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Efficacy and Safety of Medication Used to Stimulate Ovulation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02715336
Recruitment Status : Recruiting
First Posted : March 22, 2016
Last Update Posted : July 20, 2020
Sponsor:
Information provided by (Responsible Party):
Create Fertility Center

Brief Summary:

Individuals undergoing In Vitro Fertilization must undergo controlled ovarian hyperstimulation (COH) to produce enough quality eggs for fertility treatment. Ovarian follicular responsiveness to COH with gonadotropins is extremely variable between patients and even from cycle to cycle for the same patient. Achieving an ideal follicular response is critical to the success of assisted reproduction treatment (ART). Patients have been classified as 'poor', 'normal' or 'high' responders, which dictate the amount of gonadotropins that they receive. It is still important to develop treatments with high efficacy, lower multiple birth rates, and a lower complication rate for each of these groups. In an era of evidence-based medicine and with special emphasis on reducing IVF risks (mainly OHSS and pregnancies with multiples), it is very important to find optimal and safe ovulation induction and triggering regimens for each patient population.

The use of GnRH agonist (GnRHa) triggering among high responders in order to reduce or eliminate OHSS is an example of an important breakthrough in the clinical management of IVF patients. Although GnRHa triggering was shown to be as effective as human chorionic gonadotropin (hCG) at inducing oocyte maturation more than 20 years ago, its use to trigger ovulation was not possible until the introduction of GnRH antagonists for pituitary suppression.

Another prominent trend in ART in recent years has been the introduction of dual triggering, which involves a combination of GnRHa plus hCG for triggering. This regimen creates simultaneous lutenizing hormone (LH) and follicle stimulating hormone (FSH) surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, which stimulates the corpus luteum to excrete sufficient hormonal endometrial support. Since its introduction, dual triggering has been gaining popularity due to outstanding results in retrospective studies among both normal and high responders. Moreover, in spite of the encouraging retrospective reports, prospective randomized controlled trials (RCT) on dual triggering have not been reported to date. The aim of the current proposed study is to compare the efficacy of dual triggering and conventional triggering among the three IVF populations (high, normal and poor responders).


Condition or disease Intervention/treatment Phase
IVF Cycle Ovarian Stimulation Egg Retrieval Pregnancy Miscarriages Ovarian Hyperstimulation Drug: Ovulation induction with hCG and Lupron (GnRH agonist) Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 666 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Pre-retrieval Triggering Methods in in Vitro Fertilization Patients Classified as Low, Normal or High Responder
Study Start Date : October 2015
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2021

Arm Intervention/treatment
Experimental: Study group: High Responders
1000 units hCG
Drug: Ovulation induction with hCG and Lupron (GnRH agonist)
Patients treated for infertility are categorized as a low-, normal- or high responder according to their estimated ovarian response to hormonal stimulation. This classification dictates the hormonal stimulation regimen that they will receive. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. A combination of GnRHa plus hCG for triggering creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, stimulating the corpus luteum to excrete sufficient hormonal endometrial support.

No Intervention: Control group: High Responders
1000 units hCG
Experimental: Study group: Normal Responders
5000 units hCG
Drug: Ovulation induction with hCG and Lupron (GnRH agonist)
Patients treated for infertility are categorized as a low-, normal- or high responder according to their estimated ovarian response to hormonal stimulation. This classification dictates the hormonal stimulation regimen that they will receive. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. A combination of GnRHa plus hCG for triggering creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, stimulating the corpus luteum to excrete sufficient hormonal endometrial support.

No Intervention: Control group: Normal Responders
5000 units hCG
Experimental: Study group: Low Responders
10000 units hCG
Drug: Ovulation induction with hCG and Lupron (GnRH agonist)
Patients treated for infertility are categorized as a low-, normal- or high responder according to their estimated ovarian response to hormonal stimulation. This classification dictates the hormonal stimulation regimen that they will receive. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. A combination of GnRHa plus hCG for triggering creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, stimulating the corpus luteum to excrete sufficient hormonal endometrial support.

No Intervention: Control group: Low Responders
10000 units hCG



Primary Outcome Measures :
  1. Implantation rate [ Time Frame: 14 days post IVF procedure ]
  2. Human Chorionic Gonadotropin serum levels [ Time Frame: 2-4 weeks post IVF procedure ]
  3. Ongoing pregnancy rate [ Time Frame: 9 months post IVF procedure ]
  4. Miscarriage rate [ Time Frame: 9 months post procedure ]
  5. Ovarian hyperstimulation syndrome [ Time Frame: 7 days post IVF procedure ]

    Mild OHSS:

    1. Grade 1: Abdominal distention, Ovaries <6 cm
    2. Grade 2: Abdominal distention and nausea, vomiting and diarrhea, Ovaries <6 cm

    Moderate OHSS:

    a) Grade 3: Grade II criteria and ultrasound ascites/weight gain, Ovaries 6-12 cm

    Severe OHSS:

    1. Grade 4: Ascites/hydrothorax, Ovaries >12 cm
    2. Grade 5: Ascites/hydrothorax and hypovolemia, hemoconcentration, coagulation disorder, oliguria, shock, Ovaries >12 cm

  6. Fetal heartbeat measured by ultrasound [ Time Frame: 2-4 weeks post IVF procedure ]

Secondary Outcome Measures :
  1. Number of retrieved oocytes [ Time Frame: 5 days post IVF procedure ]
  2. Number of retrieved Meiosis II oocytes [ Time Frame: 5 days post IVF procedure ]
  3. Fertilization rate [ Time Frame: 5 days post IVF procedure ]
  4. Number of Day 3 embryos/eggs retrieved [ Time Frame: 5 days post IVF procedure ]
  5. Number of blastocysts/eggs retrieved [ Time Frame: 5 days post IVF procedure ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

A) Dual triggering vs. GnRH agonist alone in high responders IVF patients

Inclusion Criteria - At least one of the following risk factors:

  • AMH > 29 pmol/L
  • AFC > 16
  • PCOS diagnosed according to Rotterdam criteria: any two of the following three features: 1) oligo- or anovulation; 2) clinical and/or biochemical hyper-androgenemia; and 3) PCO-US with exclusion of other etiologies as mentioned in the National Institute of Child Health and Human Development (NICHD) criteria
  • Previous OHSS
  • Previous cycle cancellation due to OHSS risk
  • Previous coasting
  • Participants initially recruited to the normal responders study who exhibit excessive ovarian response markers on triggering day: high amount of middle-large follicles (> 13 follicles ≥ 11mm on triggering day). All previous inclusion criteria are assessed before initiation of the IVF cycle and ovarian stimulation, and all of them represent pre-stimulation risk factors for high ovarian response. The patient's actual response will be assessed on triggering day (after completion of ovarian stimulation). Final assignment of responder category followed by randomization will only be performed on the day of triggering
  • informed consent obtained
  • Must be 18 years or older
  • Ability to speak and read English, or understand French, Mandarin, Cantonese, Arabic, or Filipino.

Exclusion criteria:

  • Chronic disease
  • Hypogonadotrophic hypogonadism
  • Untreated uterine abnormalities
  • E2>4000 pg/ml (>14,680 pmol/L) on trigger day. These very high risk patients will undergo GnRHa only trigger and will be excluded from the trial.

B) Dual triggering vs. 5000 units hCG in normal responders

Inclusion criteria:

  • Age above 18 years and less than 40 years
  • Do not fulfill criteria for poor responder or high responder

Exclusion criteria:

  • Bologna criteria for poor responders exclusion: two of the following should need to be fulfilled:

    1. Age > 40 or other risk factor for decreased ovarian reserve (ex. ovarian surgery)
    2. Single abnormal test for ovarian reserve (AFC < 6 or AMH < 8 pmol/L)
    3. Previous poor response in previous cycle: cancellation or < 4 retrieved oocytes in response to daily 150 FSH units
  • Criteria for high responders' exclusion

    1. AMH > 29 pmol/L
    2. AFC > 16
    3. PCOS diagnosed according to Rotterdam criteria [19, 28]: any two of the following three features: 1) oligo- or anovulation; 2) clinical and/or biochemical hyper-androgenemia; and 3) PCO-US with exclusion of other etiologies as mentioned in the NICHD criteria
    4. Previous OHSS
    5. Previous cycle cancellation due to OHSS risk
    6. Previous coasting
    7. Excessive ovarian response markers on triggering day such as high amount of middle-large follicles (> 13 follicles ≥ 11mm on triggering day) and E2 concentration (optional E2 > 14500 pmol/L on triggering day). These patients will be allocated to the high responders group.
  • Untreated uterine abnormalities
  • Chronic disease

C) Dual Triggering for Poor Responders

Inclusion criteria: According to Bologna criteria two of the following should be fulfilled:

  • Age > 40 or other risk factor for decreased ovarian reserve (ex. ovarian surgery).
  • Single abnormal test for ovarian reserve (AFC < 6 or AMH < 8 pmol/L).
  • Previous poor response in previous cycle: cancellation or < 4 retrieved oocytes in response to daily 150 FSH units.

Exclusion criteria:

  • Chronic disease
  • Untreated uterine abnormalities
  • Response consistent with normal or high responder, as defined above

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02715336


Contacts
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Contact: Noga Weizman, MD 416323772 drweizman@createivf.com
Contact: Kevin Quach, MSc 4163237727 kev.quach@mail.utoronto.ca

Locations
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Canada, Ontario
Create Fertility Centre Recruiting
Toronto, Ontario, Canada, M5G1N8
Contact: Deborah Davies, RN    416-813-4702      
Principal Investigator: Clifford Librach, MD         
Sub-Investigator: Ari Baratz, MD         
Sub-Investigator: Itai Gat, MD         
Sub-Investigator: Prati Sharma, MD         
Sub-Investigator: Karen Glass, MD         
Sponsors and Collaborators
Create Fertility Center
Investigators
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Principal Investigator: Clifford Librach, MD University of Toronto
Publications:

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Responsible Party: Create Fertility Center
ClinicalTrials.gov Identifier: NCT02715336    
Other Study ID Numbers: CFC-01
First Posted: March 22, 2016    Key Record Dates
Last Update Posted: July 20, 2020
Last Verified: July 2020
Keywords provided by Create Fertility Center:
In vitro fertilization
IVF
Assisted Reproductive Technologies
ART
OHSS
Ovarian hyperstimulation
dual triggering
GnRH
Additional relevant MeSH terms:
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Abortion, Spontaneous
Pregnancy Complications
Leuprolide
Fertility Agents, Female
Fertility Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents