Single subject trials as a research instrument in gastrointestinal pharmacology
L. G. Madsen,
P. Bytzer,
L. G. Madsen
Department of Medical Gastroenterology M, Glostrup University Hospital, Glostrup, Denmark
Search for more papers by this authorP. Bytzer
Department of Medical Gastroenterology M, Glostrup University Hospital, Glostrup, Denmark
Search for more papers by this authorL. G. Madsen,
P. Bytzer,
L. G. Madsen
Department of Medical Gastroenterology M, Glostrup University Hospital, Glostrup, Denmark
Search for more papers by this authorP. Bytzer
Department of Medical Gastroenterology M, Glostrup University Hospital, Glostrup, Denmark
Search for more papers by this author
Dr P. Bytzer, Department of Medical Gastroenterology M, Glostrup University Hospital, DK-2600 Glostrup, Denmark. E-mail: [email protected]
Abstract
The single subject trial is a randomized controlled trial carried out in the individual patient, and the result obtained is specific to the individual patient and the drug being investigated. This type of trial offers a supplement to traditional parallel group trials, especially in patients with heterogeneous disorders, often characterized by varying treatment responses and/or high placebo response rates. Pooled results from several individual single subject trials could extend the conclusions beyond the individual patient, and help to characterize a subset of responders to a specific treatment or clarify the heterogeneity of the disease.
The basic principles of the different single subject trial designs are described. Advantages and limitations are reviewed with a special focus on published trials in functional gastrointestinal disorders.
The single subject trial may be a valuable supplement to traditional drug treatment trials, either used as isolated trials in individual patients to determine optimal therapy, or in groups of patients to identify those with a uniform response to treatment. However, the lack of validation and reliability studies limits the value of the single subject trials presented so far.
References
- 1 Guyatt G, Sackett D, Adachi J, et al. A clinician’s guide for conducting randomized trials in individual patients. Can Med Assoc J 1988; 139: 497–503.
- 2 Johannessen T. Controlled trials in single subjects. 1 Value in clinical medicine. Br Med J 1991; 303: 173–4.
- 3 Sackett DL, Haynes R, Guyatt GH, Tugwell P. Deciding on the best therapy. In: Sackett DL, Haynes R, Guyatt GH, Tugwell P, eds. Clinical Epidemiology: A Basic Science for Clinical Medicine. Boston: Little, Brown and Co., 1991: 187–248.
- 4 Farup PG, Hovde O, Breder O. Are frequent short gastro- oesophageal reflux episodes the cause of symptoms in patients with non-ulcer dyspepsia responding to treatment with ranitidine? Scand J Gastroenterol 1995; 30: 829–32.
- 5 Farup PG, Larsen S, Ulshagen K, Osnes M. Ranitidine for non-ulcer dyspepsia. A clinical study of the symptomatic effect of ranitidine and a classification and characterization of the responders to treatment. Scand J Gastroenterol 1991; 26: 1209–16.
- 6 Larsen S, Farup P, Flaten O, Osnes M. The multi-crossover model for classifying patients as responders to a given treatment. Scand J Gastroenterol 1991; 26: 763–70.
- 7 Farup PG, Wetterhus S, Osnes M, Ulshagen K. Ranitidine effectively relieves symptoms in a subset of patients with functional dyspepsia. Scand J Gastroenterol 1997; 32: 755–9.
- 8 Johannessen T, Fjøsne U, Kleveland PM, et al. Cimetidine responders in non-ulcer dyspepsia. Scand J Gastroenterol 1988; 23: 327–36.
- 9 Kleveland PM, Larsen S, Sandvik L, et al. The effect of cimetidine in non-ulcer dyspepsia. Experience with a multi-cross-over model. Scand J Gastroenterol 1985; 20: 19–24.
- 10 Guyatt GH, Keller J, Jaeschke R, et al. The n-of-1 randomized controlled trial: clinical usefulness. Our three years experience. Ann Intern Med 1990; 112: 293–9.
- 11 Mahon J, Laupacis A, Donner A, Wood T. Randomised study of n of 1 trials versus standard practice. Br Med J 1996; 312: 1069–74.
- 12 Mahon JL, Laupacis A, Hodder RV, et al. Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice. Chest 1999; 115: 38–48.
- 13 Johannessen T, Petersen H, Kristensen P, et al. Cimetidine on-demand in dyspepsia. Experience with randomized controlled single-subject trials. Scand J Gastroenterol 1992; 27: 189–95.
- 14 Bytzer P, Hansen JM, Rune S, et al. Identifying responders to acid suppression in dyspepsia using a random starting day trial. Aliment Pharmacol Ther 2000; 11: 1485–94.
- 15 Senn S. Applying results of randomised trials to patients. N of 1 trials are needed. Br Med J 1998; 317: 537–8.
- 16 McLeod RS, Taylor DW, Cohen Z, Cullen JB. Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir. Lancet 1986; 1: 726–8.
- 17 Langer JC, Winthrop AL, Issenman RM. The single-subject randomized trial. A useful clinical tool for assessing therapeutic efficacy in pediatric practice. Clin Pediatr (Phila) 1993; 32: 654–7.
- 18 Magee LA & Redman CW. An N-of-1 trial for treatment of hyperemesis gravidarum. Br J Obstet Gynaecol 1996; 103: 478–80.
- 19 Bruera E, Schoeller T, MacEachern T. Symptomatic benefit of supplemental oxygen in hypoxemic patients with terminal cancer: the use of the N of 1 randomized controlled trial. J Pain Symptom Manage 1992; 7: 365–8.
- 20 Wiebe E. N of 1 trials. Managing patients with chronic fatigue syndrome: two case reports. Can Fam Physician 1996; 42: 2214–7.
- 21 Jaeschke R, Adachi J, Guyatt G, Keller J, Wong B. Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials. J Rheumatol 1991; 18: 447–51.
- 22 March L, Irwig L, Schwarz J, et al. N of 1 trials comparing a non-steroidal anti-inflammatory drug with paracetamol in osteoarthritis. Br Med J 1994; 309: 1041–5.
- 23 Chatellier G, Day M, Bobrie G, Menard J. Feasibility study of N-of-1 trials with blood pressure self-monitoring in hypertension. Hypertension 1995; 25: 294–301.
- 24 Irvine EJ, Lumb B, Gaebel K, Collins SM. A new study design explains lack of treatment efficacy in irritable bowel syndrome (IBS). Gastroenterology 1993; 104: A526–A526(Abstract).
- 25 Haines DR & Gaines SP. N of 1 randomised controlled trials of oral ketamine in patients with chronic pain. Pain 1999; 83: 283–7.
- 26 Kent MA, Camfield CS, Camfield PR. Double-blind methylphenidate trials: practical, useful, and highly endorsed by families. Arch Pediatr Adolesc Med 1999; 153: 1292–6.
- 27 Guyatt GH, Heyting A, Jaeschke R, et al. N of 1 randomized trials for investigating new drugs. Controlled Clin Trials 1990; 11: 88–100.
- 28 Lashner BA, Hanauer SB, Silverstein MD. Testing nicotine gum for ulcerative colitis patients. Experience with single-patient trials. Dig Dis Sci 1990; 35: 827–32.
- 29 Privitera MD, Treiman DM, Pledger GW, et al. Dezinamide for partial seizures: results of an n-of-1 design trial. Neurology 1994; 44: 1453–8.
- 30 Denburg SD, Carbotte RM, Denburg JA. Corticosteroids and neuropsychological functioning in patients with systemic lupus erythematosus. Arthr Rheum 1994; 37: 1311–20.
- 31 Molloy DW, Guyatt GH, Standish T, et al. Effect of a new nootropic agent, CGS 5649B, on cognition, function, and behavior in dementia. J Gen Intern Med 1993; 8: 444–7.
- 32 Böllert F, Paton J, Marshall T, et al. Recombinant DNase in cystic fibrosis: a protocol for targeted introduction through n-of-1 trials. Eur Respir J 1999; 13: 107–13.
- 33 Ottenbacher KJ. Interrater agreement of visual analysis in single-subject decisions: quantitative review and analysis. Am J Ment Retard 1993; 98: 135–42.
- 34 Keller JL, Guyatt GH, Roberts RS, Adachi JD, Rosenbloom D. An N of 1 service: applying the scientific methods in clinical practice. Scand J Gastroenterol Suppl 1988; 147: 22–9.
- 35 Guyatt GH, Juniper EF, Walter SD, Griffith LE, Goldstein RS. Interpreting treatment effects in randomised trials. Br Med J 1998; 316: 690–3.
- 36 Spiegelhalter DJ. Statistical issues in studies of individual response. Scand J Gastroenterol Suppl 1988; 147: 40–5.
- 37 Johannessen T, Fosstvedt D, Petersen H. Combined single subject trials. Scand J Prim Health Care 1991; 9: 23–7.
- 38 Zucker DR, Schmid CH, McIntosh MW, et al. Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J Clin Epidemiol 1997; 50: 401–10.
Citing Literature
