Injection Free IVF

Injection Free Natural Cycle In Vitro Fertilisation by Using a Nasal GnRH Agonist to Induce Ovulation. Is it More Comfortable for Patients and Equally Effective as Subcutaneous hCG Injection?

Investigation of Natural Cycle In vitro Fertilisation (NC-IVF) treatment with ovulation induction with a nasal GnRH agonist instead of regular NC-IVF treatment with subcutaneous application of hCG with the objective of increasing treatment tolerability and reducing discomfort while being equally successful in terms of embryo transfer rates.

Study Overview

• Status: Not yet recruiting
• Conditions: Fertility Disorders
• Intervention / Treatment: Drug: hCG Injection; Drug: Nafarelin nasal spray

Detailed Description

In vitro Fertilisation (IVF) treatments can be performed without gonadotropins to reduce side effects. These kinds of IVF treatments are called Natural Cycle IVF (NC-IVF). As NC-IVFs are almost equally effective as classical IVF with gonadotropins but less stressful, they are preferred by many women.

However, a relevant burden in NC-IVF still is the ovulation induction by self-injection of human Chorionic Gonadotropin (hCG).

Replacing hCG injection by a nasally applicable Gonadotropin-Releasing Hormone agonist (GnRHa) might reduce this discomfort. GnRHa are already used to induce ovulation in classical IVF treatments.

The objective of our study ist to answer the question whether NC-IVF treatment with a nasal GnRH agonist can increase treatment tolerability and reduce discomfort while being equally successful in terms of embryo transfer rates than NC-IVF treatment with subcutaneous application of hCG.

The study will be a randomized controlled proof-of-concept trial. It will be performed in two steps whereas the power analysis only relates to the first step which is prospective-randomized and will be performed as follows:

Step 1:

Prior to the start of the first NC-IVF treatment cycle the patients will be randomized in equal parts by electronic randomisation to receive either the standard therapy with hCG injection (Intervention A) or the study therapy with nasal GnRHa (Intervention B).

• Intervention A: As soon as the expected follicle size is >15 mm, ovulation will be induced by injecting 5.000 IU hCG. The follicle aspiration, including flushing of the follicle will be performed 36 hours later. The transfer of the embryo will be performed 2-5 days after the aspiration.

In order to determine estradiol- and progesterone concentrations blood will be taken 10±1 days after the hCG application. Pregnancy will be confirmed or excluded by hCG testing in serum or urine 14-21 days after the follicle aspiration. In case of positive hCG testing, clinical pregnancy will be confirmed by vaginal ultrasound 4-6 weeks after follicle aspiration.

• Intervention B: The study therapy (Intervention B) will be performed identically as Intervention A with the following exception: Instead of injecting subcutaneous hCG the patients will apply 1 hub of a GnRHa nasal spray (200 microg Nafarelin) to induce ovulation.

Step 2:

If there is no pregnancy achieved in the first treatment cycle, the patients will switch to the respective other intervention (cross-over design). This procedure allows for an intraindividual comparison of the main outcomes (treatment tolerability and discomfort). Again, the two interventions will be performed as described in step 1.

Questionnaires:

At the beginning of the study, all participants will fill in the Fertility Quality of Life (FertiQoL) Core questionnaire.

For each treatment cycle, they will additionally fill in the FertiQoL Treatment questionnaire and a set of visual analog scale (VAS) questions concerning the level of discomfort encountered in the treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 112
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael von Wolff, Prof.; Phone Number: +41 31 632 13 01; Email: Michael.vonWolff@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital, University Womens Hospital
    • Contact: Michael von Wolff, Prof.; Phone Number: +41 31 632 13 01; Email: Michael.vonWolff@insel.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Indication for IVF
• Wish to perform NC-IVF
• Regular menstruation cycles (26-32 days)
• Orthotopic localization of ovaries
• Age 18-42
• Written informed consent

Exclusion Criteria:

• Endometrioses III°-IV°
• ≥ 3 embryo transfers in previous IVF therapies without pregnancy
• Contraindications or allergies against study medications
• < 18 and > 42 years of age
• Known or suspected non-compliance
• Inability of the participant to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc.
• Participation in another study with investigational drug within the 30 days preceding and during the present study
• Previous enrolment into the current study
• Enrolment of the investigators, their family members, employees and other dependent persons

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention A: hCG injection; Ovulation induction by subcutaneous injection of 5.000 IU hCG	Drug: hCG Injection; Ovulation will be induced by subcutaneous hCG injection
Experimental: Intervention B: nasal application of Nafarelin; Ovulation induction by nasal application of 200 microgram Nafarelin	Drug: Nafarelin nasal spray; Ovulation will be induced by nasal application of Nafarelin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment tolerability	Treatment tolerability will be measured with the Treatment tolerability subscale of the Fertility Quality of Life (FertiQoL) Treatment questionnaire. The subscale assesses the experience of mental and physical symptoms and disruption in daily life due to treatment. It consists of 4 items. Each item has a set of 5 possible responses, from which patients have to chose the one that most closely reflects how they think and feel.	It will be assessed between Ovulation induction and follicle aspiration. It takes about 3 minutes to complete in the questionnaire
Discomfort of treatment	The level of discomfort of the treatment encountered by the patients will be measured with 3 Visual Analogue Scale (VAS) questions ranging from 1 - 10 to specifically compare the discomfort imposed by the two treatments.	It will be assessed between Ovulation induction and follicle aspiration. It takes about 2 minutes to complete in the questionnaire

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Embryo transfer rate	Number of embryos transferred in the two groups	It will be documented after the embryo transfer (2-5 days after follicle aspiration)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oocyte collection rate	Oocyte collection rate	It will be reported by the IVF-laboratory 2-5 days after the follicle aspiration
Number of mature Oocytes	Number of mature Oocytes	It will be reported by the IVF-laboratory 2-5 days after the follicle aspiration
Fertilisation rate per aspirated oocyte	Fertilisation rate per aspirated oocyte	It will be reported by the IVF-laboratory 2-5 days after follicle aspiration
Estradiol concentration 10 ±1 day after follicle aspiration	9-11 days after the follicle aspiration, venous blood will be drawn in order to determine Estradiol concentration in serum	Blood withdrawal (5 min.) 9-11 days after follicle aspiration
Progesterone concentration 10 ±1 day after follicle aspiration	9-11 days after the follicle aspiration, venous blood will be drawn in order to determine Progesterone concentration in serum	Blood withdrawal (5 min.) 9-11 days after follicle aspiration
Clinical pregnancy rate per initiated cycle	Clinical pregnancy rate (positive pregnancy test 14-21 days after the follicle aspiration) per initiated cycle	Pregnancy test 14-21 days after follicle aspiration
Duration of luteal phase	If the pregnancy test 14-21 days after the follicle aspiration is negative, we will inquire and document the length of the luteal phase	14-21 days after follicle aspiration, if pregnancy test ist negative

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Investigators: Principal Investigator: Michael von Wolff, Prof., University Womens Hospital, Bern, Switzerland

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2021
• Primary Completion (Anticipated): March 31, 2024
• Study Completion (Anticipated): March 31, 2024

Study Registration Dates

• First Submitted: March 1, 2021
• First Submitted That Met QC Criteria: April 19, 2021
• First Posted (Actual): April 20, 2021

Study Record Updates

• Last Update Posted (Actual): April 20, 2021
• Last Update Submitted That Met QC Criteria: April 19, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Ovulation induction; GnRHa; In vitro fertilization, IVF
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Nafarelin
• Other Study ID Numbers: BASEC Project-ID 2020-03007

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