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

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 Overview

• Status: Completed
• Conditions: Placebo Effect; Placebo Drug Interaction
• Intervention / Treatment: Drug: Hydroxizine; Other: Placebo; Drug: hydroxyzine/placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 480
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Saudi Arabia
  • Riyadh, Saudi Arabia, 11211
    • King Faisal Specialist Hospital & Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Hydroxizine; 25 mg orally, one time on two different days, 72 hours apart
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: Placebo; Matching placebo once on two different days, 72 hours apart.
Other: Hydroxyzine/placebo; This group will receive hydroxyzine and placebo in a randomized double-blind placebo-controled crossover design.	Drug: hydroxyzine/placebo; 25 mg hydroxyzine or placebo once on two different days, 72 hours apart

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: King Faisal Specialist Hospital & Research Center

Publications and helpful links

General Publications

• Hammami MM, Hammami S, Al-Swayeh R, Al-Gaai E, Farah FA, De Padua SJ. Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design. BMC Med Res Methodol. 2016 Nov 29;16(1):166. doi: 10.1186/s12874-016-0269-1.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: December 25, 2011
• First Submitted That Met QC Criteria: December 28, 2011
• First Posted (Estimate): December 29, 2011

Study Record Updates

• Last Update Posted (Actual): March 3, 2017
• Last Update Submitted That Met QC Criteria: March 1, 2017
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Placebo effect; placebo drug interaction; placebo -controlled clinical trials
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Hydroxyzine
• Other Study ID Numbers: RAC 2111001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No