Asking Simple Questions and Doing Cutting Edge Clinical Trials

1. Asking Simple Questions and Doing Cutting Edge Clinical Trials Sidhartha Tan, MD Clinical Professor Department of Pediatrics NorthShore University HealthSystem and University of Chicago

2. The Problem with Doing Clinical Trials • Pubmed search for “Saudi Arabia neonatology” yields 4 publications in 2010. • “Saudi Arabia and newborn” 48 in 2010. • It is not too difficult if you ask the right questions and do the correct methodology.

3. Clinical Trials • Harder to do than bench research. • All big clinical trials in Neonatology want Neurodevelopmental follow up, but it takes too long. • Phase III trials take a huge number of subjects. • One NICU has few patients per year. • Takes a lot of time and effort.

4. Scientist I question everything Evangelical I question nothing Fundamentalist I answer everything

5. Ask Simple Questions • There is a lot unknown in neonatology. • Witness the diversity of opinion of how each neonatologist and NICU differs from one another. • Even well established fields generate a lot of questions.

6. Ask the Right Question • Question could be answered by a literature search. ALWAYS DO A LITERATURE SEARCH FIRST. • The best place to find simple questions is the end of discussion of manuscripts. • Ask an expert who may have an opinion that is the basis of experience. • A clinical trial may already have been done, e.g. pharmaceutical company that developed the drug in question.

7. Doctor Knows Best

8. Ask the Right Question • Seek the simplest variable. • Ask a specific question. • Do not try to ask a global question. • The more variables, the more complicated the study.

9. Ask the Right Question • Ask questions that can be answered. • Can the right controls be obtained? • Do not fall into the trap of only comparing with existing therapy.

10. Ask the Right Question • A good starting point is to look at existing protocols in the NICU. • Now you want to improve the protocols. • Pick one question, one variable to test, and divide your NICU into half (time, space, caretakers).

11. Avoiding Bias • Blinding • Randomization • Time, space, caretakers

12. Single blind Patient blinded • Double blind Patient and caretaker blinded • Triple blind Patient and caretaker and support staff blinded

13. Randomization • Good way to avoid bias. • Sometimes have to consider what statistical test is undertaken at the end to consider what type of randomization.

14. You are only as good as your controls

15. Hypothesis 1 A lower oxygen saturation would reduce the incidence of bad outcome among extreme premature infants

16. Hypothesis 2 Primary peritoneal drainage improves survival 90 days postoperatively as compared with laparotomy and resection for very-low-birth-weight (less than 1500 g) premature infants with perforated necrotizing enterocolitis

17. The Right Controls • What controls would you use? • A starting point is the old way of doing things. • So simple straightforward testing of a new target versus the old way of doing things.

18. Randomization • What randomization would you use? • If use simple randomization, in a small study may not get equal numbers in both groups • So use block randomization. Blocks of Treatment A and Treatment B. • Block of 4: 6 combinations of AABB, ABBA, BBAA, BAAB, ABAB, BABA. • At end of each block, evenly balanced groups

19. Randomization • How about different age groups? • Separate blocks for different age groups. • Note the decision for grouping matters. If group less than 30 weeks and >30 weeks, stratified block randomization will not get equivalent groups in 28 and 29 weeks gestation.

20. Randomization Strategies • Date of birth. • Order of entry into NICU. • Day of week admitted. • Odd, even hour born. • Room number. Are these strategies appropriate?

21. Single blind Patient blinded • Double blind Patient and caretaker blinded • Triple blind Patient and caretaker and support staff blinded

22. Blinding Problem • Oxygen saturation is available to everyone. • How will you blind the caretakers testing Hypothesis 1? • Different populations may be favored by old way of doing things. • How do you blind laparotomy/peritoneal drainage in Hypothesis 2?

23. 1 2

24. Support Trial for Target Oxygen Saturation • Low oxygen saturation : 85-89%. • Control oxygen saturation: 91-95%. • Infants born 24 0/7 to 27 6/7 weeks. • Permuted-block randomization • Stratification according to center and gestational age group. • 24 0/7 to 25 6/7 and 26 0/7 to 27 6/7 weeks.

25. Support Trial for Target Oxygen Saturation Composite outcome of severe retinopathy of prematurity or death Choose endpoint carefully.

26. Peritoneal Drainage vs Laparotomy • Target: Peritoneal Drainage • Control: Laparotomy with intestinal resection • Infants <1500 g. • Permuted-block randomization • Stratification according to birth weight. • <1000 g and 1000-1499 g.

27. Peritoneal Drainage vs Laparotomy Primary Outcome: Survival

28. The Right Controls • Blinding was maintained in SUPPORT with the use of electronically altered pulse oximeters that showed saturation levels of 88 to 92% for both targets • For example, a reading of 90% corresponded to actual 87% in the group assigned to lower oxygen saturation (85 to 89%) and 93% in the group assigned to higher oxygen saturation (91 to 95%).

29. Difficulty in Controls • In the NEC trial, laparotomy patients could undergo a second laparotomy. • Peritoneal drainage patients could undergo a second drain and protocol allowed laparotomy. Early laparotomy was allowed for but “did not encourage”. Laparotomy allowed for stricture or bowel obstruction.

30. Protection of Patients • In SUPPORT, Oxygen-saturation reading gradually changed and reverted to actual (nonskewed) values when it was less than 84% or higher than 96% in both treatment groups. • In NEC trial, repeat procedures were allowed. Data and monitoring safety board analyzed data at mid-point.

31. Outcome of Support Trial

32. Outcome of Support Trial Best of intentions are not enough

33. Single blind Patient blinded • Double blind Patient and caretaker blinded • Triple blind Patient and caretaker and support staff blinded

34. Verify Blinding • Outside person not connected or affected by study needs to check if blinding is working.

35. Outcome of NEC Trial • Mortality not different between Peritoneal Lavage (34.5%) and Laparotomy (35.5%). • Dependence on TPN at 90 days not different (47.2% vs 40%). • No difference in hospital stay (126±58 vs 116±56 days).

36. Conclusions • Ask a simple question. • Think about what is achievable. • Choose the end-points carefully. • Choose the correct controls. • Check the statistical test to be used. • Randomization to avoid bias. • Blind all caretakers.

37. Epidemiological Studies • Randomized clinical trial • Cohort study • Case-control study • Case series • Case reports

38. RCT Advantages Disadvantages • Most convincing design • Only design that controls for unknown/unmeasurable confounders • Most expensive • Artificial • Logistically most difficult • Ethical objections

39. Cohort Study Advantages Disadvantages • Can study multiple outcomes • Can study uncommon exposures • Selection bias less likely • Unbiased exposure data • Incidence data available • Possibly biased outcome data • More expensive • If done prospectively may take years to complete • Need to make sure that cases and controls did not have the outcome to begin with.

40. Case-Control Study Advantages Disadvantages • Can study multiple outcomes • Can study uncommon exposures • Logistically easier and faster • Less expensive • Well suited to rare and long latency diseases • Rapid to initiate and conduct. • Control selection problematic • Possibly biased exposure data • Always retrospective. • As good as the data base: Beware of “Garbage in, garbage out”.

41. Another case?

42. Observation About a fifth of apnea occur with gastroesophageal reflux.

43. Hypothesis Gastroesophageal reflux would prolong duration of apnea when they occur together

45. Methods • an overnight bedside cardiorespiratory monitoring study done on patients with GER with or without apnea. • respiratory inductance plethysmography, • oxygen saturation (SaO2), • pulse wave form, • heart rate • esophageal pH (electrode confirmed by X-ray) • Retrospective study • Scoring done by counting apnea (respiratory arrest >10 sec) 30 seconds before, during or after episode of GER.

46. Study Characteristics • Controls? • Blinding? • Randomization?

47. Study Characteristics • Controls: Own controls. Comparing 30 sec period before GER to during and after GER. • Blinding: Scorer could not be blinded to GER. • Randomization: None.

48. Results Apnea>15 sec Apnea>10 sec Before During After Before During After 83 of 119 infants 27 of 119 infants No difference

49. Type II error • Post hoc analysis: Power of 80% to detect increaseof 25% of apnea in response to GER with α=0.05 for 27 patients. • The power of a hypothesis test is the probability of rejecting the null hypothesis when the null hypothesis is false. • The 3 requisites of power. • Was the effect size clinically meaningful? • Standard deviation • Number of patients that can be enrolled.

50. Results S.D. 27 of 119 infants No difference