pErsonalised Nocebo Assessment of Beta-blockEr Symptoms in Heart Failure

NCT07029906 | Recruiting

• 1 other identifier: PG/22/10715
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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. 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. 2.To determine whether, on average, symptoms are worse when taking beta-blocker compared to placebo tablets or no treatment.
3. 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.

Conditions

Side-Effect; Heart Failure

Keywords

Side-effect; Beta-blocker; Nocebo; Heart Failure Reduced Ejection Fraction; HFrEF; Heart Failure

Outcome Measures

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

  From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks

Secondary Outcomes (2)

• Difference in Symptom Intensity Scores Between Beta-Blocker and Placebo

  From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks

• Change in Symptom Intensity Scores after Receiving n-of-1 Personalised Results

  From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks

Study Arms (3)

Blinded bisoprolol tablets

EXPERIMENTAL

The protocol includes a randomised, blinded nine week phase in which participants take either bisoprolol, no tablets or placebo. They will be randomly assigned to take three weeks in total of blinded bisoprolol tablets.

Drug: Bisoprolol 2.5 mg

Blinded placebo

PLACEBO COMPARATOR

Participants will be randomly assigned to take three weeks of blinded placebo tablets. They will be unaware as to whether they are consuming bisoprolol or placebo in this phase.

Drug: Placebo

No tablet

NO INTERVENTION

There will be three weeks in total during the randomised phase in which patients do not consume any tablets.

Interventions

Bisoprolol 2.5 mg DRUG

Active bisoprolol 2.5mg tablets

Blinded bisoprolol tablets

Placebo DRUG

Blinded placebo for a total of 3 weeks

Blinded placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Documented anaphylaxis to beta-blockers
• Clinical contraindication to Bisoprolol including (but not limited to):
• Asthma requiring BTS treatment step 3 or higher
• Marked bradycardia (\<50 bpm)
• Symptomatic hypotension (systolic BP \<85mmHg)
• Metabolic acidosis
• Phaeochromocytoma
• st degree heart block with PR interval \>250ms
• nd degree or complete heart block
• Sick sinus syndrome
• Acute pulmonary oedema
• Life expectancy \<1 year
• Patient refusal or inability to participate in the study

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (1)

Imperial College London

London, W12 0HS, United Kingdom

RECRUITING

Related Publications (3)

• Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. Int J Cardiol. 2013 Oct 9;168(4):3572-9. doi: 10.1016/j.ijcard.2013.05.068. Epub 2013 Jun 21.

  PMID: 23796325 BACKGROUND

• Cole GD, Patel SJ, Zaman N, Barron AJ, Raphael CE, Mayet J, Francis DP. "Triple therapy" of heart failure with angiotensin-converting enzyme inhibitor, beta-blocker, and aldosterone antagonist may triple survival time: shouldn't we tell patients? JACC Heart Fail. 2014 Oct;2(5):545-8. doi: 10.1016/j.jchf.2014.04.012.

  PMID: 25301161 BACKGROUND

• Zaman S, Zaman SS, Scholtes T, Shun-Shin MJ, Plymen CM, Francis DP, Cole GD. The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets. Eur J Heart Fail. 2017 Nov;19(11):1401-1409. doi: 10.1002/ejhf.838. Epub 2017 Jun 8.

  PMID: 28597606 BACKGROUND

Related Links

• ENABLE-HF Website

MeSH Terms

Conditions

Heart Failure; Heart Failure, Systolic

Interventions

Bisoprolol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Study Officials

• Graham Cole, MB BChir

  Imperial College NHS Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sameer Zaman, MBBS

CONTACT

020 3313 1000; sameer.zaman1@nhs.net

Amanpal Sidhu, MBChB

CONTACT

020 3313 1000; asidhu@ic.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, N-of-1 study of symptoms in 150 participants with heart failure with reduced ejection fraction. Each participant will follow an individualised protocol after randomly being assigned to a regime.

Study Record Dates

• First Submitted: April 29, 2025
• First Posted: June 19, 2025
• Study Start: April 29, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: June 19, 2025

Record last verified: 2025-06

Locations

GB (1)