Indomethacin vs Ibuprofen for Preterm Labor

(TOCO Trial)

Overseen By Pamela Simmons, DO

Age: 18+

Sex: Female

Trial Phase: Academic

Sponsor: Woman's

Must not be taking: Ibuprofen, Indomethacin

Disqualifiers: Fetal anomaly, Prior cerclage, others

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

Compensation: Varies

Number of Visits: 1

Duration: 24 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether indomethacin or ibuprofen better extends pregnancy for women with cervical insufficiency, a condition where the cervix opens too early, risking pregnancy loss. Both medications are administered around the time of a cerclage procedure, a stitch placed to help keep the cervix closed. The trial compares the effectiveness of these drugs in prolonging pregnancy after the procedure. It seeks participants with a single pregnancy, between 16 and 23 weeks along, who need a cerclage as identified by an exam or ultrasound. As an unphased trial, this study offers participants the chance to contribute to important research that could improve pregnancy outcomes for women with cervical insufficiency.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken ibuprofen or indomethacin in the 7 days before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using ibuprofen to delay labor has little impact on the fluid around the baby or the baby's heart function. However, the FDA advises against using ibuprofen and similar drugs after 20 weeks of pregnancy due to possible risks, such as reduced fluid around the baby. Studies have also linked these drugs to risks like early birth and low birth weight.

In contrast, clinical trials have found that indomethacin is generally safe and effective for delaying early labor. It is known for its ability to extend pregnancy, though concerns exist about long-term use. While both drugs carry risks, they are used carefully to help manage early labor. Participants should consider this information and discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for preterm labor because they offer alternatives to the current standard options like nifedipine and magnesium sulfate. Indomethacin and ibuprofen are both nonsteroidal anti-inflammatory drugs (NSAIDs) that work by reducing the production of prostaglandins, which are chemicals involved in initiating labor. This different mechanism of action could potentially provide effective management of preterm labor with a shorter duration of treatment. Additionally, the use of these medications after emergent cerclage placement—a procedure to prevent early cervical opening—could enhance their effectiveness in delaying premature birth.

What evidence suggests that this trial's treatments could be effective for cervical insufficiency?

This trial will compare the effectiveness of Indomethacin and Ibuprofen for preterm labor. Research has shown that Indomethacin can delay early labor by 2 to 7 days and works better than some other methods in slowing down early labor. However, it carries possible risks, such as a type of brain injury in premature babies.

Studies suggest that Ibuprofen, the other treatment option in this trial, might increase the chances of high blood pressure in newborns and early birth when used during pregnancy. Although Ibuprofen is commonly used, concerns exist about its safety during pregnancy. Overall, both treatments in this trial can be effective but come with potential risks. ^{1 3 6 7 8}

Who Is on the Research Team?

Pamela Simmons, DO

Principal Investigator

Woman's Hospital, Louisiana

Are You a Good Fit for This Trial?

This trial is for pregnant women between 16 and nearly 24 weeks along, with a single baby and intact membranes needing emergency cerclage to prevent early labor. They must be over 18, planning to deliver at Woman's Hospital, and not have used ibuprofen or indomethacin recently.

Inclusion Criteria

Intact membranes at time of enrollment

You are pregnant with only one baby and it is healthy.

Planning to deliver at Woman's Hospital

Exclusion Criteria

You have a significant birth defect in your baby.

Temperature greater than 100.4

I have had a stitch placed in my cervix to prevent early labor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either ibuprofen or indomethacin as perioperative prophylactic treatment following emergent cerclage placement

24 hours

1 visit (in-person)

Follow-up

Participants are monitored for gestational latency and preterm birth until delivery

Up to 26 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ibuprofen
• Indomethacin

Trial Overview The study compares two drugs—ibuprofen (2400mg) and indomethacin (150mg)—to see which one better prolongs pregnancy after an emergency stitch (cerclage) is placed in the cervix due to premature dilation.

How Is the Trial Designed?

Group I: Ibuprofen Active Control 1 Intervention

Ibuprofen 600 mg q6 hours for 24 hours- total dose of 2400mg- after emergent cerclage placement

Group II: Indomethacin Active Control 1 Intervention

Indomethacin 50 mg q8 hours for 24 hours- total dose of 150mg- after emergent cerclage placement

Ibuprofen is already approved in United States, Canada, European Union, Japan, China, Switzerland for the following indications:

Approved in United States as Advil for:

• Pain relief
• Fever reduction
• Inflammation

Approved in Canada as Motrin for:

• Pain relief
• Fever reduction
• Inflammation

Approved in European Union as Nurofen for:

• Pain relief
• Fever reduction
• Inflammation

Approved in Japan as Ibuprofen for:

• Pain relief
• Fever reduction
• Inflammation

Approved in China as Ibuprofen for:

• Pain relief
• Fever reduction
• Inflammation

Approved in Switzerland as Ibuprofen for:

• Pain relief
• Fever reduction
• Inflammation

Who Is Running the Clinical Trial?

Woman's

Lead Sponsor

Trials

18

Recruited

1,400+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8451913/

Early exposure of pregnant women to non‐steroidal anti ... Overall, non‐selective NSAID use (delivered outside hospitals) during the first 22WG was found to be associated with an increased risk of prematurity.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6135701/

Antenatal exposure to nonsteroidal anti‐inflammatory ... The results of our study suggest an association between prenatal exposure to nonsteroidal anti‐inflammatory drugs and neonatal hypertension.

3. jamanetwork.com jamanetwork.com/journals/jamapediatrics/fullarticle/2828039

Gestational Exposure to Nonsteroidal Anti-Inflammatory ... This cohort study of children in Taiwan evaluates the association between NSAID exposure during different trimesters of pregnancy and the ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0146000525000515

Pain medication use during pregnancy Use of ibuprofen during the first trimester has been linked to increased risks of spontaneous abortions, anatomic defects in the infant, and other adverse ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2305582

Trial of Selective Early Treatment of Patent Ductus ... A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9970080/

Neonatal and maternal adverse outcomes and exposure to ... The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs ...

7. journals.lww.com journals.lww.com/greenjournal/abstract/2014/05001/safety_of_ibuprofen_tocolysis.309.aspx

Safety of Ibuprofen Tocolysis : Obstetrics & Gynecology This unique study demonstrates that ibuprofen has minimal effects on amniotic fluid level or fetal cardiac function.

8. fda.gov fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic

FDA recommends avoiding use of NSAIDs in pregnancy at ... FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid · 10-15-2020 FDA Drug ...