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

Overview

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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Basic Science
    • Masking: Triple (Participant, Care Provider, Outcomes Assessor)
  • Study Primary Completion Date: October 2015

Detailed Description

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.

Interventions

  • Drug: Hydroxizine
    • 25 mg orally, one time on two different days, 72 hours apart
  • Other: Placebo
    • Matching placebo once on two different days, 72 hours apart.
  • Drug: hydroxyzine/placebo
    • 25 mg hydroxyzine or placebo once on two different days, 72 hours apart

Arms, Groups and Cohorts

  • Other: Hydroxyzine
    • 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.
  • Other: Placebo
    • 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: Hydroxyzine/placebo
    • This group will receive hydroxyzine and placebo in a randomized double-blind placebo-controled crossover design.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Mean percent of time of reporting drowsiness on a dichotomous scale.
    • Time Frame: seven hours
    • Mean percent of time of reporting drowsiness on a dichotomous scale will also be determined.
  • Mean percent of time of reporting dryness of mouth
    • Time Frame: seven hours
    • Mean percent of time of reporting dryness of mouth on a dichotomous scale will also be determined.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • King Faisal Specialist Hospital & Research Center
  • Provider of Information About this Clinical Study
    • Sponsor

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