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

Primary Purpose

Premature Ovarian Insufficiency, Infertility, Female, Sterility, Female

Status

Recruiting

Phase

Not Applicable

Locations

Germany

Study Type

Interventional

Intervention

autologous PRP (platelet rich plasma)

Saline solution (NaCL) Injection

About this trial

This is an interventional treatment trial for Premature Ovarian Insufficiency focused on measuring poor ovarian response, low ovarian response, ICSI, IVF, ART, Platelet rich plasma, PRP

Eligibility Criteria

18 Years - 42 Years (Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

University of LuebeckRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Autologous intra-ovarian PRP injection

intra-ovarian saline solution (NaCL) injection

Arm Description

Study group, treated with autologous intra-ovarian PRP injection and undergoing a subsequent fresh ET-IVF/ICSI cycle in the third cycle after intervention

Control group, treated with intra-ovarian NaCl injection and undergoing a subsequent fresh ET-IVF/ICSI cycle in the third cycle after intervention

Outcomes

Primary Outcome Measures

Ovarian response

Number of retrieved COCs per intention-to-treat

Secondary Outcome Measures

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)

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)

COCs and MII oocytes

Mean number of retrieved COCs per protocol and mean number of metaphase II (MII) oocytes per protocol

Number of 2PN oocytes

Mean number per protocol

Mean number and quality of embryos

Grade a for cleavage stage embryo, >=3BB for blastocyst

Biochemical pregnancy rate

Incidence of serum beta-hCG test > 25 mIU/ml per ITT and PP

Clinical pregnancy rate

Incidence of gestational sac with heartbeat assessed by TVS per ITT and PP

Ongoing pregnancy rate

Incidence of at least one foetus with heart beat assessed by TVS

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

Still birth rate

Incidence of the delivery of a dead fetus

Live birth rate

Incidence of the birth of at least one live newborn after 22 weeks of gestation

Gestational age

Gestational week estimated by calculating days from oocyte retrieval + 14 days

Weight of newborn

Birth weight measured in gram

Length of newborn

Birth length measured in centimeter

Incidence of birth sex

Incidence of female or male newborn

Incidence of multiple birth

Incidence of singleton/multiple newborns

Neonatal health

major and minor congenital anomalies

Post procedure pain

measured by a numerical rating scale from 0 (no pain) to 10 (worst pain)

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".

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Incidence of adverse and serious adverse events with potential relationship to treatment

Full Information

NCT ID

NCT05279560

First Posted

January 16, 2022

Last Updated

May 8, 2023

Sponsor

University of Luebeck

1. Study Identification

Unique Protocol Identification Number

NCT05279560

Brief Title

Ovarian PRP (Platelet Rich Plasma) Injection for Follicular Activation

Acronym

OPIF

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 17, 2022 (Actual)

Primary Completion Date

March 17, 2024 (Anticipated)

Study Completion Date

March 17, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Luebeck

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

poor ovarian response, low ovarian response, ICSI, IVF, ART, Platelet rich plasma, PRP

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Autologous intra-ovarian PRP injection

Arm Type

Experimental

Arm Description

Study group, treated with autologous intra-ovarian PRP injection and undergoing a subsequent fresh ET-IVF/ICSI cycle in the third cycle after intervention

Arm Title

intra-ovarian saline solution (NaCL) injection

Arm Type

Placebo Comparator

Arm Description

Control group, treated with intra-ovarian NaCl injection and undergoing a subsequent fresh ET-IVF/ICSI cycle in the third cycle after intervention

Intervention Type

Biological

Intervention Name(s)

autologous PRP (platelet rich plasma)

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Saline solution (NaCL) Injection

Intervention Description

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.

Primary Outcome Measure Information:

Title

Ovarian response

Description

Number of retrieved COCs per intention-to-treat

Time Frame

34-36 hours following hCG administration at the end of ovarian stimulation

Secondary Outcome Measure Information:

Title

Hormone levels

Description

Time Frame

Follow-up period of three months entailing monthly evaluation

Title

Follicular response

Description

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)

Time Frame

On the day of triggering of final oocyte maturation or the day before

Title

COCs and MII oocytes

Description

Mean number of retrieved COCs per protocol and mean number of metaphase II (MII) oocytes per protocol

Time Frame

Day 0 after follicle puncture

Title

Number of 2PN oocytes

Description

Mean number per protocol

Time Frame

Day 1 after follicle puncture

Title

Mean number and quality of embryos

Description

Grade a for cleavage stage embryo, >=3BB for blastocyst

Time Frame

Day 2-5 after follicle puncture

Title

Biochemical pregnancy rate

Description

Incidence of serum beta-hCG test > 25 mIU/ml per ITT and PP

Time Frame

12-16 days after oocyte pick-up

Title

Clinical pregnancy rate

Description

Incidence of gestational sac with heartbeat assessed by TVS per ITT and PP

Time Frame

4 weeks after embryo transfer

Title

Ongoing pregnancy rate

Description

Incidence of at least one foetus with heart beat assessed by TVS

Time Frame

8-10 weeks after embryo transfer

Title

Miscarriage rate

Description

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

Time Frame

early (week 7-12 weeks of gestation); late (between 12 to 22 weeks of gestation)

Title

Still birth rate

Description

Incidence of the delivery of a dead fetus

Time Frame

after 22 weeks of gestation

Title

Live birth rate

Description

Incidence of the birth of at least one live newborn after 22 weeks of gestation

Time Frame

at a follow-up time of 30 days after delivery

Title

Gestational age

Description

Gestational week estimated by calculating days from oocyte retrieval + 14 days

Time Frame

at the day of delivery

Title

Weight of newborn

Description

Birth weight measured in gram

Time Frame

at the day of delivery

Title

Length of newborn

Description

Birth length measured in centimeter

Time Frame

at the day of delivery

Title

Incidence of birth sex

Description

Incidence of female or male newborn

Time Frame

at the day of delivery

Title

Incidence of multiple birth

Description

Incidence of singleton/multiple newborns

Time Frame

at the day of delivery

Title

Neonatal health

Description

major and minor congenital anomalies

Time Frame

at a follow-up time of 30 days after delivery

Title

Post procedure pain

Description

measured by a numerical rating scale from 0 (no pain) to 10 (worst pain)

Time Frame

on the day of follicle puncture

Title

Fertility Quality of Life Questionnaire

Description

Time Frame

on the day of follicle puncture and embryo transfer

Title

Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Description

Incidence of adverse and serious adverse events with potential relationship to treatment

Time Frame

at a follow-up time after 1, 2 and 5 years

10. Eligibility

Sex

Female

Gender Based

Yes

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

42 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Georg Griesinger, MD

Phone

+49 451-500-41950

georg.griesinger@uni-luebeck.de

First Name & Middle Initial & Last Name or Official Title & Degree

Tanja Eggersmann, MD

Phone

+49 451-500-41950

TanjaKristina.Eggersmann@uksh.de

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Georg Griesing, MD

Organizational Affiliation

University of Luebeck

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Luebeck

City

Luebeck

State/Province

Schleswig-Holstein

ZIP/Postal Code

23562

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Tanja Eggersmann, MD

Phone

0451-505778-10

TanjaKristina.Eggersmann@uksh.de

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

Citations:

PubMed Identifier

8167237

Citation

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PubMed Identifier

32006776

Citation

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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.

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Ovarian PRP (Platelet Rich Plasma) Injection for Follicular Activation

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