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Medical Management of Late Intrauterine Death. (INPer)

Primary Purpose

Cervical Pregnancy, Maternal Care for Late Fetal Death

Status
Completed
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Isosorbide Dinitrate
Misoprostol
Oxytocin
Sponsored by
National Institute of Perinatology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cervical Pregnancy focused on measuring Isosorbide dinitrate gel solution, late intrauterine death, nitric oxide donors

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Closed cervix without evidence of cervical dilation or baseline uterine activity.
  • A Bishop score of <5, having intact membranes.
  • Gestation greater than or equal to 20 weeks established by the date of menstruation or by fetometry and ultrasound-confirmed late IUFD.

Exclusion Criteria:

  • Multiple pregnancies.
  • IUFD after late foeticide or the management of specific medical conditions associated with an increase in the risk of IUFD.
  • Patients with a history of hypertension.
  • Women with a history of unexplained antepartum haemorrhage, pelvic dystocia or any another counter-indications where medications were used.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    isosorbide dinitrate-oxytocin

    misoprostol-oxytocin

    Arm Description

    Preinduction with isosorbide dinitrate gel solution (80 mg/1.5 mL) were administered in the posterior fornix every 3 hours. Once a Bishop score of over 7 was reached, oxytocin was infused in a balanced electrolyte solution beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and doubling the dose every 15 minutes. If the cervical conditions (<7 Bishop Score) did not change after the treatment application, a new dose, without exceeding 4 doses, to facilitate cervical ripening.

    Preinduction with misoprostol gel solution (100 mcg/1.5 mL) were administered in the posterior fornix every 3 hours. Once a Bishop score of over 7 was reached, oxytocin was infused in a balanced electrolyte solution beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and doubling the dose every 15 minutes. If the cervical conditions (<7 Bishop score) did not change after the treatment application, participants received a new dose, without exceeding 4 doses, to facilitate cervical ripening.

    Outcomes

    Primary Outcome Measures

    Rates of uterine expulsion in the women who received the isosorbide dinitrate-oxytocin regimen

    Secondary Outcome Measures

    A Bishop score of >7 of administration of the first dose of isosorbide dinitrate

    Full Information

    First Posted
    June 26, 2015
    Last Updated
    July 22, 2015
    Sponsor
    National Institute of Perinatology
    Collaborators
    National Council of Science and Technology, Mexico
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02488642
    Brief Title
    Medical Management of Late Intrauterine Death.
    Acronym
    INPer
    Official Title
    Medical Management of Late Intrauterine Death Using a Therapeutic Combination of Isosorbide Dinitrate and Oxytocin.
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2015
    Overall Recruitment Status
    Completed
    Study Start Date
    May 2008 (undefined)
    Primary Completion Date
    September 2013 (Actual)
    Study Completion Date
    May 2014 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    National Institute of Perinatology
    Collaborators
    National Council of Science and Technology, Mexico

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The purpose of this study is to assess the therapeutic efficacy and safety of isosorbide dinitrate-oxytocin in combination in the management of late intrauterine foetal death.
    Detailed Description
    A prospective, randomised, double-blind, controlled clinical trial (RCT) was conducted to compare the efficacy and clinical safety of the induction of labour using the combination of isosorbide dinitrate-oxytocin (experimental arm, X = 1) compared to misoprostol-oxytocin (standard arm, X = 0). The main result of the study was the success rate of foetal expulsion within 15 hours, while the average administration induction interval defined the secondary result. A total of 60 women with pregnancies greater than 20 weeks gestation were referred for foetal evacuation. We defined late intrauterine foetal death (IUFD) as babies without signs of life in the uterus after 20 complete weeks of pregnancy. The approval to conduct the study was obtained from the institutional board ethical committees of both hospitals. All participants were informed about the objectives of the study, and informed consent was required. Patients with the following characteristics were included: closed cervix without evidence of cervical dilation or baseline uterine activity, A Bishop score of <5, having intact membranes, gestation greater than or equal to 20 weeks established by the date of menstruation or by fetometry and ultrasound-confirmed late IUFD. This study did not include the medical management of multiple pregnancies, IUFD after late foeticide or the management of specific medical conditions associated with an increase in the risk of IUFD or patients with a history of hypertension, along with women with a history of unexplained antepartum haemorrhage, pelvic dystocia or any another counter-indications where medications were used. Patients were assigned through a computational random number generator to receive isosorbide dinitrate or misoprostol. Allocation to groups was predetermined and arranged in numerical order. All participants were given a vaginal exam by the same person, who was blinded to the treatment allocation. The medications were administered in the posterior fornix, and cervical activity was evaluated at baseline and every 3 hours to monitor any change based on the Bishop score. If the cervical conditions did not change after the treatment application, participants received a new dose, without exceeding 4 doses, to facilitate cervical ripening. Once a Bishop score of over 7 was reached, oxytocin was infused in a balanced electrolyte solution beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and doubling the dose every 15 minutes. The labour induction time from the first application of medication to the expulsion of the foetus was determined with a digital stopwatch. Each woman's vital signs were verified to determine that she was in stable condition and demonstrated haemodynamic stability as a requirement for the application of a new dose. During this time, the data and medical information were collected on paper and were later entered into a computational database. The participants remained at rest during the evaluation of adverse effects, such as headache, abdominal pain, pelvic pain, lower back pain, nausea, dizziness, and vomiting. The lack of cervical activity after 4 doses of medication was considered treatment failure. A base solution of isosorbide dinitrate and misoprostol was prepared to obtain a concentration of 20 micrograms per milliliter (mcg/mL) in 10% lactose solution. Serial dilutions were performed using known concentrations in mobile phase buffer solution (150 g ammonium acetate and 11.5 mL glacial acetic acid to 1 L water), methanol and water in a proportion of 350:100:550, respectively. The concentration of both drugs was determined using a ultraviolet (UV) light spectrophotometer reading at lambda 220 nm and a reference filter of lambda 278 nm. The mean absorbance for each set of standards, controls and samples was calculated by a standard plot curve. Computer-based curve-fitting statistical software was employed. Peak absorption and area under the curve were taken into account to determine stability of the pharmacological integration. Known samples of isosorbide dinitrate and misoprostol were added to 100% glycerin to prepare the gel solution. The reagents had final concentrations of either 80 mg of isosorbide dinitrate in 1.5 ml of gel solution or 100 micrograms of misoprostol in the same presentation. Both solutions were packed in syringes that had the same appearance for the purpose of keeping the physician, patient and researcher blinded. The pharmacist was the only participant who knew the contents of the syringes. Four syringes were placed in an opaque and sealed envelope consecutively numbered with a unique study number. The envelopes were opened by the physician who applied the contents of the syringe, repeating the administration every 3 hours according to the prior selection and random allocation of patients. The entire "stock" of reagents remained stable for a period of 20 days and was maintained at room temperature (18-25° C) before using. The calculation of the sample size was based on the Cox regression model using the risk quotient (log Hazard Ratio) and a 95% confidence interval (95% CI).17 To reach a power (superiority of the clinical trial) of 80% and an α value of 0.05, with a standard deviation of 0.5 and under the assumption that 25% of all women will fail to induce labour, the estimated sample size required for the trial was 60 patients (30 in each arm). All continuous variables were summarised using histograms and the measures of central tendency before conducting the statistical analyses. The statistical analyses were performed using the Chi-Square test, Fisher's exact test and the Mantel-Haenszel test, and Student's t test when appropriate. The Shapiro-Wilk test was used to verify the normality of the data. To model the time-event of labour induction after IUFD, Cox regression was utilised, controlling for the covariates maternal age, foetal size and weight, and weeks of gestation. The proportional hazards assumption was evaluated using the two graphed lines, which corresponded to the survival curves (absence of crossing) and the log-log plots in the figure. Respiratory and cardiac rate, temperature (measured orally) and systolic and diastolic blood pressures (recorded using sphygmomanometry) were determined at baseline and every 3 hours until the trial ended. Relative risks (RRs) and 95% CIs were estimated utilising bivariate analysis, including non-serious adverse events among the treatment groups. Attributable risk was calculated to determine the probability of total risk of each adverse effect observed with the use of isosorbide dinitrate or misoprostol. All of the tests were two-tailed, and results that had values of p < 0.05 were considered statistically significant.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Cervical Pregnancy, Maternal Care for Late Fetal Death
    Keywords
    Isosorbide dinitrate gel solution, late intrauterine death, nitric oxide donors

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantCare ProviderInvestigatorOutcomes Assessor
    Allocation
    Randomized
    Enrollment
    60 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    isosorbide dinitrate-oxytocin
    Arm Type
    Experimental
    Arm Description
    Preinduction with isosorbide dinitrate gel solution (80 mg/1.5 mL) were administered in the posterior fornix every 3 hours. Once a Bishop score of over 7 was reached, oxytocin was infused in a balanced electrolyte solution beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and doubling the dose every 15 minutes. If the cervical conditions (<7 Bishop Score) did not change after the treatment application, a new dose, without exceeding 4 doses, to facilitate cervical ripening.
    Arm Title
    misoprostol-oxytocin
    Arm Type
    Placebo Comparator
    Arm Description
    Preinduction with misoprostol gel solution (100 mcg/1.5 mL) were administered in the posterior fornix every 3 hours. Once a Bishop score of over 7 was reached, oxytocin was infused in a balanced electrolyte solution beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and doubling the dose every 15 minutes. If the cervical conditions (<7 Bishop score) did not change after the treatment application, participants received a new dose, without exceeding 4 doses, to facilitate cervical ripening.
    Intervention Type
    Drug
    Intervention Name(s)
    Isosorbide Dinitrate
    Other Intervention Name(s)
    Isordil, Dilatrate-SR, Sorbitrate
    Intervention Type
    Drug
    Intervention Name(s)
    Misoprostol
    Other Intervention Name(s)
    Cytotec
    Intervention Type
    Drug
    Intervention Name(s)
    Oxytocin
    Intervention Description
    Oxytocin was infused in a balanced electrolyte solution beginning with an infusion rate of 2 milli-International Units per minute (mIU/min) and doubling the dose every 15 minutes.
    Primary Outcome Measure Information:
    Title
    Rates of uterine expulsion in the women who received the isosorbide dinitrate-oxytocin regimen
    Time Frame
    within 15 hours of administration
    Secondary Outcome Measure Information:
    Title
    A Bishop score of >7 of administration of the first dose of isosorbide dinitrate
    Time Frame
    within 12 hours

    10. Eligibility

    Sex
    Female
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Closed cervix without evidence of cervical dilation or baseline uterine activity. A Bishop score of <5, having intact membranes. Gestation greater than or equal to 20 weeks established by the date of menstruation or by fetometry and ultrasound-confirmed late IUFD. Exclusion Criteria: Multiple pregnancies. IUFD after late foeticide or the management of specific medical conditions associated with an increase in the risk of IUFD. Patients with a history of hypertension. Women with a history of unexplained antepartum haemorrhage, pelvic dystocia or any another counter-indications where medications were used.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Gabriel Arteaga-Troncoso, PhD.
    Organizational Affiliation
    National Institute of Perinatology
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    Citation
    World Health Organization. Induction and augmentation of labour. In: WHO, UNFPA, UNICEF, World Bank, editor. Managing Complications in Pregnancy and Childbirth: A Guide for Midwives and Doctors. Geneva: WHO; 2000. pp. 17-25.
    Results Reference
    background
    PubMed Identifier
    23784865
    Citation
    Koopmans L, Wilson T, Cacciatore J, Flenady V. Support for mothers, fathers and families after perinatal death. Cochrane Database Syst Rev. 2013 Jun 19;2013(6):CD000452. doi: 10.1002/14651858.CD000452.pub3.
    Results Reference
    result
    PubMed Identifier
    8646141
    Citation
    Radestad I, Steineck G, Nordin C, Sjogren B. Psychological complications after stillbirth--influence of memories and immediate management: population based study. BMJ. 1996 Jun 15;312(7045):1505-8. doi: 10.1136/bmj.312.7045.1505.
    Results Reference
    result
    PubMed Identifier
    20661052
    Citation
    Silver RM, Heuser CC. Stillbirth workup and delivery management. Clin Obstet Gynecol. 2010 Sep;53(3):681-90. doi: 10.1097/GRF.0b013e3181eb3297.
    Results Reference
    result
    PubMed Identifier
    11336776
    Citation
    Hughes EG, Kelly AJ, Kavanagh J. Dinoprostone vaginal insert for cervical ripening and labor induction: a meta-analysis. Obstet Gynecol. 2001 May;97(5 Pt 2):847-55. doi: 10.1016/s0029-7844(00)01216-3.
    Results Reference
    result
    PubMed Identifier
    11194687
    Citation
    Neiger R, Greaves PC. Comparison between vaginal misoprostol and cervical dinoprostone for cervical ripening and labor induction. Tenn Med. 2001 Jan;94(1):25-7.
    Results Reference
    result
    PubMed Identifier
    14749647
    Citation
    Bolnick JM, Velazquez MD, Gonzalez JL, Rappaport VJ, McIlwain-Dunivan G, Rayburn WF. Randomized trial between two active labor management protocols in the presence of an unfavorable cervix. Am J Obstet Gynecol. 2004 Jan;190(1):124-8. doi: 10.1016/s0002-9378(03)00952-9.
    Results Reference
    result
    PubMed Identifier
    15121558
    Citation
    Khan RU, El-Refaey H, Sharma S, Sooranna D, Stafford M. Oral, rectal, and vaginal pharmacokinetics of misoprostol. Obstet Gynecol. 2004 May;103(5 Pt 1):866-70. doi: 10.1097/01.AOG.0000124783.38974.53.
    Results Reference
    result
    PubMed Identifier
    16305563
    Citation
    Arteaga-Troncoso G, Villegas-Alvarado A, Belmont-Gomez A, Martinez-Herrera FJ, Villagrana-Zesati R, Guerra-Infante F. Intracervical application of the nitric oxide donor isosorbide dinitrate for induction of cervical ripening: a randomised controlled trial to determine clinical efficacy and safety prior to first trimester surgical evacuation of retained products of conception. BJOG. 2005 Dec;112(12):1615-9. doi: 10.1111/j.1471-0528.2005.00760.x.
    Results Reference
    result
    PubMed Identifier
    6115052
    Citation
    Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther. 1981 Sep;218(3):739-49. No abstract available.
    Results Reference
    result
    PubMed Identifier
    2564216
    Citation
    Ignarro LJ. Heme-dependent activation of soluble guanylate cyclase by nitric oxide: regulation of enzyme activity by porphyrins and metalloporphyrins. Semin Hematol. 1989 Jan;26(1):63-76. No abstract available.
    Results Reference
    result
    PubMed Identifier
    7688574
    Citation
    Schmidt HH, Lohmann SM, Walter U. The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta. 1993 Aug 18;1178(2):153-75. doi: 10.1016/0167-4889(93)90006-b. No abstract available.
    Results Reference
    result
    PubMed Identifier
    7913616
    Citation
    Murad F. Regulation of cytosolic guanylyl cyclase by nitric oxide: the NO-cyclic GMP signal transduction system. Adv Pharmacol. 1994;26:19-33. doi: 10.1016/s1054-3589(08)60049-6.
    Results Reference
    result
    PubMed Identifier
    2110975
    Citation
    Chung SJ, Fung HL. Identification of the subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells. J Pharmacol Exp Ther. 1990 May;253(2):614-9.
    Results Reference
    result
    PubMed Identifier
    1656970
    Citation
    Feelisch M, Kelm M. Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun. 1991 Oct 15;180(1):286-93. doi: 10.1016/s0006-291x(05)81290-2.
    Results Reference
    result
    PubMed Identifier
    7690516
    Citation
    Michel T, Smith TW. Nitric oxide synthases and cardiovascular signaling. Am J Cardiol. 1993 Sep 9;72(8):33C-38C. doi: 10.1016/0002-9149(93)90253-9.
    Results Reference
    result
    PubMed Identifier
    11146149
    Citation
    Hsieh FY, Lavori PW. Sample-size calculations for the Cox proportional hazards regression model with nonbinary covariates. Control Clin Trials. 2000 Dec;21(6):552-60. doi: 10.1016/s0197-2456(00)00104-5.
    Results Reference
    result
    PubMed Identifier
    12013166
    Citation
    Wagaarachchi PT, Ashok PW, Narvekar NN, Smith NC, Templeton A. Medical management of late intrauterine death using a combination of mifepristone and misoprostol. BJOG. 2002 Apr;109(4):443-7. doi: 10.1111/j.1471-0528.2002.01238.x.
    Results Reference
    result
    PubMed Identifier
    10863541
    Citation
    Espey MG, Miranda KM, Feelisch M, Fukuto J, Grisham MB, Vitek MP, Wink DA. Mechanisms of cell death governed by the balance between nitrosative and oxidative stress. Ann N Y Acad Sci. 2000;899:209-21. doi: 10.1111/j.1749-6632.2000.tb06188.x.
    Results Reference
    result
    PubMed Identifier
    6149646
    Citation
    Rapoport RM, Draznin MB, Murad F. Endothelium-dependent vasodilator-and nitrovasodilator-induced relaxation may be mediated through cyclic GMP formation and cyclic GMP-dependent protein phosphorylation. Trans Assoc Am Physicians. 1983;96:19-30. No abstract available.
    Results Reference
    result
    PubMed Identifier
    12648175
    Citation
    Lokugamage AU, Forsyth SF, Sullivan KR, El Refaey H, Rodeck CH. Randomized trial in multiparous patients: investigating a single vs. two-dose regimen of intravaginal misoprostol for induction of labor. Acta Obstet Gynecol Scand. 2003 Feb;82(2):138-42. doi: 10.1034/j.1600-0412.2003.00084.x.
    Results Reference
    result
    PubMed Identifier
    2201190
    Citation
    Cabrol D, Dubois C, Cronje H, Gonnet JM, Guillot M, Maria B, Moodley J, Oury JF, Thoulon JM, Treisser A, et al. Induction of labor with mifepristone (RU 486) in intrauterine fetal death. Am J Obstet Gynecol. 1990 Aug;163(2):540-2. doi: 10.1016/0002-9378(90)91193-g.
    Results Reference
    result
    PubMed Identifier
    2266162
    Citation
    Urquhart DR, Templeton AA. The use of mifepristone prior to prostaglandin-induced mid-trimester abortion. Hum Reprod. 1990 Oct;5(7):883-6. doi: 10.1093/oxfordjournals.humrep.a137203.
    Results Reference
    result
    PubMed Identifier
    20927722
    Citation
    Hofmeyr GJ, Gulmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2010 Oct 6;2010(10):CD000941. doi: 10.1002/14651858.CD000941.pub2.
    Results Reference
    result
    PubMed Identifier
    3144030
    Citation
    Mariani Neto C, Leao EJ, Barreto EM, Kenj G, De Aquino MM, Tuffi VH. [Use of misoprostol for labor induction in stillbirth]. Rev Paul Med. 1987 Nov-Dec;105(6):325-8. No abstract available. Portuguese.
    Results Reference
    result
    PubMed Identifier
    10960643
    Citation
    Bartha JL, Comino-Delgado R, Garcia-Benasach F, Martinez-Del-Fresno P, Moreno-Corral LJ. Oral misoprostol and intracervical dinoprostone for cervical ripening and labor induction: a randomized comparison. Obstet Gynecol. 2000 Sep;96(3):465-9. doi: 10.1016/s0029-7844(00)00954-6.
    Results Reference
    result
    PubMed Identifier
    11284645
    Citation
    Titiz H, Wallace A, Voaklander DC. Manual removal of the placenta--a case control study. Aust N Z J Obstet Gynaecol. 2001 Feb;41(1):41-4. doi: 10.1111/j.1479-828x.2001.tb01292.x.
    Results Reference
    result
    PubMed Identifier
    17961568
    Citation
    Gomez Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007 Dec;99 Suppl 2:S190-3. doi: 10.1016/j.ijgo.2007.09.010. Epub 2007 Oct 24.
    Results Reference
    result
    PubMed Identifier
    11303205
    Citation
    Nicoll AE, Mackenzie F, Greer IA, Norman JE. Vaginal application of the nitric oxide donor isosorbide mononitrate for preinduction cervical ripening: a randomized controlled trial to determine effects on maternal and fetal hemodynamics. Am J Obstet Gynecol. 2001 Apr;184(5):958-64. doi: 10.1067/mob.2001.111797.
    Results Reference
    result
    PubMed Identifier
    31751343
    Citation
    Arteaga-Troncoso G, Chacon-Calderon AE, Martinez-Herrera FJ, Cruz-Nunez SG, Lopez-Hurtado M, Belmont-Gomez A, Guzman-Grenfell AM, Farfan-Labonne BE, Neri-Mendez CJ, Zea-Prado F, Guerra-Infante FM. A randomized controlled trial comparing isosorbide dinitrate-oxytocin versus misoprostol-oxytocin at management of foetal intrauterine death. PLoS One. 2019 Nov 21;14(11):e0215718. doi: 10.1371/journal.pone.0215718. eCollection 2019.
    Results Reference
    derived

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