Ondansetron for Sleep Fainting

(POST9 Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Calgary

Must be taking: Ondansetron

Disqualifiers: Pregnancy, QT interval > 500 ms, 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: 14

Duration: 6 months

24 Participants Needed

Trial Summary

What is the purpose of this trial?

At least 5% of patients with vasovagal syncope also have Sleep Syncope. Patients awake from sleep with profound malaise and gastrointestinal vagal symptoms. About 75% have severe nausea and about 40% have lower abdominal cramps. Some faint while supine, but most find their symptoms so severe that they rise quickly and hurry to the bathroom. Sometime either on the way to the toilet, near it, or shortly afterwards they faint. The nausea is followed by vomiting, and the cramps by watery diarrhea. After relief the patients remain presyncopal, diaphoretic, and tired. Almost all patients also have clinical vasovagal syncope during daytime hours. The cause of this is unknown. Orthostatic stress cannot be a factor in triggering the event, and in isolated case reports it occurs during non-REM sleep. There is no classic provocative situation of pain, the sight of trauma, or the presence of medical settings. These suggest the importance of central processes and the reduced likelihood that strategies that target maintaining preload (such as with midodrine and fludrocortisone) would be helpful. As well, midodrine is avoided during the night. Recently the investigators reasoned that if the investigators could rapidly suppress the nausea patients could remain supine, wait out the nausea, and not faint with orthostatic stress. Ondansetron is a potent anti-nausea medication that has rapidly dissolving preparations. Nine patients were instructed to keep one at the bedside, insert it upon waking up with nausea, remain in bed, and raise their legs (if possible). There was partial success with ondansetron 4 mg and complete success with ondansetron 8 mg. This remarkable but anecdotal observation requires formal testing. Research Objectives: the investigators will test the hypothesis that ondansetron 8 mg prn sublingually on awakening with moderate to severe nausea prevents loss of consciousness in patients with prior Sleep Syncope who awaken with malaise and nausea. Study Design \& Methodology: The main study will be a placebo-controlled, double-blind, randomized, crossover clinical trial. The primary outcome will be the progression of awakening with nausea to syncope. Thirty patients with Sleep Syncope will be randomized 1:1 to receive packages of either ondansetron 8 mg sublingual tablets or matching placebo. They will each receive 3 boxes of 10 tabs, with refills available if needed. Each crossover period will last 6 months. In a substudy the investigators will test whether the predominant disturbed physiology is bradycardia, decreased venous return, or decreased systemic vascular resistance. This will be assessed using a unique, small, wearable blood pressure sensor that can be rapidly donned on the ear. It records heart rate and beat-to-beat waveforms, which permit estimating stroke volume, systemic vascular resistance, and cardiac output. the investigators will record these variables in all patients continuously from when the device is put on until 30 minutes afterwards. the investigators hypothesize that unlike during syncope provoked by head-up tilt testing, here there will be no decrease in preload until patients arise, and that the main physiologic disturbance during syncope is hypotension due to decreased preload superimposed on heart rate collapse. Anticipated Outcomes: If successful, this research would be i) the first to report a well-tolerated and highly effective treatment for most sleep syncope, and ii) the first to report the physiology of brain-initiated vasovagal syncope in the community outside a laboratory environment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Ondansetron for sleep fainting?

Ondansetron has been shown to be effective in preventing nausea and vomiting caused by chemotherapy, radiotherapy, and anesthesia, with high response rates and minimal side effects. It has also been associated with better survival outcomes in patients with acute pancreatitis, suggesting its potential effectiveness in managing other conditions. ^{1 2 3 4 5}

Is ondansetron safe for use in humans?

Ondansetron, also known as Zofran, has been shown to be generally safe in humans, with studies reporting no major adverse effects. Some minor side effects like headache and constipation have been observed, but overall, it is considered a safe antiemetic (prevents nausea and vomiting) for various conditions. ^{1 5 6 7 8}

How is the drug ondansetron unique for treating sleep fainting?

Ondansetron is unique because it works by blocking serotonin receptors, specifically the 5-HT3 subtype, which may help reduce sleep-related breathing issues. This mechanism is different from other treatments that do not target serotonin pathways. ^{9 10 11 12 13}

Eligibility Criteria

This trial is for adults over 18 who experience fainting during sleep and meet certain criteria for vasovagal syncope. They must have had at least one such episode in the past year and score a specific minimum on a syncope symptom scale. Pregnant individuals, those unable to consent, or not using birth control, as well as anyone with a long QT interval on an ECG are excluded.

Inclusion Criteria

You have experienced fainting as outlined in the American College of Cardiology Guidelines from 2017.

You have a Calgary Syncope Symptom Score of at least -2 for structurally normal hearts.

I am 18 years or older and have given my informed consent.

Exclusion Criteria

Your heart's QT interval is longer than 500 milliseconds without any fixable reasons.

I am unable to understand and agree to the study's details on my own.

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either ondansetron 8 mg sublingual tablets or matching placebo upon awakening with nausea

6 months

Visits at baseline, 3 months, and 6 months

Crossover

Participants switch from one treatment arm to the other

6 months

Visits at 9 months and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Ondansetron

Trial Overview The study tests if Ondansetron (an anti-nausea medication) can prevent fainting when taken sublingually upon waking with nausea due to Sleep Syncope. It's compared against a placebo in a double-blind crossover design where participants switch between treatments after six months.

Participant Groups

Group I: Ondansetron Active Control 1 Intervention

ondansetron 8 mg prn sublingually when awakening with nausea. as per the FDA label for ondansetron.

Group II: Placebo Placebo Group 1 Intervention

Matching placebo will be identical in appearance to the active treatment pill.

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

Approved in United States as Zofran for:

• Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy
• Prevention of postoperative nausea and/or vomiting

Approved in European Union as Zofran for:

• Prevention of nausea and vomiting associated with chemotherapy
• Prevention of postoperative nausea and vomiting

Approved in Canada as Zofran for:

• Prevention of nausea and vomiting associated with chemotherapy
• Prevention of postoperative nausea and vomiting

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Findings from Research

In a study of 35 children undergoing highly emetogenic chemotherapy, ondansetron was found to be highly effective in preventing nausea and vomiting, achieving complete or major responses in 85.3% of patients without cisplatin and 71.4% with cisplatin, compared to only 38.8% with traditional antiemetics.

Ondansetron was administered at lower than recommended doses for 85 days without any adverse effects, indicating it is a safe and effective antiemetic option, especially since it does not cause sedation and was well-received by patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ondansetron as an effective drug in prophylaxis of chemotherapy--induced emesis in children. Kołecki, P., Wachowiak, J., Beshari, SE.[2013]

Ondansetron is highly effective in treating acute nausea and vomiting, outperforming metoclopramide, and shows minimal toxicity, making it particularly beneficial for young patients.

While ondansetron demonstrates consistent effectiveness in non-cisplatin and radiotherapy settings, its efficacy in cisplatin-related delayed emesis remains uncertain, highlighting the importance of patient preferences in choosing anti-emetic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Introduction: the clinical challenge. Schmoll, HJ.[2013]

In a pilot study of 20 patients with acute unilateral vestibular neuritis, ondansetron treatment resulted in a significantly lower early caloric vestibular deficit compared to metoclopramide, suggesting it may be more effective in managing vestibular symptoms.

Patients receiving ondansetron also experienced shorter hospital stays and quicker times to independent walking, indicating that it not only helps with symptoms but may also improve recovery times.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A protective effect of 5-HT3 antagonist against vestibular deficit? Metoclopramide versus ondansetron at the early stage of vestibular neuritis: a pilot study. Venail, F., Biboulet, R., Mondain, M., et al.[2014]

Ondansetron effectively controlled acute emesis in 53% of patients on a specific dosing schedule after non-cisplatin-based chemotherapy, demonstrating its potential as a treatment for those previously resistant to standard antiemetics.

The drug maintained its antiemetic efficacy across multiple treatment cycles, with no major toxicity reported, making it a safe option for patients experiencing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The 5-HT3 receptor antagonist ondansetron re-establishes control in refractory emesis induced by non-cisplatin chemotherapy. Seynaeve, C., de Mulder, PH., Lane-Allman, E., et al.[2019]

Ondansetron, administered intravenously at 4 mg once daily for 3-5 days, effectively controlled nausea in 59% and emesis in 68% of patients receiving non-platinum anticancer drugs, demonstrating its efficacy as an anti-emetic.

The safety profile of Ondansetron was strong, with 98% of cases showing no safety issues, and only minor side effects like headache and constipation reported in a few instances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Examination of anti-emetic effect and safety of multiple intravenous doses of ondansetron in patients receiving nonplatinum anti-cancer drugs]. Nukariya, N., Niitani, H., Taguchi, T., et al.[2013]

In a study of 40 patients with advanced tumors receiving various chemotherapy regimens, ondansetron demonstrated a strong prophylactic antiemetic effect, particularly in the CHOP group, where 64% experienced full control of nausea and vomiting.

No significant side effects were reported from ondansetron treatment, indicating it is a safe option for managing chemotherapy-induced nausea and loss of appetite in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Novel pharmacologic form of ondansetron (Zofran)--lingual tablets in the prevention of cytostatic chemotherapy-induced loss of appetite, nausea and vomiting]. Gershanovich, ML., Beresneva, IA., Makhnova, EV.[2015]

References

1. Poland pubmed.ncbi.nlm.nih.gov

Ondansetron as an effective drug in prophylaxis of chemotherapy--induced emesis in children. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Introduction: the clinical challenge. [2013]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Ondansetron: recommended antiemetics for patients with acute pancreatitis? a population-based study. [2023]

4. France pubmed.ncbi.nlm.nih.gov

A protective effect of 5-HT3 antagonist against vestibular deficit? Metoclopramide versus ondansetron at the early stage of vestibular neuritis: a pilot study. [2014]

5. England pubmed.ncbi.nlm.nih.gov

The 5-HT3 receptor antagonist ondansetron re-establishes control in refractory emesis induced by non-cisplatin chemotherapy. [2019]

6. England pubmed.ncbi.nlm.nih.gov

The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. [2013]

7. Japan pubmed.ncbi.nlm.nih.gov

[Examination of anti-emetic effect and safety of multiple intravenous doses of ondansetron in patients receiving nonplatinum anti-cancer drugs]. [2013]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Novel pharmacologic form of ondansetron (Zofran)--lingual tablets in the prevention of cytostatic chemotherapy-induced loss of appetite, nausea and vomiting]. [2015]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment with the novel TAAR1 agonist ulotaront is associated with reductions in quantitative polysomnographic REM sleep without atonia in healthy human subjects: Results of a post-hoc analysis. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

The effects of ondansetron on sleep-disordered breathing in the English bulldog. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Once-nightly sodium oxybate (FT218) improved symptoms of disrupted nighttime sleep in people with narcolepsy: a plain language summary. [2023]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Medications as a Trigger of Sleep-Related Eating Disorder: A Disproportionality Analysis. [2023]