Recombinant FSH Investigation in the Treatment of Infertility With Assisted Reproductive Technology (ART) (RITA-2)

Study Overview
=================
Brief Summary
-----------------
This trial investigates the effects of FE 999049 compared to placebo.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicenter Trial Investigating the Efficacy and Safety of FE 999049 in Controlled Ovarian Stimulation in Women Aged 35-42 Years Undergoing Assisted Reproductive Technology

Conditions
-----------------
Infertility, Female

Intervention / Treatment
-----------------
* Drug: Follitropin delta
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed Consent Documents signed prior to any trial-related procedure. In good physical and mental health in the judgement of the investigator. Pre-menopausal women between the ages of 35 and 42 years. The subjects must be at least 35 years (including the 35th birthday) when they sign the informed consent and no more than 42 years (up to the day before the 43rd birthday) at the time of randomization. Body mass index (BMI) between 17.5 and 38.0 kg/m^2 (both inclusive) at screening. Infertile women diagnosed with tubal infertility, unexplained infertility, endometriosis stage I/II or with partners diagnosed with male factor infertility, eligible for in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) using fresh or frozen ejaculated sperm from male partner or sperm donor. Documented history of infertility for at least 6 months before randomization (not applicable in case of tubal or severe male factor infertility, or when the use of donor sperm is indicated). Regular menstrual cycles of 24-35 days (both inclusive). Hysterosalpingography, hysteroscopy or saline infusion sonography, documenting a uterus consistent with expected normal function (e.g. no evidence of clinically interfering uterine fibroids defined as submucous fibroids of any size or intramural fibroids larger than 3 cm in diameter, no polyps and no congenital structural abnormalities which are associated with a reduced chance of pregnancy) at screening or within 1 year prior to screening. Transvaginal ultrasound documenting presence and adequate visualization of both ovaries, without evidence of significant abnormality (e.g. enlarged ovaries which would contraindicate the use of gonadotropins) and normal adnexa (e.g. no hydrosalpinx) at screening. Both ovaries must be accessible for oocyte retrieval. Early follicular phase (cycle day 2-4) serum levels of FSH between 1 and 15 IU/L (results obtained within 3 months prior to randomization). Negative serum Hepatitis B Surface Antigen (HBsAg), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) antibody tests at screening or within 6 months prior to screening. Willing to accept the blastocyst transfer policy for the fresh cycle and the cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation using blastocysts obtained in this trial, i.e. transfer of one blastocyst (if a good-quality blastocyst is available) or transfer of one or two blastocysts (if no good-quality blastocyst is available). Exclusion Criteria: More than one previous controlled ovarian stimulation cycle for IVF/ICSI. Known endometriosis stage III-IV (defined by the revised ASRM classification, 2012). Known history of anovulation. One or more follicles greater than or equal to 10 mm (including cysts) observed on the transvaginal ultrasound prior to randomization on stimulation day 1. Known history of recurrent miscarriage (defined as three consecutive losses after ultrasound confirmation of pregnancy [excluding ectopic pregnancy] and before week 24 of pregnancy). Known abnormal karyotype of subject or of her partner / sperm donor, as applicable, depending on source of sperm used for insemination in this trial. In case partner sperm will be used and the sperm production is severely impaired (concentration less than 1 million/mL), normal karyotype, including no Y-chromosome microdeletion, must be documented. Any known clinically significant systemic disease (e.g. insulin-dependent diabetes). Known inherited or acquired thrombophilia. Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events. Any known endocrine or metabolic abnormalities (pituitary, adrenal, pancreas, liver or kidney) with the exception of pharmacologically controlled sub-clinical hypothyroidism. Known tumors of the ovary, breast, uterus, adrenal gland, pituitary or hypothalamus which would contraindicate the use of gonadotropins. Known moderate or severe impairment of renal or hepatic function. Any abnormal finding of clinical chemistry, hematology, thyroid-stimulating hormone (TSH) or prolactin, or vital signs at screening, which is judged clinically significant by the investigator. Known abnormal cervical cytology of clinical significance observed within three years prior to randomization (unless the clinical significance has been resolved). Findings at the gynecological examination at screening which preclude gonadotropin stimulation or are associated with a reduced chance of pregnancy, e.g. congenital uterine abnormalities or retained intrauterine device. Pregnancy (negative urinary pregnancy tests must be documented at screening and prior to randomization) or contraindication to pregnancy. Known current active pelvic inflammatory disease. Use of fertility modifiers during the last menstrual cycle before randomization, including dehydroepiandrosterone (DHEA), metformin or cycle programming with oral contraceptives, progestogen or estrogen preparations.

Ages Eligible for Study
-----------------
Minimum Age: 35 Years
Maximum Age: 42 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Follitropin delta<br> | Drug: Follitropin delta<br>* Follitropin delta<br>* Other names: Rekovelle;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative ongoing pregnancy rate after the fresh cycle and cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation (COS) |  | 8-9 weeks after transfer (up to and approximately 16 months after start of stimulation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rate in the fresh cycle and in the cryopreserved cycles |  | 8-9 weeks after transfer (up to approximately 16 months after start of stimulation) | 
| Time from start of controlled ovarian stimulation (COS) to ongoing pregnancy across the fresh and cryopreserved cycles |  | 8-9 weeks after transfer (up to approximately 16 months after start of stimulation) | 
| Ongoing implantation rate in the fresh cycle, the cryopreserved cycles and cumulatively |  | 8-9 weeks after transfer (up to approximately 16 months after start of stimulation) | 
| Clinical pregnancy rate in the fresh cycle, the cryopreserved cycles and cumulatively |  | 5-6 weeks after transfer (up to approximately 15 months after start of stimulation) | 
| Vital pregnancy rate in the fresh cycle, the cryopreserved cycles and cumulatively |  | 5-6 weeks after transfer (up to approximately 15 months after start of stimulation) | 
| Implantation rate in the fresh cycle, the cryopreserved cycles and cumulatively |  | 5-6 weeks after transfer (up to approximately 15 months after start of stimulation) | 
| Positive beta human chorionic gonadotropin (βhCG) rate in the fresh cycle, the cryopreserved cycles and cumulatively |  | 10-14 days after transfer (up to approximately 14 months after start of stimulation) | 
| Proportion of participants in the fresh cycle with triggering of final follicular maturation (with human chorionic gonadotropin [hCG], with gonadotropin releasing hormone [GnRH] agonist, and in total), cycle cancellation and transfer cancellation |  | Up to 5 days after oocyte retrieval (up to 27 days after start of stimulation) | 
| Number of follicles on stimulation day 5 | The total number of follicles and the number of follicles per size category will be reported | On stimulation day 5 | 
| Number of follicles at end-of-stimulation | The total number of follicles and the number of follicles per size category will be reported | At end-of-stimulation (up to 20 stimulation days) | 
| Number of oocytes retrieved |  | On day of oocyte retrieval (up to 22 days after start of stimulation) | 
| Proportion of participants with <4, 4-7, 8-14, 15-19 and ≥20 oocytes retrieved |  | On day of oocyte retrieval (up to 22 days after start of stimulation) | 
| Number of metaphase II oocytes |  | On day of oocyte retrieval (up to 22 days after start of stimulation) | 
| Number of fertilized oocytes and fertilization rate |  | On day 1 after oocyte retrieval (up to 23 days after start of stimulation) | 
| Number of blastocysts on Day 5 after oocyte retrieval | The number of blastocysts (total and good-quality) will be reported. Blastocyst quality is assessed by blastocyst expansion and hatching status, blastocyst inner cell mass grading, and trophectoderm grading. The scoring is based on the classification system by Gardner and Schoolcraft, with additional categories for inner cell mass (degenerative or no inner cell mass) and trophectoderm (degenerative or very large cells) | On day 5 after oocyte retrieval | 
| Endometrial thickness | Mean endometrial thickness will be reported | On stimulation day 5 and at end-of-stimulation (up to 20 stimulation days) | 
| Echogenicity pattern | The distribution of subjects with hypoechogenic, isoechogenic, or hyperechogenic endometrium will be reported | On stimulation day 5 and at end-of-stimulation (up to 20 stimulation days) | 
| Oocyte utilization rate |  | On day of oocyte retrieval up to 12 months after start of controlled ovarian stimulation (COS) | 
| Oocyte efficiency index | The oocyte efficiency index will be calculated based on the number of oocytes retrieved and the cumulative number of ongoing pregnancies | 8-9 weeks after transfer | 
| Percentage of blastocysts surviving cryopreservation |  | 0 hour (+0.5 hour) after thawing | 
| Percentage of blastocysts with re-expansion after cryopreservation |  | 2.5 hour (±0.5 hour) after thawing | 
| Number of cryopreserved cycles initiated within 12 months from the start of controlled ovarian stimulation (COS), and number of cryopreserved cycles with blastocyst transfer | The total number of cryopreserved cycles initiated and the number of cryopreserved cycles with blastocyst transfer will be reported | Up to 12 months after start of stimulation | 
| Circulating concentrations of anti-mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, inhibin A and inhibin B |  | From screening to the day of oocyte retrieval (up to 22 days after start of stimulation) | 
| Total gonadotropin dose |  | Up to 20 stimulation days | 
| Number of stimulation days |  | Up to 20 stimulation days | 
| Number of dose adjustments |  | Up to 20 stimulation days | 
| Frequency and intensity of adverse events | From time of signing informed consent until the end-of-cycle visit in the fresh cycle (up to approximately 6 months) | From time of signing informed consent until the end-of-cycle visit in the fresh cycle (approximately 6 months), and again in any cryopreserved cycle from cycle initiation until the end-of-cycle visit (approximately 3 months) | 
| Changes in circulating levels of clinical chemistry compared to baseline | Measured by CHEM-20 | From screening to the end-of-cycle visit in the fresh cycle (approximately 6 months) | 
| Changes in haematology parameters compared to baseline | Measured by complete blood count (CBC) | From screening to the end-of-cycle visit in the fresh cycle (approximately 6 months) | 
| Frequency and intensity of injection site reactions (redness, pain, itching, swelling and bruising) assessed by the participant during the stimulation period |  | Up to 20 stimulation days | 
| Proportion of participants with treatment-induced anti-FSH antibodies |  | Up to 28 days after end of the stimulation period | 
| Frequency and intensity of immune-related adverse events |  | From time of signing informed consent for participation in the trial until the end-of-cycle visit in the fresh cycle (approximately 6 months) | 
| Proportion of participants with cycle cancellations due to an adverse event, including immune-related adverse events, or due to technical malfunctions of the administration pen |  | Up to 20 stimulation days | 
| Proportion of participants with ovarian hyperstimulation syndrome (OHSS), overall and by grade, and proportion of participants with moderate/severe OHSS |  | ≤9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation (late OHSS) | 
| Proportion of participants hospitalized due to ovarian hyperstimulation syndrome OHSS and proportion of participants undergoing paracentesis due to OHSS |  | ≤9 days after triggering of final follicular maturation (early OHSS), >9 days after triggering of final follicular maturation (late OHSS) | 
| Rate of multi-fetal gestation, biochemical pregnancy, spontaneous abortion, ectopic pregnancy (with and without medical/surgical intervention) and vanishing twins in the fresh cycle and in the cryopreserved cycles | The percentage of subjects with each of these events will be reported | Up to 8-9 weeks after transfer | 
| Technical malfunctions of the administration pen |  | Up to 20 stimulation days |