Recombinant Follicle Stimulating Hormone (FSH) (Gonal-f®): Use in Ovulation Induction

This study has been completed.
Sponsor:
Collaborator:
Merck Serono Middle East FZ-LLC, United Arab Emirates, an affiliate of Merck KGaA, Darmstadt, Germany
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01081626
First received: March 4, 2010
Last updated: January 20, 2014
Last verified: January 2014
  Purpose

This is an open-label, prospective, randomized, controlled, multicentric, multinational, phase IV study to evaluate the use of Gonal-f in inducing ovulation in female subjects with chronic anovulation. It has been observed that conventional high dose set up regimen of gonadotropin and human chorionic gonadotropin (hCG) is effective in anovulatory subjects in terms of overall pregnancy rates. However, development of multiple follicles leading to multiple pregnancy and/or ovarian hyperstimulation syndrome (OHSS) is the major complications associated with this high dose set up. Chronic low-dose (CLD) protocols of follicle stimulating hormone (FSH), aimed at finding the threshold amount of FSH necessary to promote monofolliculogenesis, have been found to be successful in reducing the rate of OHSS almost to nil and the rate of multiple pregnancies to a minimum. This post-marketing study will investigate tailoring of recombinant follicle stimulating hormone (r-FSH) in a large population (N=310) of subjects from a region (North Africa/Middle East) that has not been included in previous studies of ovulation induction in subjects with chronic anovulation. The study aims to increase current knowledge of the efficacy and safety of Gonal-f, and provide fertility physicians with experience in Gonal-f treatment in anovulatory infertility, thereby contributing to the development of FSH dosing guidelines for ovulation induction by defining the optimal CLD and Low dose (LD) regimens.


Condition Intervention Phase
Ovulation Induction
Drug: Recombinant FSH (follitropin alpha)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase IV, Open-label, Post Marketing, Prospective, Randomized, Controlled, Multicentre, Multinational Study to Investigate Tailoring of Recombinant FSH Use in Ovulation Stimulation Treatment in Chronic Anovulatory Subjects (WHO Group II)

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Percentage of Participants With a Mono-follicular Development [ Time Frame: Day 0 (first dose) up to Days 35-42 post human chorionic gonadotropin [hCG] administration (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: No ]
    Mono-follicular development was defined as the development of only 1 follicle of greater than or equal to (>=) 17 millimeter (mm) diameter and no more than 2 other follicles larger than 14 mm in diameter at or before Days 35-42 of stimulation period assessed by means of a transvaginal ultrasound scan.


Secondary Outcome Measures:
  • Number of Participants With Multi-follicular Development [ Time Frame: Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: No ]
    Multi-follicular development was defined as the development of more than 3 follicles >= 15 mm in diameter at or before Days 35-42 of stimulation period assessed by means of a transvaginal ultrasound scan.

  • Number of Participants With Adverse Events (AEs) [ Time Frame: Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: Yes ]
    AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug.

  • Number of Participants With Multiple Pregnancies [ Time Frame: Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: Yes ]
    Multiple pregnancy is a pregnancy where more than one fetus develops simultaneously in the womb. There are two types of twinning—identical and fraternal. Identical twins represent the splitting of a single fertilized zygote (union of two gametes or male/female sex cells that produce a developing fetus) into two separate individuals.

  • Number of Participants With Injection Tolerability [ Time Frame: Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: Yes ]
    Participants who did not show any injection site reactions such as pain, redness, bruises, swelling and irritation were considered to have injection tolerability.

  • Number of Participants Who Received Human Chorionic Gonadotropin (hCG) [ Time Frame: End of stimulation cycle (less than or equal to [<=] 35 days) ] [ Designated as safety issue: No ]
  • Number of Participants With Cancelled Cycles [ Time Frame: End of stimulation cycle (less than or equal to [<=] 35 days) ] [ Designated as safety issue: No ]
    Participants with cancelled cycles were those who did not achieve adequate follicular formation (at least 17 mm) for hCG administration.

  • Number of Participants With Clinical Pregnancies [ Time Frame: Day 0 (first dose) up to Days 35-42 post hCG administration (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: No ]
    Clinical pregnancy was defined as pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy. It includes ectopic pregnancy.

  • Duration of Follicle Stimulating Hormone (FSH) [ Time Frame: End of stimulation cycle (less than or equal to [<=] 35 days) ] [ Designated as safety issue: No ]
  • Total Follicle Stimulating Hormone (FSH) Dose [ Time Frame: End of stimulation cycle (less than or equal to [<=] 35 days ] [ Designated as safety issue: No ]
  • Number of Participants Who Answered Ease of Use of Gonal-f® Pen Questionnaire [ Time Frame: On hCG administration day (end of stimulation cycle {less than or equal to [<=] 35 days}) ] [ Designated as safety issue: No ]
    Ease of use of Gonal-f® pen was assessed through a questionnaire consisting of 23 questions and the number of participants who responded to the questionnaire was recorded.


Enrollment: 310
Study Start Date: March 2009
Study Completion Date: March 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group I: Chronic Low dose Protocol
Gonal-f will be injected on the second or third day of a spontaneous or progestogen-induced menstrual cycle (Day 0), with a daily dose of 75 International Units (IU) for 7 days. Ovarian response will be assessed on Day 7 of stimulation by ultrasound scan. If no follicle has reached at least 10 to 12 millimeter (mm) diameter, stimulation will be continued with the same dose for further 7 days. On Day 14 of stimulation, if no ovarian response is seen, the dose will be increased by 37.5 IU (total 112.5 IU) and administered for the next 7 days. Subsequent increments of 37.5 IU, at intervals of 7 days up to Day 35 of stimulation would be made, depending on ovarian response.
Drug: Recombinant FSH (follitropin alpha)
A starting dose of 75 IU and a first adjustment on Day 14 or Day 7 of stimulation in Group I and II respectively, if no ovarian response is observed.
Other Names:
  • Gonal-f®
  • Follitropin alpha
Experimental: Group II: Low dose Protocol
Gonal-f will be administered on the second or third day of a spontaneous or progestogen-induced menstrual cycle (Day 0), with a daily dose of 75 IU for 7 days. Ovarian response will be assessed on Day 7 of stimulation by ultrasound scan. If no follicle has reached at least 10 to 12 mm diameter, the dose will be increased by 37.5 IU (total 112.5 IU) and administered for the next 7 days. Subsequent increments of 37.5 IU, at intervals of 7 days up to Day 35 of stimulation will be made, depending on ovarian response.
Drug: Recombinant FSH (follitropin alpha)
A starting dose of 75 IU and a first adjustment on Day 14 or Day 7 of stimulation in Group I and II respectively, if no ovarian response is observed.
Other Names:
  • Gonal-f®
  • Follitropin alpha

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 37 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Premenopausal female subjects, aged between 18 and 37 years inclusive
  • Subjects willing to conceive
  • Subjects who are infertile due to chronic anovulation demonstrated by a cycle duration of > 35 days, or regular cycles with progesterone (P4) levels < 1 nanomole/milliliter (nmol/mL) during luteal phase (Day 25)
  • Subjects who have experienced spontaneous menses, menses induced by clomiphene citrate therapy, or a positive progestin-induced withdrawal within the previous year
  • Subjects with FSH and PRL serum values within the normal range in the early follicular phase
  • Subjects with total antral follicle count (AFC) > 10 (of follicle size ≥ 2 mm and < 11 mm) in both ovaries
  • Subjects with at least 1 patent tube, as documented by recent (within 2 years before treatment assignment) hysterosalpingography (HSG)
  • Subjects with normal uterine cavity, as documented by recent (within 2 years before treatment assignment) hysteroscopy, HSG or ultrasound scan
  • Subjects with body mass index (BMI) >20 and ≤32 kilogram square per meter (kg/m^2)
  • Subjects with negative cervical Papanicolaou (PAP) test within the 6 months prior to screening
  • Male partners of female subjects with sperm compatible with non assisted fertilization
  • Subjects who are willing and able to participate in the study and have provided written, informed consent

Exclusion Criteria:

  • Subjects with history of hypersensitivity to the active substance follitropin alpha, FSH, or to any of the excipients of Gonal-f
  • Subjects with ovarian enlargement or ovarian cyst unrelated to PCOS, and of unknown origin on ultrasound
  • Subjects with evidence of diminished ovarian reserve (cycle length < 26 days; FSH above the upper limit of local serum FSH values, total AFC in both ovaries < 10)
  • Subjects with myomatous uterus, which in the opinion of the investigator could impair pregnancy evolution
  • Subjects who have undergone 3 or more previous miscarriages
  • Subjects with any previous extrauterine pregnancy
  • Pregnant or lactating female subjects
  • Subjects with abnormal gynecological bleeding of unknown etiology
  • Subjects with previous history of severe OHSS
  • Subjects who have undergone operative pelvic surgery which could induce mechanical infertility (e.g tubes blockage) or pelvic inflammatory disease (PID) before treatment assignment excluding curettage and hysteroscopy
  • Subjects with tumors of the hypothalamus and pituitary gland
  • Subjects with ovarian, uterine or mammary carcinoma
  • Subjects treated with clomiphene citrate or gonadotropins within 1 month of the screening evaluation
  • Subjects with any medical condition which, in the opinion of the investigator, would prevent an effective response, such as primary ovarian failure, or malformations of the reproductive organs incompatible with pregnancy
  • Subjects with any medical condition which, in the opinion of the investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug
  • Subjects with any clinically significant systemic disease (e.g. insulin-dependent diabetes) or any contraindication to being pregnant and/or carrying a pregnancy to term; also including subjects with non insulin dependent diabetes mellitus (NIDDM)
  • An active substance abuser
  • Subjects with known infection with Human Immunodeficiency Virus (HIV), Hepatitis B or C virus in the trial subject or her male partner
  • Subjects who have simultaneously participated in another clinical trial
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01081626

Locations
Kuwait
New Mowasat Hospital
Salmiya, P.O.Box 6661, Kuwait, 22077
Lebanon
Mount Lebanon Hospital
Hazmieh, P.O.Box 470, Lebanon
Saudi Arabia
King Abdel Aziz University Hospital
Jeddah, P.O.Box 80215, Saudi Arabia, 21589
Sponsors and Collaborators
Merck KGaA
Merck Serono Middle East FZ-LLC, United Arab Emirates, an affiliate of Merck KGaA, Darmstadt, Germany
Investigators
Study Director: Khaled Esmat, MD Merck Serono Middle East FZ-LLC, United Arab Emirates, an affiliate of Merck KGaA, Darmstadt, Germany
  More Information

No publications provided by Merck KGaA

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01081626     History of Changes
Other Study ID Numbers: EMR 700623-501
Study First Received: March 4, 2010
Results First Received: September 3, 2012
Last Updated: January 20, 2014
Health Authority: Iran: Ministry of Health
Egypt: Ministry of Health and Population
Lebanon: Ministry of Public Health
Saudi Arabia: Ministry of Health
United Arab Emirates: Drug Control Department - Medicines and Pharmacy Control - Ministry of Health

Keywords provided by Merck KGaA:
Infertility
Ovulation induction
Gonal-f
Follitropin alpha
Polycystic ovarian syndrome
Anovulatory infertility

Additional relevant MeSH terms:
Follicle Stimulating Hormone
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 20, 2014