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

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ClinicalTrials.gov Identifier: NCT05279560
Recruitment Status : Recruiting
First Posted : March 15, 2022
Last Update Posted : May 9, 2023
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. med. M.Sc. Georg Griesinger, University of Luebeck

Tracking Information
First Submitted Date  ICMJE January 16, 2022
First Posted Date  ICMJE March 15, 2022
Last Update Posted Date May 9, 2023
Actual Study Start Date  ICMJE March 17, 2022
Estimated Primary Completion Date March 17, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 6, 2022)
Ovarian response [ Time Frame: 34-36 hours following hCG administration at the end of ovarian stimulation ]
Number of retrieved COCs per intention-to-treat
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2022)
  • Hormone levels [ Time Frame: Follow-up period of three months entailing monthly evaluation ]
    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 [ Time Frame: On the day of triggering of final oocyte maturation or the day before ]
    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 [ Time Frame: Day 0 after follicle puncture ]
    Mean number of retrieved COCs per protocol and mean number of metaphase II (MII) oocytes per protocol
  • Number of 2PN oocytes [ Time Frame: Day 1 after follicle puncture ]
    Mean number per protocol
  • Mean number and quality of embryos [ Time Frame: Day 2-5 after follicle puncture ]
    Grade a for cleavage stage embryo, >=3BB for blastocyst
  • Biochemical pregnancy rate [ Time Frame: 12-16 days after oocyte pick-up ]
    Incidence of serum beta-hCG test > 25 mIU/ml per ITT and PP
  • Clinical pregnancy rate [ Time Frame: 4 weeks after embryo transfer ]
    Incidence of gestational sac with heartbeat assessed by TVS per ITT and PP
  • Ongoing pregnancy rate [ Time Frame: 8-10 weeks after embryo transfer ]
    Incidence of at least one foetus with heart beat assessed by TVS
  • Miscarriage rate [ Time Frame: early (week 7-12 weeks of gestation); late (between 12 to 22 weeks of gestation) ]
    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 [ Time Frame: after 22 weeks of gestation ]
    Incidence of the delivery of a dead fetus
  • Live birth rate [ Time Frame: at a follow-up time of 30 days after delivery ]
    Incidence of the birth of at least one live newborn after 22 weeks of gestation
  • Gestational age [ Time Frame: at the day of delivery ]
    Gestational week estimated by calculating days from oocyte retrieval + 14 days
  • Weight of newborn [ Time Frame: at the day of delivery ]
    Birth weight measured in gram
  • Length of newborn [ Time Frame: at the day of delivery ]
    Birth length measured in centimeter
  • Incidence of birth sex [ Time Frame: at the day of delivery ]
    Incidence of female or male newborn
  • Incidence of multiple birth [ Time Frame: at the day of delivery ]
    Incidence of singleton/multiple newborns
  • Neonatal health [ Time Frame: at a follow-up time of 30 days after delivery ]
    major and minor congenital anomalies
  • Post procedure pain [ Time Frame: on the day of follicle puncture ]
    measured by a numerical rating scale from 0 (no pain) to 10 (worst pain)
  • Fertility Quality of Life Questionnaire [ Time Frame: on the day of follicle puncture and embryo transfer ]
    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] [ Time Frame: at a follow-up time after 1, 2 and 5 years ]
    Incidence of adverse and serious adverse events with potential relationship to treatment
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ovarian PRP (Platelet Rich Plasma) Injection for Follicular Activation
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE
  • Premature Ovarian Insufficiency
  • Infertility, Female
  • Sterility, Female
  • PRP
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • 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
    Intervention: Biological: autologous PRP (platelet rich plasma)
  • 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
    Intervention: Other: Saline solution (NaCL) Injection
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 6, 2022)
140
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 17, 2027
Estimated Primary Completion Date March 17, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years to 42 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Georg Griesinger, MD +49 451-500-41950 georg.griesinger@uni-luebeck.de
Contact: Tanja Eggersmann, MD +49 451-500-41950 TanjaKristina.Eggersmann@uksh.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05279560
Other Study ID Numbers  ICMJE Aktenzeichen 21-348
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD will be shared upon reasonable request.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data will not be available before 2027
Access Criteria: reasonable request
Current Responsible Party Prof. Dr. med. M.Sc. Georg Griesinger, University of Luebeck
Original Responsible Party Prof. Dr. med. M.Sc. Georg Griesinger, University of Luebeck, Professor Dr. med. M.Sc.
Current Study Sponsor  ICMJE University of Luebeck
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Georg Griesing, MD University of Luebeck
PRS Account University of Luebeck
Verification Date May 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP