Ovarian PRP (Platelet Rich Plasma) Injection for Follicular Activation

Study Overview
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Brief Summary
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The primary objective is to investigate the efficacy, defined as an increase in oocyte numbers upon ovarian stimulation, and safety of a single intra-ovarian PRP injection vs. saline solution (NaCl) injection (Placebo) transvaginally or laparoscopically for follicular activation in patients with child wish and with low ovarian reserve/expected poor ovarian response planning to undergo IVF or ICSI using own eggs. Pain score as numerical rating score and validated quality of life questionnaire will be requested after the procedure. Longterm follow-up of all participants will be performed 1, 2 and 5 years after end of study.

Detailed Description
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Age-related infertility and premature loss of ovarian reserve has become a major challenge for ART professionals as the the average age at first child wish has dramatically increased over time. Under physiological circumstances, most follicles in the human ovary remain dormant throughout the female life span and eventually become atretic, however, histological samples reveal that the follicular pool in the ovary is completely exhausted only as late as the early 70ies and that the ovary holds oogonial stem cells, which may have the ability to differentiate into functional follicles. The pressing problem for reproductive medicine is therefore the question how to reactivate some of the putative ovarian 'reproductive reserve' in those women with premature follicular depletion or those who wish to become pregnant at advanced age. Platelet rich plasma (PRP) is a blood-derived product, characterized by high concentrations of growth factors and chemokines. PRP is produced by centrifuging a small quantity of the patient's own blood and extracting the active, platelet-rich fraction. The platelet-rich fraction is applied to the human body typically by injection. PRP is used for therapeutic purposes in different medical areas ranging from orthopedics to plastic surgery, for its putative ability to stimulate and facilitate cell proliferation and thereby tissue differentiation and regeneration. In the context of reproductive medicine, PRP has been proposed to increase pregnancy rates after uterine flushing in women with recurrent implantation failure or thin endometrium. Intra-ovarian injection of PRP has been proposed to activate dormant ovarian follicles pre IVF-treatment in cases of idiopathic low ovarian reserve, premature ovarian insufficiency or ovarian depletion because of advanced maternal age. To date, there is no randomized placebo-controlled trial available that has evaluated intra-ovarian PRP injection in terms of efficacy and safety for premature ovarian failure, and, more specifically, also not in patients with depleted ovarian reserve/poor ovarian response (POR) who constitute a significant proportion of patients undergoing assisted reproduction.

Official Title
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The Efficacy and Safety of Intra-ovarian PRP Injection Within a Prospective, Single-blinded, Placebo-controlled, Randomized, Clinical Superiority Trial in Subjects With Low Ovarian Reserve/Expected Poor Ovarian Response

Conditions
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PRP, Premature Ovarian Insufficiency, Infertility, Female, Sterility, Female

Intervention / Treatment
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* Biological: autologous PRP (platelet rich plasma)
* Other: Saline solution (NaCL) Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Serum AMH < 0.5 ng/ml (at screening visit and in the absence of OC or sex-steroid intake) Antral follicular count (AFC) in both ovaries ≤ 5 (at screening visit and in the absence of OC or sex-steroid intake) Spontaneous cycle, menstrual cycle length 21-35 days Body mass index (BMI) ≥18 kg/m2 and ≤38 kg/m2 Both ovaries must be visible by transvaginal ultrasound examination Both ovaries must be judged accessible by transvaginal puncture Indication for IVF or ICSI treatment Willingness to participate and provide written consent prior to initiation of any study-related procedures The subject and male partner must agree to participate in the infant follow-up if she becomes pregnant The subject must be able to communicate well with the investigator and research staff and to comply with the requirements of the study protocol. Exclusion Criteria: ≥ four cumulus-oocyte-complexes (COCs) retrieved in a previous IVF cycles with a conventional stimulation protocol (within 6 months before enrollment) Serum value of FSH ≥25 IU/l (within 12 months measured in the absence of OC or hormone replacement intake) Thrombocytopenia defined as < 100.000 platelets/µl at screening Oral contraceptive or sex steroid intake within 1 month prior to enrollment Presence of structural or numerical chromosomal abnormality in cytogenetic analysis Relevant autoimmune disease History of malignancy and systemic chemotherapy or pelvic radiation Severe endometriosis (stage III-IV) Ovaries located outside the inner pelvis Presence of unilateral or bilateral hydrosalpinx Relevant endocrine disorders such as hypothalamic-pituitary disorder or thyroid dysfunction (except substituted Hashimoto's thyroiditis or latent hypothyroidism) Relevant thrombophilic disorder Contraindication for pregnancy Contraindication for transvaginal ovarian puncture (such as previous major lower abdominal surgery and known severe pelvic adhesion) Uterine malformations or pathologies (such as sub mucosal fibroid(s), endometrial hyperplasia, endometrial fluid accumulation, or endometrial adhesions) Mental disability or any other lack of fitness, in the investigator's opinion, to preclude subjects in or to complete the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous intra-ovarian PRP injection<br>Study group, treated with autologous intra-ovarian PRP injection and undergoing a subsequent fresh ET-IVF/ICSI cycle in the third cycle after intervention | Biological: autologous PRP (platelet rich plasma)<br>* The required volume of PRP will be extracted from 60 ml of the patient's peripheral blood. Injecting PRP into the ovaries will be performed likewise to the standard operating procedure of oocyte retrieval. After centrifugation of the whole blood, 5ml PRP will be injected in each ovary intra-medullar and subcortical using a 17-gauge single lumen needle under sedation und under transvaginal ultrasound monitoring.<br>|
| Placebo Comparator: intra-ovarian saline solution (NaCL) injection<br>Control group, treated with intra-ovarian NaCl injection and undergoing a subsequent fresh ET-IVF/ICSI cycle in the third cycle after intervention | Other: Saline solution (NaCL) Injection<br>* Injecting NaCL into the ovaries will be performed likewise to the standard operating procedure of oocyte retrieval. NaCL will be injected in each ovary intra-medullar and subcortical using a 17-gauge single lumen needle under sedation und under transvaginal ultrasound monitoring.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ovarian response | Number of retrieved COCs per intention-to-treat | 34-36 hours following hCG administration at the end of ovarian stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hormone levels | Change from baseline in absolute and relative terms for Anti-Müllerian hormone (AMH), serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T) and antral follicle count (AFC) | Follow-up period of three months entailing monthly evaluation | 
| Follicular response | Number of follicles (classified and summarised for every ovary as follows: mean diameter 10.0 - 11.9 mm, 12.0 - 13.9 mm, 14.0 - 15.9 mm, 16.0 - 17.9 mm, 18.0 - 19.9 mm and larger 19.9 mm) | On the day of triggering of final oocyte maturation or the day before | 
| COCs and MII oocytes | Mean number of retrieved COCs per protocol and mean number of metaphase II (MII) oocytes per protocol | Day 0 after follicle puncture | 
| Number of 2PN oocytes | Mean number per protocol | Day 1 after follicle puncture | 
| Mean number and quality of embryos | Grade a for cleavage stage embryo, >=3BB for blastocyst | Day 2-5 after follicle puncture | 
| Biochemical pregnancy rate | Incidence of serum beta-hCG test > 25 mIU/ml per ITT and PP | 12-16 days after oocyte pick-up | 
| Clinical pregnancy rate | Incidence of gestational sac with heartbeat assessed by TVS per ITT and PP | 4 weeks after embryo transfer | 
| Ongoing pregnancy rate | Incidence of at least one foetus with heart beat assessed by TVS | 8-10 weeks after embryo transfer | 
| Miscarriage rate | Defined as spontaneous loss of a clinical pregnancy rate, where embryo(s) or fetus(es) is/are nonviable and is/are not spontaneously absorbed or expelled from the uterus or surgically removed | early (week 7-12 weeks of gestation); late (between 12 to 22 weeks of gestation) | 
| Still birth rate | Incidence of the delivery of a dead fetus | after 22 weeks of gestation | 
| Live birth rate | Incidence of the birth of at least one live newborn after 22 weeks of gestation | at a follow-up time of 30 days after delivery | 
| Gestational age | Gestational week estimated by calculating days from oocyte retrieval + 14 days | at the day of delivery | 
| Weight of newborn | Birth weight measured in gram | at the day of delivery | 
| Length of newborn | Birth length measured in centimeter | at the day of delivery | 
| Incidence of birth sex | Incidence of female or male newborn | at the day of delivery | 
| Incidence of multiple birth | Incidence of singleton/multiple newborns | at the day of delivery | 
| Neonatal health | major and minor congenital anomalies | at a follow-up time of 30 days after delivery | 
| Post procedure pain | measured by a numerical rating scale from 0 (no pain) to 10 (worst pain) | on the day of follicle puncture | 
| Fertility Quality of Life Questionnaire | FertiQoL International is a validated relational scale to assess the relational domain regarding quality of life in women undergoing infertility treatment. For each question, the patient will check the response that is closest to her current thoughts and feelings. Scale reaches depending on the question from very dissatisfied to very satisfied, always to never or an extreme amount to not at all. | on the day of follicle puncture and embryo transfer | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Incidence of adverse and serious adverse events with potential relationship to treatment | at a follow-up time after 1, 2 and 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ART, PRP, poor ovarian response, low ovarian response, ICSI, IVF, Platelet rich plasma