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Study Title and Description

Interaction between drug and placebo effects: a cross-over balanced placebo design trial.



Key Questions Addressed
1 For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on cardiovascular outcomes?
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Primary Publication Information
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TitleData
Title Interaction between drug and placebo effects: a cross-over balanced placebo design trial.
Author MM Hammami,EA Al-Gaai,S Alvi,MB Hammami,
Country
Year 2010
Numbers

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Cardiovascular Design
Design Details
Question... Follow Up Answer Follow-up Answer
What outcome is being evaluated in this paper? Cardiovascular
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What is the objective of the study (as reported by the authors)? Using a novel cross-over balanced placebo design, we measured the placebo effect on continuous and binary scales to: 1) explore potential interaction of drug and placebo effects by comparing the difference between receiving placebo described as caffeine or as placebo (placebo effect) to the difference between receiving caffeine described as caffeine or as placebo (placebo+interaction effect) and by comparing measured total medication effect to the sum of drug and placebo effects, 2) estimate the relative size of the placebo effect, and 3) explore the placebo effect on caffeine pharmacokinetics.
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Provide a general description of the methods as reported by the authors. Information should be extracted based on relevance to the SR (i.e., caffeine related methods) Study design: Participants were block-randomized (block size of four) to one of two randomized cross-over studies, one using caffeine described as caffeine or placebo and one using placebo described as placebo or caffeine. A 14 hour pharmacokinetics study was nested in the caffeine crossover study. The wash-out time between the two periods of each balanced randomized cross-over study was 48 hours to allow for clearance of plasma caffeine and most of caffeine (and caffeine withdrawal) effects, and minimize the occurrence of intra-subject differences. Balanced design was used to eliminate any differential residual carryover effect. Participants: Eligibility criteria for participants included an age of 18 to 50 years; being healthy, non-smoker, medication-free for one week, and able to reproducibly express oneself using a 100 mm visual analog scale (VAS); and daily caffeine consumption between 100 to 300 mg. The study was conducted at the King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh in February 2007 through February 2009, from 8-9 am to 12-1 pm. All participants gave written consent being informed that the study is designed to compare the effects of capsules containing placebo or 300 mg caffeine (equivalent to 3 cups of brewed coffee), that the study aims to determine how much of the observed changes is not related to caffeine but to the placebo effect, and that they have a 50/50 chance of receiving a placebo or caffeine. Intervention: Participants assigned to caffeine received 300 mg caffeine twice, 48 hours apart, one time dispensed from a bottle labelled " caffeine" and one time from a bottle labelled " placebo" in a random fashion. Participants assigned to placebo received placebo twice, 48 hours apart, one time dispensed from a bottle labelled " caffeine" and one time from a bottle labelled " placebo" in a random fashion. Caffeine and placebo were administered in the form of 2 capsules with 250 ml of water at ambient temperature, 15 to 30 minutes after a standardized light breakfast. Participants then abstained from food for four hours and remained ambulatory or seated upright until the end of the study. To enhance blinding and verify compliance, blood was drawn via intravenous cannula from all participants for caffeine level before and 3 hours after capsules’ administration. Outcomes: Measurements were obtained before, and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours after intervention, in the following order: systolic blood pressure; VAS for energy, sleepiness, and nausea; and binary data for not energetic, sleepy, and nauseated. Caffeine levels were blindly measured by a locally validated, modified high performance liquid chromatography assay. Randomization: The randomization schedule was generated by one of the authors (MMH) using a program available on-line http://www.randomization.com. Group assignment was concealed before randomization from participants and study coordinators who enrolled them. Interventions were assigned to participants by two of the investigators (MMH and EAG). Blinding: Study coordinators who collected data were blinded to study design and participants’ assignments. Caffeine levels were determined by one of the authors (SA) who was blinded to study design and participants’ assignment. Participants were deceived as to the true aim of the study and to their assignment.
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How many outcome-specific endpoints are evaluated? 1
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What is the (or one of the) endpoint(s) evaluated? (Each endpoint listed separately) Systolic blood pressure
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List additional health endpoints (separately). 2
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List additional health endpoints (separately).3
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List additional health endpoints (separately).4
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List additional health endpoints (separately).5
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List additional health endpoints (separately).6
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Clinical, physiological, other Physiological
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What is the study design? Controlled Trial
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Randomized or Non-Randomized? RCT
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What were the diagnostics or methods used to measure the outcome? Objective
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Optional: Name of Method or short description Blood pressure was taken before, and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours after intervention.
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Caffeine (general) Caffeine (general)
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Coffee, Chocolate, energy drink, gum, medicine/supplement, soda, tea, other?
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Measured or self reported? Measured
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Children, adolescents, adults, or pregnant included? Adults
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What was the reference, comparison, or control group(s)? (e.g. high vs low consumption, number of cups, etc.) Placebo.
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What were the listed confounders or modifying factors as stated by the authors? (e.g. multi-variable components of models.  Copy from methods) The ANCOVA model included group and subjects nested within groups (as appropriate), period, intervention, and baseline value. Mean percentage of time participants reported being not-energetic, sleepy, or nauseated was evaluated by the t test. We assumed that outcome measures associated with receiving placebo described as placebo represent baseline value, including non-specific changes, outcome measures associated with receiving placebo described as caffeine represent placebo effect + baseline value, outcome measures associated with receiving caffeine described as placebo represent drug effect + baseline value, and outcome measures associated with receiving caffeine described as caffeine represent drug effect + placebo effect + interaction effect (drug effect * placebo effect) + baseline value. Drug effect was estimated by comparing receiving caffeine described as placebo to receiving placebo, described as placebo, placebo effect by comparing receiving placebo described as caffeine to receiving placebo described as placebo, placebo+interaction effect by comparing receiving caffeine described as caffeine to receiving caffeine described as placebo, and total effect by comparing receiving caffeine described as caffeine to receiving placebo described as placebo. Total effect would include drug and placebo effects and their interaction. We excluded from analysis participants who later withdrew from the study (3 randomized to placebo, 2 to caffeine) or did not adequately abstain from caffeine (baseline caffeine levels in the study periods differed by ≥ 1 μ g/ml (2 randomized to placebo and 5 to caffeine).
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What conflicts of interest were reported? The authors declare that they have no competing interests.
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Refid 21092089
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What were the sources of funding? The study was funded by a grant from The King Abdul-Aziz City for Science and Technology (KACST), Riyadh, Saudi Arabia to MMH (ARP-26-45). KACST had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Special thanks to the participants of the study for their dedication and contribution to research and to the staff of the Center for Clinical Studies and Empirical Ethics.
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Results & Comparisons

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