<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04404686</url>
  </required_header>
  <id_info>
    <org_study_id>TOCOMED-HMO-CTIL</org_study_id>
    <nct_id>NCT04404686</nct_id>
  </id_info>
  <brief_title>Vaginal Indomethacin for Preterm Labor</brief_title>
  <acronym>TOCOMED</acronym>
  <official_title>Vaginal Indomethacin Versus Oral Nifedipine for Preterm Labor; a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hadassah Medical Organization</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Soroka University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hadassah Medical Organization</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Indometacin is a cyclooxygenase agent from the NSAID family that has been used to treat&#xD;
      preterm contractions since the 70's by preventing the synthesis of prostaglandins. It has&#xD;
      been shown to be significantly more effective than placebo and postpone labor for 7-10 days,&#xD;
      prolong pregnancies above 37 weeks of gestation and reduce numbers of small for gestational&#xD;
      age neonates.&#xD;
&#xD;
      Nifedipine is a calcium channel blocker agent that has been shown to reduce rates of labor&#xD;
      within 48 hours from treatment.&#xD;
&#xD;
      Previous studies comparing rectal Indometacin to oral nifedipine were inconclusive.&#xD;
&#xD;
      Prostaglandins are synthesized in the uterus and the uterine cervix and therefore local&#xD;
      administration of Indometacin may be more effective than other forms of administration, as&#xD;
      been shown in a previous study.&#xD;
&#xD;
      In this study we aim to compare vaginal Indometacin administration to a commonly used&#xD;
      tocolytic agent, nifedipine.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">October 2020</start_date>
  <completion_date type="Anticipated">April 2025</completion_date>
  <primary_completion_date type="Anticipated">April 2024</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Investigator, Outcomes Assessor)</masking>
    <masking_description>Caregivers will receive a closed envelope with the drug to be used. since the routes of administration are different, from that point on the caregiver and patient will be aware of chosen drug</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time to delivery</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>The time from administration of intervention do delivery</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Gestational age</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>Days from last menstrual period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of preterm deliveries</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>Rate of deliveries under 37+0/7 weeks of gestation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of remote from term deliveries</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>Rate of deliveries under 34+0/7 weeks of gestation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of extreme preterm deliveries</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>Rate of deliveries under 28+0/7 weeks of gestation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>neonatal immediate outcomes</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>Neonatal Apgar scores</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal immediate outcome</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>Neonatal umbilical cord pH levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal birth weight</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>birth wight as recorded in chart in grams</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neonatal outcomes</measure>
    <time_frame>through study completion, approximately 1 year</time_frame>
    <description>neonatal intensive care unit administration rate</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Obstetric Labor, Premature</condition>
  <arm_group>
    <arm_group_label>Indomethacin group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group of patients receiving Indomethacin for preterm labor treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nifedipine group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group of patients receiving Nifedipine for preterm labor treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Indomethacin</intervention_name>
    <description>Per vagina administration of 100 mg followed by a second 100 mg dosage the following day</description>
    <arm_group_label>Indomethacin group</arm_group_label>
    <other_name>Indomed</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nifedipine</intervention_name>
    <description>Per os administration according to current protocol of 20mg each 20 minutes for 1 hour followed by 20 mg q8 for 48 hours.</description>
    <arm_group_label>Nifedipine group</arm_group_label>
    <other_name>Pressolat</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Singe fetus&#xD;
&#xD;
          -  Gestational age between 24+0/7 and 31+6/7&#xD;
&#xD;
          -  At least one uterine contraction in ten minutes for at least 20 minutes upon&#xD;
             tocography admission&#xD;
&#xD;
          -  Cervical parameters: 1 cm dilation or more or 80% cervical effacement or cervical&#xD;
             length 20mm or less&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Rupture of membranes&#xD;
&#xD;
          -  Vaginal bleeding&#xD;
&#xD;
          -  Cervical dilation ≥5cm&#xD;
&#xD;
          -  Known fetal malformations&#xD;
&#xD;
          -  Fetal heart rate abnormalities&#xD;
&#xD;
          -  Suspected placental abruption of adherent placental syndrome&#xD;
&#xD;
          -  Known sensitivity to one of the drugs used in the study (Indometacin and nifedipine)&#xD;
&#xD;
          -  Maternal hypotension and known aortic or mitral stenosis&#xD;
&#xD;
          -  Presence of cervical cerclage&#xD;
&#xD;
          -  Previous administration of tocolytic drugs in current pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant women</gender_description>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hila Hochler, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hadassah Medical Organization</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Hila Hochler, MD</last_name>
    <phone>00 972 52 300 3722</phone>
    <email>hilahochler@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hadas Lemberg, PhD</last_name>
    <phone>00 972 2 6777572</phone>
    <email>lhadas@hadassah.org.il</email>
  </overall_contact_backup>
  <reference>
    <citation>Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, Egner PG. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol. 1980 Apr 15;136(8):1014-9. doi: 10.1016/0002-9378(80)90629-8.</citation>
    <PMID>7369252</PMID>
  </reference>
  <reference>
    <citation>Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. Part II double-blind study. J Perinat Med. 1984;12(1):25-9. doi: 10.1515/jpme.1984.12.1.25.</citation>
    <PMID>6374098</PMID>
  </reference>
  <reference>
    <citation>Besinger RE, Niebyl JR, Keyes WG, Johnson TR. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol. 1991 Apr;164(4):981-6; discussion 986-8. doi: 10.1016/0002-9378(91)90569-d.</citation>
    <PMID>2014850</PMID>
  </reference>
  <reference>
    <citation>Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol. 2009 Mar;113(3):585-594. doi: 10.1097/AOG.0b013e318199924a.</citation>
    <PMID>19300321</PMID>
  </reference>
  <reference>
    <citation>O'Brien WF. The role of prostaglandins in labor and delivery. Clin Perinatol. 1995 Dec;22(4):973-84.</citation>
    <PMID>8665768</PMID>
  </reference>
  <reference>
    <citation>Bry K, Hallman M. Prostaglandins, inflammation, and preterm labor. J Perinatol. 1989 Mar;9(1):60-5.</citation>
    <PMID>2496208</PMID>
  </reference>
  <reference>
    <citation>Abramov Y, Nadjari M, Weinstein D, Ben-Shachar I, Plotkin V, Ezra Y. Indomethacin for preterm labor: a randomized comparison of vaginal and rectal-oral routes. Obstet Gynecol. 2000 Apr;95(4):482-6. doi: 10.1016/s0029-7844(99)00578-5.</citation>
    <PMID>10725476</PMID>
  </reference>
  <reference>
    <citation>Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014 Jun 5;2014(6):CD002255. doi: 10.1002/14651858.CD002255.pub2.</citation>
    <PMID>24901312</PMID>
  </reference>
  <reference>
    <citation>Reinebrant HE, Pileggi-Castro C, Romero CL, Dos Santos RA, Kumar S, Souza JP, Flenady V. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2015 Jun 5;2015(6):CD001992. doi: 10.1002/14651858.CD001992.pub3.</citation>
    <PMID>26042617</PMID>
  </reference>
  <reference>
    <citation>Kashanian M, Bahasadri S, Zolali B. Comparison of the efficacy and adverse effects of nifedipine and indomethacin for the treatment of preterm labor. Int J Gynaecol Obstet. 2011 Jun;113(3):192-5. doi: 10.1016/j.ijgo.2010.12.019. Epub 2011 Apr 1.</citation>
    <PMID>21457979</PMID>
  </reference>
  <reference>
    <citation>Klauser CK, Briery CM, Keiser SD, Martin RW, Kosek MA, Morrison JC. Effect of antenatal tocolysis on neonatal outcomes. J Matern Fetal Neonatal Med. 2012 Dec;25(12):2778-81. doi: 10.3109/14767058.2012.714819. Epub 2012 Aug 20.</citation>
    <PMID>22873356</PMID>
  </reference>
  <reference>
    <citation>Klauser CK, Briery CM, Martin RW, Langston L, Magann EF, Morrison JC. A comparison of three tocolytics for preterm labor: a randomized clinical trial. J Matern Fetal Neonatal Med. 2014 May;27(8):801-6. doi: 10.3109/14767058.2013.847416. Epub 2013 Oct 11.</citation>
    <PMID>24090282</PMID>
  </reference>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>May 7, 2020</study_first_submitted>
  <study_first_submitted_qc>May 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>August 10, 2020</last_update_submitted>
  <last_update_submitted_qc>August 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 11, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hadassah Medical Organization</investigator_affiliation>
    <investigator_full_name>Hila Hocler MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>preterm labor</keyword>
  <keyword>tocolysis</keyword>
  <keyword>prematurity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obstetric Labor, Premature</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Indomethacin</mesh_term>
    <mesh_term>Nifedipine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04404686
org study id: TOCOMED-HMO-CTIL
nct id: NCT04404686
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Indometacin is a cyclooxygenase agent from the NSAID family that has been used to treat
      preterm contractions since the 70's by preventing the synthesis of prostaglandins. It has
      been shown to be significantly more effective than placebo and postpone labor for 7-10 days,
      prolong pregnancies above 37 weeks of gestation and reduce numbers of small for gestational
      age neonates.

      Nifedipine is a calcium channel blocker agent that has been shown to reduce rates of labor
      within 48 hours from treatment.

      Previous studies comparing rectal Indometacin to oral nifedipine were inconclusive.

      Prostaglandins are synthesized in the uterus and the uterine cervix and therefore local
      administration of Indometacin may be more effective than other forms of administration, as
      been shown in a previous study.

      In this study we aim to compare vaginal Indometacin administration to a commonly used
      tocolytic agent, nifedipine.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Investigator, Outcomes Assessor)
masking description: Caregivers will receive a closed envelope with the drug to be used. since the routes of administration are different, from that point on the caregiver and patient will be aware of chosen drug
measure: Time to delivery
time frame: through study completion, approximately 1 year
description: The time from administration of intervention do delivery
measure: Gestational age
time frame: through study completion, approximately 1 year
description: Days from last menstrual period
measure: Rate of preterm deliveries
time frame: through study completion, approximately 1 year
description: Rate of deliveries under 37+0/7 weeks of gestation
measure: Rate of remote from term deliveries
time frame: through study completion, approximately 1 year
description: Rate of deliveries under 34+0/7 weeks of gestation
measure: Rate of extreme preterm deliveries
time frame: through study completion, approximately 1 year
description: Rate of deliveries under 28+0/7 weeks of gestation
measure: neonatal immediate outcomes
time frame: through study completion, approximately 1 year
description: Neonatal Apgar scores
measure: Neonatal immediate outcome
time frame: through study completion, approximately 1 year
description: Neonatal umbilical cord pH levels
measure: Neonatal birth weight
time frame: through study completion, approximately 1 year
description: birth wight as recorded in chart in grams
measure: Neonatal outcomes
time frame: through study completion, approximately 1 year
description: neonatal intensive care unit administration rate
arm group label: Indomethacin group
arm group type: Experimental
description: Group of patients receiving Indomethacin for preterm labor treatment.
arm group label: Nifedipine group
arm group type: Active Comparator
description: Group of patients receiving Nifedipine for preterm labor treatment.
intervention type: Drug
intervention name: Indomethacin
description: Per vagina administration of 100 mg followed by a second 100 mg dosage the following day
arm group label: Indomethacin group
other name: Indomed
intervention type: Drug
intervention name: Nifedipine
description: Per os administration according to current protocol of 20mg each 20 minutes for 1 hour followed by 20 mg q8 for 48 hours.
arm group label: Nifedipine group
other name: Pressolat
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant women
minimum age: 16 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Hila Hochler, MD
role: Principal Investigator
affiliation: Hadassah Medical Organization
last name: Hila Hochler, MD
phone: 00 972 52 300 3722
email: hilahochler@gmail.com
last name: Hadas Lemberg, PhD
phone: 00 972 2 6777572
email: lhadas@hadassah.org.il
citation: Niebyl JR, Blake DA, White RD, Kumor KM, Dubin NH, Robinson JC, Egner PG. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol. 1980 Apr 15;136(8):1014-9. doi: 10.1016/0002-9378(80)90629-8.
PMID: 7369252
citation: Zuckerman H, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. Part II double-blind study. J Perinat Med. 1984;12(1):25-9. doi: 10.1515/jpme.1984.12.1.25.
PMID: 6374098
citation: Besinger RE, Niebyl JR, Keyes WG, Johnson TR. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol. 1991 Apr;164(4):981-6; discussion 986-8. doi: 10.1016/0002-9378(91)90569-d.
PMID: 2014850
citation: Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger TW, Golichowski AM. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol. 2009 Mar;113(3):585-594. doi: 10.1097/AOG.0b013e318199924a.
PMID: 19300321
citation: O'Brien WF. The role of prostaglandins in labor and delivery. Clin Perinatol. 1995 Dec;22(4):973-84.
PMID: 8665768
citation: Bry K, Hallman M. Prostaglandins, inflammation, and preterm labor. J Perinatol. 1989 Mar;9(1):60-5.
PMID: 2496208
citation: Abramov Y, Nadjari M, Weinstein D, Ben-Shachar I, Plotkin V, Ezra Y. Indomethacin for preterm labor: a randomized comparison of vaginal and rectal-oral routes. Obstet Gynecol. 2000 Apr;95(4):482-6. doi: 10.1016/s0029-7844(99)00578-5.
PMID: 10725476
citation: Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014 Jun 5;2014(6):CD002255. doi: 10.1002/14651858.CD002255.pub2.
PMID: 24901312
citation: Reinebrant HE, Pileggi-Castro C, Romero CL, Dos Santos RA, Kumar S, Souza JP, Flenady V. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2015 Jun 5;2015(6):CD001992. doi: 10.1002/14651858.CD001992.pub3.
PMID: 26042617
citation: Kashanian M, Bahasadri S, Zolali B. Comparison of the efficacy and adverse effects of nifedipine and indomethacin for the treatment of preterm labor. Int J Gynaecol Obstet. 2011 Jun;113(3):192-5. doi: 10.1016/j.ijgo.2010.12.019. Epub 2011 Apr 1.
PMID: 21457979
citation: Klauser CK, Briery CM, Keiser SD, Martin RW, Kosek MA, Morrison JC. Effect of antenatal tocolysis on neonatal outcomes. J Matern Fetal Neonatal Med. 2012 Dec;25(12):2778-81. doi: 10.3109/14767058.2012.714819. Epub 2012 Aug 20.
PMID: 22873356
citation: Klauser CK, Briery CM, Martin RW, Langston L, Magann EF, Morrison JC. A comparison of three tocolytics for preterm labor: a randomized clinical trial. J Matern Fetal Neonatal Med. 2014 May;27(8):801-6. doi: 10.3109/14767058.2013.847416. Epub 2013 Oct 11.
PMID: 24090282
responsible party type: Principal Investigator
investigator affiliation: Hadassah Medical Organization
investigator full name: Hila Hocler MD
investigator title: Principal Investigator
mesh term: Obstetric Labor, Premature
mesh term: Indomethacin
mesh term: Nifedipine
sharing ipd: No