Atomoxetine for Fainting (Vasovagal Syncope)

(POST7 Trial)

Overseen By Robert Sheldon

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Calgary

Must not be taking: MAO inhibitors, Beta-blockers, SSRIs, others

Disqualifiers: Orthostatic hypotension, Pregnancy, Hypertension, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months per arm with a 1-week washout period

180 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests atomoxetine, a medication, to determine if it can prevent fainting spells in individuals with recurrent vasovagal syncope, a condition causing sudden drops in heart rate and blood pressure that lead to fainting. The goal is to find a simple treatment to reduce fainting incidents and improve the quality of life for those affected. Participants will receive either atomoxetine or a placebo (a harmless pill with no active drug) to compare results. Individuals who have fainted at least twice in the past year due to vasovagal syncope might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications before participating in this trial. Specifically, you cannot be on β-blockers, bupropion, α1-adrenergic agonists or antagonists, tricyclic antidepressants, serotonin reuptake inhibitors, scopolamine, theophylline, or fludrocortisone.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that atomoxetine, a drug approved for treating attention deficit disorder, is being tested for its potential to help with vasovagal syncope, a type of fainting spell. In earlier studies, participants who took atomoxetine fainted less often than those who received a placebo. Specifically, one study found that fewer participants fainted during a tilt test after taking atomoxetine compared to a placebo (10 out of 29 with atomoxetine vs. 19 out of 27 with placebo).

Regarding safety, atomoxetine is generally well-tolerated. Since the FDA has already approved it for another use, extensive safety information is available. However, like any medication, it can have side effects. Prospective clinical trial participants should discuss these potential side effects with their healthcare provider to make an informed decision. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for fainting?

Unlike the standard treatments for vasovagal syncope, which often include lifestyle changes and medications like beta-blockers or fludrocortisone, atomoxetine offers a unique approach. Atomoxetine is traditionally used for ADHD and works by increasing norepinephrine levels, which may help stabilize blood pressure and reduce fainting episodes. This new mechanism of action is what excites researchers, as it targets the condition from a different angle, potentially offering relief for those who don't respond well to existing therapies.

What evidence suggests that atomoxetine might be an effective treatment for vasovagal syncope?

Research has shown that atomoxetine, a medication typically used for attention deficit disorder, might help reduce fainting episodes in people with vasovagal syncope. In this trial, participants will receive either atomoxetine or a placebo. One study found that fewer people fainted when taking atomoxetine compared to those taking a placebo. Specifically, only 10 out of 29 people fainted on atomoxetine, while 19 out of 27 fainted on the placebo. Another study found that 11 out of 12 people improved with atomoxetine, and 7 of them did not faint at all. These results suggest that atomoxetine may help prevent fainting by affecting a part of the body that controls reflexes related to fainting. This makes atomoxetine a possible treatment for those who often experience troublesome fainting spells. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults who've fainted at least twice in the past year due to vasovagal syncope, as defined by American College of Cardiology Guidelines. Participants must be over 18 and score at least -2 on a specific Syncope Symptom Score. Those with uncontrolled blood pressure or thyroid issues, pacemakers, certain eye conditions, or taking conflicting medications cannot join.

Inclusion Criteria

You have a low score on the Syncope Symptom Score for Structurally Normal Hearts.

You have experienced fainting as defined by the American College of Cardiology Guidelines in 2017.

I have fainted at least twice in the last year.

Exclusion Criteria

I need medication for my condition that affects norepinephrine levels.

I have been diagnosed with pheochromocytoma.

I have experienced fainting due to reasons other than my heart.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either atomoxetine 40 mg twice daily or matching placebo in a double-blind, crossover trial

6 months per arm with a 1-week washout period

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Optional open-label extension for continued monitoring and assessment of long-term effects

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Atomoxetine Hydrochloride

Trial Overview

The study tests if Atomoxetine Hydrochloride (40 mg twice daily) can prevent fainting in people with recurrent vasovagal syncope compared to a placebo. It's a double-blind crossover trial where patients switch between the drug and placebo after six months with a one-week break in between.

How Is the Trial Designed?

Group I: Atomoxetine Active Control 1 Intervention

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.

Group II: Placebo Placebo Group 1 Intervention

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

Atomoxetine Hydrochloride is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in European Union as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Approved in Canada as Strattera for:

• Attention Deficit Hyperactivity Disorder (ADHD)

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Published Research Related to This Trial

Atomoxetine, a nonstimulant medication approved for ADHD, works as a selective norepinephrine reuptake inhibitor and is structurally related to fluoxetine, an antidepressant.

While common side effects include gastrointestinal disturbances, this case highlights potential cardiovascular issues such as syncope, orthostatic hypotension, and tachycardia, which may arise from increased noradrenergic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular side effects of atomoxetine and its interactions with inhibitors of the cytochrome p450 system. Kasi, PM., Mounzer, R., Gleeson, GH.[2021]

A case of a 17-year-old girl who overdosed on 2840 mg of atomoxetine resulted in a seizure and mild cardiac issues, highlighting the potential risks associated with high doses of this medication.

Despite the overdose, the patient showed significant improvement within 24 hours, indicating that while atomoxetine can cause serious effects in overdose situations, recovery is possible with appropriate medical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolated atomoxetine overdose resulting in seizure. Kashani, J., Ruha, AM.[2015]

In a study involving 56 patients with vasovagal syncope, atomoxetine (40 mg) significantly reduced the incidence of tilt-induced syncope compared to placebo, with fewer patients fainting (10 out of 29 with atomoxetine vs. 19 out of 27 with placebo).

The mechanism of action for atomoxetine appears to involve the inhibition of reflex bradycardia, which helps maintain blood pressure and cardiac output during tilt tests, thus preventing syncope.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A proof of principle study of atomoxetine for the prevention of vasovagal syncope: the Prevention of Syncope Trial VI. Sheldon, RS., Lei, L., Guzman, JC., et al.[2020]

In a study of 12 patients with recurrent vasovagal syncope, atomoxetine significantly reduced the frequency of syncope episodes, with 7 out of 12 patients experiencing no syncope during follow-up after starting the medication.

The annualized syncope frequency dropped from a median of 5.5 episodes per year to 0 while on atomoxetine, indicating its potential effectiveness as a treatment for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atomoxetine for suppression of vasovagal syncope. Sheldon, RS., Seifer, C., Parkash, R., et al.[2023]

The POST VII study is a multicenter, randomized, double-blind, placebo-controlled trial involving 180 patients with vasovagal syncope (VVS) to evaluate the efficacy of atomoxetine, a norepinephrine reuptake inhibitor, in reducing syncope recurrences over a 6-month period.

If successful, this trial could establish atomoxetine as the first-line pharmacological treatment for recurrent VVS, addressing a significant gap in effective therapies for patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Seventh Prevention of Syncope Trial (POST VII)-A randomized clinical trial of atomoxetine for the prevention of vasovagal syncope: Rationale and study design. Sandhu, RK., Raj, SR., Hamzeh, R., et al.[2023]

Atomoxetine, the first non-stimulant medication approved for ADHD in the US, was developed to provide a safer alternative to traditional stimulant medications, which have been associated with various side effects.

This case report highlights a significant safety concern, as it describes a young woman experiencing a myocardial infarction (heart attack) potentially induced by atomoxetine, indicating that cardiovascular effects may need further investigation in patients using this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atomoxetine-induced myocardial infarction. Seifi, A., Griffith, H., Avestimehr, S., et al.[2015]

Atomoxetine is an effective non-stimulant treatment for ADHD in children and adolescents, showing significant improvements in ADHD symptoms compared to placebo across six clinical trials involving over 3,000 participants.

The drug is well tolerated with minimal side effects, primarily gastrointestinal issues and decreased appetite, and it does not appear to have abuse potential, making it a safe long-term option for managing ADHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Atomoxetine (Strattera), an alternative in the treatment of attention-deficit/hyperactivity disorder (ADHD) in children]. Gaillez, C., Sorbara, F., Perrin, E.[2020]

In a placebo-controlled trial involving 46 patients with recurrent vasovagal syncope (VVS), atomoxetine significantly reduced the number of syncopal and pre-syncopal episodes after three months compared to placebo (P < 0.001).

Atomoxetine also extended the median time to the first pre-syncopal episode to 55 days in the treatment group, compared to just 27 days in the placebo group, particularly benefiting patients with low blood pressure (systolic < 110 mmHg).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atomoxetine as an adjunct to nonpharmacological treatments for preventing vasovagal attacks in patients with recurrent vasovagal syncope: A pilot randomized-controlled trial. Tajdini, M., Aminorroaya, A., Tavolinejad, H., et al.[2023]

Citations

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Atomoxetine for suppression of vasovagal syncope

While taking atomoxetine, 11/12 patients appeared to improve and 7/12 had no syncope in follow-up (p = 0.0046). The annualized syncope frequency ...

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In a recent proof of principle study, atomoxetine reduced the number of HUTT-induced syncope by about 50% compared to placebo [10]. Additionally, a recent ...

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A similar pre-post study showed that atomoxetine also reduces syncope frequency about 85% in patients with frequent and drug-intolerant or drug-resistant ...

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Conclusion. In this case series atomoxetine was effective in preventing vasovagal syncope. The novel use of the Poisson distribution permits per patient ...

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A sample size of 56 syncope patients would have 85% power to detect a 60% relative risk reduction from a placebo outcome rate of 65%, using an unmatched 2- ...

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Assuming a 33% relative risk reduction in syncope recurrence with atomoxetine, and a dropout rate of 16%, the enrollment of 180 patients will give an 85% power ...

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Atomoxetine for Fainting (Vasovagal Syncope) (POST7 Trial)

In a study involving 56 patients with vasovagal syncope, atomoxetine (40 mg) significantly reduced the incidence of tilt-induced syncope compared to placebo, ...