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Progesterone Serum Levels in Subfertile Female Patients Undergoing in Vitro Fertilisation (IVF) (PREDICT)

Primary Purpose

Infertility

Status
Completed
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
Menotrophin
Follitrophin alpha
Cetrorelix
Choriongonadotropin
Progesterone
Sponsored by
Ferring Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infertility

Eligibility Criteria

34 Years - 42 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed informed consent
  • Subfertile premenopausal female patients eligible for in vitro fertilisation (IVF) treatment
  • Aged ≥34 and ≤42 years
  • Body mass index of >18 and <28 kg/m^2
  • Normal pelvic ultrasound at Screening
  • No more than two previous gonadotrophin stimulated cycles of IVF or intracytoplasmic sperm injection (ICSI) in the history of infertility treatment (gonadotrophin stimulated cycles not used for IVF or ICSI do not count; Clomifen cycles are no exclusion criterion)
  • At least 3 consecutive ovulatory menstrual cycles of 24-35 days
  • No fertility stimulating drugs at all
  • Sperm of partner classified as normal according to World Health Organisation (WHO) 2010 criteria
  • Clinically normal baseline haematology, clinical chemistry, and urinalysis values
  • Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within the last 6 months prior to Screening
  • Endocrine test results within the clinically normal limits at Screening

Exclusion Criteria:

  • Presence of any clinically relevant systemic disease (e.g., insulin-dependent diabetes mellitus)
  • A history of or current endocrine disease (excluding treated hypothyreosis), including polycystic ovary syndrome (PCOS) and hyperprolactinaemia
  • A history of coagulation disorders
  • Persistent ovarian cysts (>3 months)
  • A history of hypersensitivity to any of the constituents of the study medication or related compounds
  • Diagnosed poor (<3 oocytes) responders to prior gonadotrophin stimulated ART-cycle
  • History of severe ovarian hyperstimulation syndrome in former gonadotrophin stimulated assisted reproductive technology (ART)-cycle

Sites / Locations

  • Fertility Center Berlin
  • Praxisklinik Sydow am Gendarmenmarkt
  • Kinderwunschzentrum Dortmund
  • Universitätsklinikum Duesseldorf, Frauenklinik
  • Praxis für Kinderwunschbehandlung
  • NOVUM Zentrum
  • IVF Zentrum
  • Endokrinologikum Ulm

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Menotrophin

Follitrophin Alpha

Arm Description

Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met. Pituitary down-regulation (cetrorelix), ovulation induction (choriongonadotropin), and luteal phase support (intravaginal progesterone) are administered the same way in both treatment arms.

Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met. Pituitary down-regulation (cetrorelix), ovulation induction (choriongonadotropin), and luteal phase support (intravaginal progesterone) are administered the same way in both treatment arms.

Outcomes

Primary Outcome Measures

Serum Progesterone (P4) Level in the Morning of the Day of Human Chorionic Gonadotrophin (hCG) Administration
Ovulation induction was performed by administration of hCG once three follicles >=17 mm diameter as shown by pelvic ultrasound examination. This outcome compares the serum progesterone level the morning prior to hCG administration across treatment arm, and also by age stratum (<39 years and >=39 years).

Secondary Outcome Measures

Receiver Operating Characteristic (ROC) Analysis of Progesterone as Predictor for Ongoing Pregnancy Rate at Day 7 and Day of hCG Administration
The influence of the progesterone level on the ongoing pregnancy rate (in relation to all randomized patients) was determined by means of the receiver operating characteristic (ROC) curve. Youden's Index (sensitivity + specificity -1) has a range of 0-1, with 0.5 indicating a random effect.
Percentage of Participants With Ongoing Pregnancy
Ongoing pregnancy is defined as having a positive foetal heart action nine or more weeks after the first positive pregnancy test.
Number of Follicles at hCG Administration
Number of follicles >=17 mm diameter detected by pelvic ultrasound examination at day of hCG administration.
Average Follicle Diameter at hCG Administration
Number of Cumulus-oocyte Complexes Retrieved
Cumulus-oocyte complexes are oocytes with surrounding cumulus cells.
Number of Pronuclear Oocytes
Pronuclear oocytes are fertilized oocytes.
Number of Participants With Pronuclear Stage Oocytes at Each Quality Grade
The count of participants with different quality grades of pronuclear stage oocytes is offered. Pronuclear stage oocytes are categorized into seven grades (0A, 0B, 1-5) representing different patterns of pronuclear morphology, according to the German Pronuclear Morphology Study Group. 0A is the highest quality oocyte and grade 5 is the lowest quality. Participants can have pronuclear stage oocytes of different grades and therefore are counted more than once.
Number of Embryos Transferred
Mean number of embryos transferred 2-3 days following oocyte retrieval.
Best Quality of an Embryo Transferred
Embryo quality was measured by the following grades: Grade 1: Evenly sized cells, regular cleavage, no fragmentation Grade 2: Regular or slightly irregular cleavage, <=20% fragmentation Grade 2.5: Regular or slightly irregular cleavage, >20%and <=50% fragmentation Grade 3: Irregular cleavage, >50% fragmentation, >1 intact cell Grade 4: Extensive fragmentation, only 1 cell intact Grade 5: Totally fragmented, no viable cells. Grade 1 represents the healthiest embryos and Grade 5 embryos are not viable.
Number of Frozen Oocytes at Pronuclear Stage
No more than three normally developed embryos were transferred 2-3 days after oocyte retrieval. Other normally developed embryos were frozen.
Endometrial Thickness on Day of hCG Administration
Endometrial thickness was assessed by pelvic ultrasound on the day of hCG administration.
Estradiol (E2) Levels on Day of hCG Administration
Percentage of Participants With Successful Embryo Transfer
Number of Days Stimulated With Gonadotrophins
Number of days in which gonadotrophins were administered until hCG criteria were met. If hCG criteria were not met by day 13, the participant was withdrawn from the study.
Number of Ampoules of Gonadotrophins Used
Number of ampoules of gonadotrophins used with the goal of reaching hCG criteria. Each ampoule contained 75 IU of either menotrophin or follitrophin alpha.
Percentage of Participants With Clinical Pregnancy 6 Weeks After the First Positive Pregnancy Test
A pelvic ultrasound scan was performed approximately 6 weeks after the first positive pregnancy test and the presence of an active foetal heart action indicated a clinical pregnancy.
Summary of Pregnancy Outcome
Pregnancy outcomes were reported at the optional long-term follow up visit.

Full Information

First Posted
October 7, 2010
Last Updated
February 17, 2014
Sponsor
Ferring Pharmaceuticals
Collaborators
Ferring Arzneimittel GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT01225835
Brief Title
Progesterone Serum Levels in Subfertile Female Patients Undergoing in Vitro Fertilisation (IVF)
Acronym
PREDICT
Official Title
Effect of Highly Purified Menotrophin and Recombinant Follicle Stimulating (rFSH, Follitrophin Alpha) in Subfertile Female Patients Undergoing IVF on Progesterone Serum Levels During the Follicular Phase and Their Possible Use as Predictors for the Success Rate of Ongoing Pregnancies
Study Type
Interventional

2. Study Status

Record Verification Date
February 2014
Overall Recruitment Status
Completed
Study Start Date
October 2010 (undefined)
Primary Completion Date
January 2013 (Actual)
Study Completion Date
June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ferring Pharmaceuticals
Collaborators
Ferring Arzneimittel GmbH

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study is aimed to demonstrate that highly purified Menotrophin produces significant lower progesterone serum levels during the follicular phase in comparison to Follitropin alpha in the treatment of subfertile females undergoing an in vitro fertilisation (IVF) and to investigate if the progesterone serum levels might be a useful predictor for the success rate of the ongoing pregnancy rates

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infertility

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
124 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Menotrophin
Arm Type
Experimental
Arm Description
Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met. Pituitary down-regulation (cetrorelix), ovulation induction (choriongonadotropin), and luteal phase support (intravaginal progesterone) are administered the same way in both treatment arms.
Arm Title
Follitrophin Alpha
Arm Type
Active Comparator
Arm Description
Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met. Pituitary down-regulation (cetrorelix), ovulation induction (choriongonadotropin), and luteal phase support (intravaginal progesterone) are administered the same way in both treatment arms.
Intervention Type
Drug
Intervention Name(s)
Menotrophin
Other Intervention Name(s)
Menogon® HP
Intervention Description
Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met.
Intervention Type
Drug
Intervention Name(s)
Follitrophin alpha
Other Intervention Name(s)
Gonal-f®
Intervention Description
Starting on Day 2 or 3 of the menstrual cycle, 150 IU (up to 300 IU) by subcutaneous injection once per day in the morning for up to 12 days until human chorionic gonadotropin (hCG) criteria are met.
Intervention Type
Drug
Intervention Name(s)
Cetrorelix
Other Intervention Name(s)
Cetrotide®, GnRH antagonist
Intervention Description
Participants self-inject subcutaneously Cetrorelix in the morning at a daily dose of 0.25 mg/day from Day 5 of gonadotrophin administration on and continue throughout the period of gonadotrophin treatment up to day 12 as a maximum. The last dose of Cetrorelix is given on the day of ovulation induction.
Intervention Type
Drug
Intervention Name(s)
Choriongonadotropin
Other Intervention Name(s)
Brevactid®, human chorionic gonadotropin (hCG)
Intervention Description
10,000 IU administered by the Investigator or designated personnel in the evening of the day on which the hCG criterion is met (no later than Day 13). The criterion for hCG administration is three follicles >+17 mm diameter as shown by pelvic ultrasound examination.
Intervention Type
Drug
Intervention Name(s)
Progesterone
Other Intervention Name(s)
Crinone®, intravaginal progesterone
Intervention Description
Vaginal gel progesterone is used once daily at a dose of 90 mg for a period of 30 days starting on the day of oocyte retrieval (approximately Day 14).
Primary Outcome Measure Information:
Title
Serum Progesterone (P4) Level in the Morning of the Day of Human Chorionic Gonadotrophin (hCG) Administration
Description
Ovulation induction was performed by administration of hCG once three follicles >=17 mm diameter as shown by pelvic ultrasound examination. This outcome compares the serum progesterone level the morning prior to hCG administration across treatment arm, and also by age stratum (<39 years and >=39 years).
Time Frame
approximately day 10
Secondary Outcome Measure Information:
Title
Receiver Operating Characteristic (ROC) Analysis of Progesterone as Predictor for Ongoing Pregnancy Rate at Day 7 and Day of hCG Administration
Description
The influence of the progesterone level on the ongoing pregnancy rate (in relation to all randomized patients) was determined by means of the receiver operating characteristic (ROC) curve. Youden's Index (sensitivity + specificity -1) has a range of 0-1, with 0.5 indicating a random effect.
Time Frame
Day 7, approximately Day 10 (hCG Administration)
Title
Percentage of Participants With Ongoing Pregnancy
Description
Ongoing pregnancy is defined as having a positive foetal heart action nine or more weeks after the first positive pregnancy test.
Time Frame
approximately 3.5 months from study start (at least 9 weeks after first positive pregnancy test)
Title
Number of Follicles at hCG Administration
Description
Number of follicles >=17 mm diameter detected by pelvic ultrasound examination at day of hCG administration.
Time Frame
approximately day 10
Title
Average Follicle Diameter at hCG Administration
Time Frame
approximately day 10
Title
Number of Cumulus-oocyte Complexes Retrieved
Description
Cumulus-oocyte complexes are oocytes with surrounding cumulus cells.
Time Frame
approximately day 12 after study start
Title
Number of Pronuclear Oocytes
Description
Pronuclear oocytes are fertilized oocytes.
Time Frame
approximately day 13 after study start
Title
Number of Participants With Pronuclear Stage Oocytes at Each Quality Grade
Description
The count of participants with different quality grades of pronuclear stage oocytes is offered. Pronuclear stage oocytes are categorized into seven grades (0A, 0B, 1-5) representing different patterns of pronuclear morphology, according to the German Pronuclear Morphology Study Group. 0A is the highest quality oocyte and grade 5 is the lowest quality. Participants can have pronuclear stage oocytes of different grades and therefore are counted more than once.
Time Frame
approximately day 13
Title
Number of Embryos Transferred
Description
Mean number of embryos transferred 2-3 days following oocyte retrieval.
Time Frame
approximately day 14
Title
Best Quality of an Embryo Transferred
Description
Embryo quality was measured by the following grades: Grade 1: Evenly sized cells, regular cleavage, no fragmentation Grade 2: Regular or slightly irregular cleavage, <=20% fragmentation Grade 2.5: Regular or slightly irregular cleavage, >20%and <=50% fragmentation Grade 3: Irregular cleavage, >50% fragmentation, >1 intact cell Grade 4: Extensive fragmentation, only 1 cell intact Grade 5: Totally fragmented, no viable cells. Grade 1 represents the healthiest embryos and Grade 5 embryos are not viable.
Time Frame
approximately day 14
Title
Number of Frozen Oocytes at Pronuclear Stage
Description
No more than three normally developed embryos were transferred 2-3 days after oocyte retrieval. Other normally developed embryos were frozen.
Time Frame
approximately day 14
Title
Endometrial Thickness on Day of hCG Administration
Description
Endometrial thickness was assessed by pelvic ultrasound on the day of hCG administration.
Time Frame
approximately day 10
Title
Estradiol (E2) Levels on Day of hCG Administration
Time Frame
approximately day 10
Title
Percentage of Participants With Successful Embryo Transfer
Time Frame
approximately day 18
Title
Number of Days Stimulated With Gonadotrophins
Description
Number of days in which gonadotrophins were administered until hCG criteria were met. If hCG criteria were not met by day 13, the participant was withdrawn from the study.
Time Frame
Day 1 up to Day 12
Title
Number of Ampoules of Gonadotrophins Used
Description
Number of ampoules of gonadotrophins used with the goal of reaching hCG criteria. Each ampoule contained 75 IU of either menotrophin or follitrophin alpha.
Time Frame
Day 1 up to Day 12
Title
Percentage of Participants With Clinical Pregnancy 6 Weeks After the First Positive Pregnancy Test
Description
A pelvic ultrasound scan was performed approximately 6 weeks after the first positive pregnancy test and the presence of an active foetal heart action indicated a clinical pregnancy.
Time Frame
approximately 2.5 months from start of study, 6 weeks after first positive pregnancy test
Title
Summary of Pregnancy Outcome
Description
Pregnancy outcomes were reported at the optional long-term follow up visit.
Time Frame
up to 10 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
34 Years
Maximum Age & Unit of Time
42 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent Subfertile premenopausal female patients eligible for in vitro fertilisation (IVF) treatment Aged ≥34 and ≤42 years Body mass index of >18 and <28 kg/m^2 Normal pelvic ultrasound at Screening No more than two previous gonadotrophin stimulated cycles of IVF or intracytoplasmic sperm injection (ICSI) in the history of infertility treatment (gonadotrophin stimulated cycles not used for IVF or ICSI do not count; Clomifen cycles are no exclusion criterion) At least 3 consecutive ovulatory menstrual cycles of 24-35 days No fertility stimulating drugs at all Sperm of partner classified as normal according to World Health Organisation (WHO) 2010 criteria Clinically normal baseline haematology, clinical chemistry, and urinalysis values Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests within the last 6 months prior to Screening Endocrine test results within the clinically normal limits at Screening Exclusion Criteria: Presence of any clinically relevant systemic disease (e.g., insulin-dependent diabetes mellitus) A history of or current endocrine disease (excluding treated hypothyreosis), including polycystic ovary syndrome (PCOS) and hyperprolactinaemia A history of coagulation disorders Persistent ovarian cysts (>3 months) A history of hypersensitivity to any of the constituents of the study medication or related compounds Diagnosed poor (<3 oocytes) responders to prior gonadotrophin stimulated ART-cycle History of severe ovarian hyperstimulation syndrome in former gonadotrophin stimulated assisted reproductive technology (ART)-cycle
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Development Support
Organizational Affiliation
Ferring Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Fertility Center Berlin
City
Berlin
Country
Germany
Facility Name
Praxisklinik Sydow am Gendarmenmarkt
City
Berlin
Country
Germany
Facility Name
Kinderwunschzentrum Dortmund
City
Dortmund
Country
Germany
Facility Name
Universitätsklinikum Duesseldorf, Frauenklinik
City
Dusseldorf
Country
Germany
Facility Name
Praxis für Kinderwunschbehandlung
City
Erlangen
Country
Germany
Facility Name
NOVUM Zentrum
City
Essen
Country
Germany
Facility Name
IVF Zentrum
City
Saar
Country
Germany
Facility Name
Endokrinologikum Ulm
City
Ulm
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

Progesterone Serum Levels in Subfertile Female Patients Undergoing in Vitro Fertilisation (IVF)

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