Different Induction Protocols in PCOS After Clomiphene Citrate Failed Pregnancy in Non-IVF Cycles

The aim of this study will be to compare between 4 different induction protocols in women who:

1. Failed to achieve ovulation after clomiphene citrate treatment at a dose of 150mg daily (if the patient can tolerate this dose) for 5 days for 3 cycles or only 100 mg daily for the same duration (if she can't tolerate higher dose)
2. Failed to achieve pregnancy after 3 cycles of ultrasound indicated ovulation with clomiphene citrate treatment at a dose of 100mg or 150mg daily.

All induction protocols will be carried out in non-IVF cycles, and continued for 3 cycles or until pregnancy whichever will be earlier.

Study Overview

• Status: Not yet recruiting
• Conditions: Infertility, Female
• Intervention / Treatment: Drug: Letrozol (Femara, Novartis); Drug: Letrozol (Femara, Novartis) combined with Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt); Drug: highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland); Drug: highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland) combined with metformin

Detailed Description

The study will include 4 treatment groups:

GROUP 1: Participants of this group will receive Letrozol (Femara, Novartis) at a dose of 2.5mg twice daily starting from day 3 of the cycle for 5 days.

GROUP 2: Participants of this group will receive Letrozol (Femara, Novartis) at a dose of 2.5mg twice daily starting from day 3 of the cycle for 5 days. Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt) 500 mg twice daily will also started from day 3 till the date of doing pregnancy test GROUP 3: Participants of this group will receive highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland.) at a dose of 75IU S.C or IM starting from day 3 of the cycle for 5 days. Readjustment of the dose will occur upon the results of day 8 folliculometry.

GROUP 4: Participants of this group will receive highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland.) at a dose of 75IU S.C or IM starting from day 3 of the cycle for 5 days. Readjustment of the dose will occur upon the results of day 8 folliculometry. Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt) 500 mg twice daily will also started from day 3 till the date of doing pregnancy test For follow up:US folliculometry will be done on Day 8 in all groups. Further appointments for folliculometry will be given upon the response. Dominant follicle will be diagnosed on Day 8 if the average follicular diameter is 12mm or more (taken in 2 perpendicular diameters) then follow up will be continued till the diameter reaching 18-22mm so that triggering ovulation will be carried out by administration of human chorionic gonadotrophins (Epifasi 5000 IU, ampoule, EIPICO pharmaceuticals, Egypt). All women will be advised to receive the injection within 12 hours of the last follicular measurement. Women will be advised to have unprotected intercourse 24-36h following hCG injection. Serum β-hCG will be measured after 2 weeks to check for pregnancy and US will be performed after 2-4 weeks from B-hCG results to confirm the presence of pregnancy.

Each couple will be involved in the study for 3 treatment cycles if pregnancy will not occur but still having the option not to continue in our study where we will manage them outside the study protocol.

Women who will get pregnant will be followed for 12w gestational age for possible detection of 1st trimester abortion.

• Study Type: Interventional
• Enrollment (Anticipated): 176
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Women aged between 20-35 years
2. Body mass index ≤ 30
3. Primary or secondary infertility for ≥1 year due to PCOS (diagnosed based on Rotterdam criteria which require the presence of two of the following: Oligo\an ovulation , hyperandrogenism, polycystic ovaries on ultrasound)
4. Failure to achieve ovulation after clomiphene citrate treatment at a dose of 150mg daily (if the patient can tolerate this dose) for 5 days for 3 cycles or only 100 mg daily for the same duration (if she can't tolerate higher dose)
5. Failure to achieve pregnancy after 3 cycles of ultrasound indicated ovulation with clomiphene citrate treatment at a dose of 100mg or 150mg daily.
6. Day-2 follicle-stimulating hormone less than 12 IU/ml
7. Normal serum prolactin and thyroid function
8. Normal uterine cavity
9. At least one patent tube
10. Male partner with normal semen count and motility according to WHO criteria

Exclusion Criteria:

1. Male factor infertility
2. Bilateral tubal block
3. Uncontrolled thyroid dysfunction
4. Uterine factor of infertility.
5. Known cases with endometriosis.

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GROUP 1; GROUP 1: Participants of this group will receive Letrozol (Femara, Novartis) at a dose of 2.5mg twice daily starting from day 3 of the cycle for 5 days.	Drug: Letrozol (Femara, Novartis); Letrozol (Femara, Novartis) at a dose of 2.5mg twice daily starting from day 3 of the cycle for 5 days.
Active Comparator: GROUP 2; GROUP 2: Participants of this group will receive Letrozol (Femara, Novartis) at a dose of 2.5mg twice daily starting from day 3 of the cycle for 5 days. Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt) 500 mg twice daily will also started from day 3 till the date of doing pregnancy test	Drug: Letrozol (Femara, Novartis) combined with Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt); Participants of this group will receive Letrozol (Femara, Novartis) at a dose of 2.5mg twice daily starting from day 3 of the cycle for 5 days. Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt) 500 mg twice daily will also started from day 3 till the date of doing pregnancy test
Active Comparator: GROUP 3; Participants of this group will receive highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland.) at a dose of 75IU S.C or IM starting from day 3 of the cycle for 5 days. Readjustment of the dose will occur upon the results of day 8 folliculometry.	Drug: highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland); Participants of this group will receive highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland) at a dose of 75IU S.C or IM starting from day 3 of the cycle for 5 days. Readjustment of the dose will occur upon the results of day 8 folliculometry.
Active Comparator: GROUP 4; Participants of this group will receive highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland.) at a dose of 75IU S.C or IM starting from day 3 of the cycle for 5 days. Readjustment of the dose will occur upon the results of day 8 folliculometry. Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt) 500 mg twice daily will also started from day 3 till the date of doing pregnancy test	Drug: highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland) combined with metformin; Participants of this group will receive highly purified lyophilized Uroffollitropin (Fostimon, IBSA Institut Biochimique SA, Lugano, Switzerland.) at a dose of 75IU S.C or IM starting from day 3 of the cycle for 5 days. Readjustment of the dose will occur upon the results of day 8 folliculometry. Metformin (Cidophage 500 mg, Cid Pharmaceuticals, Egypt) 500 mg twice daily will also started from day 3 till the date of doing pregnancy test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of ovulation	US detection of one or more follicles of 18mm or more	18 month
Number of dominant follicles	US detection of follicles >18mm	18 month
Endometrial thickness	US assessment of endometrial thickness	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of pregnancy which will be subdivided into: chemical pregnancy or clinical pregnancy	type of pregnancy	18 months
Total number of patients getting pregnant after each treatment cycle in each group	record occurrence of pregnancy	18 months
Number of cycles cancelled in each group	detect cycle cancellation	18 months
Number of patients developing OHSS in each group	detect ovarian hyperstimulation syndrom	18 months
Number of patients having multiple pregnancy in each group	detect multiple pregnancy	18 months
Number of patients ended by 1st trimester miscarriage in each group	detect miscarriage	18 months
Side effects recorded in each group	record side effects that patients complaint	18 months

Collaborators and Investigators

• Sponsor: Menoufia University

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2022
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: May 2, 2022
• First Submitted That Met QC Criteria: May 2, 2022
• First Posted (Actual): May 5, 2022

Study Record Updates

• Last Update Posted (Actual): May 5, 2022
• Last Update Submitted That Met QC Criteria: May 2, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; Infertility, Female; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Cathartics; Letrozole; Metformin; Lactitol
• Other Study ID Numbers: 3/2022/OBG

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
• product manufactured in and exported from the U.S.: No