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

Front 16

At least 40 patients need to be treated in order to prevent one death from septic shock by 28 days.

Back 16

Right answer.
This statement is true. The number-needed-to-treat to prevent one death is calculated as 1/0.025 = 40.

Hint 16

The summary of a double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock (Abraham E et al. Lancet 1998; 351: 929-933) is shown below.

Background: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock.

Methods: In a randomized, multicentre, double-blind placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.

Findings: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, P=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy, but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, P<0.001; day 28, P=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group.

Interpretation: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.

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The authors assessment of the usefulness of TNF alpha MAb must be modified in light of the high rate of serious adverse events in the treated group.

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Wrong answer.
This statement is false. Whilst the number of adverse events in the treated group is high, it is also high in the placebo group. Therefore, the drug does not lead to a large proportion of adverse events that would otherwise be unexpected.

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The summary of a double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock (Abraham E et al. Lancet 1998; 351: 929-933) is shown below.

Background: Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40-70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor alpha (TNF alpha MAb) in the treatment of septic shock.

Methods: In a randomized, multicentre, double-blind placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7.5 mg/kg TNF alpha MAb (n=949) or placebo (0.25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days.

Findings: 382 (40.3%) of 948 patients who received TNF alpha MAb and 398 (42.8%) of 930 who received placebo had died at 28 days (95% CI -0.02 to 0.07, P=0.27). We found no association between therapy with TNF alpha MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNF alpha MAb therapy. Coagulopathy, but not other organ or system failures, was significantly decreased in the TNF alpha MAb group compared with placebo (day 7, P<0.001; day 28, P=0.005). Serious adverse events were reported in 55.2% of patients given placebo and 54.1% in the TNF alpha MAb group.

Interpretation: We did not find an improvement in survival after septic shock with TNF alpha MAb. Therapy not solely dependent on TNF alpha blockade may be required to improve survival.