Cyproheptadine for Mitral Valve Regurgitation

(CYPRO-MR Trial)

Overseen By Jonathan Beaudoin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Laval University

Must not be taking: SSRIs, Sedatives

Disqualifiers: Atrial fibrillation, Pregnancy, Renal failure, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

214 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is intended to investigate the effect of cyproheptadine (a 5HT2B receptor blocker) on mitral regurgitation severity.

Will I have to stop taking my current medications?

The trial requires that you stop taking selective serotonin reuptake inhibitors (SSRIs) and sedative medications. If you are on these medications, you would need to discontinue them to participate.

Is cyproheptadine generally safe for humans?

Cyproheptadine is generally considered safe, with mild side effects like drowsiness being common. Rarely, it can cause liver issues, so monitoring is advised. ^{1 2 3 4 5}

How does the drug cyproheptadine differ from other treatments for mitral valve regurgitation?

Cyproheptadine is unique because it has inhibitory activities for calcium channels and serotonin receptors, which might offer a novel approach to treating mitral valve regurgitation, a condition with limited standard drug treatments. Its potential to affect calcium channels could influence heart function differently than traditional therapies. ^{4 6 7 8 9}

Eligibility Criteria

This trial is for adults aged 18-80 who've had a first heart attack with blocked arteries and have specific types of heart muscle damage or weakness. It's not for those on sedatives, pregnant, with severe kidney issues, unable to consent, permanent irregular heartbeat, other major valve diseases, planned heart surgery soon, MRI contraindications, on antidepressants (SSRIs), cognitive disorders or at risk for urinary blockage/glaucoma.

Inclusion Criteria

My heart's pumping ability is reduced and I have specific heart valve or wall motion issues.

Exclusion Criteria

I am scheduled for heart surgery within the next 3 months.

My heart valve condition is due to infection, rheumatic disease, wear and tear, or was present at birth.

My kidney function is severely reduced.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cyproheptadine or placebo orally three times a day for 3 months, with dose titration based on tolerance

3 months

Regular visits for dose titration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including imaging and health status assessments

9 months

Periodic visits for imaging and assessments

Treatment Details

Interventions

• Cyproheptadine 4 Mg Oral Tablet
• Placebo

Trial Overview The study tests if cyproheptadine (a serotonin receptor blocker) can reduce the severity of leaky mitral valves in the heart after an ischemic event like a heart attack. Participants will either receive cyproheptadine tablets or placebo pills without active medication.

Participant Groups

Group I: Cyproheptadine 4 Mg Oral Tablet Experimental Treatment 1 Intervention

Participants will receive cyproheptadine 4mg tablet orally three times a day for three months, with a daily increase of 4mg/dose if the previous dose was well tolerated, up to 0.5 mg/kg/day.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive a matched placebo orally three times a day for 3 months. Daily titration similar to the treatment arm.

Cyproheptadine 4 Mg Oral Tablet is already approved in United States, European Union for the following indications:

Approved in United States as Periactin for:

• Allergic Reactions
• Allergic Rhinitis
• Allergies
• Anorexia
• Anorexia Nervosa
• Cluster Headaches
• Cushing's Syndrome
• Failure to Thrive
• Migraine
• Pruritus
• Sexual Dysfunction, SSRI Induced
• Unintentional Weight Loss (Underweight)
• Urticaria

Approved in European Union as Periactin for:

• Allergic Reactions
• Migraine Prevention
• Hay Fever
• Cyclical Vomiting Syndrome
• Psychogenic Itch
• Drug-induced Hyperhidrosis
• Prevention of Blister Formation in Epidermolysis Bullosa Simplex

Who Is Running the Clinical Trial?

Laval University

Lead Sponsor

Trials

439

Recruited

178,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

In a study involving pregnant rats, cyproheptadine HCL was administered at varying doses (0.5, 2.5, and 5 mg/kg/day) to assess its teratogenic effects, with no significant differences found in birth rates, fetal resorption rates, or malformation rates compared to a control group.

The results indicate that cyproheptadine does not have teratogenic effects in rats, even at higher doses that were toxic to the mothers, suggesting it may be safe for use during pregnancy in this animal model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Teratogenicity of cyproheptadine in pregnant rats. Weinstein, D., Ornoy, A., Ben-Zur, Z., et al.[2013]

A review of the French pharmacovigilance database revealed that cyproheptadine has a generally safe profile, with mild neurological effects being the most common adverse reactions, while serious liver complications are rare.

Despite its safety, there is a need for randomized controlled trials to further assess the efficacy and safety of cyproheptadine for stimulating appetite, particularly in children, as current studies are limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review. Bertrand, V., Massy, N., Vegas, N., et al.[2021]

A case study of a 42-year-old woman revealed that her death was due to intoxication from cyproheptadine and citalopram, highlighting the potential dangers of these medications, especially in overdose situations.

Despite cyproheptadine being widely available over-the-counter, this case underscores the rarity of reported fatalities associated with it, providing valuable data for forensic toxicology regarding its effects and concentrations in postmortem analysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fatality due to cyproheptadine and citalopram. Hargrove, V., Molina, DK.[2022]

Cyproheptadine (Cyp) has been found to inhibit N-type calcium channels, in addition to its known effects on histamine and serotonin receptors, suggesting a potential new mechanism for pain relief.

After optimizing Cyp, a new compound (referred to as 13) was developed that selectively blocks N-type calcium channels with lower activity against other receptors, and it demonstrated effective oral analgesic action in a rat pain model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery, structure-activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity. Yamamoto, T., Niwa, S., Iwayama, S., et al.[2014]

In a study of 50 patients with chronic urticaria, the new antihistamine HC 20-511 at a dose of 4 mg daily was found to be the most effective treatment compared to cyproheptadine (8 mg daily), providing rapid and long-lasting relief.

HC 20-511 caused less sedation than cyproheptadine, making it a potentially safer option for patients, while both medications had similar appetite-stimulating effects, although this was not observed with the lower dose of HC 20-511.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of a new antihistamine HC 20-511 with cyproheptadine (Periactin) in chronic urticaria. Kuokkanen, K.[2019]

A series of new compounds related to cyproheptadine were synthesized and tested, but only two showed activity against serotonin-induced contractions in rat stomach, and their effectiveness was lower than that of cyproheptadine itself.

The study found that the decreased potency of these new compounds may be linked to their greater conformational flexibility, which affects their ability to maintain an active form compared to cyproheptadine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyproheptadine analogues: synthesis, antiserotoninergic activity, and structure-activity relationships. Loza, MI., Sanz, F., Cadavid, MI., et al.[2019]

Cyproheptadine (CY) has been shown to significantly stimulate appetite and promote weight gain in various underweight populations, as evidenced by 39 out of 46 studies reviewed, including 32 randomized controlled trials.

While CY is generally safe and well-tolerated, it showed minimal benefit in patients with severe conditions like HIV and cancer, and the most common side effect reported was mild to moderate sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review. Harrison, ME., Norris, ML., Robinson, A., et al.[2020]

The compound (+/-)-3-methoxycyproheptadine is a peripheral serotonin antagonist that is only half as potent as cyproheptadine, indicating it may have a reduced efficacy in blocking serotonin compared to the original drug.

The study reveals that the anticholinergic activity is found only in the (+) enantiomer, while the (-) enantiomer retains antiserotonin, antihistaminic, and orexigenic properties, but these effects are weaker than those of cyproheptadine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

(+)- and (-)-3-Methoxycyproheptadine. A comparative evaluation of the antiserotonin, antihistaminic, anticholinergic, and orexigenic properties with cyproheptadine. Remy, DC., Rittle, KE., Hunt, CA., et al.[2019]

In a study involving 16 dogs with allergic pruritus, the administration of cyproheptadine hydrochloride at doses of 0.1 to 0.2 mg/kg/day did not result in any improvement in their condition.

The treatment caused polyphagia (increased appetite) in 25% of the dogs, indicating a potential side effect without therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Failure of cyproheptadine hydrochloride as an antipruritic agent in allergic dogs: results of a double-blinded, placebo-controlled study. Scott, DW., Miller, WH., Decker, GA., et al.[2013]

References

1. Belgium pubmed.ncbi.nlm.nih.gov

Teratogenicity of cyproheptadine in pregnant rats. [2013]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review. [2021]

3. England pubmed.ncbi.nlm.nih.gov

A fatality due to cyproheptadine and citalopram. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Discovery, structure-activity relationship study, and oral analgesic efficacy of cyproheptadine derivatives possessing N-type calcium channel inhibitory activity. [2014]

5. Denmark pubmed.ncbi.nlm.nih.gov

Comparison of a new antihistamine HC 20-511 with cyproheptadine (Periactin) in chronic urticaria. [2019]

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

Cyproheptadine analogues: synthesis, antiserotoninergic activity, and structure-activity relationships. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review. [2020]

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

(+)- and (-)-3-Methoxycyproheptadine. A comparative evaluation of the antiserotonin, antihistaminic, anticholinergic, and orexigenic properties with cyproheptadine. [2019]

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

Failure of cyproheptadine hydrochloride as an antipruritic agent in allergic dogs: results of a double-blinded, placebo-controlled study. [2013]