Ovarian PRP (Platelet Rich Plasma) Injection for Follicular Activation (OPIF)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Infertility, Female; Sterility, Female; PRP; Premature Ovarian Insufficiency
• Intervention / Treatment: Biological: autologous PRP (platelet rich plasma); Other: Saline solution (NaCL) Injection

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Georg Griesinger, MD; Phone Number: +49 451-500-41950; Email: georg.griesinger@uni-luebeck.de
• Study Contact Backup: Name: Tanja Eggersmann, MD; Phone Number: +49 451-500-41950; Email: TanjaKristina.Eggersmann@uksh.de

Study Locations

• Germany
  • Schleswig-Holstein
    • Luebeck, Schleswig-Holstein, Germany, 23562
      • Recruiting
      • University of Luebeck
      • Contact: Tanja Eggersmann, MD; Phone Number: 0451-505778-10; Email: TanjaKristina.Eggersmann@uksh.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Autologous intra-ovarian PRP injection; 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); 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.
Placebo Comparator: intra-ovarian saline solution (NaCL) injection; 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; 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.

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: University of Luebeck
• Investigators: Principal Investigator: Georg Griesing, MD, University of Luebeck

Publications and helpful links

General Publications

• Gougeon A, Ecochard R, Thalabard JC. Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod. 1994 Mar;50(3):653-63. doi: 10.1095/biolreprod50.3.653.
• Sills ES, Rickers NS, Li X, Palermo GD. First data on in vitro fertilization and blastocyst formation after intraovarian injection of calcium gluconate-activated autologous platelet rich plasma. Gynecol Endocrinol. 2018 Sep;34(9):756-760. doi: 10.1080/09513590.2018.1445219. Epub 2018 Feb 28.
• Farimani M, Heshmati S, Poorolajal J, Bahmanzadeh M. A report on three live births in women with poor ovarian response following intra-ovarian injection of platelet-rich plasma (PRP). Mol Biol Rep. 2019 Apr;46(2):1611-1616. doi: 10.1007/s11033-019-04609-w. Epub 2019 Feb 5.
• Sills ES, Wood SH. Autologous activated platelet-rich plasma injection into adult human ovary tissue: molecular mechanism, analysis, and discussion of reproductive response. Biosci Rep. 2019 Jun 4;39(6):BSR20190805. doi: 10.1042/BSR20190805. Print 2019 Jun 28.
• Martin JJ, Woods DC, Tilly JL. Implications and Current Limitations of Oogenesis from Female Germline or Oogonial Stem Cells in Adult Mammalian Ovaries. Cells. 2019 Jan 28;8(2):93. doi: 10.3390/cells8020093.
• Maleki-Hajiagha A, Razavi M, Rouholamin S, Rezaeinejad M, Maroufizadeh S, Sepidarkish M. Intrauterine infusion of autologous platelet-rich plasma in women undergoing assisted reproduction: A systematic review and meta-analysis. J Reprod Immunol. 2020 Feb;137:103078. doi: 10.1016/j.jri.2019.103078. Epub 2019 Dec 31.
• Danforth DR, Arbogast LK, Ghosh S, Dickerman A, Rofagha R, Friedman CI. Vascular endothelial growth factor stimulates preantral follicle growth in the rat ovary. Biol Reprod. 2003 May;68(5):1736-41. doi: 10.1095/biolreprod.101.000679. Epub 2002 Dec 11.
• Quintana R, Kopcow L, Sueldo C, Marconi G, Rueda NG, Baranao RI. Direct injection of vascular endothelial growth factor into the ovary of mice promotes follicular development. Fertil Steril. 2004 Oct;82 Suppl 3:1101-5. doi: 10.1016/j.fertnstert.2004.03.036.
• Bakacak M, Bostanci MS, Inanc F, Yaylali A, Serin S, Attar R, Yildirim G, Yildirim OK. Protective Effect of Platelet Rich Plasma on Experimental Ischemia/Reperfusion Injury in Rat Ovary. Gynecol Obstet Invest. 2016;81(3):225-31. doi: 10.1159/000440617. Epub 2015 Oct 24.
• Ozcan P, Takmaz T, Tok OE, Islek S, Yigit EN, Ficicioglu C. The protective effect of platelet-rich plasma administrated on ovarian function in female rats with Cy-induced ovarian damage. J Assist Reprod Genet. 2020 Apr;37(4):865-873. doi: 10.1007/s10815-020-01689-7. Epub 2020 Feb 4.
• Atkinson L, Martin F, Sturmey RG. Intraovarian injection of platelet-rich plasma in assisted reproduction: too much too soon? Hum Reprod. 2021 Jun 18;36(7):1737-1750. doi: 10.1093/humrep/deab106.
• Melo P, Navarro C, Jones C, Coward K, Coleman L. The use of autologous platelet-rich plasma (PRP) versus no intervention in women with low ovarian reserve undergoing fertility treatment: a non-randomized interventional study. J Assist Reprod Genet. 2020 Apr;37(4):855-863. doi: 10.1007/s10815-020-01710-z. Epub 2020 Feb 7.
• Urman B, Boza A, Balaban B. Platelet-rich plasma another add-on treatment getting out of hand? How can clinicians preserve the best interest of their patients? Hum Reprod. 2019 Nov 1;34(11):2099-2103. doi: 10.1093/humrep/dez190.
• Hsu CC, Hsu L, Hsu I, Chiu YJ, Dorjee S. Live Birth in Woman With Premature Ovarian Insufficiency Receiving Ovarian Administration of Platelet-Rich Plasma (PRP) in Combination With Gonadotropin: A Case Report. Front Endocrinol (Lausanne). 2020 Feb 19;11:50. doi: 10.3389/fendo.2020.00050. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): March 17, 2022
• Primary Completion (Anticipated): March 17, 2024
• Study Completion (Anticipated): March 17, 2027

Study Registration Dates

• First Submitted: January 16, 2022
• First Submitted That Met QC Criteria: March 6, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: IVF; ART; ICSI; poor ovarian response; Platelet rich plasma; PRP; low ovarian response
• Additional Relevant MeSH Terms: Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Infertility; Primary Ovarian Insufficiency; Menopause, Premature; Infertility, Female
• Other Study ID Numbers: Aktenzeichen 21-348

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be shared upon reasonable request.
• IPD Sharing Time Frame: Data will not be available before 2027
• IPD Sharing Access Criteria: reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No