A Phase 3 interventional study of GONAL-f® and Luveris® in Infertility, Fertility and Follicle Stimulating Hormone Deficiency, sponsored by Merck KGaA, Darmstadt, Germany. Terminated at 1 site in United Arab Emirates. Open to female participants aged 36 Years to 42 Years. Per ClinicalTrials.gov, last updated 2015-11-09.
Sponsored by Merck KGaA, Darmstadt, Germany · Phase 3, Interventional, and Supportive care
This is a phase IIIb, interventional, multicenter, multinational, randomised, open-label, comparative trial which primary objective is to generate data on the ovarian stimulation profile obtained when Luveris® is started either on Day 1 or Day 6 in women in advanced reproductive age (36-42) undergoing Assisted Reproductive Technique (ART).
The subjects who complete the screening assessments and fulfil all the eligibility criteria will start down-regulation treatment on day 21-22 of the cycle.
Down-regulation treatment must start within 2 months following the screening visit. The routine long luteal phase protocol for Gonadotrophin-releasing hormone (GnRH) agonist treatment will be followed.
Once down-regulation has been confirmed, a pregnancy test will be performed within 1 week prior to start of Recombinant human follicle stimulating hormone (r-hFSH) treatment to rule out any pre-existing pregnancy. If the result is negative, the subject will be randomly assigned to one of the two treatment arms of the trial:
Randomization across the two treatment arms will be kept balanced in a 1:1 ratio. Subjects will be provided with a subject diary (including r-hCG and Crinone® administration and safety information) to record daily dosing information for GONAL-f® and Luveris®.
Follicular development will be monitored according to the center's standard practice by US and/or Oestradiol (E2) levels, until the protocol r-hCG requirement is met (i.e., at least 1 follicle greater or equal to 18 mm and 2 follicles greater or equal to 16 millimeter [mm]). After this, a single injection of 250 microgram (mcg) of r-hCG (Ovidrel®/Ovitrelle®), will be administered in order to induce final oocyte maturation.
At a time of 34-38 hours after r-hCG administration, oocytes will be recovered vaginally under US monitoring. Oocytes will then be fertilized in vitro and embryos replaced 2-3 days after oocyte recovery. Ovum pick up (OPU), in vitro fertilization (IVF), Embryo Transfer (ET) and luteal support will be performed as per center's standard practice. In addition, Crinone® 8% (progesterone gel) will be administered once daily.
A post-treatment safety visit will be performed for all subjects who received r-hCG (pregnant and non-pregnant) on post r-hCG Day 15-20. For subjects who have withdrawn from treatment (i.e. after starting Luveris® or GONAL f® but before r-hCG is given) this visit will take place 20-30 days after their first Luveris® or GONAL-f® treatment injection (excluding pregnancy testing).
2,506 studies on the registry are indexed under Infertility; 407 are open to participants now.
This study's enrollment of 174 is above the median of 120 across 1,698 interventional studies indexed under Infertility.
Browse Infertility studies →Merck KGaA, Darmstadt, Germany is the lead sponsor of 269 studies on the registry; none are open to participants now.
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Exclusion Criteria:
GONAL f® 300 international units \[IU\] per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 1 until required recombinant human chorionic gonadotropin (r-hCG) level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Drug: GONAL-f® · Drug: Luveris® · Biological: Recombinant human chorionic gonadotropin (r-hCG)
GONAL-f® 300 IU per day as subcutaneous injection using liquid pen from stimulation Day 1-5 followed by Luveris® 150 IU per day lyophilized powder for subcutaneous injection from stimulation Day 6 until required r-hCG level is met. The dose will be adjusted from stimulation Day 6 (increased or decreased) based upon the subject's ovarian response and according to the center's standard practice.
Drug: GONAL-f® · Drug: Luveris® · Biological: Recombinant human chorionic gonadotropin (r-hCG)
GONAL f® 300 international units \[IU\] per day as subcutaneous injection using liquid pen.
Luveris® 150 IU per day lyophilized powder for subcutaneous injection.
A single injection of r-hCG (Ovidrel®/Ovitrelle®) 250 mcg to induce final oocyte maturation.
Total Number of Oocytes Retrieved Per Subject Following Ovarian Stimulation
Ovarian stimulation was performed using in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The total number of oocytes collected per subject following stimulation was reported.
Time frame: 34-38 hours post r-hCG administration
Total Dose and Mean Daily Dose of Follicle Stimulating Hormone (FSH)
Mean daily dose of FSH was to be determined by dividing the total daily dose by the number of stimulation days.
Time frame: Screening
Total Number of Stimulation Treatment Days
The total number of stimulation treatment days for each subject was determined based on the treatment administration information collected in the case report form.
Time frame: 6 days post stimulation (Number of stimulation days+6 days)
Implantation Rate
The implantation rate was determined as number of fetal sacs divided by the number of embryos transferred post r-hCG administration.
Time frame: 35-42 days post r-hCG administration
Number of Fetal Sacs With Activity
Number of fetal sacs with activity was evaluated by ultrasound scan (US) on Days 35-42 post r-hCG to confirm clinical pregnancy.
Time frame: 35-42 days post r-hCG administration
Number of Fetal Sacs With Detectable Heart Beats
Number of fetal sacs with detectable heart beats was evaluated by US on Days 35-42 post r-hCG to confirm clinical pregnancy
Time frame: 35-42 days post r-hCG administration
Total Pregnancy Rate and Clinical Pregnancy Rate
The subject was considered to have a positive pregnancy result if beta-hCG \>10 international units per liter (IU/L) and the subject had not menstruated between post-r-hCG Days 15-20. Clinical pregnancy was defined as the existence of at least an US confirmed gestational sac in the uterus with fetal heart activity post-r-hCG Days 35-42.
Time frame: 35-42 days post r-hCG administration
Cycle Cancellation Rate Prior to r-hCG
If the subject was not administered with r-hCG and withdrew prematurely from the trial, it was considered as cycle cancellation.
Time frame: Up to 85 days
Number of Subjects With Biochemical Pregnancies
Biochemical pregnancy was defined as the pregnancy diagnosed only by the detection of hCG in serum or urine and that does not develop into a clinical pregnancy. Subjects with beta-hCG concentration greater than 10 IU/L were considered as biochemical pregnant.
Time frame: 35 to 42 days post r-hCG administration
Number of Subjects With Multiple Pregnancies
Multiple pregnancy was defined as the existence of more than one ultrasound confirmed gestational sac in the uterus with fetal heart activity at post-r-hCG Days 35-42.
Time frame: 35 to 42 days post r-hCG administration
Number of Subjects With Any Adverse Events (AEs), Serious AEs, AEs Leading to Death, and AEs Leading to Discontinuation
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Time frame: Baseline up to 15-20 days post r-hCG administration
| Milestone | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Started | 89 | 85 |
| Completed | 72 | 70 |
| Not completed | 17 | 15 |
| Withdrew: Lost to follow-up | 1 | 0 |
| Withdrew: Protocol violation | 0 | 2 |
| Withdrew: Withdrawal by subject | 2 | 1 |
| Withdrew: Excessive/lack of response to treatment | 1 | 0 |
| Withdrew: Risk of ohss | 1 | 0 |
| Withdrew: No oocytes retrieved | 3 | 2 |
| Withdrew: No fertilisation | 6 | 5 |
| Withdrew: Intention to freeze all embryos | 0 | 1 |
| Withdrew: All embryos discarded | 0 | 3 |
| Withdrew: Other | 3 | 1 |
Ovarian stimulation was performed using in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). The total number of oocytes collected per subject following stimulation was reported.
| oocytes | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Total Number of Oocytes Retrieved Per Subject Following Ovarian Stimulation | 8.6 ± 6.54 | 8.7 ± 5.77 |
Mean daily dose of FSH was to be determined by dividing the total daily dose by the number of stimulation days.
No measurements were reported for this outcome.
The total number of stimulation treatment days for each subject was determined based on the treatment administration information collected in the case report form.
| days | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Total Number of Stimulation Treatment Days | 11.1 ± 2.42 | 11.3 ± 2.24 |
The implantation rate was determined as number of fetal sacs divided by the number of embryos transferred post r-hCG administration.
| fetal sacs/embryo transferred | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Implantation Rate | 0.5 ± 0.51 | 0.4 ± 0.51 |
Number of fetal sacs with activity was evaluated by ultrasound scan (US) on Days 35-42 post r-hCG to confirm clinical pregnancy.
| Fetal sacs | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Number of Fetal Sacs With Activity | 0.8 ± 0.42 | 1.1 ± 0.54 |
Number of fetal sacs with detectable heart beats was evaluated by US on Days 35-42 post r-hCG to confirm clinical pregnancy
| Fetal sacs | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Number of Fetal Sacs With Detectable Heart Beats | 0.6 ± 0.50 | 1.0 ± 0.45 |
The subject was considered to have a positive pregnancy result if beta-hCG \>10 international units per liter (IU/L) and the subject had not menstruated between post-r-hCG Days 15-20. Clinical pregnancy was defined as the existence of at least an US confirmed gestational sac in the uterus with fetal heart activity post-r-hCG Days 35-42.
| percentage of subjects | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Total pregnancy | 20 | 27 |
| Clinical pregnancy | 17 | 23 |
If the subject was not administered with r-hCG and withdrew prematurely from the trial, it was considered as cycle cancellation.
| percentage of subjects | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Cycle Cancellation Rate Prior to r-hCG | 0 | 0 |
Biochemical pregnancy was defined as the pregnancy diagnosed only by the detection of hCG in serum or urine and that does not develop into a clinical pregnancy. Subjects with beta-hCG concentration greater than 10 IU/L were considered as biochemical pregnant.
| subjects | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Number of Subjects With Biochemical Pregnancies | 2 | 1 |
Multiple pregnancy was defined as the existence of more than one ultrasound confirmed gestational sac in the uterus with fetal heart activity at post-r-hCG Days 35-42.
| subjects | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Number of Subjects With Multiple Pregnancies | 0 | 4 |
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious AE is an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
| subjects | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| AEs | 27 | 28 |
| Serious AEs | 4 | 5 |
| AEs Leading to Death | 0 | 0 |
| AEs Leading to Discontinuation | 1 | 3 |
Collected over Baseline up to 15-20 days post r-hCG administration. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Gonal-f®+Luveris | — | 4/89 (4.5%) | 24/89 (27%) |
| Gonal-f® Followed by Luveris | — | 5/85 (5.9%) | 27/85 (31.8%) |
| Event | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| Abortion spontaneousPregnancy, puerperium and perinatal conditions | 2/89 | 4/85 |
| Ovarian cystReproductive system and breast disorders | 2/89 | 1/85 |
| Event | Gonal-f®+Luveris | Gonal-f® Followed by Luveris |
|---|---|---|
| OverdoseInjury, poisoning and procedural complications | 13/89 | 14/85 |
| Oestradiol increasedInvestigations | 8/89 | 8/85 |
| Abortion spontaneousPregnancy, puerperium and perinatal conditions | 2/89 | 5/85 |
| Progesterone increasedInvestigations | 0/89 | 1/85 |
| HyperglycaemiaMetabolism and nutrition disorders | 0/89 | 1/85 |
| Breast painReproductive system and breast disorders | 1/89 | 0/85 |
Baseline analysis population included all the subjects randomized in the study.
| Age, Continuous(years) | Gonal-f®+Luveris | Gonal-f® Followed by Luveris | Total |
|---|---|---|---|
| Mean | 37.8 ± 1.6 | 38 ± 1.7 | 37.9 ± 1.65 |
| Sex: Female, Male(Participants) | Gonal-f®+Luveris | Gonal-f® Followed by Luveris | Total |
|---|---|---|---|
| Female | 89 | 85 | 174 |
| Male | 0 | 0 | 0 |
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Merck KGaA, Darmstadt, Germany