Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00439829 |
| Other study ID # |
BIO-REB 06-03 |
| Secondary ID |
HlthCanadaFile#9 |
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
February 13, 2007 |
| Last updated |
May 21, 2010 |
| Start date |
February 2007 |
| Est. completion date |
May 2010 |
Study information
| Verified date |
May 2010 |
| Source |
University of Saskatchewan |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Canada: Health Canada |
| Study type |
Interventional
|
Clinical Trial Summary
The objective of the study is to elucidate the effect of synchronizing initiation of ovarian
stimulation treatment with follicular wave emergence in poor responder patients undergoing
IVF/ICSI and ET. We hypothesize that initiating treatment on day 1 versus day 4 of the cycle
will increase the number of follicles recruited and oocytes retrieved.
Description:
Sample Population Eligible patients undergoing IVF or ICSI for the treatment of infertility
in the Assisted Reproductive Technologies Center at the University of Saskatchewan (ARTUS;
Department of Obstetrics, Gynecology and Reproductive Sciences) in Saskatoon, Saskatchewan
and the Genesis Fertility Centre in Vancouver, British Columbia will be identified by study
physicians and nurses. Patients with a history of poor response to ovarian stimulation
therapy in a previous IVF or ICSI cycle, who have already decided to undergo a subsequent
treatment cycle, will be contacted by a study physician and offered enrolment into the
study. Patients exhibiting all inclusion criteria and no exclusion criteria will be eligible
to participate.
Inclusion Criteria:
- Informed consent obtained
- Age of 43 years or younger
- 18
- History of poor response to ovarian stimulation as determined by:
- previously cancelled oocyte retrieval procedure due to < 4 follicles greater than 12 mm
on ultrasound OR
- < 3 mature oocytes
- Physical exam performed within the past 12 months
- Normal or corrected levels of TSH and Prolactin within the past 12 months
- Has not taken ovarian suppression therapy within 1 month of initiating study drug
Exclusion Criteria:
- Chronic medical conditions such as renal failure
- Documented ovarian failure
- Presence of only one ovary
- Serum Day 3 FSH > 12 IU/L within the past 6 months
- Ovaries inaccessible transvaginally
- Concomitant glucocorticoid use
- Ongoing pregnancy
- Any contraindications to ovarian stimulation treatment
- Participation in an investigational drug trial in the 30 days prior to the pre-study
visit
Cycle Cancellation Criteria:
- The development of < 3 follicles > 12 mm.
Sample Size A sample size of 80 women (40 women per treatment group) has been chosen. This
calculation was based on a standard deviation of 3.0 in each treatment group, a significance
level of 0.05 (2-tailed test), a mean difference of 2.0 follicles and a power of 80%. The
standard deviation used in the power calculation was based on similar studies performed in
domestic animal species. Approximately 120 IVF/ICSI cycles are performed each year in the
Department of Obstetrics, Gynecology and Reproductive Sciences at the University of
Saskatchewan and approximately 600 cycles are performed at the Genesis Fertility Centre.
Approximately 5-10% of patients are proven poor responders. Thus, with an anticipated 75%
recruitment rate, we expect to recruit 80 patients in the study over a 24 month period. It
is expected that 25% of research subjects will be enrolled at the ARTUS Centre and 75% of
subjects will be enrolled at the Genesis Fertility Centre.
Study Procedures Women who are believed to be eligible for the study will be asked to visit
the Assisted Reproductive Technologies Center at the University of Saskatchewan (ARTUS) or
the Genesis Fertility Centre in Vancouver, British Columbia for a pre-study appointment. At
this visit, inclusion and exclusion criteria will be reviewed. If patients meet all study
criteria, consent will be obtained and each woman will be randomized to either the control
group (i.e. treatment starting on day 4) or experimental group (i.e., treatment starting on
day 1). A medical history and vital signs will be performed. Study drug administration,
diary card use and potential adverse reactions will be reviewed at the pre-study visit.
Diary cards will be used to monitor study drug administration, adverse reactions, and
concomitant medications used during the study. Diary cards will be reviewed with the patient
by study personnel throughout the duration of the study. Serious adverse events will be
reported by the investigators to the drug safety group of the study drug manufacturers and
the Biomedical Research Ethics Board, in accordance with Tri-Council Policy guidelines.
All patients will be instructed to call the clinic on day 1 of menses. If menses begins
before 6 pm, that day will be considered day 1. If menses begins after 6 pm, the next day
will be considered day 1. Women randomized to the day 1 treatment group will be instructed
to begin ovarian stimulation therapy (Gonal-f, Serono Canada) on day 1 and visit the clinic
to undergo their first transvaginal ultrasound examination on day 2. Women randomized to the
day 4 treatment group will be instructed to begin ovarian stimulation on day 4 and visit the
clinic on day 4 for their first transvaginal ultrasound examination. Ultrasound examinations
will be performed to determine the number of follicles developing in the ovaries. Ultrasound
examinations will continue every 2-4 days for each woman, as per the normal standard of
care. Blood will be drawn intermittently during stimulation to determine serum
concentrations of estradiol-17B. Each participant will be asked to perform a home urine
pregnancy test before taking their first dose of study medication. If a woman is found to be
pregnant, she will be withdrawn from the study.
When a follicle > 13 mm is detected OR if 6 or more follicles > 10 mm develop and E2 is >
1000 pmol/L, women will be instructed to begin taking a Gonadotropin Releasing Hormone
Antagonist (Cetrotide, Serono Canada) and recombinant Luteinizing Hormone (Luveris, Serono
Canada). Gonal F, Cetrotide and Luveris administration will continue daily until human
Chorionic Gonadotropin (hCG, Pharmaceutical Partners of Canada Inc.) is administered when >
3 follicles reach > 17 mm in diameter. It is anticipated that the duration of ovarian
stimulation therapy will be 8-16 days. Shorter or longer stimulation intervals may result in
cycle cancellation. Oocytes will be isolated, evaluated and fertilized following hCG
administration, according to the normal standard of care.
The type and dose of stimulation therapy will be standardized among women as noted in
Appendix B. Women will be asked to visit the clinic for a follow-up appointment with the
physician and study nurse approximately 4 weeks after the oocyte retrieval. Adverse events,
concomitant medications and diaries will be reviewed at this time. After the follow-up
appointment, women will have completed all study-related procedures. Adverse events
persisting at the time of study completion will be followed as deemed medically appropriate.
All procedures performed in this study adhere to Good Clinical Practice guidelines. The only
procedures that differ from those carried out for routine patient care are the initiation of
ovarian stimulation therapy on day 1, the urine pregnancy test prior to initiating therapy
and the completion of diary cards by the patients to monitor study drug administration,
adverse events and concomitant medications.
Study Endpoints
Primary study endpoints include:
- number of follicles > 15 mm on day of hCG
- peak serum estradiol concentrations
Secondary study endpoints include:
- number of antral follicles (day 1 or day 4)
- number of follicles aspirated
- number of oocytes obtained
- oocyte morphology
- fertilization rates
- number of viable embryos (day 3 and day 5)
- blastocyst rate
- number of embryos transferred
- clinical pregnancy rate (serum ß-hCG)
All study endpoints will be compared between women in the control versus experimental group.
An interim analysis will be performed by the study investigators once 40 patients have
completed study procedures. The overall incidence of Ovarian Hyperstimulation Syndrome
(OHSS) requiring hospitalization in women undergoing IVF/ICSI is approximately 3%.
Therefore, in 40 normal responder patients we would expect an incidence of OHSS-related
hospitalization to be approximately 1.2%. If more than 1 patient in each treatment group has
been admitted to the hospital for OHSS after 40 women have completed study procedures, the
study will be reviewed for possible termination.
Foreseeable Risks and Discomfort
Potential risks during study participation include:
- discomfort during transvaginal ultrasound examination
- discomfort and bruising at the site of venipuncture
- redness, swelling and discomfort at the drug injection site
- ovarian hyperstimulation
In 1-10% of normally-responding patients, ovarian hyperstimulation syndrome (OHSS) occurs in
which too many follicles develop, placing the woman at risk for hospitalization. Because a
suboptimal number of follicles develop in women who respond poorly to ovarian stimulation
therapy, we believe that the risk of ovarian hyperstimulation is extremely low to zero.
However, because we cannot predict the outcome of initiating therapy on day 1 of the
menstrual cycle, we cannot guarantee that hyperstimulation will not occur.
All of the above-mentioned risks are related to current standard of care for IVF. The risks
of OHSS will be minimized by adherence to the usual standard of care for ovarian stimulation
monitoring. Patients felt to be at risk for developing OHSS will have their dose of
exogenous FSH and hCG therapy dropped, as per the usual standard of care.
In the event that patients become ill or injured as a result of participating in this study,
necessary medical treatment will be made available at no additional cost to the patient. By
signing the consent form, patients do not waive any of their legal rights.
Benefits There are no guaranteed benefits for women participating in this study. However, if
our hypothesis is proven, women may benefit from an increased number of recruited follicles.
We anticipate that the results of this study will increase our understanding of poor
response to ovarian stimulation, and lead to the development of better treatments for
couples undergoing IVF/ICSI and ET in the future.
Costs Partial drug coverage will be provided by Serono Canada Inc. to participants in this
study.
Confidentiality All participants will be identified in the study by their initials and
assigned patient study number. Only study personnel will have access to study-related
records during the conduct of the study. The contents of study related records will not be
available to any party other than the University of Saskatchewan Ethics Board, the study
sponsor, and government regulatory agencies unless required by law. A report of the results
of this study may be made to Health Canada (HC) and the Food and Drug Administration (FDA,
USA) while maintaining confidentiality of patient identification. The results of this study
may also be used for medical and scientific publications but patient identity will not be
disclosed. Study files will be archived by the scientific investigator for 25 years at Royal
University Hospital.
Voluntary Participation/Withdrawal from Study Participation in this study is voluntary.
Patients may decide not to participate or may withdraw at any time. Refusal to participate
in, or withdrawal from, the study will not affect the future medical care of the patient.
Participation in this study may be ended at any time, without patient consent. Reasons may
include, but are not limited to, patient's failure to follow study instructions, the
appearance of side effects, or study cancellation due to administrative reasons. If < 3
follicles develop to a diameter of 12 mm or larger, the patient will be withdrawn from the
study and the IVF/ICSI cycle may be cancelled.
