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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether cyproheptadine, a medication that blocks a specific receptor, can reduce the severity of mitral regurgitation. In this heart condition, the mitral valve doesn't close tightly, causing blood to flow backward in the heart. Participants will receive either cyproheptadine or a placebo to compare effects. Those with a recent heart attack and specific heart function issues might be suitable candidates. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

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 there any evidence suggesting that cyproheptadine is likely to be safe for humans?

Research has shown that cyproheptadine, a medication that blocks certain signals in the body, might help with heart valve problems. People taking cyproheptadine experienced fewer heart valve issues after a heart attack. However, possible side effects include drowsiness and slower reactions, so caution is advised when driving or operating machinery. Cyproheptadine is already approved for other uses, indicating it is generally safe when used properly. Participants should discuss any concerns with their doctor before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for mitral valve regurgitation?

Cyproheptadine is unique because it offers a fresh approach to treating mitral valve regurgitation by utilizing an antihistamine typically used for allergies. Unlike the standard of care options like diuretics, ACE inhibitors, or beta-blockers, which focus on managing symptoms or reducing heart strain, cyproheptadine's action as a serotonin antagonist might directly influence the remodeling of the heart valve itself. Researchers are excited about this because it could mean more effective management of the condition by potentially addressing one of its underlying causes rather than just alleviating symptoms.

What evidence suggests that cyproheptadine might be an effective treatment for mitral valve regurgitation?

In this trial, participants will receive either cyproheptadine or a placebo to study its effects on mitral valve regurgitation, a condition where the heart valve leaks. Research has shown that cyproheptadine might help treat this condition by blocking a specific serotonin receptor, which lowers serotonin levels after a heart attack. This action helps prevent the heart valve from becoming too stiff or thick. In previous studies, patients who took cyproheptadine demonstrated improvements in the shape and function of their mitral valve. These findings suggest that cyproheptadine may help reduce the severity of valve leakage. ^{1 3 4 5 6}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. jacc.org jacc.org/doi/10.1016/j.jacc.2022.05.025

Effects of Cyproheptadine on Mitral Valve Remodeling and ... Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0735109722051646

Effects of Cyproheptadine on Mitral Valve Remodeling and ... Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35902173/

Effects of Cyproheptadine on Mitral Valve Remodeling and ... Conclusions: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with ...

4. jacc.org jacc.org/doi/abs/10.1016/j.jacc.2022.05.025

Effects of Cyproheptadine on Mitral Valve Remodeling and ... Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve ...

5. researchgate.net researchgate.net/publication/362265695_Effects_of_Cyproheptadine_on_Mitral_Valve_Remodeling_and_Regurgitation_After_Myocardial_Infarction

Effects of Cyproheptadine on Mitral Valve Remodeling and ... Conclusions Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger ...

6. rxlist.com rxlist.com/cyproheptadine/generic-drug.htm

Cyproheptadine: Side Effects, Uses, Dosage, Interactions, ... Documented hypersensitivity · May cause central nervous system (CNS) depression, which may impair mental abilities; use caution when operating heavy machinery.