pErsonalised Nocebo Assessment of Beta-blockEr Symptoms in Heart Failure
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
SponsorImperial College London
About this trial
Beta-blocker tablets are an effective treatment for heart failure that make people live longer and reduce the need to be admitted to hospital. Many patients who are at high risk of death are prescribed beta-blockers, but later choose to stop taking them because of symptoms that they perceive to be side-effects. Some patients' symptoms may genuinely be side-effects due to the beta-blocker tablets, but, in reality, many of the symptoms which may lead to people stopping beta-blockers are actually experienced at similar rates compared to placebo. The symptoms may be caused by heart failure itself, or the expectation that they will have a side effect when they take a tablet (the nocebo effect). There is a need to be able to identify the majority of patients who aren't actually having side-effects so that they can restart beta-blockers and not miss out on life-prolonging treatment. To answer this question reliably and with high precision requires a personalised approach with an 'N-of-1' study. This study will measure participants' symptoms in three scenarios: taking a beta-blocker tablet (bisoprolol 2.5mg) or a placebo tablet or no study medication in a randomised order.
The primary aim of this study is to determine, for an individual, whether the adverse effects of beta-blockade in heart failure are genuine. Specifically, the objectives are:
1. To determine the proportion of a patient's symptoms that are due to taking beta-blocker tablets, and the proportion that are due to the expectation that the treatment will cause symptoms (the nocebo effect). 2. To determine whether, on average, symptoms are worse when taking beta-blocker compared to placebo tablets or no treatment. 3. To determine whether on average symptom intensity associated with beta-blockade decreases after receiving a report on how much of their symptoms are due to the beta-blocker.
Throughout the protocol participants report daily the intensity of the symptom that previously led to their beta-blocker cessation via a smartphone app. Participants will report weekly their adherence, general heart failure symptoms and quality of life. In this way the investigators will discover, for an individual patient, the proportion of their symptom that is due to the beta-blocker tablet, and whether knowing their personalised results helps them to restart beta-blocker tablets.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Heart failure with index LVEF <40%
Not currently taking beta-blocker tablets
Previously tried one of beta-blocker tablet, and stopped taking it due to symptoms attributed to the beta-blocker
Consenting to participate in the study
Disqualifiers
Documented anaphylaxis to beta-blockers
Asthma requiring BTS treatment step 3 or higher
Marked bradycardia (<50 bpm)
Symptomatic hypotension (systolic BP <85mmHg)
Trial design
Design model
Single group
Treatments tested in this trial
Bisoprolol 2.5 mg
DrugActive bisoprolol 2.5mg tablets
Placebo
DrugBlinded placebo for a total of 3 weeks
Treatment groups
150 Participants
are divided into 3 treatment groupsGroup A: Blinded bisoprolol tabletsExperimental treatment 1 intervention
Group B: Blinded placeboPlacebo comparator 1 intervention
Group C: No tabletNo intervention 0 interventions
Trial outcomes
Primary outcomes
1
Nocebo Fraction
For each participant, we will primarily calculate the 'nocebo fraction'. This is a measure of the proportion of an individual patient's symptoms which are due to beta-blocker and which are due to the nocebo effect. It is calculated by measuring and averaging the daily symptom intensity (scored from 0 to 100) when taking: \[A\] beta-blocker tablet \[B\] placebo (blank) tablet \[C\] no tablet
Time frame
From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeksSecondary outcomes
1
Difference in Symptom Intensity Scores Between Beta-Blocker and Placebo
At enrolment, patients will establish one primary symptom that previously resulted in their cessation of taking beta-blockade. This intensity of this symptom will be enquired about on a daily basis through all phases of the trial. To establish how beta-blockers impact this symptom intensity, the difference in average symptom intensity (scored from 0-100) taking a beta-blocker will be compared to that whilst taking a placebo across the population. Symptom intensity will be measured using the self-reported symptom scores that participants report in the app.
Time frame
From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks2
Change in Symptom Intensity Scores after Receiving n-of-1 Personalised Results
To determine whether average symptom scores are affected by insights from the n-of-1 period, we will compare the average symptom scores during open-label beta-blocker treatment before the n-of-1 period to those after the n-of-1 period, following receipt of a personalised symptom report. Statistical significance will be assessed using a comparison of means, such as Student's t-test, or non-parametric alternatives if the data are not normally distributed.
Time frame
From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeksSponsors and contacts
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Source ClinicalTrials.gov