Interaction Between Drug and Placebo Effect:Randomized Placebo Controlled Trials May Not be Accurate in Determining Drug Effect Size

Study Overview
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Brief Summary
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The total effect of a medication is the sum of its drug effect, placebo effect (meaning response of placebo), and their possible interaction. Current interpretation of the results of clinical trials (the gold standard in evidence based medicine) assumes no such interaction. Using a novel cross-over balanced placebo design and caffeine as a model drug, the investigators have recently shown that a negative interaction does exist; suggesting that the size of drug effect as currently measured by clinical trials may not be accurate. Due to the novelty of the findings and their important clinical practice and research implications, they need to be confirmed using another drug; and the size of drug effect measured using the novel design need to be directly compared to that measured using conventional clinical trial design. The results of the study are expected to further our understanding of a widely used medical intervention, i.e., placebo, and help assess the appropriateness of randomized clinical trials in determining the size of drug effect.

Detailed Description
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BACKGROUND: The total effect of a medication is the sum of its drug effect, placebo effect (meaning response of placebo), and their possible interaction. Current interpretation of the results of clinical trials (the gold standard in evidence based medicine) assumes no such interaction. Using a novel cross-over balanced placebo design and caffeine as a model drug we have recently shown that a negative interaction does exist; suggesting that the size of drug effect as currently measured by clinical trials may not be accurate. Due to the novelty of the findings and their important clinical practice and research implications, they need to be confirmed using another drug; and the size of drug effect measured using the novel design need to be directly compared to that measured using conventional clinical trial design. DESIGN: A cross-over balanced placebo plus randomized placebo-controlled clinical trial design. METHODS: 480 adults will be double-blindly randomized to three groups: first generation H-1 receptor antagonist- hydroxyzine (25 mg), placebo, or hydroxyzine+placebo group. The first two groups will receive the assigned intervention described by the investigators as hydroxyzine or placebo, in a randomized crossover design. The third group will receive hydroxyzine and placebo in a randomized double-blind placebo-controled crossover design. Group assignment will be concealed from volunteers and recruiters. Data collectors will be blinded to group assignment and intervention assignment. Volunteers will be partially deceived to the intervention assignment in the first two groups and blinded in the third group. The interventions to the third group will be also administered blindly. Serum hydroxyzine levels will be determined 3 hours post intervention from all volunteers to verify compliance and help maintain deception/blinding. The results of the study are expected to further our understanding of a widely used medical intervention, i.e., placebo, and help assess the appropriateness of randomized clinical trials in determining the size of drug effect.

Official Title
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Interaction Between Drug and Placebo Effect:Randomized Placebo Controlled Trials May Not be Accurate in Determining Drug Effect Size

Conditions
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Placebo Effect, Placebo Drug Interaction

Intervention / Treatment
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* Drug: Hydroxizine
* Other: Placebo
* Drug: hydroxyzine/placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 to 50 years; Being healthy, Able to abstain from smoking and alcohol Medication-free for one week Able to reproducibly express oneself using a 100 mm visual analog scale (VAS). Exclusion Criteria: clinically relevant deviation from normal health pregnancy or lactation hypersensitivity to hydroxyzine or related compounds

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Hydroxyzine<br>This group will receive a first generation H-1 receptor antagonist, hydroxyzine (25 mg) twice on two days; on one day described by the investigator as hydroxyzine and on the other day described by the investigator as placebo, in a randomized balanced crossover design. | Drug: Hydroxizine<br>* 25 mg orally, one time on two different days, 72 hours apart<br>|
| Other: Placebo<br>This group will receive a placebo twice on two days; on one day described by the investigator as hydroxyzine and on the other day described by the investigator as placebo, in a randomized balanced crossover design. | Other: Placebo<br>* Matching placebo once on two different days, 72 hours apart.<br>|
| Other: Hydroxyzine/placebo<br>This group will receive hydroxyzine and placebo in a randomized double-blind placebo-controled crossover design. | Drug: hydroxyzine/placebo<br>* 25 mg hydroxyzine or placebo once on two different days, 72 hours apart<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area-under-the-curve for drowsiness | Seven-hour-area-under-the-curve of drowsiness on 100 mm visual analog scales will be determined | seven hours | 
| Area-under-the-curve for dryness of the mouth | Seven-hour-area-under-the-curve of dryness of the mouth on 100 mm visual analog scales will be determined | seven hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean percent of time of reporting drowsiness on a dichotomous scale. | Mean percent of time of reporting drowsiness on a dichotomous scale will also be determined. | seven hours | 
| Mean percent of time of reporting dryness of mouth | Mean percent of time of reporting dryness of mouth on a dichotomous scale will also be determined. | seven hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Placebo effect, placebo drug interaction, placebo -controlled clinical trials