Ultrasound Imaging for Ovulatory Dysfunction

Overseen By Angela R Baerwald, PhD,MD,CCFP

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: University of Saskatchewan

Must not be taking: Hormonal contraception

Disqualifiers: Pregnancy, Smoking, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 3

Duration: 1-7 days

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of 2D and 3D ultrasound in diagnosing ovulation problems. It focuses on women with regular menstrual cycles to determine if these imaging methods enhance understanding of ovulation and non-ovulation. Participants will take indomethacin, a medication that might affect the ovulation process, to aid data collection. Women with regular menstrual cycles and no history of infertility or reproductive health issues may be suitable candidates. As a Phase 4 trial, this research explores how an FDA-approved treatment can benefit more patients.

Will I have to stop taking my current medications?

The trial requires that participants are not on any hormonal medications that affect reproduction, including hormonal contraception. If you are taking such medications, you would need to stop them to participate.

What is the safety track record for Indomethacin?

Research has shown that indomethacin, the treatment in this trial, has been safely used in humans for other conditions. It belongs to a group of medications called NSAIDs, which reduce inflammation and pain. Some studies have found that it can cause side effects like stomach pain, headaches, or dizziness. However, these side effects are usually mild, and not everyone will experience them.

Caution is advised when using indomethacin if certain conditions, such as mental health issues or epilepsy, are present due to possible risks. Additionally, it is not recommended for pregnant women after 30 weeks. These guidelines help ensure safe use of the medication.

Since this trial is in its final phase, earlier studies provide strong evidence that indomethacin is generally well-tolerated. For those considering joining the trial, these findings suggest that the treatment's safety is well understood. Always consult a healthcare professional if there are concerns about possible side effects. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard treatments for ovulatory dysfunction, which typically focus on hormone therapies, indomethacin offers a different approach by targeting inflammation. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) known for its ability to reduce inflammation and pain. Researchers are excited because it may provide a quicker intervention option, potentially showing results in just a few days. This could be a game-changer for those who don't respond well to hormone-based therapies or need a faster solution.

What evidence suggests that this treatment might be an effective treatment for ovulatory dysfunction?

Research has shown that indomethacin, which participants in this trial will receive, might not effectively stop early ovulation. Some studies have found that it doesn't significantly reduce the chances of ovulating too soon. For example, one study found that indomethacin had little effect on preventing early ovulation. However, it has been noted to lower the number of times a treatment cycle is stopped due to early ovulation in some cases. Overall, limited evidence supports its effectiveness for this purpose. ^{6 7 8 9 10}

Who Is on the Research Team?

Angela R Baerwald, PhD,MD,CCFP

Principal Investigator

University of Saskatchewan

Are You a Good Fit for This Trial?

This trial is for individuals experiencing ovulatory dysfunction. To participate, they must meet certain health criteria that will be determined by the study team.

Inclusion Criteria

I am a healthy woman.

Regular menstrual cycles (21-35 days)

Exclusion Criteria

Pregnancy

I have had a hysterectomy or oophorectomy.

Breastfeeding mothers

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive indomethacin 30 mg three times daily for 1-7 days, with daily 2D and 3D ultrasound scans and hormonal assays

1-7 days

Daily visits (in-person)

Follow-up

Participants are monitored with ultrasound scans and hormonal assays on days 1, 3, and 7 after anovulation

1 week

3 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Indomethacin

Trial Overview The study is testing the effectiveness of using both 2D and 3D ultrasonography to diagnose ovulation versus anovulation, alongside finger prick blood tests and urine tests.

How Is the Trial Designed?

Group I: Indomethacin Experimental Treatment 4 Interventions

Oral indomethacin 50 mg three times daily for 1-7 days. The administration is terminated when signs of anovulation are observed.

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

Approved in United States as Indocin for:

• Ankylosing Spondylitis
• Back Pain
• Bartter Syndrome
• Bursitis
• Cluster Headaches
• Frozen Shoulder
• Gitelman Syndrome
• Gout, Acute
• Langerhans' Cell Histiocytosis
• Osteoarthritis
• Pain
• Patent Ductus Arteriosus
• Rheumatoid Arthritis
• Sciatica
• Tendonitis

Approved in European Union as Indomethacin for:

• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Gout
• Painful shoulder caused by bursitis or tendinitis

Who Is Running the Clinical Trial?

University of Saskatchewan

Lead Sponsor

Trials

261

Recruited

156,000+

Published Research Related to This Trial

Indomethacin, when administered at a maximum therapeutic dose of 4 mg/kg, caused significant ulceration and damage in the stomach pylorus and proximal duodenum during the first two weeks of treatment, indicating its potential for gastrointestinal toxicity.

After three weeks of treatment, the severity of damage decreased, suggesting that prolonged use may lead to a reduced impact on the gastrointestinal tract, although initial lesions were still observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological changes in parts of foregut of rat after indomethacin administration. Ilahi, M., Khan, J., Inayat, Q., et al.[2013]

The study found that both intraobserver and interobserver variability in measuring ovarian volume using three-dimensional power Doppler ultrasonography was very good, with correlation coefficients of 1.00 and 0.99, respectively, indicating high reliability in these measurements.

While measurements of vascularization index (VI), vascularization flow index (VFI), and mean grayness (MG) showed good reproducibility, the flow index (FI) had poor interobserver reproducibility (inter-CC = 0.29), suggesting that caution should be taken when interpreting FI measurements in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraobserver and interobserver variability of ovarian volume, gray-scale and color flow indices obtained using transvaginal three-dimensional power Doppler ultrasonography. Järvelä, IY., Sladkevicius, P., Tekay, AH., et al.[2016]

The study involving 48 women showed that using an oil-based contrast medium (Lipiodol UF) during ultrasound-imaged hysterosalpingography is safe and feasible, with no serious adverse events reported.

However, the ongoing pregnancy rate was lower in the oil-contrast group (17%) compared to the saline group (37%), and there were minor changes in thyroid function observed in the oil group, indicating a need for further investigation into its effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oil-based or saline contrast for sono-hysterosalpingography in infertile women: a pilot randomized controlled double blind trial. Legro, RS., Stetter, CM., Kunselman, AR., et al.[2023]

In a 12-week clinical trial involving 219 patients with rheumatoid arthritis, aceclofenac (100 mg bid) demonstrated comparable efficacy to indomethacin (50 mg bid), with significant improvements in joint pain, swelling, and grip strength.

Aceclofenac was better tolerated than indomethacin, with fewer reported adverse effects (18.4% vs. 29.1%), suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of aceclofenac compared to indomethacin in patients with rheumatoid arthritis. Kornasoff, D., Maisenbacher, J., Bowdler, J., et al.[2019]

In a study comparing 133 children and adolescents with Graves' disease treated with either propylthiouracil (PTU) or methimazole (MMI), both medications showed similar effectiveness in normalizing thyroid hormone levels and achieving remission rates after 10 years.

However, PTU was associated with a longer time to normalize T4 levels and a higher incidence of minor adverse effects, particularly at higher doses, suggesting that MMI may be the preferred initial treatment option for this age group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome. Sato, H., Minagawa, M., Sasaki, N., et al.[2022]

Pregnant women treated with methimazole (MMI) have a higher risk of congenital anomalies compared to those treated with propylthiouracil (PTU), suggesting that PTU is a safer option during pregnancy.

Switching between MMI and PTU does not significantly reduce the risk of birth defects compared to using PTU alone, indicating that PTU should be the preferred treatment for hyperthyroidism in pregnant women, especially during the first trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the safety between propylthiouracil and methimazole with hyperthyroidism in pregnancy: A systematic review and meta-analysis. Liu, Y., Li, Q., Xu, Y., et al.[2023]

Propylthiouracil (PTU) significantly increases the expression of the sodium/iodide symporter (NIS) in rat thyroid cells, enhancing iodide uptake, while methimazole (MMI) does not have this effect.

The study suggests that although both PTU and MMI are effective in blocking thyroid hormone production, their differing impacts on thyroid-specific gene expression and function could influence their overall therapeutic effectiveness in treating Graves' disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH. Sue, M., Akama, T., Kawashima, A., et al.[2021]

The study successfully used an ovine model to visualize ovarian microcirculation using the contrast agent Sonovue, showing a significant enhancement of 248% in visualization for an average duration of 74.2 seconds after injection.

No adverse side effects were observed from Sonovue, indicating its safety for use in this model, and the results demonstrated that the ovary undergoing ovulation had a much stronger enhancement compared to the non-ovulating ovary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovine model to evaluate ovarian vascularization by using contrast-enhanced sonography. Marret, H., Brewer, M., Giraudeau, B., et al.[2019]

The prodrug 1-(2,6-dichlorophenyl)indolin-2-one shows significant anti-inflammatory effects similar to diclofenac but without causing gastric ulceration, making it a safer long-term NSAID option.

This prodrug effectively reduces levels of PGE(2), COX-2 expression, and cellular influx in inflammation models, indicating its potential for treating inflammatory conditions without the common side effects associated with traditional NSAIDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. Santos, JL., Moreira, V., Campos, ML., et al.[2021]

In a study involving 107 normally fertile women and 794 ultrasound scans, the disappearance or sudden decrease in follicle size was found to be the most reliable indicator of ovulation, with a sensitivity of 84% and specificity of 89.2%.

Ultrasonic echoes in the follicle showed significantly lower sensitivity (38.4%) and specificity (79.7%) compared to other ultrasound indices, indicating it is less effective for confirming ovulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitivity and specificity of ultrasound indices of ovulation in spontaneous cycles. Ecochard, R., Marret, H., Rabilloud, M., et al.[2022]

In a study of over 2.2 million individuals in Denmark, the use of antithyroid drugs (ATDs) like methimazole (MMI) and propylthiouracil (PTU) was linked to a low incidence of serious side effects, with agranulocytosis occurring in 0.16% and liver failure in 0.03% of those exposed.

Among pregnant women using ATDs, birth defects were observed in 3.4% of exposed children, indicating a significantly higher risk compared to the rare occurrences of agranulocytosis and liver failure, suggesting that careful management of ATD use in early pregnancy could help reduce these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithyroid Drug Side Effects in the Population and in Pregnancy. Andersen, SL., Olsen, J., Laurberg, P.[2022]

Tenoxicam is effective for treating acute and painful rheumatic conditions, showing a rapid onset of action and reliable pain relief after both intramuscular (i.m.) and intravenous (i.v.) administration.

The drug is well tolerated, with only about 10% of patients experiencing typical non-steroidal anti-inflammatory drug (NSAID) related adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tenoxicam used as a parenteral formulation for acute pain in rheumatic conditions. Jeunet, F., Enz, W., Guentert, T.[2019]

In a study involving 60 outpatients with rheumatoid arthritis and osteoarthritis, the new drug acemetacin was found to be effective in treating pain and inflammation associated with these conditions.

Acemetacin was better tolerated than indomethacin, with a notable reduction in the occurrence of headaches, which are common side effects of indole compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Open clinical study on the efficacy and tolerance of acemetacin in rheumatoid arthritis and osteoarthrosis]. Gospodinoff, A., Fiore, L., Dardano, B., et al.[2014]

Monitoring ovulation induction solely with ultrasound (US) is safe and effective, showing strong correlations between follicular growth, uterine measurements, and endometrial thickness with estradiol (E2) concentrations.

An endometrial thickness of 11 mm or greater in the midluteal phase is a good predictor of early pregnancy, while thickness of 7 mm or less is associated with no pregnancies after hCG administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is it possible to run a successful ovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements. Shoham, Z., Di Carlo, C., Patel, A., et al.[2019]

A network meta-analysis of 21 trials found that methimazole (MMI) combined with cholestyramine or iodine effectively regulates thyroid hormones (FT3 and FT4) in the early stages of Graves hyperthyroidism, showing significant advantages in reducing these hormone levels.

Long-term treatment with MMI combined with immunosuppressants not only helps in regulating FT3 and FT4 but also reduces relapse rates in patients with Graves hyperthyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

THERAPEUTIC EFFECTS OF COMBINATION REGIMENS INCLUDING METHIMAZOLE ON GRAVES HYPERTHYROIDISM: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS. Wang, M., Yu, Y.[2021]

Citations

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The impact of indomethacin on the number of oocytes ... Indomethacin can reduce cycle cancelation rate due to premature ovulation in POR. · While the cycle cancellation rate decreases, oocyte quality is not affected.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23876971/

Effectiveness of indometacin to prevent ovulation in ... Indometacin had no significant influence on the probability of a premature ovulation in patients during the six cycles (OR 2.38, 95% CI 0.94- ...

3. rbmojournal.com rbmojournal.com/article/S1472-6483(13)00285-X/fulltext

Effectiveness of indometacin to prevent ovulation in ... Therefore, it has been suggested that indometacin may improve the effectiveness of modified natural-cycle IVF. In this study, we assigned 120 women aged 27–36 ...

4. ejog.org ejog.org/article/S0301-2115(21)00378-X/abstract

The impact of indomethacin on the number of oocytes ... Based on data from this study, it can be concluded that indomethacin reduces cycle cancelation due to PO in patients with POR –without ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S147264831300285X

Effectiveness of indometacin to prevent ovulation in ... Based on these data, it can be concluded that indometacin is not effective in preventing premature ovulation (OR 2.38, 95% CI 0.94–6.04).

6. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=04ca474c-798e-43dd-be7a-1b36720e6a3d

Label: TIVORBEX- indomethacin capsule - DailyMed - NIH Avoid use of NSAIDs, including TIVORBEX, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well- ...

7. reference.medscape.com reference.medscape.com/drug/indocin-indomethacin-343290

Indocin (indomethacin) dosing, indications, interactions, ... Inflammatory/Rheumatoid Disorders. <2 years: Safety and efficacy not established. 2-14 years: 1-2 mg/kg/day PO divided q6-12hr; not to exceed 4 mg/kg/day or ...

8. medcentral.com medcentral.com/drugs/monograph/8880-381027/indomethacin-oral

Indomethacin: uses, dosing, warnings, adverse events, ... CNS Effects. Indomethacin should be used with extreme caution in patients with a history of mental depression or other psychiatric disorder, epilepsy, or ...

9. go.drugbank.com go.drugbank.com/drugs/DB00328

Indomethacin: Uses, Interactions, Mechanism of Action Acute oral LD50 is 2.42 mg/kg in rats and 13 mg/kg in mice. The oral LD50 of indomethacin in mice and rats (based on 14-day mortality response) was 50 and 12 mg ...

10. empr.com empr.com/drug/indomethacin-suppositories/

Indomethacin Suppositories Prescription & Dosage ... Based on available published clinical data, indomethacin may be present in human milk. ... indomethacin, may be associated with a reversible delay in ovulation.