The Use of Low Dose Metronidazole to Decrease Postoperative Pain After Endometriosis Surgery

• ClinicalTrials.gov Identifier: NCT04554693
• Recruitment Status: Recruiting
• First Posted: September 18, 2020
• Last Update Posted: October 27, 2023
• Sponsor: University of Louisville
• Information provided by (Responsible Party): Resad Pasic, University of Louisville

Tracking Information

• First Submitted Date: September 5, 2020
• First Posted Date: September 18, 2020
• Last Update Posted Date: October 27, 2023
• Actual Study Start Date: October 19, 2020
• Estimated Primary Completion Date: September 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2021)

Self-reported pain persistence [ Time Frame: 6 weeks postoperatively. ]

The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.

Original Primary Outcome Measures (submitted: September 13, 2020)

• Self-reported pain persistence [ Time Frame: 6 weeks postoperatively. ]
  The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.
• Self-reported pain persistence [ Time Frame: 6 months postoperatively. ]
  The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.
• Self-reported pain persistence [ Time Frame: 1 year postoperatively. ]
  The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.
• Self-reported pain persistence [ Time Frame: 5 years postoperatively ]
  The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.

Current Secondary Outcome Measures (submitted: February 3, 2021)

• Quality of life scores [ Time Frame: 1 year postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Quality of life scores [ Time Frame: 6 months postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Quality of life scores [ Time Frame: 6 weeks postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Quality of life scores [ Time Frame: 5 years postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Sexual health [ Time Frame: 6 weeks postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Sexual health [ Time Frame: 6 months postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Sexual health [ Time Frame: 1 year postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Sexual health [ Time Frame: 5 year postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Self-reported pain persistence [ Time Frame: 1 year postoperatively. ]
  The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.
• Self-reported pain persistence [ Time Frame: 6 months postoperatively. ]
  The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.

Original Secondary Outcome Measures (submitted: September 13, 2020)

• Quality of life scores [ Time Frame: 6 weeks postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Quality of life scores [ Time Frame: 6 months postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Quality of life scores [ Time Frame: 1 year postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Quality of life scores [ Time Frame: 5 years postoperatively. ]
  Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome
• Sexual health [ Time Frame: 6 weeks postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Sexual health [ Time Frame: 6 months postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Sexual health [ Time Frame: 1 year postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction
• Sexual health [ Time Frame: 5 year postoperatively. ]
  Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction

Current Other Pre-specified Outcome Measures (submitted: September 13, 2020)

• Fertility [ Time Frame: 6 months postoperatively ]
  Number of pregnancies and miscarriages postoperatively will be compared
• Fertility [ Time Frame: 1 year postoperatively ]
  Number of pregnancies and miscarriages postoperatively will be compared
• Fertility [ Time Frame: 5 years postoperatively ]
  Number of pregnancies and miscarriages postoperatively will be compared

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: The Use of Low Dose Metronidazole to Decrease Postoperative Pain After Endometriosis Surgery
• Official Title: The Use of Low Dose Metronidazole to Decrease Postoperative Pain After Endometriosis Surgery: A Prospective, Randomized, Placebo-Controlled Trial
• Brief Summary: The purpose of this study is to determine a difference in participant reported pain after endometriosis surgery in participants given oral metronidazole versus placebo.

Detailed Description

The study is a prospective, randomized, placebo-controlled trial. Women scheduled for endometriosis surgery between 18-50 years of age will be invited to participate in the study.

Participants with surgically staged endometriosis will be randomized to the metronidazole plus routine postoperative care arm or the placebo plus routine postoperative care arm. Participants will take study or placebo drug for a total of 14 days.

Participants will complete surveys at baseline and postoperatively at 6 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years reporting intensity of endometriosis associated pain on a visual analog scale, pregnancy outcomes, quality of life, and sexual health.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Endometriosis
• Endometriosis-related Pain

Intervention

• Drug: Metronidazole Oral
  250 mg oral three times a day for 14 days
• Drug: Placebo
  Halal and Kosher certified gelatin placebo capsules oral three times a day for 14 days

Study Arms

• Experimental: Metronidazole
  Metronidazole
  Intervention: Drug: Metronidazole Oral
• Placebo Comparator: Placebo
  Halal and Kosher certified gelatin placebo capsules
  Intervention: Drug: Placebo

Publications *

• Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20.
• Working group of ESGE, ESHRE and WES; Saridogan E, Becker CM, Feki A, Grimbizis GF, Hummelshoj L, Keckstein J, Nisolle M, Tanos V, Ulrich UA, Vermeulen N, De Wilde RL. Recommendations for the Surgical Treatment of Endometriosis. Part 1: Ovarian Endometrioma. Hum Reprod Open. 2017 Dec 19;2017(4):hox016. doi: 10.1093/hropen/hox016. eCollection 2017.
• Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010 Jul;116(1):223-236. doi: 10.1097/AOG.0b013e3181e8b073. No abstract available.
• Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. 2004 Oct;82(4):878-84. doi: 10.1016/j.fertnstert.2004.03.046.
• Sutton CJ, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril. 1994 Oct;62(4):696-700. doi: 10.1016/s0015-0282(16)56990-8.
• Quaranta G, Sanguinetti M, Masucci L. Fecal Microbiota Transplantation: A Potential Tool for Treatment of Human Female Reproductive Tract Diseases. Front Immunol. 2019 Nov 26;10:2653. doi: 10.3389/fimmu.2019.02653. eCollection 2019.
• Leonardi M, Hicks C, El-Assaad F, El-Omar E, Condous G. Endometriosis and the microbiome: a systematic review. BJOG. 2020 Jan;127(2):239-249. doi: 10.1111/1471-0528.15916. Epub 2019 Sep 19.
• Chadchan SB, Cheng M, Parnell LA, Yin Y, Schriefer A, Mysorekar IU, Kommagani R. Antibiotic therapy with metronidazole reduces endometriosis disease progression in mice: a potential role for gut microbiota. Hum Reprod. 2019 Jun 4;34(6):1106-1116. doi: 10.1093/humrep/dez041.
• Simoens S, Hummelshoj L, D'Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update. 2007 Jul-Aug;13(4):395-404. doi: 10.1093/humupd/dmm010.
• Nogueira F, Sharghi S, Kuchler K, Lion T. Pathogenetic Impact of Bacterial-Fungal Interactions. Microorganisms. 2019 Oct 16;7(10):459. doi: 10.3390/microorganisms7100459.
• Mert I, Walther-Antonio M, Mariani A. Case for a role of the microbiome in gynecologic cancers: Clinician's perspective. J Obstet Gynaecol Res. 2018 Sep;44(9):1693-1704. doi: 10.1111/jog.13701. Epub 2018 Aug 2.
• Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome. CNS Neurosci Ther. 2016 Feb;22(2):102-17. doi: 10.1111/cns.12490. Epub 2015 Dec 10.
• Guo R, Chen LH, Xing C, Liu T. Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth. 2019 Nov;123(5):637-654. doi: 10.1016/j.bja.2019.07.026. Epub 2019 Sep 21.
• Glick LR, Sossenheimer PH, Ollech JE, Cohen RD, Hyman NH, Hurst RD, Rubin DT. Low-Dose Metronidazole is Associated With a Decreased Rate of Endoscopic Recurrence of Crohn's Disease After Ileal Resection: A Retrospective Cohort Study. J Crohns Colitis. 2019 Sep 19;13(9):1158-1162. doi: 10.1093/ecco-jcc/jjz047.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 13, 2020): 90
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2027
• Estimated Primary Completion Date: September 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Able to give informed consent
• Women aged 18-50 years old
• Scheduled to undergo excision of endometriosis
• Able to read and write in English and or Spanish
• Pain score > 2 on a 10 point visual analogue scale at baseline
• Negative screening by CAGE questionnaire

Exclusion Criteria:

• Refusal to surgery
• Contraindication to surgery
• Known allergy to metronidazole
• Known allergy to any component in gelatin placebo capsules
• Scheduled hysterectomy
• Endometriosis excision surgery within the last 3 months
• Elevated serum creatinine
• Abnormal liver function test greater than 2 times the normal
• Current pregnancy
• Breastfeeding
• Use of Disulfiram within the last 2 weeks
• History of Cockayne syndrome
• Inability to abstain from alcohol during the use of study drug

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Female participants

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Amira Quevedo, MD; 5025884400; amira.quevedo@uoflhealth.org

Contact: Resad Pasic, MD, PhD; 5025884400; resad.pasic@louisville.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04554693
• Other Study ID Numbers: 200544
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Resad Pasic, University of Louisville
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Louisville
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Resad Pasic, MD, PhD; University of Louisville

• PRS Account: University of Louisville
• Verification Date: October 2023