Side-EffectENABLE-HFNCT07029906
pErsonalised Nocebo Assessment of Beta-blockEr Symptoms in Heart Failure
A study testing Bisoprolol 2.5 mg in people with Side-Effect and Heart Failure, run by Imperial College London at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Side-Effect, Heart Failure
- What is being tested?
- Bisoprolol 2.5 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 150 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 29 Apr 2025to Dec 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 13Show fewer
- Phaeochromocytoma
- 1st degree heart block with PR interval >250ms
- 2nd degree or complete heart block
- Sick sinus syndrome
- Acute pulmonary oedema
- Life expectancy <1 year
- Patient refusal or inability to participate in the study
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site, 1 recruiting
- Recruiting
Imperial College London
London, W12 0HS
Amanpal Sidhu, MBChB, 020 3313 1000, asidhu@ic.ac.uk
Sameer Zaman, MBBS, 020 3313 1000, sameer.zaman1@nhs.net
About this study
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:
Read more
- 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).
- To determine whether, on average, symptoms are worse when taking beta-blocker compared to placebo tablets or no treatment.
- 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.
Read the detailed description
Method:
ENABLE-HF is a prospective, N-of-1 randomised study of symptoms in participants with HFrEF. The study population will be patients who have an indication for oral beta-blockade due to HFrEF, and are currently not taking any beta-blockers licenced for HFrEF, having previously tried and stopped taking them due to perceived symptoms that they and/or their clinician(s) attributed to the beta-blocker(s).
Participants' suitability will be assessed by a detailed clinical history, clinical examination and review of their medical history to confirm the diagnosis of HFrEF, indication for beta-blocker therapy and that they are currently not taking it. The inclusion and exclusion criteria will be applied. At enrolment, a researcher will generate and allocate an unused randomisation code to the participant. This will also determine the contents of their 9 study bottles to be taken in Phase 2. The participant will then be provided with packs containing all phases' medications, and a smartphone if required.
The study protocol has three main phases:
(i) Phase 1 - a two week, open-label period of 2.5mg bisoprolol daily
(ii) Phase 2 - a nine week double blinded n-of-1 phase consisting of three separate weeks of daily bisoprolol 2.5mg, three separate weeks of daily matched placebo, and three separate weeks of no study tablet. The order of the nine weeks will be randomised at the outset.
(iii) Phase 3 - another two week, open-label period of 2.5mg bisoprolol daily.
Patients will report the intensity of the main symptom that led to them stopping beta-blocker tablets using a smartphone app daily. They will answer a weekly quality-of-life questionnaire. 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.
Each participant will receive a personalised report of their symptom scores from the n-of-1 Phase 2 period. At this point patients and researchers will be unblinded and patients will be counselled by a Cardiologist from research team about what these results mean and how much of their perceived side-effects are attributable to the beta-blocker. These findings will be delivered using pre-determined standardised language.
This study will develop a novel method to provide patients with HFrEF who are currently missing out on the prognostic benefits of beta-blockers with personalised information about their symptom aetiology. It is expected that getting these personalised results will improve long-term beta-blocker adherence in heart failure.
- Conditions
- Side-Effect, Heart Failure
- Being tested
- Bisoprolol 2.5 mg, Placebo
- Keywords
- Side-effect, Beta-blocker, Nocebo, Heart Failure Reduced Ejection Fraction, HFrEF, Heart Failure
- Medical subject headings
- Heart Failure, Heart Failure, Systolic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bisoprolol 2.5 mgDrug
Active bisoprolol 2.5mg tablets
PlaceboDrug
Blinded placebo for a total of 3 weeks
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
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.
Measured: 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
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.
Measured: From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2025
- Study start29 Apr 2025
- Primary completionDec 2027 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Side-EffectStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Single group
- Model description
- 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.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Graham Cole, MB BChir, Principal investigator, Imperial College NHS Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07029906
- Sponsor's protocol ID
- PG/22/10715
- Acronym
- ENABLE-HF
- Status last verified
- Jun 2025
- First submitted
- 29 Apr 2025
- Last updated
- 19 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
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.
PubMed 23796325Cole 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.
PubMed 25301161Zaman 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.
PubMed 28597606
Study at a glance
From the registry record, last updated by the sponsor on 19 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- pErsonalised Nocebo Assessment of Beta-blockEr Symptoms in Heart Failure
- ClinicalTrials.gov ID
- NCT07029906
- Acronym / sponsor ID
- ENABLE-HF / PG/22/10715
- Conditions
- Side-Effect, Heart Failure
- Keywords
- Side-effect, Beta-blocker, Nocebo, Heart Failure Reduced Ejection Fraction, HFrEF, Heart Failure
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Study start
- 29 Apr 2025 (actual)
- Primary completion
- Dec 2027 (estimated)
- Study completion
- Dec 2027 (estimated)
- First posted
- 19 Jun 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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).
- To determine whether, on average, symptoms are worse when taking beta-blocker compared to placebo tablets or no treatment.
- 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.
Detailed description
Method:
ENABLE-HF is a prospective, N-of-1 randomised study of symptoms in participants with HFrEF. The study population will be patients who have an indication for oral beta-blockade due to HFrEF, and are currently not taking any beta-blockers licenced for HFrEF, having previously tried and stopped taking them due to perceived symptoms that they and/or their clinician(s) attributed to the beta-blocker(s).
Participants' suitability will be assessed by a detailed clinical history, clinical examination and review of their medical history to confirm the diagnosis of HFrEF, indication for beta-blocker therapy and that they are currently not taking it. The inclusion and exclusion criteria will be applied. At enrolment, a researcher will generate and allocate an unused randomisation code to the participant. This will also determine the contents of their 9 study bottles to be taken in Phase 2. The participant will then be provided with packs containing all phases' medications, and a smartphone if required.
The study protocol has three main phases:
(i) Phase 1 - a two week, open-label period of 2.5mg bisoprolol daily
(ii) Phase 2 - a nine week double blinded n-of-1 phase consisting of three separate weeks of daily bisoprolol 2.5mg, three separate weeks of daily matched placebo, and three separate weeks of no study tablet. The order of the nine weeks will be randomised at the outset.
(iii) Phase 3 - another two week, open-label period of 2.5mg bisoprolol daily.
Patients will report the intensity of the main symptom that led to them stopping beta-blocker tablets using a smartphone app daily. They will answer a weekly quality-of-life questionnaire. 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.
Each participant will receive a personalised report of their symptom scores from the n-of-1 Phase 2 period. At this point patients and researchers will be unblinded and patients will be counselled by a Cardiologist from research team about what these results mean and how much of their perceived side-effects are attributable to the beta-blocker. These findings will be delivered using pre-determined standardised language.
This study will develop a novel method to provide patients with HFrEF who are currently missing out on the prognostic benefits of beta-blockers with personalised information about their symptom aetiology. It is expected that getting these personalised results will improve long-term beta-blocker adherence in heart failure.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Blinded bisoprolol tablets | Experimental | Drug: Bisoprolol 2.5 mgThe 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. |
| Blinded placebo | Placebo comparator | Drug: PlaceboParticipants 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. |
| No tablet | No intervention | –There will be three weeks in total during the randomised phase in which patients do not consume any tablets. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (13 listed)
- Documented anaphylaxis to beta-blockers
- Clinical contraindication to Bisoprolol including (but not limited to):
- Life expectancy <1 year
- Patient refusal or inability to participate in the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bisoprolol 2.5 mgActive bisoprolol 2.5mg tablets | Drug | Blinded bisoprolol tablets |
| PlaceboBlinded placebo for a total of 3 weeks | Drug | Blinded placebo |
Primary outcome
Nocebo Fraction
Time frame: From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks
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
2 secondary outcomes
Difference in Symptom Intensity Scores Between Beta-Blocker and Placebo
Time frame: 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
Time frame: From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jun 2025.
- Background: PubMed 23796325Barron 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.
- Background: PubMed 25301161Cole 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.
- Background: PubMed 28597606Zaman 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.
- ENABLE-HF WebsiteLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Graham Cole, MB BChir principal investigator
Imperial College NHS Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Bisoprolol 2.5 mg in people with Side-Effect and Heart Failure, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 19 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sameer Zaman, MBBS (020 3313 1000, sameer.zaman1@nhs.net), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Nocebo Fraction (time frame: From start of protocol to end of second open-label beta-blocker phase, an average of 15 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07029906, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jun 2025.