The Time Course of Placebo Response in Clinical Trials

The Time Course of Placebo Response in Clinical Trials Do Antidepressants Really Take 2 s To Work? Nick Holford Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand

Clinical Pharmacology = Disease Progress + Drug Action NHG Holford, 05, all rights reserved.

Old Model - New Meaning E max Conc E = E0 + EC50 + Conc Disease Progress Drug Action NHG Holford, 05, all rights reserved.

Components of a Disease Progression Model Baseline Disease State Natural History Placebo Response Active Treatment Response S(t) = S0 +Nat. Hx. + Plac + Active NHG Holford, 05, all rights reserved.

Linear + Offset (Symptomatic) S( t) 0 ( S + E t ) + t = ( ) α status 115 1 5 0 95 90 85 80 Temporary Improvement Natural History 0 13 26 39 52 65 78 91 4 117 time NHG Holford, 05, all rights reserved.

Eptastigmine Imbimbo et al. Two-year treatment of Alzheimer's disease with eptastigmine. The Eptastigmine Study Group. Dementia and Geriatric Cognitive Disorders 1999;(2):139-47. NHG Holford, 05, all rights reserved.

Disease Progress Placebo Response Q: How can disease progress and placebo response be separated? A: Model based assumptions e.g. disease progress is linear placebo increases, reaches peak, decreases NHG Holford, 05, all rights reserved.

Placebo Response Alzheimer s Disease Disease Progress Placebo Response ADASC score 50.0 50.6 51.2 51.8 ADASC score -1.4.8.2 0.4-2 4 18 26 34 42 50 58 66 74 82 time(days) -2 4 18 26 34 42 50 58 66 74 82 time(days) Holford & Peace, Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci 89 (1992):11466-11470 NHG Holford, 05, all rights reserved.

Linear + Offset + Placebo Griggs RC, Moxley RT, Mendell JR, Fenichel GM, Brooke MH, Pestronk A, et al. Prednisone in Duchenne Dystrophy: A randomized, controlled trial defining the time course and dose response. Archives of Neurology 1991;48:383-88 NHG Holford, 05, all rights reserved.

The Placebo Effect True or False? NHG Holford, 05, all rights reserved.

Anti-Depressant Response Everybody knows anti-depressants take 2 to 4 weeks to work Almost all anti-depressant drugs block amine transporter re-uptake 5-HT, dopamine, noradrenaline Know to have a rapid effect crack cocaine Serotonergic syndrome Why is the anti-depressant response delayed? NHG Holford, 05, all rights reserved.

Response 0 2 4 6 8 Placebo Treatment starts NHG Holford, 05, all rights reserved.

Simple Placebo Response S0 Baseline Tlag Lag time Drem Remission Dose Trem Remission Half-Life 0 2 4 6 8 Placebo Treatment starts NHG Holford, 05, all rights reserved.

Full Placebo Response first order absorption and elimination 25 Tlag=Lag time S0=Baseline Drem=Remission Dose 15 Trel=Relapse Half-Life Trem=Remission Half-Life 0 2 4 6 8 12 14 16 18 s NHG Holford, 05, all rights reserved.

Investigation 1 Placebo treated profiles from 4 clinical studies NHG Holford, 05, all rights reserved.

What Determines the Time Course of Placebo Response? Placebo Arm of Double Blind Randomized Phase II Study of Four New Potential Anti- Depressants Total 582 patients, 3864 observations Developer 1, Study A (154 patients) Developer 1, Study B (141 patients) Developer 2, Study C (149 patients) Developer 2, Study D (138 patients) NHG Holford, 05, all rights reserved.

Study A Placebo ID 04 06 13 17 23 40 60 40 60 40 60 40 60 40 60 33 36 44 50 40 60 40 60 40 60 40 60 40 60 51 62 69 71 77 40 60 40 60 40 60 40 60 40 60 81 87 92 22 27 40 60 40 60 40 60 40 60 40 60 NHG Holford, 05, all rights reserved.

Study B Placebo ID 5124 5128 51 5135 5140 40 60 40 60 40 60 40 60 40 60 5149 5150 5155 5161 5168 40 60 40 60 40 60 40 60 40 60 5172 5178 5185 5187 5192 40 60 40 60 40 60 40 60 40 60 5195 5198 57 5212 5216 40 60 40 60 40 60 40 60 40 60 NHG Holford, 05, all rights reserved.

Study Placebo Model 4 Placebo Data Sets Parameter Description Estimate Units S0 Baseline 24 Tlag Lag time 4.7 days Drem Remission dose.6 Trem Remission half-life 60 days Trel Relapse half-life 280 days NHG Holford, 05, all rights reserved. iba_plaro_sdymixfix_s0sexwtsdyfix_tlwt_teme

Relapse Mixture Model Assume some patients have relapse Patients who do not relapse have infinite relapse half-life Probability of patient having a relapse is estimated NHG Holford, 05, all rights reserved.

Relapse Probability Study A Study B Study C Study D 98% 45% 29% 18% There are clearly study specific influences on the probability of relapse during the clinical trial NHG Holford, 05, all rights reserved. iba_plaro_sdymixfix_s0sexwtsdyfix_tlwt_teme

Is It a Design Issue? Observation Times Study A Study B 24 24 18 18 12 12 6 6 0 0 14 28 42 56 OBS Day Study C 0 0 14 28 42 56 70 84 OBS Day Study D 24 24 18 18 12 12 6 6 0 0 28 56 84 112 140 168 196 OBS Day 0 0 28 56 84 112 140 168 196 224 OBS Day NHG Holford, 05, all rights reserved.

A Second Kind of Placebo Effect The Observation Placebo Each observation acts as a dose of observation placebo Observation placebo conc rises and falls like oral drug absorption model Observation placebo conc can shorten remission and relapse half-lives of the study placebo model NHG Holford, 05, all rights reserved.

Observation Placebo Effect Obs Placebo onset half-life Obs Placebo disappearance half-life Obs Placebo effect on remission Obs Placebo effect on relapse 0.12 days 31 days -40% -64% NHG Holford, 05, all rights reserved. iba_plaro_sdymixfix_s0sexwtsdyfix_tlwt_teme

Investigation 2 A traditional placebo controlled study of a potential new antidepressant NHG Holford, 05, all rights reserved.

Model Models Equations Disease Progression S ( t) = S0 Placebo Response ( ln(2)/ Trem ( t Tlag) Placebo( t) = Drem 1 e ) Effect Compartment Concentration Ce( t) = DoseRate Clearance ln(2)/ Teq t ( 1 e ) Drug Action PD( Ce) = Beta Ce Time Course ( t) = S( t) + Placebo( t) + PD( Ce( t)) NHG Holford, 05, all rights reserved.

Typical Profiles ID 1 2 3 4 5 0 40 0 40 0 40 0 40 0 40 50 6 7 8 9 0 40 50 0 5 0 5 15 0 0.2 0.4 0.6 0.8 1 0 40 11 12 13 14 15 0 40 0 0 40 0 40 0 40 16 17 18 19 0 40 0 40 0 0.2 0.4 0.6 0.8 1 0 40 0 40 NHG Holford, 05, all rights reserved.

DOSE 0 Placebo ID 1 2 3 4 5 0 40 60 0 40 0 40 60 0 40 0 40 60 6 7 8 9 0 40 50 0 40 60 0 5 15 0 0.2 0.4 0.6 0.8 1 0 40 60 11 12 13 14 15 0 40 0 40 60 0 40 0 40 0 40 60 16 17 18 19 0 40 60 0 40 60 0 0.2 0.4 0.6 0.8 1 0 40 0 40 60 NHG Holford, 05, all rights reserved.

DOSE 1 New AntiDepressant ID 1 2 3 4 5 0 40 0 40 60 0 40 0 40 60 0 40 50 6 7 8 9 0 40 60 0 5 0 40 60 0 40 60 0 40 11 12 13 14 15 0 40 60 0 0 40 60 0 40 60 0 40 16 17 18 19 0 40 0 40 0 40 60 0 40 60 0 40 NHG Holford, 05, all rights reserved.

Parameter Estimates Parameter S0 Tlag Drem Trem Beta Teq RUV Description Baseline Lag time Remission decrease Remission half-life Effect potency Equilibration half-life Residual Error Units units days units days units days units Estimate.7 3.76-18.1.2-1.46 0.5 FIX* 2.69 PPV PPV=Population Parameter Variability (coefficient of variation of a log normal distribution) RUV=Residual Unidentified Variability (standard deviation of a normal distribution) 0.045 0.845 0 FIX 0.929 0.718 0 FIX 0.134 *=Longer Teq worsened objective function. Design of trial did not allow estimation of shorter Teq. 0.5 days is PK half-life. NHG Holford, 05, all rights reserved.

Bootstrap Statistics Table 3 Bootstrap Statistics (00 replicates) of Parameter Estimates for the Model Parameter Population Estimate Population Parameter Variability Median Lower 2.5% ile Upper 97.5%ile Median Lower 2.5% ile Upper 97.5%ile S0.70. 21. 0.0448 0.05 0.0519 Tlag 3.75 2.61 4.22 0.849 0.760 0.980 Drem -17.90-19. -16.80 0 FIX - - Trem. 15.80 21.40 0.9 0.764 0.984 Beta -1.45* -1.62.25 0.718 0.443 1.836 RUV 2.70 2.48 2.95 0.134 0.123 0.188 * = Significantly different from zero based on 95% bootstrap confidence interval NHG Holford, 05, all rights reserved.

Investigation 2 Conclusion Big placebo response Small antidepressant effect Rapid onset of active drug? NHG Holford, 05, all rights reserved.

Investigation 3 Retrospective analysis of large clinical database Positive and Negative trials NHG Holford, 05, all rights reserved.

Patients with Major Depressive Disorder enrolled in Placebo Controlled Clinical Trials of Anti-Depressants Data Set 4 Marketed Antidepressants + 2 IND (Active) Drugs + Placebo Patients 2,794 15,968 NHG Holford, 05, all rights reserved.

Placebo 39 40 42 43 46 0 5 0 2 4 6 8 0 2 4 6 0 5 0 2 4 47 49 50 52 53 0 5 0 5 0 5 0 2 4 6 8 0 2 4 6 8 56 58 60 62 63 0 2 4 6 8 0 5 0 2 4 6 8 0 1 2 3 4 0 5 64 65 67 71 72 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 1 2 3 NHG Holford, 05, all rights reserved.

Marketed Active Drug 123 126 127 128 129 0 5 0 2 4 6 0 5 0 5 0 2 4 6 8 133 138 142 143 146 0 5 0 2 4 6 8 0 1 2 0 5 0 2 4 6 8 147 148 150 151 152 0 5 0 2 4 6 8 0 2 4 6 8 0 5 0 0.2 0.4 0.6 0.8 160 161 163 164 165 0 2 4 6 8 0 5 0 1 2 3 0 2 4 6 8 0 2 4 6 8 NHG Holford, 05, all rights reserved.

Placebo 35 25 15 5 0 ' 0 2 4 6 8 12 s Hi Median Lo Placebo NHG Holford, 05, all rights reserved.

Marketed Active Drug 35 25 15 5 0 ' 0 2 4 6 8 12 s Hi Median Lo Obs NHG Holford, 05, all rights reserved.

Placebo Response Parameters Parameter Units Population Variability Estimate (PPV x 0) S0 23.0 11 Tlag Day 7.3 65 Remission Dose -15.9 7 Thalf Remission Day 36.9 139 Thalf Relapse Day 217 8 RUV 2.96 13 PPV=Population Parameter Variability (coefficient of variation of a log normal distribution) RUV=Residual Unidentified Variability (standard deviation of a normal distribution) NHG Holford, 05, all rights reserved.

Active Treatment Effects Parameter Units Population Variability Estimate (PPV x 0) Emax -3.4 74 ED50 dose/day * 0.73 51 Teq days 0.44 85 Teq=Effect compartment equilibration half-life *=Dose rate for each drug normalized to the median dose NHG Holford, 05, all rights reserved.

Placebo and Active Drug Response 24 19 14 9 0 4 8 12 16 24 s Active Treatment start NHG Holford, 05, all rights reserved.

Investigation 3 Conclusion Big placebo response Small antidepressant effect Rapid onset of (marketed) active drugs NHG Holford, 05, all rights reserved.

Application of Placebo Models to Depression Clearer description of depression Separation of Magnitude and Time Course of Drug Action Dispel unsubstantiated mythology! NHG Holford, 05, all rights reserved.