Sulfasalazine for Preventing Premature Birth

Overseen By Todd Rosen, MD

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

Trial Summary

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.

What data supports the effectiveness of the drug sulfasalazine for preventing premature birth?

Research shows that sulfasalazine can reduce inflammation, which is a key factor in preventing infection-related preterm birth in mice. Additionally, sulfasalazine is used safely during pregnancy for inflammatory bowel disease, suggesting it may be a viable option for preventing premature birth. ^{1 2 3 4 5}

Is sulfasalazine generally safe for humans?

Sulfasalazine has been used for conditions like inflammatory bowel disease, but some people experience side effects such as stomach upset, skin rash, fever, and allergic reactions. During pregnancy, it may slightly increase the risk of certain complications, and there have been rare cases of severe anemia in fetuses. Always consult with a healthcare provider for personalized advice. ^{3 6 7 8 9}

How is the drug sulfasalazine unique in preventing premature birth?

Sulfasalazine is unique because it targets the inflammatory response by blocking a protein called nuclear factor-kappa B (NF-kappaB), which is involved in early signals of inflammation that can lead to preterm birth. This approach is different from other treatments that may not specifically target this pathway. ^{1 2 3 4 10}

What is the purpose of this trial?

The goal of this randomized clinical trial is to assess sulfasalazine as a potential treatment to prevent recurrent preterm birth. The main questions it aims to answer are: * Does sulfasalazine down regulate corticotropin releasing hormone (CRH) levels in pregnant persons with a prior history of preterm birth? * Does sulfasalazine reduce the incidence of recurrent preterm birth in pregnant persons given drug vs. controls? Consenting participants will be randomized to receive sulfasalazine or to a control group and will undergo serial blood draws to assess plasma CRH levels.

Research Team

Todd Rosen, MD

Principal Investigator

Rutgers Robert Wood Johnson Medical School

Eligibility Criteria

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 must have their pregnancy dates confirmed by ultrasound

Exclusion Criteria

Participants with cerclage

Participants with a cervical length less than 25 mm

I have kidney problems.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

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

2. England pubmed.ncbi.nlm.nih.gov

Sulfasalazine augments a pro-inflammatory response in interleukin-1β-stimulated amniocytes and myocytes. [2022]

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

Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis. [2013]

4. Denmark pubmed.ncbi.nlm.nih.gov

Can sulfasalazine prevent infection-mediated pre-term birth in a murine model? [2013]

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

Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. [2013]

6. England 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. [2019]

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

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

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

Hypersensitivity to salicylazosulfapyridine: renal and hepatic toxic reactions. [2019]

9. Spain pubmed.ncbi.nlm.nih.gov

[Susceptibility of the spanish population to adverse effects by sulfasalazine: systematic review]. [2011]

10. Denmark pubmed.ncbi.nlm.nih.gov

Effect of sulfasalazine on basal and bacteria-stimulated interleukin-8 production by endocervical epithelial cells. [2013]