Indomethacin for Premature Birth

(SPIN Trial)

Not yet recruiting at 18 trial locations

Overseen By Souvik Mitra, MD, PhD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: University of British Columbia

Must not be taking: Inhaled nitric oxide, Hydrocortisone

Disqualifiers: Duct dependent CHD, Renal anomalies, 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: Single dose

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a single low dose of indomethacin can safely reduce severe brain bleeding in extremely premature babies born before 26 weeks. Indomethacin has shown promise in reducing brain bleeds, but its current multi-dose use can cause gut side effects and other risks. The trial compares a single dose of indomethacin with a placebo to determine if it improves survival without causing severe brain bleeds. Babies born very early or with a birth weight under 750 grams (a little more than 1.5 pounds) might be suitable for this study. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. However, it mentions possible harm when indomethacin is used with other medications, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that indomethacin has been studied for its ability to delay preterm birth. Studies confirm it can effectively delay delivery by at least 48 hours, and sometimes up to 7 days. This delay can be crucial for the health of very early babies. However, concerns exist about its safety, especially when used before birth. Some evidence suggests it might increase the risk of serious problems in babies born at or before 30 weeks.

Indomethacin can affect the stomach and intestines and might not be safe when combined with other medications. Despite these concerns, it is commonly used because it reduces serious brain bleeding in preterm babies. While the safety of indomethacin is well-known, doctors sometimes debate its use due to these potential risks.

This trial explores whether a single low dose is as effective and potentially safer than the usual three doses. The goal is to determine if this approach can lower the risk of severe brain bleeding without causing more harm. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for preventing complications in premature infants, which typically involve a range of medications or supportive care measures, the study treatment, indomethacin, is distinct because it is used as a single-dose prophylactic measure. Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) that is administered intravenously within 12 hours of birth, potentially reducing the risk of certain complications right from the start. Researchers are excited about this treatment because it offers a proactive approach that could streamline care for premature infants and possibly improve outcomes with just one dose.

What evidence suggests that a single low-dose indomethacin regimen might be an effective treatment for preventing severe brain bleeding in extremely preterm babies?

Research has shown that indomethacin can lower the risk of serious brain bleeding in very premature babies. Studies have found that administering indomethacin through an IV in several doses reduces the chance of brain bleeding. In this trial, participants in the experimental arm will receive a single low dose of indomethacin, which some evidence suggests might be equally effective. Despite concerns about side effects, indomethacin's ability to prevent severe problems makes it an important option to consider. This treatment could significantly improve the survival and health of these vulnerable infants. ^{2 3 6 7 8}

Who Is on the Research Team?

Souvik Mitra, MD, PhD

Principal Investigator

University of British Columbia

Are You a Good Fit for This Trial?

This trial is for extremely preterm infants born at less than 26 weeks of gestation or with a birth weight under 750 grams. The study aims to include about 500 babies from NICUs in Canada, the US, and Australia over three years.

Inclusion Criteria

My baby was born before 26 weeks or weighed less than 750g at birth.

Exclusion Criteria

Acute hypoxic respiratory failure defined as fraction of inspired oxygen (FiO2) greater than 0.60 for at least 2 hours

Initial platelet count less than 50x10^9/L

I have chosen not to receive treatments that would prolong my life.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Within 12 hours of birth

Treatment

Infants receive a single 0.1 mg/kg dose of intravenous indomethacin or placebo within 12 hours of birth

Single dose

Administered in NICU

Follow-up

Participants are monitored for survival without severe intraventricular hemorrhage (sIVH) and other secondary outcomes

Approximately 20 weeks postnatal age

Long-term Follow-up

Assessment of neurodevelopmental impairment at 24 (±6) months postmenstrual age

24 (±6) months postmenstrual age

What Are the Treatments Tested in This Trial?

Interventions

• Indomethacin

Trial Overview

The trial is testing if a single dose of indomethacin can improve survival without severe brain bleeding compared to a placebo. Babies are randomly assigned to receive either the drug or placebo within 12 hours of birth.

How Is the Trial Designed?

Group I: Single-dose prophylactic indomethacin - SPIN Experimental Treatment 1 Intervention

Infants randomized to the SPIN group will receive a single 0.1 mg/kg dose of intravenous indomethacin within 12h of birth as a slow infusion over 20 mins.

Group II: Control Placebo Group 1 Intervention

Equal volume saline placebo administered intravenously over 20 mins

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 British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Published Research Related to This Trial

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]

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]

A new indole derivative, compound 4f, demonstrated superior anti-inflammatory effects and a much safer profile compared to traditional indomethacin, achieving 90.5% edema inhibition with a low ulcerogenic liability.

Compound 4f selectively inhibited COX-2 over COX-1, with a selective index of 65.71, indicating its potential as a safer alternative for treating inflammation without the severe gastric damage associated with indomethacin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity. Amin, NH., El-Saadi, MT., Hefny, AA., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9021553/

Use of Prophylactic Indomethacin in Preterm Infants

Although indomethacin administration showed favorable outcomes in reducing IVH incidence, many concerns have arised regarding its effect on ...

2.

nature.com

nature.com/articles/s41598-025-01259-w

The association between antenatal indomethacin exposure ...

A meta-analysis has shown that indomethacin could postpone preterm delivery for a duration ranging from 48 h to 7 days. Furthermore, according ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT01869361

NCT01869361 | Indomethacin for Tocolysis of Preterm Labor

Background: Indomethacin is frequently used as a tocolytic, however there is currently only scant evidence to support its efficacy. Goals: To delay preterm ...

4.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0029784499005785

Indomethacin for preterm labor: a randomized comparison ...

Conclusion: Intravaginal indomethacin is more effective than intrarectal plus oral application in delaying preterm labor and is associated with higher birth ...

5.

gulhanemedj.org

gulhanemedj.org/pdf/37eae217-e8b5-4f55-976f-35df98003e83/articles/gulhane.galenos.2021.81300/GMJ-64-79-En.pdf

Nifedipine and indomethacin in preventing preterm labor ...

Comparison of the efficacy and adverse effects of nifedipine and indomethacin for the treatment of preterm labor. Int J Gynaecol Obstet ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11129938/

Indomethacin Pharmacokinetics and Pharmacodynamics in ...

Clinical trials have confirmed that indomethacin is safe and effective and delays delivery by at least 7 days. Despite the widely accepted use of indomethacin ...

7.

sciencedirect.com

sciencedirect.com/science/article/pii/0002937893901389

Efficacy and safety of indomethacin compared with ...

Indomethacin was as effective as magnesium sulfate in delaying delivery > 48 hours, 90% versus 85%, and together with oral terbutaline in extending the ...

8.

nejm.org

nejm.org/doi/full/10.1056/NEJM199311253292202

Neonatal Complications after the Administration ...

Antenatal indomethacin therapy for preterm labor appears to increase the risk of serious neonatal complications in infants born at or before 30 weeks' ...