Progesterone for Pre-eclampsia

(PROGRESS Trial)

Overseen By Lorena M Amaral, Ph.D.

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: Babbette Lamarca

Disqualifiers: Gestational age, Maternal compromise, Fetal compromise, 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: 18

Duration: Until delivery

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if 17-hydroxyprogesterone caproate (17 OHPC), a form of progesterone, can improve outcomes for mothers and babies when the mother has preeclampsia, a pregnancy complication causing high blood pressure, diagnosed before 34 weeks. Participants will either receive 17 OHPC or join a control group with no added treatment. The trial seeks pregnant individuals between 23 and 34 weeks with preeclampsia who can understand the study and provide consent. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that 17 OHPC is likely to be safe for humans?

Research has shown that 17-hydroxyprogesterone caproate (17 OHPC) is usually well-tolerated. A safety review found its safety comparable to a placebo, indicating it is generally safe to use. However, some studies noted a slight increase in certain pregnancy-related issues compared to control groups.

This treatment has been studied in various contexts, and despite some concerns, it maintains a good overall safety record. For those considering participation in a trial with 17 OHPC, these findings suggest it is generally safe but not without some risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pre-eclampsia?

Most treatments for pre-eclampsia focus on managing symptoms and delaying delivery, often using medications like antihypertensives to control blood pressure. But 17 OHPC, a form of progesterone, offers a different approach by potentially improving both maternal and perinatal outcomes. Researchers are excited about 17 OHPC because it targets hormonal pathways that could stabilize and improve conditions for both the mother and baby, unlike traditional options that primarily address symptoms. This novel mechanism may provide a more comprehensive management strategy for severe pre-eclampsia diagnosed before 34 weeks of gestation.

What evidence suggests that 17 OHPC might be an effective treatment for pre-eclampsia?

Research has shown that 17-hydroxyprogesterone caproate (17 OHPC) might help with preeclampsia, a condition in pregnant women that leads to high blood pressure and can harm organs. Animal studies, such as those conducted on rats, have found that 17 OHPC can reduce high blood pressure, a major issue in preeclampsia. These studies also suggest that 17 OHPC may improve health outcomes for both the mother and baby. In this trial, participants in the experimental arm will receive 17 OHPC to determine if it improves maternal and perinatal outcomes in cases of severe preeclampsia diagnosed before 34 weeks gestation. While these results are encouraging, studies in humans are needed to confirm its effectiveness in pregnant women. ^{1 6 7 8 9}

Who Is on the Research Team?

Sheila S Belk

Principal Investigator

UMMC Pharmacology and Toxicology

Babbette LaMarca, PhD

Principal Investigator

University of Missisippi Medical Center

Are You a Good Fit for This Trial?

This trial is for pregnant patients at UMMC with preterm preeclampsia between 23 and 34 weeks of gestation, who can consent to study procedures. It excludes those with conditions like PPROM after 34 weeks, low platelets, liver issues, severe fetal growth restriction, eclampsia, or any maternal/fetal condition requiring urgent delivery.

Inclusion Criteria

UMMC antepartum patients with preterm PE between 23 0/7ths and 34 0/7ths weeks gestation when initially evaluated

Willing and able to understand study procedures and to provide informed consent

Exclusion Criteria

Gestational age >33 weeks or <23 weeks

Fetal compromise requiring emergent delivery (fetal bradycardia, recurrent late fetal heart rate decelerations, minimal to absent fetal heart rate variability)

Eclampsia

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants receive 17 OHPC, 250mg IM at admission and every 7 days thereafter until delivery

Until delivery

Weekly visits for 17 OHPC administration

Monitoring

Blood samples collected at baseline, 24 hours after first dose, every 72 hours until delivery, and 24 hours after delivery

Until delivery

Multiple visits for blood sampling

Follow-up

Participants are monitored for safety and effectiveness after treatment

Until discharge

In-hospital monitoring until discharge

What Are the Treatments Tested in This Trial?

Interventions

• 17 OHPC

Trial Overview The study investigates whether the hormone medication called 17-hydroxyprogesterone caproate (17 OHPC) can improve outcomes for mothers and babies when preeclampsia occurs before the baby is full-term.

How Is the Trial Designed?

Group I: Experimental Experimental Treatment 1 Intervention

To determine if the addition of 17 OHPC to the management of Severe PE diagnosed prior to 34 weeks gestation improves maternal and perinatal outcomes.

Group II: Control Active Control 1 Intervention

To determine how close the molecular markers are with 17 OHPC added to the management protocol.

17 OHPC is already approved in United States, European Union for the following indications:

Approved in United States as Makena for:

• Prevention of preterm birth in high-risk pregnant individuals
• Advanced adenocarcinoma of the uterine corpus (Stage III or IV)
• Management of amenorrhea (primary and secondary) and abnormal uterine bleeding due to hormonal imbalance

Approved in European Union as Proluton for:

• Habitual and imminent abortion
• Infertility due to corpus luteum insufficiency
• Primary and secondary amenorrhea

Who Is Running the Clinical Trial?

Babbette Lamarca

Lead Sponsor

Trials

1

Recruited

60+

University of Mississippi Medical Center

Lead Sponsor

Trials

185

Recruited

200,000+

Published Research Related to This Trial

In a study involving pregnant rats, the administration of 17-hydroxyprogesterone caproate (17-OHPC) significantly reduced hypertension caused by elevated soluble fms-like tyrosine kinase-1 (sFlt-1), lowering mean arterial pressure from 115 mmHg to 102 mmHg.

17-OHPC also decreased elevated levels of preproendothelin-1 (PPET-1) mRNA in the kidneys, suggesting it may help mitigate some of the harmful effects of preeclampsia, although it did not affect pup or placental weights.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17-Hydroxyprogesterone caproate improves hypertension and renal endothelin-1 in response to sFlt-1 induced hypertension in pregnant rats. Amaral, LM., Cottrell, JN., Comley, KM., et al.[2023]

Women with preeclampsia (PE) have significantly lower levels of circulating progesterone compared to normal pregnant women, which is associated with increased levels of endothelin-1 (ET-1), a marker of endothelial dysfunction.

Treatment with 17-alpha-hydroxyprogesterone caproate (17-OHPC) in a rat model of preeclampsia significantly reduces hypertension and the elevated ET-1 levels, suggesting that progesterone may help mitigate the effects of placental ischemia and improve vascular function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progesterone blunts vascular endothelial cell secretion of endothelin-1 in response to placental ischemia. Kiprono, LV., Wallace, K., Moseley, J., et al.[2021]

In a study using a rat model of preeclampsia, 17-α-Hydroxyprogesterone caproate (17-OHPC) significantly reduced mean arterial pressure and inflammation, suggesting it may help manage preeclampsia symptoms.

17-OHPC improved nitric oxide levels and uterine artery resistance index, indicating its potential to enhance blood flow and reduce complications associated with preeclampsia during late gestation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17-hydroxyprogesterone caproate significantly improves clinical characteristics of preeclampsia in the reduced uterine perfusion pressure rat model. Amaral, LM., Cornelius, DC., Harmon, A., et al.[2021]

In a study of 80 women with early-onset preeclampsia, treatment with 17 hydroxy progesterone (17-OHPC) significantly reduced levels of inflammatory markers IL-6 and TNF-α compared to a control group, indicating a potential mechanism for improving the condition.

Despite the reduction in inflammatory markers, 17-OHPC did not lead to improved maternal or neonatal outcomes in these patients, suggesting that while it may influence inflammation, it does not address the overall severity of preeclampsia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of 17-Hydroxyprogesterone Caproate on Interleukin-6 and Tumor necrosis factor-alpha in expectantly managed early-onset preeclampsia. Othman, MA., Badawy, ER., Sobh, AMA., et al.[2023]

A highly sensitive and specific method for measuring 17alpha-hydroxyprogesterone caproate (17-OHPC) in human plasma was developed using high-performance liquid chromatography and mass spectrometry, demonstrating excellent extraction recoveries of over 88%.

The assay showed a linear response for 17-OHPC concentrations ranging from 0.5 to 50 ng/ml, making it a reliable tool for routine clinical applications in monitoring this hormone in plasma samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a high-performance liquid chromatography-mass spectrometric assay for the determination of 17alpha-hydroxyprogesterone caproate (17-OHPC) in human plasma. Zhang, S., Mada, SR., Mattison, D., et al.[2019]

The study found that 17-alpha hydroxyprogesterone caproate (17-OHPC) formulations remained stable over a 19-week period, regardless of the type of dispensing container or the presence of preservatives.

All tested formulations of 17-OHPC were free from microbial contamination and pyrogens, indicating that compounded versions can be safely used without compromising sterility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Qualitative and quantitative measures of various compounded formulations of 17-alpha hydroxyprogesterone caproate. Caritis, SN., Zhao, Y., Bettinger, J., et al.[2021]

This study evaluated the pharmacokinetics of 17α-hydroxyprogesterone caproate (17-OHPC) in 61 pregnant women, showing that maternal body weight significantly affects the drug's clearance and distribution, which is crucial for optimizing treatment.

The findings indicate that 17-OHPC is absorbed and eliminated in a predictable manner during pregnancy, providing a foundational understanding for its use in preventing preterm birth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of 17α-hydroxyprogesterone caproate in singleton gestation. Sharma, S., Caritis, S., Hankins, G., et al.[2021]

In utero exposure to 17α-hydroxyprogesterone caproate, particularly during the first trimester, is associated with a significantly increased risk of cancer in offspring, with an adjusted hazard ratio of 2.57 for any cancer.

Specific types of cancer, such as colorectal, prostate, and pediatric brain cancer, showed even higher risks linked to first trimester exposure, indicating a need for caution when using this medication in early pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring. Murphy, CC., Cirillo, PM., Krigbaum, NY., et al.[2023]

In a study using the RUPP rat model of preeclampsia, treatment with 17-hydroxyprogesterone caproate (17-OHPC) significantly reduced blood pressure and improved fetal weight, indicating its potential efficacy in managing preeclampsia-related hypertension.

17-OHPC treatment led to a notable decrease in natural killer (NK) cells and a shift in the CD4+ T cell population, suggesting that it may improve immune balance and contribute to better pregnancy outcomes in the context of placental ischemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

17-Hydroxyprogesterone caproate improves T cells and NK cells in response to placental ischemia; new mechanisms of action for an old drug. Elfarra, JT., Cottrell, JN., Cornelius, DC., et al.[2021]

A new auto-injector for subcutaneous administration of hydroxyprogesterone caproate (HPC) was developed to improve usability and reduce risks associated with intramuscular injections, such as human error and needlestick injuries.

Usability studies showed that with proper training and modified instructions, healthcare providers could effectively use the auto-injector, leading to successful injections and high acceptance of the device.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and usability of a new subcutaneous auto-injector device to administer hydroxyprogesterone caproate to reduce the risk of recurrent preterm birth. Travanty, MN., Calawa, B., Shalaby, WS., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10278054/

17-Hydroxyprogesterone caproate improves hypertension ... This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to elevated sFlt-1 in pregnant rats.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02989025

Study Details | NCT02989025 | Progesterone to Enhance ... To determine if the addition of 17 OHPC to the management of Severe PE diagnosed prior to 34 weeks gestation improves maternal and perinatal outcomes.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2210778920301185

17-Hydroxyprogesterone caproate improves hypertension ... This study demonstrated that 17-OHPC improves hypertension in response to elevated sFlt-1 in pregnant rats. Furthermore, 17-OHPC improved renal cortex PPET-1 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4350787/

17-HYDROXYPROGESTERONE CAPROATE ... 17-HYDROXYPROGESTERONE CAPROATE SIGNIFICANTLY IMPROVES CLINICAL CHARACTERISTICS OF PREECLAMPSIA IN THE RUPP RAT MODEL. Lorena M Amaral. Lorena M Amaral. 1 ...

5. ahajournals.org ahajournals.org/doi/pdf/10.1161/HYPERTENSIONAHA.117.09969

Continued Investigation Into 17-OHPC We hypothesized that earlier administration of 17-OHPC on day 15 of gestation could improve pathophysiology of preeclampsia and fetal outcomes in response to ...

6. nature.com nature.com/articles/s41372-020-00849-y

Safety review of hydroxyprogesterone caproate in women ... The integrated safety data demonstrates a favorable safety profile of 17P, which was comparable to placebo. References. ACOG. ACOG practice ...

7. ajog.org ajog.org/article/S0002-9378(24)00526-X/abstract

The dosing regimen for 17-hydroxyprogesterone caproate ... Data from the Obstetrical-Fetal Pharmacology Research Centers study were used to determine the relationship between dose and safety outcomes.

8. mdpi.com mdpi.com/2673-3897/3/3/19

17-α Hydroxyprogesterone Caproate Immunology, a ... 17-α hydroxyprogesterone caproate (17-OHPC) could alter the immune response and inflammation, specifically affecting the risk of preterm labor and preeclampsia.

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2013/021945s005lbl.pdf

Makena (hydroxyprogesterone caproate) injection label Certain pregnancy-related fetal and maternal complications or events were numerically increased in the Makena-treated subjects as compared to control subjects, ...