Efficacy Study of Granulocyte-macrophage Colony Stimulating Factor (GM-CSF) for Use in Human IVF
Study Details
Study Description
Brief Summary
This study is to assess whether addition of 2 ng/ml GM-CSF into a specific culture medium will increase the chance of a pregnancy after in vitro fertilisation.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
Throughout its development, the embryo is naturally exposed to a large number of cytokines and growth factors that are present in the woman's reproductive organs. A growing body of evidence indicates that these factors play a physiological role in the regulation of normal development of the pre-implanted embryo and that these factors therefore help to increase the implantation of the embryo and subsequently ensure optimal development of both foetus and placenta. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be present in the female reproductive organs during early pregnancy in mice, sheep, cows and humans.
2 ng/ml GM-CSF has been proven safe in a previous study presented at the European Society of Human Reproduction and Embrylogy (ESHRE) congress 2007 (A. Loft et al. 2007).
The present investigation (DK001) is to our knowledge the first large prospective randomised in vivo study in humans. Previous publications counting one Korean pilotstudy of 154 women prospectively randomised between culture medium with and without GM-CSF 2 ng/ml (Kim et al., 2001), showing a significant effect of GM-CSF on embryo implantation rate.
Based on this knowledge we hypothesize that culture of human embryos in the presence of GM-CSF will significantly increase the implantation rate also in a larger population.
This hypothesis is being tested by conducting a multicentre, randomised, parallel group, double-blind, placebo-controlled study with adaptive design, performed at 14 study centres. Each patient will participate in the study from retrieval of oocytes following standard hormonal treatment and until the 12th gestational week. Further a follow-up will be performed on pregnancies and children born.
The test group will include a standard culture medium with 2 ng/ml GM-CSF added from the time of insemination, and the control group will be the exact same medium but without any additions.
All procedures are according to standards of the clinic, with applied standard media except for the patient randomised study medium which is used for oocyte insemination, embryo culture and transfer. Embryo transfer will be performed Day 3.
An interim analysis has been performed for final sample size calculation.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Test culture Culture with GM-CSF |
Device: Test culture
A standard culture medium with added GM-CSF (ready-to-use)
Other Names:
|
| Placebo Comparator: Control culture Culture without GM-CSF |
Device: Control culture
The same standard culture medium, but without any additions (ready-to-use)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Ongoing Implantation Rate Week 7 [Approximately 5 weeks from oocyte pick-up (corresponding to 7 weeks from ovulation)]
Defined as number of gestational sacs with fetal heart beat, shown by ultrasound in gestational week 7 in percentage of number of embryo transferred.
Secondary Outcome Measures
- Number of Top Quality Embryos (TQE´s) [3 days from oocyte pick-up]
Number of 4-5 cell embryo at 44 hours,at least 7 cell embryo at 68 hours, maximum 20% fragmentation, equally large blastomeres (less than 25% difference in size),No signs of multinucleation. Calculated in percentage of number of 2 pronuclei (2PN) oocytes.
- Live Birth [Until 7 days after birth]
Subject having at least one live birth. Including a foetus which breathes or shows any other evidence of life after expulsion/extraction from its mother. The definition is independent of the duration of the pregnancy (ICMART/WHO criteria).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
The couple or single woman has signed an informed consent form before any trial-related activities.
-
In Vitro Fertilization (IVF) or IntraCytoplasmic Sperm Injection (ICSI) treatment indicated
-
25-39 years of age (both inclusive)
-
Regular menstrual cycle: 21-35 days (both inclusive)
-
Women treated with a standard Gonadotropin-Releasing Hormone (GnRH) agonist or antagonist protocol and a Follicle Stimulating Hormone (FSH) / human Menopausal Gonadotropin (hMG) starting dose between 100 and 300 IU daily.
-
human Chorionic Gonadotropin (hCG) administration when the leading follicle has a calculated diameter of minimum 17 mm, or the day after.
-
At least 3 follicles with a calculated diameter of ≥ 14 mm at the day of hCG.
Exclusion Criteria:
-
The woman has previously participated in the DK001 study.
-
Use of assisted hatching.
-
Indication for Testicular Sperm Aspiration (TESA) or Percutaneous Epididymal Sperm Aspiration (PESA)
-
Any medical conditions or genetic disorders prohibiting IVF/ICSI or interfering with the interpretation of results of the study (including pre-implantation genetic diagnostics).
-
Use of any investigational drug within 30 days before oocyte retrieval
-
Any severe chronic disease of relevance for reproductive function.
-
Oocyte donation patients (donor or recipient).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ciconia Aarhus Privathospital, Fertilitetsklinikken | Aarhus | Denmark | 8270 | |
| 2 | Brædstrup Sygehus; IVF-Klinikken | Brædstrup | Denmark | 8740 | |
| 3 | Rigshospitalet, Fertilitetsklinikken afd. 4071 | Copenhagen | Denmark | 2100 | |
| 4 | Fertilitetsklinikken Dronninglund | Dronninglund | Denmark | 9330 | |
| 5 | IVF-SYD | Fredericia | Denmark | 7000 | |
| 6 | Herlev Hospital, Fertilitetsklinikken G114F | Herlev | Denmark | 2730 | |
| 7 | Holbæk Sygehus, Fertilitetsklinikken | Holbæk | Denmark | 4300 | |
| 8 | Hvidovre Hospital; Fertilitetsklinikken afd. 455 | Hvidovre | Denmark | 2650 | |
| 9 | Odense Universitets Hospital, Fertilitetsklinikken | Odense | Denmark | 5000 | |
| 10 | Regionshospitalet Skive, Fertilitetsklinikken | Skive | Denmark | 7800 | |
| 11 | Maigaard Fertilitetsklinik | Århus | Denmark | 8200 | |
| 12 | IVF Kliniken Öresund | Malmö | Sweden | 205 12 | |
| 13 | Karolinska Universitetssjukhuset Huddinge, Fertilitetsenheten K59 | Stockholm | Sweden | 14186 | |
| 14 | Reproduktionscentrum | Uppsala | Sweden | 751 85 |
Sponsors and Collaborators
- Origio A/S
Investigators
- Principal Investigator: Søren Ziebe, M.Sc., Rigshospitalet, Fertilitetsklinikken afd. 4071
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- DK001
- Journal no. 8313-24
- Journal no. 461:2007/78029
Study Results
Participant Flow
| Recruitment Details | Overall recruitment period: October 2007 until August 2010. Patients were recruited at both public and private IVF clinics |
|---|---|
| Pre-assignment Detail | Patients with informed consent but where it turned out that the inclusion/exclusion criteria were not fulfilled before assignment to groups, were excluded from the per-protocol (PP) analysis. |
| Arm/Group Title | Test Culture | Control Culture |
|---|---|---|
| Arm/Group Description | Culture with 2 ng/ml GM-CSF | Culture without GM-CSF |
| Period Title: Overall Study | ||
| STARTED | 654 | 678 |
| COMPLETED | 587 | 605 |
| NOT COMPLETED | 67 | 73 |
Baseline Characteristics
| Arm/Group Title | Test Culture | Control Culture | Total |
|---|---|---|---|
| Arm/Group Description | Culture with 2 ng/ml GM-CSF | Culture without GM-CSF | Total of all reporting groups |
| Overall Participants | 654 | 678 | 1332 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
32.2
(3.7)
|
32.4
(3.8)
|
32.3
(3.8)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
654
100%
|
678
100%
|
1332
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||
| Denmark |
610
93.3%
|
635
93.7%
|
1245
93.5%
|
| Sweden |
44
6.7%
|
43
6.3%
|
87
6.5%
|
Outcome Measures
| Title | Ongoing Implantation Rate Week 7 |
|---|---|
| Description | Defined as number of gestational sacs with fetal heart beat, shown by ultrasound in gestational week 7 in percentage of number of embryo transferred. |
| Time Frame | Approximately 5 weeks from oocyte pick-up (corresponding to 7 weeks from ovulation) |
Outcome Measure Data
| Analysis Population Description |
|---|
| PP-population |
| Arm/Group Title | Test Culture | Control Culture |
|---|---|---|
| Arm/Group Description | Culture with 2 ng/ml GM-CSF | Culture without GM-CSF |
| Measure Participants | 564 | 585 |
| Measure Embryos transferred | 838 | 882 |
| Number [percentage of transferred embryos] |
23.5
|
20.0
|
| Title | Number of Top Quality Embryos (TQE´s) |
|---|---|
| Description | Number of 4-5 cell embryo at 44 hours,at least 7 cell embryo at 68 hours, maximum 20% fragmentation, equally large blastomeres (less than 25% difference in size),No signs of multinucleation. Calculated in percentage of number of 2 pronuclei (2PN) oocytes. |
| Time Frame | 3 days from oocyte pick-up |
Outcome Measure Data
| Analysis Population Description |
|---|
| PP-population |
| Arm/Group Title | Test Culture | Control Culture |
|---|---|---|
| Arm/Group Description | Culture with 2 ng/ml GM-CSF | Culture without GM-CSF |
| Measure Participants | 564 | 585 |
| Number [percentage of 2PN's] |
15.6
|
16.8
|
| Title | Live Birth |
|---|---|
| Description | Subject having at least one live birth. Including a foetus which breathes or shows any other evidence of life after expulsion/extraction from its mother. The definition is independent of the duration of the pregnancy (ICMART/WHO criteria). |
| Time Frame | Until 7 days after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| PP-population |
| Arm/Group Title | Test Culture | Control Culture |
|---|---|---|
| Arm/Group Description | Culture with 2 ng/ml GM-CSF | Culture without GM-CSF |
| Measure Participants | 564 | 585 |
| Number [percentage of transfer patients] |
28.9
|
24.1
|
Adverse Events
| Time Frame | ||||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Test Culture | Control Culture | ||
| Arm/Group Description | Culture with 2 ng/ml GM-CSF | Culture without GM-CSF | ||
All Cause Mortality |
||||
| Test Culture | Control Culture | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Test Culture | Control Culture | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 13/654 (2%) | 8/678 (1.2%) | ||
| General disorders | ||||
| Uterine retension, haematuria and cystitis | 0/654 (0%) | 0 | 1/678 (0.1%) | 1 |
| Foetus or child born with malformations | 4/654 (0.6%) | 4 | 4/678 (0.6%) | 4 |
| Pregnancy, puerperium and perinatal conditions | ||||
| Miscarriage (missed abortion) | 3/654 (0.5%) | 3 | 1/678 (0.1%) | 1 |
| Reproductive system and breast disorders | ||||
| Abdominal haemorrhage after oocyte pick-up. | 0/654 (0%) | 0 | 1/678 (0.1%) | 1 |
| Ovarian Hyperstimulation Syndrome | 2/654 (0.3%) | 2 | 1/678 (0.1%) | 1 |
| Ovarian torsion | 2/654 (0.3%) | 2 | 0/678 (0%) | 0 |
| Ectopic pregnancy | 2/654 (0.3%) | 2 | 0/678 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Test Culture | Control Culture | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/654 (0.9%) | 6/678 (0.9%) | ||
| Pregnancy, puerperium and perinatal conditions | ||||
| Miscarriage | 6/654 (0.9%) | 6 | 6/678 (0.9%) | 6 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Confidentiality until publication of the main results of the study
Results Point of Contact
| Name/Title | Chief Scientific Officer |
|---|---|
| Organization | Origio A/S |
| Phone | +45 46790200 |
| sbendz@origio.com |
- DK001
- Journal no. 8313-24
- Journal no. 461:2007/78029