Can Ibuprofen Delay Ovulation in Natural Cycle-IVF?

NCT02571543 | Completed Phase 2 DMC

• 1 other identifier: 015/15
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

Brief Summary

During natural cycle in vitro fertilisation, no gonadotropin stimulation is used to stimulate oocyte production. Ovulation is induced with HCG (human chorionic gonadotropin) and the follicle is retrieved 36 hours later. In this study the patient in the intervention group will receive Ibuprofen as a study intervention beginning at the same time as the HCG injection. The treatment dose will either be 400mg every 8 to 12 hours or 800mg every 8 to 12 hours until the follicle retrieval, totalling 5 tablets. Instead of the usual time period of 36 hours, the follicular punction will occur after 42 hours. Should the oocyte still be accessible after this time period, then it is proven that Ibuprofen delays ovulation. In this case the patient will continue the regular NC-IVF treatment cycle. The study design is a admissible two-stage design. During stage 1, 8 cycles in 8 patients will be examined. Should it be the case that after these 8 patients have completed a cycle, 4 or more show a positive treatment effect from the Ibuprofen intake, then the study will continue to stage 2 with 17 more more patients, totalling 25. Should it be the case however, that after 8 patients, 3 or less show an effect of the Ibuprofen intake, then the study will be stopped prematurely for futility. The study intervention will be increased to 800mg of Ibuprofen and the study will recommence with 8 more patients. A control group will consist of women undergoing intrauterine insemination (IUI) or timed sexual intercourse (TSI). 42 hours after Beta-HCG injection, an ultrasound examination will be performed in order to determine the number of remaining follicles in the ovary. This examination is to verify and control the proposed time limit of 42 hours.

Conditions

Ovulation; Ovulation Inhibition; Ovulation Inhibition/Drug Effects; Pregnancy; Fertilization in Vitro/Methods

Keywords

Ibuprofen; IVF; minimal stimulation; modified natural-cycle; nonsteroidal anti-inflammatory drug (NSAID); Anti-Inflammatory Agents, Non-Steroidal/therapeutic use; Oocyte Retrieval; Ovarian Follicle/drug effects

Outcome Measures

Primary Outcomes (1)

• Percentage of non ovulated follicles

  The primary outcome of this study is whether Ibuprofen delays ovulation in the test subjects. It will be measured in the percentage of non-ovulated follicles exactly 42h after HCG administration with Ibuprofen.

  42 hours after HCG injection

Secondary Outcomes (4)

• Comparison of ovulation rates between the intervention and the control groups

  42 hours after HCG injection, up to end of study duration.

• Percentage of oocytes obtained from aspirated follicles

  42 hours after HCG injection

• E2 (Estradiol) concentration in the follicular fluid

  42 hours after HCG injection

• Incidence and severity of gastrointestinal and of other side effects

  Throughout study duration, expected to be up to 11 months

Study Arms (2)

Intervention

EXPERIMENTAL

2 Stage study design. Stage 1: 8 patients will be treated with the lower dose of 400mg of Ibuprofen. Should the efficacy be insufficient (3 or less patients) then the study will stop and stage 1 will recommence with 800mg. Stage 2: 17 patients will be treated either with the lower dose of 400mg or the higher dose of 800mg of Ibuprofen should the respective stage 1 have been successful (4 or more patients showing an effect).

Drug: Ibuprofen

Control

NO INTERVENTION

The control group will consist of a no-treatment group of patients undergoing Intrauterine Insemination (IUI) or Timed Sexual intercourse (TSI), to verify the delay between LH-Peak onset and ovulation. 42h after Beta-HCG injection inducing LH-Peak, ovulation will be determined by ultrasound examination.

Interventions

Ibuprofen DRUG

Beginning with 400mg Ibuprofen, 5 times. Depending on the outcome of stage 1 the treatment dose will increase to 800mg, 5 times.

Also known as: Brufen®

Intervention

Eligibility Criteria

• Age: 18 Years - 42 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Indication for NC-IVF
• Wish for NC-IVF
• Menstruation every 26-32 days
• Accessibility of both ovaries for a follicle aspiration
• years of age
• Written informed consent
• Indication for IUI or TSI
• Wish for IUI or TSI

You may not qualify if:

• \<18 and \>42 years of age
• Gastro-intestinal diseases
• Known Ibuprofen Intolerance

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• IBSA Institut Biochimique SA: collaborator

Study Sites (1)

Department of Obstetrics and Gynecology, Bern University Hospital

Bern, 3010 Bern, Switzerland

Location

Related Publications (12)

• Espey LL. Current status of the hypothesis that mammalian ovulation is comparable to an inflammatory reaction. Biol Reprod. 1994 Feb;50(2):233-8. doi: 10.1095/biolreprod50.2.233.

  PMID: 8142541 BACKGROUND

• Tanaka N, Espey LL, Kawano T, Okamura H. Comparison of inhibitory actions of indomethacin and epostane on ovulation in rats. Am J Physiol. 1991 Feb;260(2 Pt 1):E170-4. doi: 10.1152/ajpendo.1991.260.2.E170.

  PMID: 1996619 BACKGROUND

• Diao HL, Zhu H, Ma H, Tan HN, Cong J, Su RW, Yang ZM. Rat ovulation, implantation and decidualization are severely compromised by COX-2 inhibitors. Front Biosci. 2007 May 1;12:3333-42. doi: 10.2741/2316.

  PMID: 17485303 BACKGROUND

• Gaytan M, Bellido C, Morales C, Sanchez-Criado JE, Gaytan F. Effects of selective inhibition of cyclooxygenase and lipooxygenase pathways in follicle rupture and ovulation in the rat. Reproduction. 2006 Oct;132(4):571-7. doi: 10.1530/rep.1.01236.

  PMID: 17008468 BACKGROUND

• Gaytan M, Morales C, Bellido C, Sanchez-Criado JE, Gaytan F. Non-steroidal anti-inflammatory drugs (NSAIDs) and ovulation: lessons from morphology. Histol Histopathol. 2006 May;21(5):541-56. doi: 10.14670/HH-21.541.

  PMID: 16493584 BACKGROUND

• Pall M, Friden BE, Brannstrom M. Induction of delayed follicular rupture in the human by the selective COX-2 inhibitor rofecoxib: a randomized double-blind study. Hum Reprod. 2001 Jul;16(7):1323-8. doi: 10.1093/humrep/16.7.1323.

  PMID: 11425807 BACKGROUND

• Edelman AB, Jensen JT, Doom C, Hennebold JD. Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception. 2013 Mar;87(3):352-7. doi: 10.1016/j.contraception.2012.07.004. Epub 2012 Aug 16.

  PMID: 22902348 BACKGROUND

• Bata MS, Al-Ramahi M, Salhab AS, Gharaibeh MN, Schwartz J. Delay of ovulation by meloxicam in healthy cycling volunteers: A placebo-controlled, double-blind, crossover study. J Clin Pharmacol. 2006 Aug;46(8):925-32. doi: 10.1177/0091270006289483.

  PMID: 16855077 BACKGROUND

• Jesam C, Salvatierra AM, Schwartz JL, Croxatto HB. Suppression of follicular rupture with meloxicam, a cyclooxygenase-2 inhibitor: potential for emergency contraception. Hum Reprod. 2010 Feb;25(2):368-73. doi: 10.1093/humrep/dep392. Epub 2009 Nov 19.

  PMID: 19933235 BACKGROUND

• Kadoch IJ, Al-Khaduri M, Phillips SJ, Lapensee L, Couturier B, Hemmings R, Bissonnette F. Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin. Reprod Biomed Online. 2008 Feb;16(2):245-9. doi: 10.1016/s1472-6483(10)60581-0.

  PMID: 18284881 BACKGROUND

• Kawachiya S, Matsumoto T, Bodri D, Kato K, Takehara Y, Kato O. Short-term, low-dose, non-steroidal anti-inflammatory drug application diminishes premature ovulation in natural-cycle IVF. Reprod Biomed Online. 2012 Mar;24(3):308-13. doi: 10.1016/j.rbmo.2011.12.002. Epub 2011 Dec 15.

  PMID: 22285246 BACKGROUND

• Rijken-Zijlstra TM, Haadsma ML, Hammer C, Burgerhof JG, Pelinck MJ, Simons AH, van Echten-Arends J, Arts JG, Land JA, Groen H, Hoek A. Effectiveness of indometacin to prevent ovulation in modified natural-cycle IVF: a randomized controlled trial. Reprod Biomed Online. 2013 Sep;27(3):297-304. doi: 10.1016/j.rbmo.2013.05.009. Epub 2013 May 22.

  PMID: 23876971 BACKGROUND

MeSH Terms

Interventions

Ibuprofen

Intervention Hierarchy (Ancestors)

Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Michael von Wolff, Prof. Dr.

  University of Bern

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 7, 2015
• First Posted: October 8, 2015
• Study Start: January 1, 2016
• Primary Completion: August 9, 2022
• Study Completion: August 9, 2022
• Last Updated: November 19, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share

Locations

CH (1)