Archives of Dermatological Research

, Volume 304, Issue 9, pp 707–717

Placebo response in relation to clinical trial design: a systematic review and meta-analysis of randomized controlled trials for determining biologic efficacy in psoriasis treatment

  • Sonia A. Lamel
  • Kaley A. Myer
  • Naji Younes
  • James A. Zhou
  • Hilda Maibach
  • Howard I. Maibach
Original Paper

Abstract

There is a need to better define how the efficacy of investigational drugs is affected by study design, implementation, and placebo responses in randomized controlled trials. The improvements observed in placebo groups within trials examining psoriasis treatments may be partially due to study design and implementation. We conducted a systematic review of randomized placebo-controlled trials assessing the efficacy of biologics in the treatment of psoriasis and psoriatic arthritis to evaluate rates of placebo and active drug responders to determine specific factors within study design that may contribute to placebo responses. We included randomized, placebo-controlled trials of etanercept, infliximab, adalimumab, golimumab, ustekinumab, alefacept, and efalizumab that utilized Psoriasis Area Severity Index as an outcomes measure. We compared the rates of the placebo treatment arm versus the active drug arm achieving 75 % improvement of Psoriasis Area Severity Index. 31 trials involving 8285 active treatment and 3999 placebo patients were included. Rates of placebo responders (4.14 %) were significantly lower than active drug responders (48.4 %). The overall odds ratio calculated was 23.94 (p < 0.0001, 95 % CI 16.02–35.76). Binomial regression models showed that treatment indication, randomization fraction, a PASI inclusion requirement, and the time period of outcomes measure documentation affect placebo responses. Placebo responses seen in randomized controlled trials evaluating biologics in the treatment of psoriasis are not likely due to a physiologic mechanism, but may be secondary to chronic disease course and factors of clinical trial design and implementation.

Keywords

Randomized controlled trial Study design Placebo effect Placebo response Psoriasis Psoriatic arthritis 

Abbreviations

BIW

Every other week

CART

Classification and tree

EOW

Every other week

IGA

Investigator global assessment

IM

Intramuscularly

IV

Intravenously

PASI

Psoriasis Area Severity Index

PASI 75

75 % improvement in Psoriasis Area Severity Index

PGA

Physician global assessment

PsA

Psoriatic arthritis

PsO

Psoriasis

QIW

Four times weekly

QW

Every week

RCT

Randomized controlled trial

SC

Subcutaneously

TNF

Tumor necrosis factor

References

  1. 1.
    Antoni C, Krueger GG, de Vlam K, Birbara C, Beutler A, Guzzo C, Zhou B, Dooley LT, Al Kavanaugh (2005) Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann Rheum Dis 64:1150–1157PubMedCrossRefGoogle Scholar
  2. 2.
    Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J (2005) Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 52:1227–1236PubMedCrossRefGoogle Scholar
  3. 3.
    Asahina A, Nakagawa H, Etoh T, Ohtsuki M (2010) Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a phase II/III randomized controlled study. J Dermatol 37:299–310PubMedCrossRefGoogle Scholar
  4. 4.
    Beecher HK (1955) The powerful placebo. J Am Med Assoc 159:1602–1606PubMedCrossRefGoogle Scholar
  5. 5.
    Berth-Jones J, Grotzinger K, Rainville C, Pham B, Huang J, Daly S, Herdman M, Firth P, Hotchkiss K (2006) A study examining inter- and intrarater reliability of three scales for measuring severity of psoriasis: psoriasis Area and Severity Index, Physician’s Global Assessment and Lattice System Physician’s Global Assessment. Br J Dermatol 155:707–713PubMedCrossRefGoogle Scholar
  6. 6.
    Bingel U, Colloca L, Vase L (2011) Mechanisms and clinical implications of the placebo effect: is there a potential for the elderly? A mini-review. Gerontology 57:354–363PubMedCrossRefGoogle Scholar
  7. 7.
    Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB (2001) Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357:1842–1847PubMedCrossRefGoogle Scholar
  8. 8.
    Colloca L, Miller FG (2011) How placebo responses are formed: a learning perspective. Philos Trans R Soc Lond B Biol Sci 366:1859–1869PubMedCrossRefGoogle Scholar
  9. 9.
    Cook CH, Centner RL, Michaels SE (1979) An acne grading method using photographic standards. Arch Dermatol 115:571–575PubMedCrossRefGoogle Scholar
  10. 10.
    Dubertret L, Sterry W, Bos JD, Chimenti S, Shumack S, Larsen CG, Shear NH, Papp KA (2006) Clinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial. Br J Dermatol 155:170–181PubMedCrossRefGoogle Scholar
  11. 11.
    Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56:455–463PubMedCrossRefGoogle Scholar
  12. 12.
    Enck P, Klosterhalfen S, Weimer K, Horing B, Zipfel S (2011) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc Lond B Biol Sci 366:1889–1895PubMedCrossRefGoogle Scholar
  13. 13.
    Enck P, Klosterhalfen S, Zipfel S (2011) Novel study designs to investigate the placebo response. BMC Med Res Methodol 11:90PubMedCrossRefGoogle Scholar
  14. 14.
    Feldman SR, Gordon KB, Bala M, Evans R, Li S, Dooley LT, Guzzo C, Patel K, Menter A, Gottlieb AB (2005) Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial. Br J Dermatol 152:954–960PubMedCrossRefGoogle Scholar
  15. 15.
    Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, Heffernan M, Miller B, Hamlin R, Lim L, Zhong J, Hoffman R, Okun MM (2006) Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol 55:598–606PubMedCrossRefGoogle Scholar
  16. 16.
    Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnaha BW, Menter A (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. J Am Med Assoc 290:3073–3080CrossRefGoogle Scholar
  17. 17.
    Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, Bala M, Marano CW, Menter A (2004) Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 51:534–542PubMedCrossRefGoogle Scholar
  18. 18.
    Gottlieb AB, Ford RO, Spellman MC (2003) The efficacy and tolerability of clobetasol propionate foam 0.05 % in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg 7:185–192PubMedCrossRefGoogle Scholar
  19. 19.
    Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA (2011) Efficacy and safety of briakinumab vs. etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 165:652–660PubMedCrossRefGoogle Scholar
  20. 20.
    Gottlieb AB, Matheson RT, Lowe N, Krueger GG, Kang S, Goffe BS, Gaspari AA, Ling M, Weinstein GD, Nayak A, Gordon KB, Zitnik R (2003) A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol 139:1627–1632 (discussion 32)PubMedCrossRefGoogle Scholar
  21. 21.
    Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, Guzzo C, Fretzin S, Kunynetz R, Kavanaugh A (2009) Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 373:633–640PubMedCrossRefGoogle Scholar
  22. 22.
    Hick J, Feldman SR (2007) Eligibility creep: a cause for placebo group improvement in controlled trials of psoriasis treatments. J Am Acad Dermatol 57:972–976PubMedCrossRefGoogle Scholar
  23. 23.
    Ho SG, Yeung CK, Chan HH (2010) Methotrexate versus traditional Chinese medicine in psoriasis: a randomized, placebo-controlled trial to determine efficacy, safety and quality of life. Clin Exp Dermatol 35:717–722PubMedCrossRefGoogle Scholar
  24. 24.
    Hrobjartsson A, Gotzsche PC (2001) Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 344:1594–1602PubMedCrossRefGoogle Scholar
  25. 25.
    Hrobjartsson A, Gotzsche PC (2004) Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med 256:91–100PubMedCrossRefGoogle Scholar
  26. 26.
    Icen M, Crowson CS, McEvoy MT, Dann FJ, Gabriel SE, Maradit Kremers H (2009) Trends in incidence of adult-onset psoriasis over three decades: a population-based study. J Am Acad Dermatol 60:394–401PubMedCrossRefGoogle Scholar
  27. 27.
    Irving G (2010) The placebo response: relationship to outcomes in trials of postherpetic neuralgia. Clin Drug Investig 30:739–748PubMedCrossRefGoogle Scholar
  28. 28.
    Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE, Kirsch I, Schyner RN, Nam BH, Nguyen LT, Park M, Rivers AL, McManus C, Kokkotou E, Drossman DA, Goldman P, Lembo AJ (2008) Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. Br Med J 336:999–1003CrossRefGoogle Scholar
  29. 29.
    Katz KA, Karlawish JH, Chiang DS, Bognet RA, Propert KJ, Margolis DJ (2006) Prevalence and factors associated with use of placebo control groups in randomized controlled trials in psoriasis: a cross-sectional study. J Am Acad Dermatol 55:814–822PubMedCrossRefGoogle Scholar
  30. 30.
    Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Gomez-Reino J, Papp K, Zrubek J, Mudivarthy S, Mack M, Visvanathan S, Beutler A (2009) Golimumab, a new human tumor necrosis factor alpha antibody, administered every four weeks as a subcutaneous injection in psoriatic arthritis: twenty-four-week efficacy and safety results of a randomized, placebo-controlled study. Arthritis Rheum 60:976–986PubMedCrossRefGoogle Scholar
  31. 31.
    Kelley JM, Boulos PR, Rubin PA, Kaptchuk TJ (2009) Mirror, mirror on the wall: placebo effects that exist only in the eye of the beholder. J Eval Clin Pract 15:292–298PubMedCrossRefGoogle Scholar
  32. 32.
    Klinger R, Soost S, Flor H, Worm M (2007) Classical conditioning and expectancy in placebo hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with healthy skin. Pain 128:31–39PubMedCrossRefGoogle Scholar
  33. 33.
    Kreft S, Kreft M, Resman A, Marko P, Kreft KZ (2006) Computer-aided measurement of psoriatic lesion area in a multicenter clinical trial—comparison to physician’s estimations. J Dermatol Sci 44:21–27PubMedCrossRefGoogle Scholar
  34. 34.
    Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356:580–592PubMedCrossRefGoogle Scholar
  35. 35.
    Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN (2002) A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 47:821–833PubMedCrossRefGoogle Scholar
  36. 36.
    Langley RG, Ellis CN (2004) Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician’s Global Assessment. J Am Acad Dermatol 51:563–569PubMedCrossRefGoogle Scholar
  37. 37.
    Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE (2003) An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 39:719–727CrossRefGoogle Scholar
  38. 38.
    Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, Walicke P, Dummer W, Wang X, Garovoy MR, Pariser D (2003) A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349:2004–2013PubMedCrossRefGoogle Scholar
  39. 39.
    Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371:1665–1674PubMedCrossRefGoogle Scholar
  40. 40.
    Leonardi CL, Papp KA, Gordon KB, Menter A, Feldman SR, Caro I, Walicke PA, Compton PG, Gottlieb AB (2005) Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 52:425–433PubMedCrossRefGoogle Scholar
  41. 41.
    Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB (2003) Etanercept as monotherapy in patients with psoriasis. N Engl J Med 349:2014–2022PubMedCrossRefGoogle Scholar
  42. 42.
    Levine D, Even-Chen Z, Lipets I, Pritulo OA, Svyatenko TV, Andrashko Y, Lebwohl M, Gottlieb A (2010) Pilot, multicenter, double-blind, randomized placebo-controlled bilateral comparative study of a combination of calcipotriene and nicotinamide for the treatment of psoriasis. J Am Acad Dermatol 63:775–781PubMedCrossRefGoogle Scholar
  43. 43.
    Levine JD, Gordon NC, Fields HL (1978) The mechanism of placebo analgesia. Lancet 2:654–657PubMedCrossRefGoogle Scholar
  44. 44.
    Light RJ, Pillemer DB (1984) Summing up: the science of reviewing research. Harvard University Press, CambridgeGoogle Scholar
  45. 45.
    Linde K, Witt CM, Streng A, Weidenhammer W, Wagenpfeil S, Brinkhaus B, Willich SN, Melchart D (2007) The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128:264–271PubMedCrossRefGoogle Scholar
  46. 46.
    Mease PJ, Gladman DD, Ritchlin CT, Ruderman EM, Steinfeld SD, Choy EH, Sharp JT, Ory PA, Perdok RJ, Weinberg MA (2005) Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52:3279–3289PubMedCrossRefGoogle Scholar
  47. 47.
    Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356:385–390PubMedCrossRefGoogle Scholar
  48. 48.
    Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, Salonen D, Rubenstein J, Sharp JT, Tsuji W (2004) Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 50:2264–2272PubMedCrossRefGoogle Scholar
  49. 49.
    Meissner K, Distel H, Mitzdorf U (2007) Evidence for placebo effects on physical but not on biochemical outcome parameters: a review of clinical trials. BMC Med 5:3PubMedCrossRefGoogle Scholar
  50. 50.
    Meissner K, Kohls N, Colloca L (2011) Introduction to placebo effects in medicine: mechanisms and clinical implications. Philos Trans R Soc Lond B Biol Sci 366:1783–1789PubMedCrossRefGoogle Scholar
  51. 51.
    Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, Strober BE, Kaul M, Gu Y, Okun M, Papp K (2008) Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol 58:106–115PubMedCrossRefGoogle Scholar
  52. 52.
    Papp KA, Bressinck R, Fretzin S, Goffe B, Kempers S, Gordon KB, Caro I, Walicke PA, Wang X, Menter A (2006) Safety of efalizumab in adults with chronic moderate to severe plaque psoriasis: a phase IIIb, randomized, controlled trial. Int J Dermatol 45:605–614PubMedCrossRefGoogle Scholar
  53. 53.
    Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich K (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371:1675–1684PubMedCrossRefGoogle Scholar
  54. 54.
    Papp KA, Tyring S, Lahfa M, Prinz J, Griffiths CE, Nakanishi AM, Zitnik R, van de Kerkhof PC, Melvin L (2005) A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol 152:1304–1312PubMedCrossRefGoogle Scholar
  55. 55.
    Pollo A, Carlino E, Benedetti F (2011) Placebo mechanisms across different conditions: from the clinical setting to physical performance. Philos Trans R Soc Lond B Biol Sci 366:1790–1798PubMedCrossRefGoogle Scholar
  56. 56.
    Radziwill K, Kruszewski (2011) Evaluation of the size of the placebo effect in treatments of allergic diseases and asthma based on a meta-analysis of efficacy trials of drugs. Post Dermatol Alergol 28:372–377Google Scholar
  57. 57.
    Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, Li S, Dooley LT, Griffiths CE (2005) Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366:1367–1374PubMedCrossRefGoogle Scholar
  58. 58.
    Robinson A, Kardos M, Kimball AB (2012) Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis. J Am Acad Dermatol 66:369–375PubMedCrossRefGoogle Scholar
  59. 59.
    Spuls PI, Lecluse LL, Poulsen ML, Bos JD, Stern RS, Nijsten T (2010) How good are clinical severity and outcome measures for psoriasis?: quantitative evaluation in a systematic review. J Invest Dermatol 130:933–943PubMedCrossRefGoogle Scholar
  60. 60.
    Stein LF, Sherr A, Solodkina G, Gottlieb AB, Chaudhari U (2001) Betamethasone valerate foam for treatment of nonscalp psoriasis. J Cutan Med Surg 5:303–307PubMedCrossRefGoogle Scholar
  61. 61.
    Stewart-Williams S, Podd J (2004) The placebo effect: dissolving the expectancy versus conditioning debate. Psychol Bull 130:324–340PubMedCrossRefGoogle Scholar
  62. 62.
    Stone DA, Kerr CE, Jacobson E, Conboy LA, Kaptchuk TJ (2005) Patient expectations in placebo-controlled randomized clinical trials. J Eval Clin Pract 11:77–84PubMedCrossRefGoogle Scholar
  63. 63.
    Strafella AP, Ko JH, Monchi O (2006) Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: the contribution of expectation. NeuroImage 31:1666–1672PubMedCrossRefGoogle Scholar
  64. 64.
    Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA (2011) Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol 165:661–668PubMedCrossRefGoogle Scholar
  65. 65.
    Thiboutot D, Pariser DM, Egan N, Flores J, Herndon JH Jr, Kanof NB, Kempers SE, Maddin S, Poulin YP, Wilson DC, Hwa J, Liu Y, Graeber M (2006) Adapalene gel 0.3 % for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad Dermatol 54:242–250PubMedCrossRefGoogle Scholar
  66. 66.
    Torii H, Nakagawa H (2010) Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial. J Dermatol Sci 59:40–49PubMedCrossRefGoogle Scholar
  67. 67.
    Tsai TF, Ho JC, Song M, Szapary P, Guzzo C, Shen YK, Li S, Kim KJ, Kim TY, Choi JH, Youn JI (2011) Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 63:154–163PubMedCrossRefGoogle Scholar
  68. 68.
    van de Kerkhof PC, Segaert S, Lahfa M, Luger TA, Karolyi Z, Kaszuba A, Leigheb G, Camacho FM, Forsea D, Zang C, Boussuge MP, Paolozzi L, Wajdula J (2008) Once weekly administration of etanercept 50 mg is efficacious and well tolerated in patients with moderate-to-severe plaque psoriasis: a randomized controlled trial with open-label extension. Br J Dermatol 159:1177–1185PubMedGoogle Scholar
  69. 69.
    Young MS, Horn EJ, Cather JC (2011) The ACCEPT study: ustekinumab versus etanercept in moderate-to-severe psoriasis patients. Expert Rev Clin Immunol 7:9–13PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sonia A. Lamel
    • 1
  • Kaley A. Myer
    • 1
  • Naji Younes
    • 2
  • James A. Zhou
    • 2
  • Hilda Maibach
    • 2
  • Howard I. Maibach
    • 1
  1. 1.Department of Dermatology, San Francisco School of MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.Social and Scientific Systems, Inc.Silver SpringUSA

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