Indomethacin for Premature Birth

(SPIN Trial)

Recruiting at 12 trial locations

Overseen By Souvik Mitra, MD, PhD

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: University of British Columbia

Must not be taking: Inhaled nitric oxide, Hydrocortisone

Disqualifiers: Duct dependent CHD, Renal anomalies, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

In Canada, about 900 babies each year are born very early (\<26 weeks of gestation) and have a high chance of dying or having a serious bleed in the brain. Families of these extremely preterm babies consider preventing severe brain bleeding as critical to their child's health and well-being. A medicine called indomethacin, when given intravenously in 3-doses, is known to reduce severe brain bleeding. But use of this drug is variable among clinicians working in the neonatal intensive care unit (NICU) due to (a) its side effects on the gut; (b) possible harm when used with other medications; (c) a notion that despite reducing brain bleeds, the child's long-term brain development is not improved. Emerging evidence suggests that a single low-dose indomethacin regimen may be equally effective in reducing severe brain bleeding as compared to a traditional 3-dose regimen. The investigators propose a blinded randomized controlled trial, a study design where babies born \<26 weeks will be randomly assigned within 12 hours of birth to either a single dose of intravenous indomethacin or similar looking placebo in the form a saline solution. The study will test if a single dose indomethacin regimen is effective in improving survival of these babies without the devastating complication of severe brain bleeding. In this study the care providers and researchers will be unaware as to which baby receives indomethacin and which baby receives placebo to ensure no one's expectations or biases can influence the results. The investigators will conduct the study in multiple NICUs across Canada, the United States and Australia and will enroll 500 babies born \<26 weeks or \<750 g birth weight over a period of 3 years. This study will help the investigators determine in the most unbiased way whether a single dose of indomethacin given immediately after birth in the smallest babies born \<26 weeks of gestation can safely and effectively reduce severe brain bleeding.

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 indomethacin generally safe for human use?

Indomethacin is known to be effective but can cause stomach issues like ulcers. Some studies have developed new versions of indomethacin that are less likely to cause stomach problems, showing promise for safer use. ^{1 2 3 4 5}

What makes the drug Indomethacin unique for treating premature birth?

Indomethacin is unique because it can be formulated as a prodrug that significantly reduces the risk of gastric ulcers, a common side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). This makes it potentially safer for long-term use compared to other NSAIDs. ^{2 3 6 7 8}

What data supports the effectiveness of the drug Indomethacin for premature birth?

Research shows that Indomethacin is effective in reducing inflammation and swelling, as seen in studies on postsurgical edema in rats and its anti-inflammatory action in other conditions. This suggests potential benefits in managing inflammation-related issues in premature birth. ^{3 4 9 10 11}

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]

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]

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]

Citations

1. Italy pubmed.ncbi.nlm.nih.gov

[Open clinical study on the efficacy and tolerance of acemetacin in rheumatoid arthritis and osteoarthrosis]. [2014]

2. Japan pubmed.ncbi.nlm.nih.gov

Design, synthesis and antiinflammatory activity of a new indomethacin ester. 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetate. [2019]

3. Japan pubmed.ncbi.nlm.nih.gov

Interaction of indometacin farnesil, a new nonsteroidal antiinflammatory drug with peripheral blood mononuclear cells from patients with rheumatoid arthritis. [2019]

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

Effect of indomethacin on postsurgical edema in rats. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

New indomethacin analogs as selective COX-2 inhibitors: Synthesis, COX-1/2 inhibitory activity, anti-inflammatory, ulcerogenicity, histopathological, and docking studies. [2021]

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

Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Synthesis and biological evaluation of 3-[4-(amino/methylsulfonyl)phenyl]methylene-indolin-2-one derivatives as novel COX-1/2 and 5-LOX inhibitors. [2010]

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

Comparative activities, tolerances and safety of nonsteroidal anti-inflammatory agents in rats. [2006]

9. Germany pubmed.ncbi.nlm.nih.gov

Synthesis and Biological Evaluation of Novel Indomethacin Derivatives as Potential Anti-Colon Cancer Agents. [2017]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. [2021]

11. Spain pubmed.ncbi.nlm.nih.gov

Pharmacological activity, blood and tissue levels of indomethacin after single oral administration of two long-acting forms in the rat. [2013]