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Use of Sildenafil Citrate in Management of Mild Pre-eclampsia

Sponsor
Assiut University (Other)
Overall Status
Unknown status
CT.gov ID
NCT03262961
Collaborator
(none)
80
Enrollment
1
Location
2
Arms
16
Anticipated Duration (Months)
5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

  • Mild pre-eclampsia represents 75% of cases with pre-eclampsia, possible progression to severe pre-eclampsia makes mild pre-eclampsia a serious problem that requires attention.

  • Previous studies have shown that expectant and conservative management of pre-eclampsia in the context of extreme prematurity may improve perinatal outcomes. Indeed, it has been estimated that for each additional day of pregnancy prolongation between 24 and 32 weeks of gestation, there is a nonlinear corresponding gain of 1% in fetal survival.

  • Sildenafil citrate has been used for increasing utero-placental perfusion in cases with intrauterine growth restriction, which makes it a promising drug in management of mild pre-eclampsia.

Condition or Disease Intervention/Treatment Phase
  • Drug: Sildenafil 20 MG
  • Drug: Placebo Oral Tablet
 Phase 2/Phase 3

Detailed Description

  • Pre-eclampsia affects approximately 2-8% of all pregnancies worldwide. In Egypt, the prevalence of pre-eclampsia is 10.7% in a community based study. While, in hospital based studies it ranged from 9.1% to 12.5% of all deliveries. The incidence of pre-eclampsia has risen in the developing countries and even in the developed countries as the USA since the 1990s. Among the hypertensive disorders that complicate pregnancy, pre-eclampsia and eclampsia stand as major causes of maternal and perinatal morbidity and mortality worldwide. Nearly one tenth of all maternal deaths in Africa and Asia and one quarter in Latin America are associated with hypertensive diseases in pregnancy, a category that includes pre-eclampsia and the complications that are related to it.

However, the pathogenesis of pre-eclampsia is only partially understood and it is related to disturbances in placentation at the beginning of pregnancy, followed by generalized inflammation and progressive endothelial damage. There are other uncertainties too: the diagnosis, screening and management of pre-eclampsia remain controversial, as does the classification and the degree of its severity.

However, it is generally accepted as published in the different journals and in the WHO recommendations that the onset of a new episode of hypertension during pregnancy (with persistent systolic blood pressure 140 mm Hg and diastolic blood pressure 90 mm Hg or more) with the occurrence of substantial proteinuria (>0.3 g/24 h or confirmation of proteinuria by semiquantitative urine dipstick analysis with a result of at least 1+) can be used as criteria for identifying pre-eclampsia.

Although pathophysiological changes (e.g. inadequate placentation) exist from very early stages of the pregnancy, hypertension and proteinuria usually become apparent in the second half of pregnancy.

Complications of pre-eclampsia can affect both the mother and the fetus. Acutely, pre-eclampsia can be complicated by eclampsia , the development of HELLP Syndrome , hemorrhagic or ischemic stroke, liver damage and dysfunction, acute kidney injury and Acute Respiratory Distress Syndrome (ARDS).

So early detection of pre-eclampsia and prevention of the occurrence of any of its complications would save the lives of many women and prevent the possible devastating maternal and neonatal outcome of pre-eclampsia, That's why we are concerned in our study with pre-eclampsia, covering the gestational age from 28 - 36 weeks.

Mild pre-eclampsia represents 75% of cases with pre-eclampsia, possible progression to severe pre-eclampsia makes mild pre-eclampsia a serious problem that requires attention.

Previous studies have shown that expectant and conservative management of pre-eclampsia in the context of extreme prematurity may improve perinatal outcomes. Indeed, it has been estimated that for each additional day of pregnancy prolongation between 24 and 32 weeks of gestation, there is a nonlinear corresponding gain of 1% in fetal survival.

Sildenafil citrate has been used for increasing utero-placental perfusion in cases with intrauterine growth restriction, which makes it a promising drug in management of mild pre-eclampsia.

Its action is similar to the action of nitric oxide, which is a potent vasodilator, especially for the venules, besides being an inhibitor of platelet aggregation. During pregnancy, nitric oxide is synthesized in in utero-placental tissues and endothelial cells, helping to maintain low vascular resistance in the utero- and fetoplacental circulations. Phosphodiesterase metabolizes cyclic guanosine monophosphate; therefore, phosphodiesterase type 5 inhibition leads to cyclic guanosine monophosphate increase with associated vasodilation, independently of nitric oxide. Therefore, phosphodiesterase type 5 inhibitors have the potential to achieve similar therapeutic goals when compared with nitric oxide.

A potential advantage of phosphodiesterase type 5 inhibitors is that they may overcome the main limitation to nitric oxide use in pregnancy, which is tolerance and headaches. The most studied phosphodiesterase type 5 inhibitor is sildenafil citrate, which has previously shown promising outcomes both in vitro and in animal studies.

That is why we decided to study the role of Sildenafil Citrate in expectant and conservative management of mild pre-eclampsia, as it has shown its ability to be beneficial to both the mother and the fetus through increasing the maternofetal circulation perfusion and achieving a maternal hemodynamic stability and compare it to the current NICE (National Institute for Health and Care Excellence) guidelines that are currently used, that recommends conservative management of mild pre-eclampsia through control of maternal blood pressure and frequent screening of maternal laboratory investigations' abnormalities to detect possible progression to severe pre-eclamptic toxemia.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
80 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
- Double blinded, randomized, placebo-controlled trial.Double blinded, randomized, placebo-controlled trial.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
- It's a double blinded, randomized, placebo-controlled trial.
Primary Purpose:
Treatment
Official Title:
Use of Sildenafil Citrate in Management of Mild Pre-eclampsia: A Randomized Controlled Trial
Actual Study Start Date :
Sep 15, 2016
Anticipated Primary Completion Date :
Dec 15, 2017
Anticipated Study Completion Date :
Jan 15, 2018

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Intervention Group

• The intervention group will be supplied with Sildenafil Citrate (Respatio® 20mg tablets manufactured by Pharma Right Group , Egypt) according to the patient's weight by the rate of (1.5 mg/kg/day) divided into three doses per day ( every 8 hours) till termination of pregnancy.

Drug: Sildenafil 20 MG
Other Names:
  • Sildenafil Citrate 20 mg ( Respatio® 20 mg)

    		•
    Placebo Comparator: Control Group

    - The control group will be supplied with a placebo drug that has the same shape, size and color but without the active ingredient and it would also be taken in a similar way. The placebo tablet will be manufactured at the faculty of pharmacy, Assiut University.

    Drug: Placebo Oral Tablet
    Other Names:
  • Placebo drug

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Gestational age at time of termination and maternal outcome. [up to 37 weeks of gestation]

      Gestational age at time of termination and maternal outcome in terms of whether the disease would progress to severe pre-eclampsia or not.

    Secondary Outcome Measures

    1. Neonatal outcome. [up to 37 weeks of gestation]

      Neonatal outcome in terms of survival and neonatal well-being ( by obtaining the birth weight and the apgar score at 1 and 5 minutes and direct postnatal need to NICU).

    2. Control of maternal blood pressure. [up to 37 weeks of gestation]

      Control of maternal blood pressure.

    3. Method of termination of pregnancy. [up to 37 weeks of gestation]

      Method of termination of pregnancy.

    4. Identification of the side effects from the use of sildenafil citrate. [up to 37 weeks of gestation]

      Identification of possible maternal side effects from the use of sildenafil citrate i.e.; headache, flushing and dyspepsia.

    5. Evaluation of the effect of sildenafil citrate on the feto-maternal circulation through the Doppler ultrasound. [up to 37 weeks of gestation]

      Evaluation of the effect of sildenafil citrate on the feto-maternal circulation through the Doppler ultrasound.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 35 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Uncomplicated mild pre-eclampsia; No clinical or investigatory findings suggestive severe pre-eclamptic toxemia.

    2. Gestational age of 28 - 36 weeks by good dates according to ACOG's - committee on obstetric practice - Method for Estimating Due Date (2014) who will receive the study's drug for at least one week before termination.

    3. Singleton viable pregnancy.

    4. Age: 18-35 years.

    Exclusion Criteria:

    1. Severe pre-eclamptic toxemia (according to the NICE guidelines (2010): Hypertension in pregnancy: diagnosis and management)

    2. Intrauterine growth retardation.

    3. Use of medication that could interact with sildenafil citrate such as nitrates erythromycin, ketoconazole, itraconazole, antiretroviral agents and others.

    4. Presence of maternal co-morbidity disease as: DM, chronic hypertension, congestive heart failure, chronic kidney disease and SLE.

    5. Placenta previa.

    6. The patient is using aspirin.

    7. The presence of a contraindication to the use of sildenafil citrate:

    • Hypersensitivity to sildenafil citrate or any of the tablet ingredients.

    • Patients with severe cardiovascular disease such as established cardiac failure and unstable angina pectoris.

    • Previous episode of non-arteritic anterior ischaemic optic neuropathy.

    • Severe hepatic impairment.

    • Hypotension (blood pressure <90/50 mmHg).

    • Hypertension (blood pressure >170/110 mmHg).

    • Recent history of stroke or myocardial infarction.

    • Known hereditary degenerative retinal disorders such as retinitis pigmentosa.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Assiut Univeristy Hospitals Assiut Egypt 71111

    Sponsors and Collaborators

    • Assiut University

    Investigators

    • Principal Investigator: Fady Abdallah, Assiut University
    • Study Director: Hasan Kamel, Assiut University
    • Study Director: Hisham Abou-Taleb, Assiut University

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Fady Nasef Tous Abdallah, Resident of Obstetrics and Gynecology Department - Assiut University, Assiut University
    ClinicalTrials.gov Identifier:
    NCT03262961
    Other Study ID Numbers:
    • assiutu252
    First Posted:
    Aug 28, 2017
    Last Update Posted:
    Aug 28, 2017
    Last Verified:
    Aug 1, 2017
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Fady Nasef Tous Abdallah, Resident of Obstetrics and Gynecology Department - Assiut University, Assiut University
    Mild pre-eclampsia Sildenafil Citrate
    Additional relevant MeSH terms:
    Eclampsia
    Pre-Eclampsia
    Sildenafil Citrate

    Study Results

    No Results Posted as of Aug 28, 2017