Multi-centre Study to Compare Efficacy and Safety of AFOLIA and Gonal-f in Women for Assisted Reproductive Treatment

A Phase III Assessor-blinded Randomized Parallel Group Multi-centre Study to Compare Efficacy and Safety of Two r-hFSH Formulations (AFOLIA Versus Gonal-f) in Women for Assisted Reproductive Treatment

Ther purpose of this study is to show equivalence between AFOLIA and Gonal-f® with regard to the number of oocytes retrieved in women for assisted reproductive treatment.

Study Overview

• Status: Completed
• Conditions: Infertility
• Intervention / Treatment: Drug: Follitropin alfa

• Study Type: Interventional
• Enrollment (Actual): 460
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
    • Kinderwunsch Institut Schenk GmbH
  • Linz, Austria
    • Landes-Frauenklinik und Kinderklinik Linz
  • Vienna, Austria, 1090
    • AKH Vienna
  • Vienna, Austria, 11920
    • IVF Zentrum Döbling
  • Wien, Austria
    • Privatspital Goldenes Kreuz
• Denmark
  • Copenhagen, Denmark, 2100
    • Fertility Clinic
  • Copenhagen, Denmark, 2400
    • Copenhagen Fertility Center
  • Frederiksberg, Denmark, 2000
    • Dansk Fertilitetsklinik
• Germany
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn
  • Heidelberg, Germany
    • Universitäts-Frauenklinik
• Spain
  • Barcelona, Spain, 08028
    • Institut Universitari Dexeus
  • Madrid, Spain, 28023
    • IVI Madrid
• Switzerland
  • Zurich, Switzerland, 8091
    • University Hospital of Zürich
• United Kingdom
  • London, United Kingdom
    • Kings College Hospital
  • London, United Kingdom, SE1 9RT
    • Guy's and St Thomas' NHS Foundation Trust
  • London, United Kingdom
    • St Barthlomew's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Age between 20 and 38 years with regular menstrual cycles of 25-35 days
• First or second cycle in the present series of ART
• BMI ≥ 18 ≤ 30 kg/m2
• Basal FSH < 10 IU/L (cycle day 2-5)
• E2 levels < 50pg/mL (< 0.18 nmol/L) at the day of FSH administration
• Antral follicle count (AFC) ≥ 10 to ≤ 25 follicles (sum of both ovaries)
• Infertility due to any of the following factors: tubal factor, mild endometriosis (ASRM stage 1-2), male factor, unexplained infertility
• Presence of both ovaries and normal uterine cavity (confirmed by transvaginal ultrasound within 6 months before randomisation)
• Willingness to participate in the study and to comply with the study protocol
• Informed consent

Exclusion Criteria:

• Presence of pregnancy
• History of ≥2 succeeding ART cycles (IVF and/or ICSI) before the study cycle without clinical pregnancy
• Presence of clinically significant systemic disease
• Presence of chronic cardiovascular, hepatic, renal or pulmonary disease
• Presence of uncontrolled endocrine disorder
• Previous history or presence of severe ovarian hyperstimulation syndrome
• Presence of polycystic ovaries (PCO)
• Presence of severe endometriosis (ASRM stage 3 or stage 4) and hydrosalpinx
• Neoplasia, including tumors of the hypothalamus and pituitary gland
• Abnormal bleeding of undetermined origin
• History of poor response to gonadotropin treatment (defined as fewer than 5 oocytes retrieved in a previous attempt)
• Male infertility without mobile spermatozoa in the ejaculate, that need testicular of epididymal sperm retrieval (MESA/TESE/TESA)
• Endocrine abnormality such as TSH or prolactin level elevations outside the reference range if clinically relevant at screening
• Any hormonal treatment within 1 month before the start of the FSH treatment (with the exception of levothyroxin)
• History of drug, nicotine or alcohol abuse within the last 12 months (> 10 cigarettes/day)
• Administration of other investigational products within the last month
• Clinically abnormal findings at Visit 1
• Planned PGS/PGD/PBB or assisted hatching
• Concomitant participation in an other study protocol
• History of extrauterine pregnancy in the previous 3 months
• Known allergy or hypersensitivity to progesterone or to any of the excipients (including peanut oil) of the additional study medication (GnRH agonist, vitrelle®, and Utrogestan®)
• Presence or history of thrombophlebitis or thromboembolic disorders
• Presence or history of cerebral haemorrhage
• Presence or history of porphyria

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gonal-f® (Follitropin alfa)	Drug: Follitropin alfa; 150IU per day subcutaneously for a maximum of 16 days
Experimental: AFOLIA-150 (Follitropin alfa)	Drug: Follitropin alfa; 150IU per day subcutaneously for a maximum of 16 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Oocytes Retrieved (Per Protocol Population)	As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes	34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment
Number of Oocytes Retrieved (Intention-to-treat Population)	As soon as ovulation criteria were reached, HCG was given to trigger ovulation and 34-36 hours later, oocytes were retrieved. If criteria for ovulation triggering could not be reached by FSH stimulation on day 16, treatment was to be stopped. The equivalence in the number of retrieved oocytes was tested using a pre-determined clinical equivalence margin of +/- 2.9 oocytes	34-36 hours after hCG administration and after maximum 16 days of r-hFSH treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and Size of Follicles ≥ 12 mm at Day 8 of Stimulation	The number and size of follicles 12 mm or over in diameter at day 8 of stimulation were evaluated as secondary end-point.	Day 8 of stimulation
E2 Concentration at Day 8 and at Day of hCG Administration	The serum concentration of oestradiol was assessed at day 8 and the day of hCG administration.	Day 8 of stimulation and at the day of hCG administration (after max. 16 days of r-FSH treatment)
Total Dose of r-hFSH Administered	Total dose of r-hFSH required was assessed.	Day of hCG administration (after maximum 16 days of r-hFSH treatment)
Quality of Oocytes Retrieved	Number of patients with ovum pick-up	34-36 hours after hCG administration
Fertilisation Rate of Oocytes	Fertilisation rate was assessed	1 day after ovum pick-up
Embryo Quality: Mean Number of Blastomeres	Main embryo quality parameter "mean number of blastomeres"	Day 2 of OPU/fertilisation
Number of Participants With Cryopreserved 2PNs, Embryos/Blastocysts		Day 1, 2, 3 and 5 of OPU/fertilisation
Number of Days of r-hFSH Stimulation	Mean duration of stimulation was assessed.	At the day of hCG administration, up to 16 days
Number of Patients With Cycle Cancellation	Number of patients with cycle cancellation was assessed.	Until child birth/miscarriage, up to the end of the study
Number of Patients With Good Response	Good response was defined as "patients with an oocyte retrieval of four or more oocytes"	Until child birth/miscarriage, up to the end of the study
Implantation Rate	Defined as fetal sac per embryo transferred.	Five to six weeks after oocyte retrieval
Clinical Pregnancy Rate	Presence of at least one intrauterine gestational sac.	Five to six weeks after oocyte retrieval
Ongoing Pregnancy	Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.	Ten weeks after embryo transfer
Live Birth Rate	Patients with liveborn children	After childbirth with questionnaire
Embryo Quality: Absence of Multinucleation	Main embryo quality parameter "absence of multinucleation" observed.	Day 3
Quality of Oocytes Retrieved	Number of patients with transferred blastocysts	At day 4 and 5
Quality of Oocytes Retrieved	Number of embryos per blastocysts transferred	Day of embryo transfer, either 2, 3 or 5 days after oocyte retrieval
Clinical Pregnancy Rate (Second Treatment Cycle)	Presence of at least one intrauterine gestational sac.	Five to six weeks after oocyte retrieval
Ongoing Pregnancy (Second Treatment Cycle)	Ongoing pregnancy per embryo transfer. Presence of at least one viable fetus 10 weeks after embryo transfer.	10 weeks after embryo transfer
Quality of Oocytes Retrieved	The maturity of the cumulus oophorus was assessed.	After oocyte retrieval, 34 to 36 hours after hCG administration
Quality of Oocytes Retrieved	The nuclear maturity was assessed (Germinal vesicle, Metaphase I, Metaphase II).	After oocyte retrieval, 34 to 36 hours after hCG administration

Collaborators and Investigators

• Sponsor: Finox AG
• Investigators: Principal Investigator: Bruno Imthurn, University of Zurich

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: May 10, 2010
• First Submitted That Met QC Criteria: May 11, 2010
• First Posted (Estimate): May 12, 2010

Study Record Updates

• Last Update Posted (Estimate): April 15, 2016
• Last Update Submitted That Met QC Criteria: March 16, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Follitropin alfa; r-hFSH; Assisted reproductive treatment; AFOLIA; Superovulation
• Additional Relevant MeSH Terms: Infertility; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Follicle Stimulating Hormone
• Other Study ID Numbers: FIN3001; 2010-019287-37 (EudraCT Number)