Sulfasalazine for Preventing Premature Birth

Overseen By Emily Rosenfeld, DO

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Rutgers, The State University of New Jersey

Must not be taking: Digoxin

Disqualifiers: Liver disease, G6PD deficiency, 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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called sulfasalazine to determine if it can prevent premature birth in pregnant individuals with a history of preterm birth. Researchers aim to discover whether sulfasalazine can lower levels of a hormone (CRH) associated with early labor and reduce the risk of another preterm birth. Participants will either take sulfasalazine or receive standard pregnancy care, with regular blood checks. Those pregnant with one baby, who have experienced a preterm birth before, and are 12 to 22 weeks into pregnancy may be suitable candidates. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group.

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 participate if you are using digoxin or have certain medical conditions. It's best to discuss your current medications with the trial team.

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

Research has shown that sulfasalazine, a drug tested to prevent early births, presents some safety concerns. One study found that women taking sulfasalazine during pregnancy had a higher chance of birth defects, stillbirths, and early deliveries. However, this does not mean the drug is unsafe for everyone, but these risks should be considered.

Sulfasalazine is already used for other health issues and is known to reduce swelling, which might help prevent some early births. Since this trial is in an early stage, researchers are still learning about its safety for pregnant women. Participants should discuss the possible risks and benefits with their doctor before joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for preventing premature birth, which often include progesterone therapy and cervical cerclage, sulfasalazine offers a novel approach. Sulfasalazine is typically used to manage inflammatory conditions like rheumatoid arthritis, but researchers are exploring its potential to reduce inflammation that might trigger preterm labor. This unique anti-inflammatory action could provide a new way to address premature birth risks, making it an exciting possibility for improving outcomes in pregnancies at risk of preterm delivery.

What evidence suggests that sulfasalazine might be an effective treatment for preventing preterm birth?

Research suggests that sulfasalazine, which participants in this trial may receive, might help prevent early births by reducing inflammation. Studies have shown that sulfasalazine can lower the risk of preterm delivery, especially when inflammation is involved. In animal studies, sulfasalazine reduced early births and improved pregnancy outcomes in mice with infections. By decreasing inflammation, sulfasalazine might also lower levels of a hormone linked to early labor. Although more research is needed in humans, these findings offer hope that sulfasalazine could help prevent repeated early births. ^{1 2 3 4 6}

Who Is on the Research Team?

Emily Rosenfeld, DO

Principal Investigator

Rutgers Robert Wood Johnson Medical School

Are You a Good Fit for This Trial?

This trial is for pregnant women over 18, between 12-22 weeks gestation, with a history of preterm birth and a confirmed singleton pregnancy. It's not for those under 18 or with certain medical conditions like severe asthma, liver/renal dysfunction, blood disorders, G6PD deficiency, or allergies to sulfasalazine.

Inclusion Criteria

I am between 12 and 22 weeks pregnant.

Participants must have a singleton pregnancy

Participants with a history of prior preterm birth in a previous pregnancy

Exclusion Criteria

Participants with cerclage

Participants with a cervical length less than 25 mm

I have kidney problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sulfasalazine starting at 24 weeks gestational age, with dosage increasing weekly until reaching 1,000 mg twice daily, ending at 36 weeks or earlier if preterm birth occurs.

12 weeks

Weekly visits for dosage adjustment and monitoring

Monitoring

Serial blood draws to assess plasma CRH levels at 28, 32, and 36 weeks gestation.

8 weeks

3 visits (in-person) at 28, 32, and 36 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neonatal outcomes up to 28 days after birth.

4 weeks

Post-birth monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Sulfasalazine

Trial Overview The study tests if sulfasalazine can lower CRH levels in pregnant women who've had early births before and if it can prevent another premature birth. Participants will be randomly assigned to either receive the drug or be in a control group.

How Is the Trial Designed?

Group I: Sulfasalazine Experimental Treatment 1 Intervention

Pregnant persons will receive sulfasalazine daily with 500 mg/daily and increasing by 500 mg/day every week until they reach a therapeutic dose of 1,000 mg twice daily. Drug will be started at 24 weeks estimated gestational age and ended at 36 weeks or earlier if preterm birth occurs.

Group II: Standard Care Active Control 1 Intervention

Pregnant persons will receive standard care in pregnancy.

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

Approved in European Union as Sulfasalazine for:

• Ulcerative colitis
• Crohn’s disease
• Rheumatoid arthritis

Approved in United States as Sulfasalazine for:

• Ulcerative colitis
• Rheumatoid arthritis

Approved in Canada as Sulfasalazine for:

• Ulcerative colitis
• Crohn’s disease
• Rheumatoid arthritis

Who Is Running the Clinical Trial?

Rutgers, The State University of New Jersey

Lead Sponsor

Trials

471

Recruited

81,700+

Published Research Related to This Trial

Sulfasalazine (SASP) was found to require a very high concentration to inhibit inflammatory responses in cells related to preterm labor, indicating limited efficacy at therapeutic levels.

At therapeutic concentrations, SASP did not reduce inflammation and instead increased the production of pro-inflammatory cytokines, suggesting it is not a suitable candidate for preventing inflammation-induced preterm labor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulfasalazine augments a pro-inflammatory response in interleukin-1β-stimulated amniocytes and myocytes. Sykes, L., Thomson, KR., Boyce, EJ., et al.[2022]

This case study reports the first instance of severe fetal anemia linked to maternal use of mesalazine, a medication for inflammatory bowel disease, highlighting potential risks associated with its use during pregnancy.

After discontinuing mesalazine and administering intrauterine transfusions, the fetus recovered, suggesting that monitoring and managing maternal medication is crucial to prevent adverse fetal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesalazine as a cause of fetal anemia and hydrops fetalis: A case report. Ek, S., Rosenborg, S.[2022]

Salicylazosulfapyridine, commonly used to treat ulcerative colitis, can cause acute allergic reactions, as demonstrated in a case report involving fever, rash, eosinophilia, nephritis, and hepatitis.

The allergic reaction resolved completely after stopping the medication, highlighting the importance of monitoring for adverse effects even with drugs that are generally considered safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypersensitivity to salicylazosulfapyridine: renal and hepatic toxic reactions. Chester, AC., Diamond, LH., Schreiner, GE.[2019]

Sulfasalazine (SASP) effectively inhibits the production of interleukin-8 (IL-8) in human endocervical cells stimulated by bacterial pathogens linked to preterm birth, particularly at a concentration of 1.6 mm.

However, this concentration also significantly reduces cell viability, suggesting that while SASP can suppress IL-8 production, its toxic effects on the cells may limit its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of sulfasalazine on basal and bacteria-stimulated interleukin-8 production by endocervical epithelial cells. Peltier, MR., Tee, SC., Kinzler, WL., et al.[2013]

In a study of 704 patients with chronic inflammatory bowel diseases over 15 years, 17% experienced dyspeptic symptoms and 13% had extraintestinal reactions, leading to the withdrawal of sulfasalazine.

Switching from sulfasalazine to EN Salazopyrin successfully resolved dyspepsia in 102 out of 107 patients, indicating that alternative formulations may help manage side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulfasalazine intolerance. A retrospective survey of the reasons for discontinuing treatment with sulfasalazine in patients with chronic inflammatory bowel disease. Nielsen, OH.[2019]

A systematic review of 36 studies found no direct evidence that the Spanish population is more susceptible to adverse effects from sulfasalazine (SSZ) compared to other ethnic groups.

However, the prevalence of slow-acetylators, who may experience increased side effects from SSZ depending on dosage, is higher in the Spanish population, suggesting a potential for higher incidence of adverse effects in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Susceptibility of the spanish population to adverse effects by sulfasalazine: systematic review]. Alegre de Miquel, C., Santos Ramírez, C., Barceló Bru, M.[2011]

A review of 531 pregnancies showed that using corticosteroids and sulfasalazine during pregnancy for inflammatory bowel disease does not increase fetal complications compared to the general population.

Pregnant women with severe active Crohn's disease may experience more complications, but these are still lower than the general population, indicating that the disease itself poses a greater risk than the medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Mogadam, M., Dobbins, WO., Korelitz, BI., et al.[2013]

A meta-analysis of 7 studies involving 2200 pregnant women with inflammatory bowel disease (IBD) found that exposure to 5-ASA drugs (like mesalazine and sulfasalazine) does not significantly increase the risk of adverse pregnancy outcomes, such as congenital abnormalities or stillbirth.

The odds ratios for various outcomes, including stillbirth (2.38) and preterm delivery (1.35), suggest only a modest increase in risk, indicating that 5-ASA drugs can be considered relatively safe for managing IBD during pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis. Rahimi, R., Nikfar, S., Rezaie, A., et al.[2013]

In a study involving 40 CD-1 mice, sulfasalazine (SASP) significantly reduced the rate of infection-mediated pre-term birth caused by E. coli, indicating its potential effectiveness in preventing pre-term deliveries.

SASP not only decreased the incidence of pre-term births but also tended to increase litter size and significantly improved the weight of pups born to infected mothers, suggesting better overall pregnancy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can sulfasalazine prevent infection-mediated pre-term birth in a murine model? Nath, CA., Ananth, CV., Smulian, JC., et al.[2013]

Sulphasalazine has been clinically used for over 40 years and is now recognized as an effective treatment for rheumatoid arthritis and ankylosing spondylitis, showing its value as a remittive agent.

Recent controlled studies highlight sulphasalazine's role not only in treatment but also as a research tool for understanding the causes and development of these rheumatic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sulphasalazine in arthritis--an old drug rediscovered. Taggart, AJ.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05703425

The Effect of Sulfasalazine on CRH Levels in Pregnant ... The goal of this randomized clinical trial is to assess sulfasalazine as a potential treatment to prevent recurrent preterm birth.

2. withpower.com withpower.com/trial/phase-2-premature-birth-1-2023-b6773

Sulfasalazine for Preventing Premature Birth What data supports the effectiveness of the drug sulfasalazine for preventing premature birth? Research shows that sulfasalazine can reduce inflammation ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0890623825001108

Meta-analysis and systematic review on Sulfasalazine/5 ... The meta-analysis of 9 observational studies showed that SSZ/5-ASA use during pregnancy did not affect live birth (overall pooled OR 0.67, 0.43; 1.03) compared ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4693891/

Sulfasalazine augments a pro‐inflammatory response in ... Sulfasalazine therefore appears to hold promise for potential use as a therapeutic agent for the prevention of inflammation‐induced preterm labour.

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20039863/

Can sulfasalazine prevent infection-mediated pre-term birth in ... Conclusion: SASP reduced rates of pre-term delivery and improved pregnancy outcomes for mice infected with 10(4) CFU E. coli. This suggests that SASP has the ...

6. trial.medpath.com trial.medpath.com/clinical-trial/a146a37b74f5b655/nct05703425-effect-sulfasalazine-crh-levels-pregnant-women

The Effect of Sulfasalazine on CRH Levels in Pregnant Women This is a study to assess the potential for sulfasalazine to prevent recurrent preterm birth. The investigators' main objective is to assess the effects of ...