Sildenafil and Outcome of IVF/ICSI Cycles

The Effect of Vaginal Sildenafil on the Outcome of IVF/ICSI Cycles in Patients With Repeated IVF/ICSI Failure: a Pilot Study

Adequate growth of the endometrium is crucial for implantation. Accordingly, the pregnancy success rate of patients with a thin endometrium is low. Furthermore, there is a little information about the factors responsible for impaired endometrial growth in patients with a thin endometrium. The researches have revealed that nitric oxide (NO) release can cause relaxation of vascular smooth muscle through a cyclic guanyl monophosphate (cGMP)-mediated pathway. Sildenafil is a type 5-specific Phosphodiesterase inhibitor that augments the vasodilatory effects of NO on vascular smooth muscle by preventing the degradation of cGMP and could improve blood flow and endometrial thickness. This study is designed to evaluate the effect of vaginally administered sildenafil suppositories on IVF/ICSI outcome of infertile patients with repeated IVF/ICSI failures.

Study Overview

• Status: Unknown
• Conditions: Infertility, Female
• Intervention / Treatment: Drug: Sildenafil vaginal suppositories; Other: vaginal placebo; Other: vaginal placebo

Detailed Description

The proposal of this study approved by our institutional review boards and institution's ethical committee, and all participants will sign a written consent before enter to study.

The study population will consist of infertile women of <38 years of age with repeated in vitro fertilization/ intra cytoplasmic injection failures. Endometrial parameters including endometrial thickness, endometrial pattern , pulsatility index (PI) and resistance index (RI) will be evaluated with the use of color Doppler ultrasound on the day of hCG administration. Patients will be randomly divided into 3 groups, A, B and C. In the subsequent menstrual cycle, in group A, vaginal sildenafil suppositories (100 mg/day) will be given daily from the start of human menopausal gonadotropin (HMG) administration day until the day of oocyte retrieval. In group B, the women will receive daily vaginal placebo from the start of HMG administration day until 2 days before the human chronic gonadotrophin (hCG) injection day, then will be switched to vaginal sildenafil suppositories (100 mg/day) until the day of oocyte retrieval. In group C, vaginal placebo will be given daily from the start of human menopausal gonadotropin (HMG) administration day until the day of oocyte retrieval.

When the diameter of at least 2 follicles will be reached equal or greater than 18 mm, hCG 10,000 IU will be administered. In all patients, ovarian stimulation will be performed with the conventional GnRh agonist protocol. Endometrial parameters will be measured again on the day of hCG injection. Ovum pick up will be performed 34-36 h after hCG injection and embryos will be transferred 48-72 hours after oocyte retrieval. Pregnancy will be confirmed by assessment of βHCG level 14 days after embryo transfer and ultrasonographic visualization of gestational sac during the 5th week of pregnancy.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Nasser Aghdami, MD,PhD; Phone Number: 516 (+98)2123562000; Email: nasser.aghdami@royaninstitute.org
• Study Contact Backup: Name: Leila Arab, MD; Phone Number: 414 (+98)2123562000; Email: Leara91@gmail.com

Study Locations

• Iran, Islamic Republic of
  • Tehrān, Iran, Islamic Republic of
    • Recruiting
    • Royan Institute
    • Contact: Nasser Aghdami, MD,PhD; Phone Number: 516 (+98)2123562000; Email: nasser.aghdami@royaninstitute.org
    • Contact: Leila Arab, MD; Phone Number: 414 (+98)2123562000; Email: Leara91@gmail.com
    • Principal Investigator: Nadia Jahangiri, MSc
    • Principal Investigator: Maria sadeghi, MSc
    • Principal Investigator: Farideh Malekzadeh, MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 38 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women with normal ovarian reserve and had at least two prior cycle with FSH <10 mIu/ml
• Women with history of two or three prior consecutive failed IVF/ICSI attempts using at least two good quality fresh or frozen-thawed embryos.
• Endometrial thickness on the day of hCG injection was < 9 mm in all prior IVF/ICSI attempts
• Women with normal endometrial appearance in hysteroscopy or hysterosonography or hysterosalpingography

Exclusion Criteria:

• Women who had history of PCOS, myomectomy, Asherman's Syndrome and mullerian anomalies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; Sildenafil vaginal suppositories users	Drug: Sildenafil vaginal suppositories; Sildenafil vaginal suppositories (100 mg/day) from the start of HMG administration day until the day of oocyte retrieval.
Placebo Comparator: B; Daily vaginal placebo users with HMG administration	Other: vaginal placebo; Daily vaginal placebo from the start of HMG administration day until 2 days before the hCG injection day, then will be switched to vaginal sildenafil suppositories (100 mg/day) until the day of oocyte retrieval.; Other: vaginal placebo; Daily vaginal placebo from the start of HMG administration day until the day of oocyte retrieval.
Placebo Comparator: C; Daily vaginal placebo users with HMG administration day until the day of oocyte retrieval.	Other: vaginal placebo; Daily vaginal placebo from the start of HMG administration day until 2 days before the hCG injection day, then will be switched to vaginal sildenafil suppositories (100 mg/day) until the day of oocyte retrieval.; Other: vaginal placebo; Daily vaginal placebo from the start of HMG administration day until the day of oocyte retrieval.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Pregnancy rate	Evaluation the Clinical Pregnancy rate after using Sildenafil vaginal suppositories (100 mg/day) from the start of HMG administration day until the day of oocyte retrieval. It is detected by a positive ß-hCG test result and ultrasonographic visualization of at least one gestational sac	4-6 weeks after embryos transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Implantation rate	The implantation rate is defined as number of gestational sacs per transferred embryo. It Is detected by a positive ß-hCG test result and ultrasonographic visualization of at least one gestational sac 4-6 weeks after embryos transfer.	4-6 weeks
Endometrial thickness	The endometrial thickness is detected by ultrasound examination in hCG day administration.	1 day
Endometrial pattern	Comparing gray scale appearance of the endometrium to that of the adjacent myometrium at Day 14 of previous cycle.	Day 14
Pulsatility index	The variability in flow between the systole and the diastole; this measure was calculated by dividing the difference between the peak systolic and end-diastolic frequencies by the time-average of the maximum frequency shift.This is measured at hCG administration day.	1 day
Resistance index (RI)	The RI is defined as a ratio of the difference between the maximum and minimum flow velocity to maximum flow velocity.This is measured at hCG administration day.	1 day

Collaborators and Investigators

• Sponsor: Royan Institute
• Collaborators: Tehran University of Medical Sciences
• Investigators: Study Director: Ashraf Moieni, MD, Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.; Principal Investigator: Firoozeh Ahmadi, MD, Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.; Principal Investigator: Fatemeh Zafarani, MSc, Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

Publications and helpful links

General Publications

• Moini A, Zafarani F, Jahangiri N, Jahanian Sadatmahalleh SH, Sadeghi M, Chehrazi M, Ahmadi F. The Effect of Vaginal Sildenafil on The Outcome of Assisted Reproductive Technology Cycles in Patients with Repeated Implantation Failures: A Randomized Placebo-Controlled Trial. Int J Fertil Steril. 2020 Jan;13(4):289-295. doi: 10.22074/ijfs.2020.5681. Epub 2019 Nov 11.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Anticipated): August 1, 2017
• Study Completion (Anticipated): September 1, 2017

Study Registration Dates

• First Submitted: April 30, 2017
• First Submitted That Met QC Criteria: June 18, 2017
• First Posted (Actual): June 20, 2017

Study Record Updates

• Last Update Posted (Actual): June 20, 2017
• Last Update Submitted That Met QC Criteria: June 18, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Sildenafil IVF ICI failure
• Additional Relevant MeSH Terms: Infertility; Infertility, Female; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: Royan-Emb-030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No