Clinical Trials in Conventional and Complementary Medicine

1. Clinical Trials in Conventional and Complementary Medicine Philip Prescott Emeritus Professor of Statistics Mathematical Sciences University of Southampton 17th October 2018

2. Outline • A problem that prompted more structure for clinical trials. • The phases in the development of new treatments. • Where the statistician has input into a clinical trial. • Some examples of clinical trials in a) conventional medicine b) complementary medicine

3. A wonder drug! • More than 60 years ago, Thalidomide was launched by Grünenthal on 1st October 1957. • It had been shown to act as an effective tranquiliser and painkiller and was proclaimed as a "wonder drug" for insomnia, coughs, colds and headaches. • It was also found to be effective in inhibiting morning sickness, and so thousands of pregnant women took the drug to relieve their symptoms.

4. A problem drug! • Thalidomide was sold in a number of countries across the world from 1957 until 1961. • It was withdrawn from the market after being found to be a cause of birth defects in what has been called "the biggest medical tragedy of modern times". • Estimates range from 10,000 to 20,000 worldwide victims of the drug • http://en.wikipedia.org/wiki/Thalidomide

5. Development phases for a new drug. In Phase I trials, researchers test an experimental drug or treatment in a small group of people, often 8 or 12 healthy men who are paid to take part in the study. The main aim of these ‘first time into man’ trials is to determine a safe dosage range and to identify any side effects.

6. The Drug Trial That Went Wrong: What Happened To The Infamous ‘Elephant Men’ from 2006 About 12 years ago, eight healthy young men took part in a clinical trial of an experimental leukaemia drug known as TGN1412. The drug, which manipulated the immune system, had been successfully tested on monkeys although never on humans. But what should have been a routine clinical trial at an independent clinic at north west London’s Northwick Park Hospital, soon spiralled into one of the most infamous medical emergencies in recent British history.

7. What happened next? Within an hour of receiving the drug, six of the volunteers had been rushed to intensive care where they were fighting for their lives. The other two had received a placebo. This combination of symptoms saw the men’s temperatures soar, their organs fail, and some of their bodies swelled severely. “It was all manic, everything was happening at once, they were vomiting, they were screaming in pain, people fainting.”

8. What went wrong? “This was treated as a crime scene. Something could have been tampered with, sabotaged, poisoned. They might have been the victims of foul play.” Parexel, the company which ran the clinic where the drug trial was carried out, was found to have acted within its protocols in an interim review by the Medicines and Healthcare products Regulatory Agency. A final report said the company had not been clear about what was a safe dose to start testing on humans and also said that the drug should have been tested on one person at a time.

9. Single ascending dose escalation in healthy subjects NOMINAL DOSES SHOWN, P = placebo, A to F are ascending active doses of IMP (investigational medicinal product); In each cohort, 2 subjects receive P, 6 receive IMP. Guidelines for Phase I clinical trials 2018 edition. ABPI

10. Development phases for a new drug. In Phase II trials, the experimental study drug or treatment is given to a larger group of patients (100-300) to see if it is effective and to further evaluate its safety. In Phase III trials, the experimental study drug or treatment is given to large groups of patients (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

11. Phase II and III trials Controlled: Trial drug is compared with at least one other treatment (standard or placebo). Randomised: Patients are allocated to the specific treatment (or treatment sequence) at random to avoid bias. Blinded: Patients and investigators do not know which treatment is being taken.

12. Clinical Trial Protocol • The Trial Protocol is a complete specification of the proposed procedures for carrying out a clinical trial. • This is the most important document associated with the trial since it must be submitted to the various ethics committees for approval before a trial can be carried out. • Once approved, the Protocol forms the basis of exactly what can and cannot be done. • The complete documentation of the trial forms part of the submission to the regulatory authority for approval of the drug for medical use.

13. The structure of a Protocol (1) • 1. General objectives of the study, description of the medical issues and background to the topic. • 2. Specific objectives of the study. • 3. Patient selection criteria – inclusion and exclusion criteria. • 4. Treatment schedules, dose levels, administration methods, placebos. • 5. Patient evaluation, identification of primary and secondary variables. • 6. Trial design: parallel group, cross-over, factorial design. • 7. Randomisation of patients and administration of treatments, blindness.

14. The structure of a Protocol (2) • 8. Patient consent. • 9. Power study to determine the trial size. • 10. Design of case record forms and data entry methods. • 11. Monitoring of the progress of the study, visits to investigators, collection of data. • 12. Handling of protocol violators. • 13. The statistical analysis plan gives explicit details of all statistical methods to be employed to analyse the data, details of transformations, tests, estimation methods. • 14. Administrative responsibilities.

15. Treatment period Baseline assessments Post-treatment assessments Trial designs • Parallel group experiments: Simple comparative experiments involving allocating patients to one of two or more groups, with each group receiving a specific treatment. Group 1 (n1 patients) – treatment A Group 2 (n2 patients) – treatment B

16. Treatment period 2 Treatment period 1 Post-treatment assessments Baseline assessments Trial designs • Cross-over experiments: Experiments where a group of patients is allocated to a particular sequence of treatments. The experiment involves two or more different treatment sequences. The simplest form of cross-over experiment is the two-period, two-treatment, two-sequence cross-over, also known as a A-B/B-A cross-over. Group 1 (n1 patients) – treatment A followed by B Group 2 (n2 patients) – treatment B followed by A

17. Trial designs • Factorial experiments: Experiments where two or more factors with two or more levels are included. For example, treatments (A or B) could be administered either by tablet or liquid, giving the structure below. Treatment: A B Administration: tablet liquid tablet liquid Group: 1 2 3 4 Treatments are compared using (1 + 2) vs (3 + 4) Administrations compared using (1 + 3) vs (2 + 4) Interaction examined using (1 + 4) vs (2 + 3)

18. Statistical Analyses • Simple t-tests (or non-parametric test) for comparison of means (or medians). • Analysis of variance or covariance for comparison of means with adjustments for covariates. • Repeated measures (longitudinal modelling) for assessments taken at several time periods.

19. Some examples of clinical trials Conventional medicine: 1. Parallel group – treatment of constipation in adults 2. AB/BA Cross Over – faecal fat in children with cystic fibrosis 3. Multi-period Cross over – Pre-Menstrual Syndrome Complementary Medicine: 1. Parallel group – Acupuncture for neck pain 2. 3 x 3 factorial design – Acupuncture for osteoarthritis 3. Factorial design – Homeopathy for rheumatoid arthritis

20. An open, randomised parallel group study of Lactulose (Duphalac) versus Ispaghula (Fybogel Orange) in the treatment of chronic constipation in adults • Study design: 107 patients were randomised to receive either Lactulose (n = 53) or Ispaghula (n = 54) for the treatment of their constipation over a period of 4 weeks. • Primary variables: the frequency of bowel movementseach week over the treatment period and a motion consistency score. • Reference: Rouse, Mahapatra, Atkinson and Prescott, British Journal of Clinical Practice, 1991, 45 (1), 28-30.

21. 8 Ispagula Number of bowel movements Lactulose 6 2 4 0 0 2 4 3 1 Weeks Frequency of bowel movements Mann-Whitney-test at 4 weeks indicated no significant difference between median number of bowel movements for the two groups

22. 16 Ispagula Consistency score Lactulose 12 4 8 0 0 2 1 3 4 Weeks Motion consistency scores t-test at 4 weeks indicated no significant difference between the mean motion consistency scores for the two groups

23. Where is your pancreas?

24. Pancreas The pancreas is a small flat organ (about 18-25 cm long) that is located behind the stomach and sits close to the duodenum. It is connected to the duodenum via a tube called the pancreatic duct. The pancreas has two main functions It is the source of powerful digestive enzymes required to chemically break down fats, carbohydrates and proteins. The hormone insulin is made by the pancreas - insulin helps to balance blood sugar levels in the body

25. High dose treatment for children with cystic fibrosis • Children with cystic fibrosis have a deficiency of pancreatic enzymes resulting in low fat absorption. • Study design: A two-period, two-treatment, randomised, double-blind, cross-over trial comparing double-strength Nutrizym 22 (A) with standard low-strength Nutrizym GR(B) in children at Great Ormond Street Hospital. • At the start of the study 22 patients were randomised to either A-B or B-A. • Primary variable: faecal fat excretion. Reference: Shah, Dinwiddie, Madge, Prescott and Hudson, European Journal of Paediatrics, 1993, 152, 763-764.

26. Questions. How many capsules did each child take and how was the double-blind feature of the trial achieved? • All children were initially taking the standard treatment Nutrizym GR and their dose requirement was deduced from a two-week run-in period. • During the trial each child was given two bottles and told to take 50% of their dose from each bottle. • During the Nutrizym 22 period one bottle contained Nutrizym 22 capsules and the other bottle contained matching placebo capsules.

27. Faecal fat excretions. Although faecal fat excretions were lower for both Nutrizym 22 periods, the treatment difference was not significant.

28. Problems with A-B/B-A cross-over designs. • The analysis of a cross-over design should include an assessment of any interaction between treatments and periods. • A significant interaction could be the result of a carry-over of the effect of the first treatment into the second period. In this case, the design cannot be adequately analysed. • Introduction of a wash-out period might not be appropriate. • If carry-over is present, the analysis must be based on the first period only, i.e. a parallel group design probably with fewer patients than required by a power calculation.

29. A cross-over design with more than two treatment periods. • Study design: a two-treatment, four-period, double-blind, randomised, placebo-controlled trial of dydrogesterone in patients with pre-menstrual syndrome. • Primary variable: Menstrual distress questionnaire (MDQ)- a set of 47 symptoms on 6-point scales giving 8 symptom clusters reflecting pain, concentration, behavioural change, etc. References: Sampson and Prescott, Br. J. of Psych., 1981, 138, 399-405. Sampson, Heathcote, Wordsworth, Prescott and Hodgson, Br. J. of Psych., 1988, 153, 232-235.

30. Structure for a four-period cross-over design balanced for carry-over effects. Each patient receives each treatment during two periods. Each treatment appears twice in each period. Each treatment is followed by both treatments three times. We used 16 replicates of this design for 64 patients.

31. Complementary and Alternative Medicine (CAM) • Complementary Medicine Research Unit • School of Medicine, University of Southampton • Director: Professor George Lewith • Investigators: • Acupuncture: Dr. Peter White, Dr. Val Hopwood, • Homeopathy: Dr. Sarah Brien • CAM use in Cancer Studies: Dr. Felicity Bishop

32. Trials using Acupuncture for pain relief • How do you set up a suitable trial to investigate whether acupuncture can relieve pain? • The trial should be randomised and controlled. • What is a suitable placebo? • Is blindness to treatment possible?

33. Tens Machine as an alternative (placebo) to Acupuncture • MINI-TENS 2 - Dual Channel Tens Machine • As used within the National Health Service (NHS)   • Dual Channel - uses 4 electrode pads at once. • Very Simple Operation. • Unique design to stop accidental movement of controls. • New style super tough case.  • Extended 5 year warranty • Burst, constant & modulation modes. • Variable pulse rate 2Hz - 150Hz. • Variable pulse width 30µs - 260µs

34. Comparison of acupuncture and tens machine (placebo) for neck pain. • Study Design: A randomised, placebo-controlled, parallel group trial with 1-year follow-up. 135 patients, aged 18 to 80 years who had chronic mechanical neck pain, were randomly assigned to receive 8 applications over 4 weeks with acupuncture or with mock tens machine. • The primary outcome: pain one week after treatment (week 5), according to a visual analogue scale (VAS). 124 patients completed the primary end point. Ref: White, Lewith, Prescott and Conway, Annals of Internal Medicine, 2004, 141, 911-919.

35. Baseline characteristics: • Both groups contained just over 50% females with overall mean age of about 53 years. Initial pain scores were slightly lower in the acupuncture group, 49.6 mm compared with 54.1 mm on 100 mm VAS. X No pain Extreme pain Visual analogue scale

36. Mean pain scores for Acupuncture and Mock Tens machine (Placebo) Baseline Week 5 comparison

37. Mean pain scores for Acupuncture and Mock Tens machine (Placebo) Baseline Initial analysis: ANCOVA on week 5 pain scores, adjusting for baseline. Week 5 comparison

38. Mean pain scores for Acupuncture and Mock Tens machine (Placebo) Baseline Initial analysis: ANCOVA on week 5 pain scores, adjusting for baseline. Week 5 comparison Longitudinal analysis, adjusting for baseline characteristics including hospital, baseline analgesic use, duration of problem, age, gender and baseline pain, indicated a general improvement for both groups but a significantly greater improvement for the acupuncture group (p = 0.01).

39. Placebo needles for acupuncture studies Placebo needle and verum needle have to be applied in the same manner: 1. Locate and disinfect the acupoint 2. Apply the ring at the acupoint (fig. 1) 3. Cover and fix the ring with the plaster (fig. 2) 4. Stick the needle through the plaster inside the ring (fig 3) The verum needle will penetrate the skin and has to be moved into deeper tissues until patients reaction will indicate DEQI. As soon as the placebo needle touches the skin, the handle of the needle has to be pushed over the needle (fig. 4). After treatment time (20 mins) the placebo needle has to be removed quickly gripping it at the needle, not at the handle.

40. Needle handle Needle handle Needle handle Needle Needle Plaster Plastic ring Plastic ring Plastic ring Plaster Plaster Skin surface Skin surface Skin surface Needle Streitberger Placebo-Needle Needle touching the skin Real acupuncture needle penetrating the skin Placebo-needle retracting into the handle

41. A randomised, single-blind, 3 x 3 factorial design. • Study design: Patients aged between 18 and 80 with chronic/stable pain, predominantly from a single joint (hip/knee) are allocated to one of 3 acupuncturists, to receive one of 3 treatments (real acupuncture (RA), with Streitberger needles (SN) and mock electrical stimulation (MES) as placebo controls). • Primary variable: Pain as measured on VAS. • Ref: Peter White, Felicity L Bishop, Phil Prescott, Clare Scott, Paul Little, and George Lewith, Practice, Practitioner or Placebo? A multifactorial, mixed methods RCT of acupuncture. PAIN 153, 455–462, 2012.

42. 221 randomised to treatment Practitioner 1 n=112 Practitioner 2 n=50 Practitioner 3 n=59 RA n=22 SN n=21 MES n=16 RA n=30 SN n=39 MES n=43 RA n=22 SN n=13 MES n=15 Consort diagram RA: 74, SN: 73, MES: 74

43. 6 0 5 5 S h a m e l e c t r i c a l s n a e M n i a 5 0 P 4 5 A c u p u 0 1 2 3 4 5 W e e k Mean pain scores from pre-treatment to week 5 by treatment. S t r e i t b e r g e r n e e d l e s n c t u r e

44. Mean Pain scores from pre-treatment to week 5 by practitioner

45. Conclusions • Real acupuncture and Streitberger needles reduced pain more than the mock electrical stimulation. • Pain reduction was greater with Practitioner 3 than practitioner 2 and almost significantly lower than practitioner 1

46. Homeopathy study Study design: 5 groups with three treatments (individualised homeopathy, complex homeopathy and placebo) and two consultation types (no consultation and consultation). A 3 x 2 factorial with one combination not available. Randomisation groups: Group 1 = Consultation (1) – individual (1) Group 2 = Consultation (1) – complex (2) Group 3 = Consultation (1) – placebo (3) Group 4 = No consultation (2) – complex (2) Group 5 = No consultation (2) – placebo (3) Primary outcomes:ACR 20% improvement (ACR20) criteria and patient monthly global assessment (GA). Secondary outcomes: 28-joint DAS (Disease Activity Score)

47. Conclusions. 1. No significant differences were observed for either primary outcome for either of the factors involved in the trial. • There was no clear effect due to remedy type. • Receiving a homeopathic consultation significantly improved DAS-28 [mean difference 0.623; 95% CI 0.1860, 1.060; P = 0.005; effect size (ES) 0.70]. Overall conclusion: Homeopathic consultations but not homeopathic remedies are associated with clinically relevant benefits for patients with active but relatively stable RA.

48. Rheumatology 13 November 2010 Homeopathy has clinical benefits in rheumatoid arthritis patients that are attributable to the consultation process but not the homeopathic remedy: a randomized controlled clinical trial Sarah Brien, Laurie Lachance, Phil Prescott, Clare McDermott and George Lewith. Rheumatology, 49, November, 2010.

49. Report in Sunday Telegraph 14 November 2010