Study of Atomoxetine in the Prevention of Vasovagal Syncope

NCT05159687 | Recruiting Phase 3 DMC

• 1 other identifier: POST 7
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

Brief Summary

Project rationale: Vasovagal syncope (VVS) affects up to 50% of people, and recurrent syncope markedly reduces quality of life. We recently reported that it is frequently associated with injury and not surprisingly with clinical anxiety. Although conservative measures help many patients there remain many who require more care. CIHR-funded studies have shown that fludrocortisone and midodrine are effective but cannot be used in patients with contraindications such as hypertension and heart failure. Pacemakers are partially effective in older patients, but this is established only in the small minority with proven asystole. There remains a need for a simple, once-daily medication with few contraindications that can be used as first-line therapy for most patients with recurrent vasovagal syncope. Preliminary Studies: Norepinephrine transport (NET) inhibitors show promise as a novel treatment. Three (reboxetine, sibutramine, and atomoxetine) all prevent vasovagal syncope in healthy subjects and vasovagal syncope patients on tilt tests. Atomoxetine, approved to treat attention deficit disorder, is a highly selective NET inhibitor. We reported a proof-of-principle, randomized, placebo-controlled trial of the efficacy of atomoxetine to prevent vasovagal syncope on tilt table tests. Patients underwent tilt testing after receiving either atomoxetine 40 mg or placebo. Fewer VVS patients fainted with atomoxetine than placebo (10/29 vs. 19/27; odds ratio 0.22, p \< 0.01). Our meta-analysis of the effects of NET inhibition on the vasovagal reflex induced by tilt tests was highly positive. A pre-post study showed that sibutramine reduced syncope frequency in highly symptomatic and drug-refractory patients. A similar pre-post study showed that atomoxetine also reduces syncope frequency about 85% in patients with frequent and drug-intolerant or drug-resistant vasovagal syncope. Therefore,NET inhibition by atomoxetine merits assessment based on positive proof-of-principle studies, an apparent class effect, and two open-label pre-post studies. These results provide the rationale for a formal randomized, placebo-controlled, crossover trial of atomoxetine in moderate-to-high risk patients with VVS. Hypothesis: We will test the hypothesis that oral atomoxetine prevents syncope in patients with recurrent VVS. The Study: Patients will be included based on a positive Calgary Syncope Symptom Score and a history of at least 2 faints in the previous year. Eligible patients will be randomized to atomoxetine 40 mg po twice daily or matching placebo in a randomized, placebo-controlled, parallel design, double-blind, crossover trial. Each arm will last 6 months with a 1-week washout period. The primary outcome measure will be the proportion of patients with at least 1 syncope recurrence. The study will be powered to detect a beneficial odds ratio of 0.5, selected on the basis of the control outcome rates in 2 similarly designed, previous studies and international expert requirements for effect size. A sample size of 180 subjects will provide 85% power of detecting a difference between the arms at p\<0.05. We will assess the effects of atomoxetine on quality of life, anxiety, injury, and the cost-effectiveness of atomoxetine treatment, and the effects of genetic factors on outcomes. Substudies : The quality of life scales will be the SF-36 and the Euroqol EQ5D, which will also be used as the health utility index for the economic studies. The depression and anxiety scales will be the Hospital and Anxiety Depression Score (HADS) and the General Anxiety Disorder - 7 Score (GAD-7). Clinical anxiety is highly prevalent in patients with recurrent syncope. Injury will be self-reported using our published definitions. The health economic substudy will be from the health system perspective and will use Alberta administrative data. DNA will be collected from spit acquired in the Oragene saliva self-collection kits, and an initial candidate gene study might include alleles of CYP2D6, COMT, the serotonin (SLC6A4) and norepinephrine (SLC6A2) reuptake transporters, and the 5HT1A and 5HT3 receptors. Summary: Adults who faint recurrently are highly symptomatic. There are no therapies suitable for most patients have withstood the test of randomized clinical trials. If successful, atomoxetine will reduce syncope and improve quality of life.

Conditions

Vasovagal Syncope

Keywords

reflex fainting; vasovagal syncope; randomized clinical trial; quality of life; Atomoxetine

Outcome Measures

Primary Outcomes (1)

• The primary outcome measure will be the proportion of patients having at least one syncope recurrence.

  one syncope recurrence

  Within 12 months period of the study

Secondary Outcomes (6)

• Hospital Anxiety and Depression Scale (HADS)

  every 6 months of the study up to 12 months

• Generalized Anxiety Disorder score

  every 6 months of the study up to 12 months

• EQ-5D-3L

  every 6 months of the study up to 12 months

• Rand 36 Scale

  every 6 months of the study up to 12 months

• ISQL form

  every 6 months of the study up to 12 months

Study Arms (2)

Atomoxetine

ACTIVE COMPARATOR

Atomoxetine 40 mg PO BID (morning and late afternoon) Dosing will start at 40 mg daily for 3 days1 week, followed by a forced titration to 40 mg BID, as per the FDA label for atomoxetine.

Drug: Atomoxetine Hydrochloride

Placebo

PLACEBO COMPARATOR

Matching placebo will be identical in appearance to the active treatment pill. BID (morning and late afternoon)

Drug: Placebo

Interventions

Atomoxetine Hydrochloride DRUG

Atomoxetine 40 mg PO BID (morning and late afternoon) Dosing will start at 40 mg daily for 3 days1 week, followed by a forced titration to 40 mg BID, as per the FDA label for atomoxetine

Atomoxetine

Placebo DRUG

Placebo Comparator: Placebo Matching placebo will be identical in appearance to the active treatment pill. BID (morning and late afternoon)

Placebo

Eligibility Criteria

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

You may qualify if:

• Syncope according to the American College of Cardiology Guidelines 2017
• At least 2 vasovagal syncope spells in the preceding 12 months
• At least -2 on the Syncope Symptom Score for Structurally Normal Hearts
• At least 18 years old with informed consent

You may not qualify if:

• Other cause of syncope
• A 5-minute stand test resulting in the diagnosis Orthostatic Hypotension or Postural Orthostatic Tachycardia Syndrome
• An inability to give informed consent
• Pregnant
• Unwilling or unable to use adequate birth control while on study drug.
• An important valvular, coronary, myocardial, or conduction abnormality, or significant arrhythmia
• Uncontrolled hypertension
• Uncontrolled hyperthyroidism
• A permanent pacemaker
• Taking or has recently taken a monoamine oxidase inhibitor
• Pheochromocytoma
• Glaucoma
• Prior use of atomoxetine for syncope
• Clinical need for atomoxetine or another potent norepinephrine transporter inhibitors (Ki NET \< Ki SERT, Ki NET \> 10 Ki atomoxetine),
• Current use of β-blocker, bupropion, α1-adrenergic agonists or antagonists, tricyclic antidepressants, serotonin reuptake inhibitors, scopolamine, theophylline, or fludrocortisone.

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

RECRUITING

Related Publications (1)

• Sandhu RK, Raj SR, Hamzeh R, Sheldon RS; POST 7 Investigators. The Seventh Prevention of Syncope Trial (POST VII)-A randomized clinical trial of atomoxetine for the prevention of vasovagal syncope: Rationale and study design. Am Heart J. 2023 Aug;262:49-54. doi: 10.1016/j.ahj.2023.04.012. Epub 2023 Apr 24.

  PMID: 37100187 DERIVED

MeSH Terms

Conditions

Syncope, Vasovagal

Interventions

Atomoxetine Hydrochloride

Condition Hierarchy (Ancestors)

Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Syncope; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals

Central Study Contacts

Robert Sheldon

CONTACT

4032108510; sheldon@ucalgary.ca

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2021
• First Posted: December 16, 2021
• Study Start: June 1, 2022
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2027
• Last Updated: May 9, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)