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Effect of estradiol‑based menopausal hormone therapy drug combination on QTc in peri‑ and postmenopausal women with genetically confirmed Long QT syndrome

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study examines women who have Long QT syndrome, a rare heart condition that can cause the heart to beat irregularly, especially when hormone levels change during menopause. The trial tests several forms of menopausal hormone therapy, including a skin patch called Estradot, a skin gel called Estrogel, a soft capsule called Utrogestan, a spray called Lenzetto, and an oral tablet called Norethisterone acetate. These products contain estradiol or a related hormone that replaces the hormones lost at menopause.

The purpose is to see how each regimen changes the heart’s electrical timing, measured as the QTc interval on a standard ECG. Participants will receive each hormone regimen for about four weeks in a random order, with a short break between periods. During each period, a tiny implanted device (ILR) records any serious heart rhythm problems, and regular check‑ups track symptoms and hormone effects. After the short treatment phases, participants are observed for a longer time while continuing usual care.

The research process

The trial runs in 9 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline visit and device implantation

    On the first study visit a baseline electrocardiogram (ecg) is performed to record the heart’s electrical activity before any hormone therapy is started.

    An implantable loop recorder (ilr) is placed under the skin to continuously monitor heart rhythm throughout the study.

    A questionnaire about menopausal symptoms and medical history is completed.

  2. Step 2

    Randomization to the first hormone regimen

    The patient is randomly assigned to one of the estrogen preparations that will be used for the first 4‑week treatment period.

    Possible estrogen options are:

    • estradot patch delivering 50 µg estradiol over 24 hours, applied once daily.
    • estrogel gel delivering 0.75 mg estradiol, applied once daily.
    • lenzetto spray delivering 3.06 mg estradiol, applied once daily.
    • estradiol oral tablet 1 mg, taken once daily.

    If the study protocol requires a progesterone component, the patient will also receive either utrogestan soft capsule 100 mg or norethisterone acetate tablet 0.5 mg, both taken once daily.

  3. Step 3

    Daily administration of the assigned medication

    For a transdermal patch, the patch is applied to clean, dry skin on the abdomen or buttock and replaced every 24 hours.

    For a transdermal gel, a measured amount is spread on the skin of the upper arm or abdomen and allowed to dry before dressing.

    For a transdermal spray, the spray is applied to the skin of the upper arm or abdomen once daily as directed.

    For oral tablets or capsules, the dose is swallowed with water at the same time each day.

    If a progesterone capsule or tablet is required, it is also taken once daily with water.

  4. Step 4

    Monitoring during the 4‑week treatment period

    The patient continues the assigned medication for a total of 4 weeks.

    Regular visits (typically weekly or bi‑weekly) are scheduled for repeat ecg recordings and safety checks.

    The implanted ilr continuously records heart rhythm and any ventricular arrhythmias, which are reviewed by study staff.

  5. Step 5

    Assessment at the end of the first period

    At the end of the 4‑week period a final ecg is performed to determine the maximum change in the corrected QT interval (qtc).

    The data from the ilr are examined for any ventricular arrhythmias that occurred during the period.

    The patient completes a follow‑up questionnaire about menopausal symptoms.

  6. Step 6

    Transition to the next hormone regimen

    After the first assessment the patient stops the current medication and is randomly assigned to the next estrogen preparation, following the same dosage and frequency rules described in step 2.

    If a progesterone component is required for the new regimen, the appropriate capsule or tablet is prescribed as in step 2.

  7. Step 7

    Repeat of treatment, monitoring and assessment

    The patient repeats steps 3 through 5 for each subsequent 4‑week hormone regimen.

    Each period is monitored in the same way, with weekly ecg checks, continuous ilr recording, and symptom questionnaires.

  8. Step 8

    Completion of all crossover periods

    Once all assigned hormone regimens have been completed, the active crossover phase of the study ends.

    The patient’s overall data, including the maximum qtc changes for each regimen and any recorded arrhythmias, are compiled for analysis.

  9. Step 9

    Long‑term observational follow‑up

    After the crossover phase the patient enters a long‑term observational period during which routine clinical care continues.

    Periodic study visits are scheduled (for example at 3, 6 and 12 months) to perform additional ecg recordings, review ilr data, and complete menopause rating scale questionnaires.

    No study medication is required during this follow‑up; the patient follows the hormone therapy prescribed by the regular treating physician.

Who can join the trial?

4 criteria

  • Be a woman who is 18 years of age or older.
  • Have a diagnosis of Long QT syndrome that has been proven by a genetic test; this is a heart rhythm condition that can be identified through DNA testing.
  • Be either perimenopausal (in the transition to menopause) or postmenopausal (menopause has already occurred) and have a doctor‑recommended need for systemic menopausal hormone therapy (MHT), which means taking hormone medicine that works throughout the whole body to treat low estrogen levels.
  • If you are perimenopausal and it cannot be confirmed that you are a woman of no child‑bearing potential (WNCBP), you must agree to use reliable non‑estrogen‑containing contraception (birth control that does not include estrogen) during the first part of the study.

Who cannot join the trial?

15 criteria

  • The heart’s electrical measurement called the corrected QT interval (QTc) must be less than 520 milliseconds; if it is 520 ms or higher, you cannot join the study.
  • Having other serious health problems that raise the risk of dangerous heart rhythms or make the study hard to interpret will exclude you. This includes structural heart disease, serious coronary artery disease, a heart attack in the past year, heart failure with reduced pumping ability, serious heart muscle disease, very low potassium, calcium or magnesium levels, severe kidney or liver failure, or any condition known to increase the chance of abnormal heart rhythms.
  • If you are currently taking any hormone medicines such as menopausal hormone therapy, birth control pills, or other estrogen, progesterone, or testosterone products, you must stop them and wait at least 14 days (a “washout period”) before the screening visit; otherwise you cannot take part.
  • If you have any condition that makes hormone therapy unsafe (called a contraindication), you cannot join. This includes:
    • Current, past, or suspected breast cancer (family history alone is not a reason).
    • Cancers that grow when exposed to estrogen or treatment with medicines that block estrogen production (aromatase inhibitors).
    • Unexplained heavy or irregular vaginal bleeding, or not having had a routine pelvic exam by a doctor in the last five years.
    • A recent (within one year) blood clot in a vein, such as deep‑vein thrombosis or a clot in the lungs (pulmonary embolism).
    • Blood‑clotting disorders like protein C, protein S, or antithrombin deficiency.
    • A recent (within one year) clot in an artery, such as chest pain from reduced blood flow (angina) or a heart attack.
    • Active liver disease or a history of liver problems that have not fully healed.
    • A skin condition called porphyria cutanea tarda.
    • Being pregnant.
    • If you are allergic (hypersensitive) to the study drug or any of its inactive ingredients, you cannot join.
    • If you cannot follow the study schedule, attend monitoring visits, or agree to wear a small heart monitor (implantable loop recorder), you may be allowed to join but your data will not be used for certain analyses; inability to comply may lead to exclusion.
    • If a court has placed you under legal guardianship, curatorship, or other judicial supervision, you are not eligible for the study.
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Investigated drugs

  • Estradot

    is a small patch that sticks to the skin and releases estradiol, a natural form of estrogen, continuously over a day. In this study it is used as one way to give menopausal hormone therapy to see how it may change the heart’s electrical timing.

  • Estrogel

    is a clear gel that is rubbed onto the skin. It contains estradiol, which is absorbed through the skin into the bloodstream. The trial uses this gel as another form of estrogen replacement to test its effect on the heart’s QT interval.

  • Utrogestan

    is a soft, oral capsule that holds micronised progesterone, a natural hormone that balances estrogen. Participants take this capsule as the progesterone part of their hormone therapy while researchers watch for any changes in heart rhythm.

  • Estradiol

    (oral) is a tablet that delivers estradiol directly through the stomach and into the blood. It provides an alternative way to give estrogen in the trial, allowing comparison with the skin‑applied products.

  • Lenzetto

    is a spray that is applied to the skin and contains estradiol hemihydrate. The spray quickly dries and the hormone is absorbed through the skin. This method is tested in the study to see if it affects the QTc interval differently from patches or gels.

  • Norethisterone acetate

    is an oral tablet that contains a synthetic form of progesterone called a progestin. It is used as the progesterone component of the hormone regimen in the trial, helping researchers understand its impact on heart rhythm in women with long QT syndrome.

What is already known about the treatment

  • Estradot 50 mikrog/24 timer depotplaster

    This is a small patch that sticks to the skin and releases 50 µg of estradiol each day. It is an approved estrogen product that is commonly used to treat hot flashes and protect bone health in menopausal women. The patch works by letting estradiol enter the bloodstream and bind to estrogen receptors, helping to restore normal hormone balance. It belongs to the class of estrogen hormone replacement therapies.

  • Estrogel 0,75 mg/dose transdermalgel

    This is a clear gel applied to the skin that delivers 0.75 mg of estradiol per dose. It is a licensed estrogen medication used for relief of menopausal symptoms such as night sweats and for osteoporosis prevention. The gel allows estradiol to be absorbed through the skin, where it activates estrogen receptors and supports normal hormonal function. It is classified as an estrogen hormone therapy.

  • Utrogestan 100 mg myk kapsel

    These are soft oral capsules that contain 100 mg of micronised progesterone. The product is approved for use in hormone therapy to protect the uterus when estrogen is given, and also for certain fertility treatments. After swallowing, the progesterone is absorbed and binds to progesterone receptors, helping to prepare the uterine lining and balance estrogen effects. It is classified as a progestogen (natural progesterone) medication.

  • ESTRADIOL

    This is an oral tablet that provides 1 mg of estradiol per dose. It is a well‑established estrogen drug used to treat menopausal symptoms and low estrogen levels. The tablet is absorbed in the gut, and the estradiol circulates in the blood to activate estrogen receptors, restoring normal hormone activity. It belongs to the estrogen hormone replacement therapy class.

  • Lenzetto 1,53 mg/spray transdermal spray, oppløsning

    This is a spray that is applied to the skin and delivers 3.06 mg of estradiol hemihydrate per application. It is an approved estrogen product used for relief of menopausal hot flashes and for bone health support. The spray allows estradiol to pass through the skin into the bloodstream, where it binds to estrogen receptors and helps normalize hormone levels. It is classified as an estrogen hormone therapy.

  • NORETHISTERONE ACETATE

    This is an oral tablet that contains 0.5 mg of norethisterone acetate, a synthetic progestin. It is a licensed medication for menstrual disorders and as part of hormone therapy in menopause. After ingestion, the drug is absorbed and acts on progesterone receptors, mimicking natural progesterone to control the growth of the uterine lining. It belongs to the synthetic progestogen (progestin) class.

Investigated diseases

Long QT syndrome - Long QT syndrome is a genetic condition that affects the heart’s electrical system, causing the QT interval on an ECG to be longer than normal. This prolongation can make the heart more likely to develop irregular, rapid beats, especially during physical or emotional stress. People may experience symptoms such as dizziness, fainting, or palpitations when these irregular beats occur. Over time, the frequency of these episodes can increase, leading to more noticeable disturbances in heart rhythm.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2026-526442-28-00Protocol codeLQTS-HEREstimated enrolment15 patientsSponsorOslo University Hospital HF

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