Progesterone + Testosterone for Long QT Syndrome

Recruiting at 2 trial locations

Overseen By Heather A Jaynes, MSN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Indiana University

Must not be taking: QT prolonging, CYP3A inhibitors, CYP3A inducers

Disqualifiers: Cancer, Heart failure, Arrhythmias, others

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

Compensation: Varies

Number of Visits: 2

Duration: 2 weeks for women, 1 week for men

73 Participants Needed

Trial Summary

What is the purpose of this trial?

This research will determine if: 1) Oral progesterone attenuates drug-induced QT interval, J-Tpeak and Tpeak-Tend lengthening in postmenopausal women 50 years of age or older, and 2) Transdermal testosterone attenuates drug-induced QT interval, J-Tpeak and Tpeak-Tend lengthening in men 65 years of age or older. This investigation will consist of two concurrent prospective, randomized, double-blind, placebo-controlled crossover-design studies in a) Postmenopausal women, and b) Men 65 years of age or older. Study 1: Each postmenopausal woman will take progesterone or placebo capsules for 1 week. After a 14-day "washout" (no progesterone or placebo) each subject will then take the alternative therapy (progesterone or placebo) for 1 week. After 7 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the progesterone and placebo phases will be compared. Study 2: Each man 65 years of age or older will apply transdermal testosterone or transdermal placebo gel for 3 days. After a 7-day "washout" (no testosterone or placebo) each subject will then apply the alternative therapy (testosterone or placebo gel) for 1 week. After 3 days of each treatment, subjects will present to the clinical research center to receive a small dose of the QT interval-lengthening drug ibutilide, and the effect on the QT, J-Tpeak and Tpeak-Tend intervals during the testosterone and placebo phases will be compared.

Do I need to stop my current medications to join the trial?

Yes, you will need to stop taking any medications that prolong the QT interval or affect cytochrome P450 enzymes, as these are part of the exclusion criteria for the trial.

What data supports the effectiveness of the treatment Progesterone + Testosterone for Long QT Syndrome?

Research suggests that testosterone can shorten the QT interval, which is beneficial for Long QT Syndrome. Additionally, progesterone has shown favorable effects on cardiac events in animal studies with Long QT Syndrome mutations. ^{1 2 3 4 5}

Is the combination of progesterone and testosterone generally safe for humans?

Progesterone and testosterone have been studied in various forms and doses for different conditions. Progesterone, when delivered in low doses through non-oral methods, may have fewer side effects than oral therapy, but long-term safety needs more evaluation. Testosterone patches have been tested in healthy men and appear to maintain normal hormone levels, suggesting they are safe for further testing. ^{6 7 8 9 10}

How does the drug Progesterone + Testosterone for Long QT Syndrome differ from other treatments?

This drug is unique because it combines progesterone and testosterone, which are typically used in hormone replacement therapy, and delivers them transdermally (through the skin) to potentially manage Long QT Syndrome, a condition with no standard treatment. The transdermal route allows for steady hormone levels and avoids the liver's first-pass metabolism, which can reduce side effects compared to oral administration. ^{6 7 9 11 12}

Research Team

James E Tisdale, PharmD

Principal Investigator

Purdue University

Eligibility Criteria

This trial is for postmenopausal women aged 50-99 and men aged 65-99 without certain health conditions like severe anemia, heart issues, or a history of specific cancers. Participants should not be on hormone replacement therapy or drugs that affect heart rhythm.

Inclusion Criteria

I have not had a menstrual period for at least 12 months.

I am a man aged between 65 and 99.

I am a woman aged 50-99 and have gone through menopause.

Exclusion Criteria

I am currently taking medication that can affect my heart's rhythm.

My heart's electrical activity reading (QTc) is over 450 ms.

I am an older man diagnosed with heart failure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either oral progesterone or transdermal testosterone, followed by a washout period and crossover to the alternative treatment.

2 weeks for women, 1 week for men

2 visits (in-person) for ibutilide administration

Washout

Participants undergo a washout period between treatment phases to eliminate the effects of the first treatment before starting the second.

14 days for women, 7 days for men

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse effects and QT interval changes.

8 hours post-ibutilide infusion

Monitoring during and after ibutilide infusion

Treatment Details

Interventions

• Ibutilide
• Placebo
• Progesterone
• Testosterone

Trial Overview The study tests if progesterone in women and testosterone in men can reduce changes to the heart's electrical activity caused by ibutilide, a drug known to lengthen the QT interval. It's a controlled experiment where participants randomly receive either the hormone treatment or placebo.

Participant Groups

Group I: Postmenopausal women: Progesterone Experimental Treatment 2 Interventions

Subjects will receive treatment with oral progesterone 400 mg once daily (two x 200 mg capsules) every evening for 7 days

Group II: Men 65 years of age or older: Testosterone Experimental Treatment 2 Interventions

Subjects will receive treatment with transdermal testosterone 1% (100 mg) every morning for 3 days

Group III: Men 65 years of age or older: Placebo Placebo Group 2 Interventions

Subjects will receive treatment with transdermal placebo every morning for 3 days

Group IV: Postmenopausal women: Placebo Placebo Group 2 Interventions

Subjects will receive oral placebo, two capsules once daily every evening for 7 days

Who Is Running the Clinical Trial?

Indiana University

Lead Sponsor

Trials

1,063

Recruited

1,182,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Harvard University

Collaborator

Trials

237

Recruited

588,000+

Cedars-Sinai Medical Center

Collaborator

Trials

523

Recruited

165,000+

Purdue University

Collaborator

Trials

239

Recruited

72,200+

Findings from Research

Age and gender differences in QTc-intervals are likely influenced by sex-specific hormones, with testosterone shortening the QTc-interval in males.

In females, the interaction between progesterone and estrogen is more complex, and in patients with long-QT syndrome, the effects of these hormones on QTc-intervals vary significantly depending on the specific LQTS genotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of age and gender on the QTc-interval in healthy individuals and patients with long-QT syndrome. Vink, AS., Clur, SB., Wilde, AAM., et al.[2018]

In a study involving 14 older male volunteers, transdermal testosterone significantly reduced drug-induced lengthening of both early and late ventricular repolarization, as measured by electrocardiographic parameters, compared to placebo and oral progesterone.

The results indicate that transdermal testosterone may have a protective effect on heart rhythm in older men, while oral progesterone showed minimal impact on these measures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men. Tomaselli Muensterman, E., Jaynes, HA., Sowinski, KM., et al.[2023]

A detailed clinical evaluation of patients with diagnosed long QT syndrome revealed that some cases were actually caused by hormonal imbalances (endocrinopathies) rather than genetic factors.

This suggests that hormonal conditions can mimic long QT syndrome, highlighting the importance of thorough clinical assessments before concluding a genetic cause for QT prolongation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endocrinopathies mimicking gene negative long QT syndrome. Chakraborty, P., Roberts, JD., Gollob, MH.[2022]

Endogenous sex hormones, particularly progesterone, have a significant impact on the QT interval during the menstrual cycle, with progesterone shortening the action potential and estrogen lengthening it.

Menopausal hormone therapy shows that estrogen alone lengthens the QT interval, while the combination of estrogen and progesterone does not affect it, indicating a complex interaction that warrants further research, especially regarding oral contraception and its effects on the QT interval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sex hormones and the QT interval: a review. Sedlak, T., Shufelt, C., Iribarren, C., et al.[2021]

In a study of 174 patients with long QT syndrome (LQTS), the use of oral contraceptives did not change the risk of cardiac events compared to when they were not using them, indicating no significant impact on safety or efficacy.

The analysis showed consistent results across different LQTS subtypes, suggesting that oral contraceptive therapy neither benefits nor harms patients with LQTS in terms of cardiac event risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral contraceptive use and the risk of cardiac events in patients with long QT syndrome. Abu-Zeitone, A., Peterson, DR., Polonsky, B., et al.[2021]

New non-oral hormonal replacement therapy options, such as vaginal rings, gels, and intra-uterine systems (IUSs), allow for low-dose sustained delivery of progestins, which can help achieve lower systemic levels and potentially reduce side effects compared to traditional oral methods.

While these new delivery methods, including transdermal and intranasal routes, show promise for effective hormone delivery, their long-term safety still needs to be thoroughly evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parenteral administration of progestins for hormonal replacement therapy. Nath, A., Sitruk-Ware, R.[2013]

In a phase I study involving 6 healthy male volunteers, two types of testosterone transdermal patches were tested, showing that both systems can achieve physiological testosterone levels within 24 hours.

The use of a GnRH antagonist to suppress natural testosterone production allowed for a clearer evaluation of the effects of the testosterone patches, indicating that this method is effective for future clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of new testosterone transdermal therapeutic systems in gonadotropin-releasing hormone antagonist-suppressed normal men. Rolf, C., Gottschalk, I., Behre, HM., et al.[2013]

This study is the first to compare the efficacy and potency of various progestins, including natural progesterone and synthetic options, in activating the progesterone receptor isoform A (PR-A) in breast cancer cells, revealing that different progestins have unique effects based on receptor density.

The findings suggest that the effects of progestins in contraception and menopausal hormone therapy may vary in women depending on the specific progestin used and the density of PR-A, indicating a need for personalized approaches in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The transcriptional activity of progestins used in contraception and menopausal hormone therapy via progesterone receptor A is dependent on the density of the receptor. Cartwright, M., Toit, RL., Africander, D.[2023]

Different progestins in oral contraceptives and hormone replacement therapy have varying effects based on their chemical structure, which influences their binding affinity to hormone receptors and clinical outcomes.

Norgestimate, when combined with estrogen, does not appear to diminish the cardioprotective effects of estrogen, unlike some other progestins, suggesting it may be a safer option in hormone replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical profiles of progestins used in formulations of oral contraceptives and hormone replacement therapy. Hammond, GL., Rabe, T., Wagner, JD.[2019]

A study involving healthy volunteers showed that using lower doses of testosterone pellets (400 mg) had minimal effect on sperm output, while a higher dose (800 mg) effectively suppressed sperm production, but only a few men became azoospermic.

Adding a depot progestin (300 mg DMPA) to a lower testosterone dose significantly increased the number of men achieving azoospermia, with no serious side effects observed, suggesting a promising combination for male contraception.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. Handelsman, DJ., Conway, AJ., Howe, CJ., et al.[2013]

A study using yeast-based bioassays identified that certain progestins, particularly 17alpha-ethynylated derivatives of testosterone and 19-nortestosterone, have significant androgenic potential, raising concerns about their misuse in sports doping.

The research found that while modern progestins like progesterone and its derivatives have minimal androgenic activity and pose a low risk for abuse, modifications to more androgenic progestins can lead to the creation of potent designer androgens like THG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay. McRobb, L., Handelsman, DJ., Kazlauskas, R., et al.[2016]

Transdermal delivery of reproductive hormones, such as estrogens and progestogens, is effective for both hormone replacement therapy (HRT) and contraception, providing benefits like rapid onset of action and avoidance of first-pass liver metabolism.

Transdermal systems for testosterone in men show positive effects on mood and bone mass, but require regular monitoring for prostate health, highlighting the importance of safety in hormone therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice. Henzl, MR., Loomba, PK.[2019]

References

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

Effect of age and gender on the QTc-interval in healthy individuals and patients with long-QT syndrome. [2018]

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

Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men. [2023]

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

Endocrinopathies mimicking gene negative long QT syndrome. [2022]

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

Sex hormones and the QT interval: a review. [2021]

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

Oral contraceptive use and the risk of cardiac events in patients with long QT syndrome. [2021]

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

Parenteral administration of progestins for hormonal replacement therapy. [2013]

7. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of new testosterone transdermal therapeutic systems in gonadotropin-releasing hormone antagonist-suppressed normal men. [2013]

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

The transcriptional activity of progestins used in contraception and menopausal hormone therapy via progesterone receptor A is dependent on the density of the receptor. [2023]

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

Preclinical profiles of progestins used in formulations of oral contraceptives and hormone replacement therapy. [2019]

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

Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay. [2016]

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

Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice. [2019]