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Ovarian Rejuvenation Using Platelet Rich Plasma (PRP) & Autologous Tissue Stromal Vascular Fraction (tSVF) and Cell Enriched tSVF (OVAR-REJUV)

Primary Purpose

Ovarian Failure, Perimenopausal Disorder, Hormone Disturbance

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
lipoaspiration harvest tSVF
Platelet Rich Plasma
Endovaginal Ultrasound
Cellular Isolation cSVF
Normal Saline (NS) .9% 10 mL Injection
emulsification tSVF
Sponsored by
Black Tie Medical, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ovarian Failure

Eligibility Criteria

35 Years - 60 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Symptomatology or hormonal derangement for at least 6 months
  • Stopped Hormonal Replacement Therapy (HRT) for at least 3 months prior to intervention
  • Stopped Botanotherapy / Danazol for 3 months
  • Willing to comply with study requirements, including avoiding HRT, Botanotherapy, Danazol for at least 12 months post intervention.
  • Women over the age of 35
  • Presence of at least one ovary
  • Agree to report any pregnancy to the research staff immediately.
  • Willing and able to comply with study requirements.

Exclusion Criteria:

  • Current or previous Immune Globulin A (IgA) deficiency
  • Current or previous premature ovarian failure due to a genetic origin, such as Turner's Syndrome or chromosomal abnormality
  • Current or previous injuries or adhesions to the pelvis or ovaries
  • Current and ongoing pregnancy
  • Current and ongoing anticoagulant use
  • Known bleeding diathesis
  • Current and ongoing major Mental health disorder that precludes participation in the study
  • Current and ongoing active substance abuse or dependence
  • Prior or current ovarian malignancy, or known genetic mutation
  • Current and ongoing chronic pelvic pain other than dyspareunia or vulval/vaginal integument disorders
  • History of endometriosis
  • Current diagnosis of cancer or active cancer within last 24 months
  • Ovarian inaccessibility determined by endovaginal sonography
  • Current or previous premature ovarian failure
  • Active, untreated Endocrinologic disorders (uncompensated thyroid dysfunction, insulin dependant diabetes (type 1, type2)
  • Body Mass Index (BMI) >30 kg/m2
  • Systemic autoimmune disorder
  • Know Polycystic Ovarian Syndrome
  • Unwilling to terminate ovarian pharmaceuticals or exogenous hormone treatments 3 months prior to entering study, and to avoid exogenous hormones for duration of study

Sites / Locations

  • Fanny Island Campus Medical Building

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

ARM 1 Platelet Rich Plasma

ARM 2 emulsified tSVF and PRP

ARM 3 emulsified tSVF and PRP, enriched with cSVF

ARM 4 Intra-ovarian guided placement

Arm Description

Blood draw, processing of PRP, white blood cell poor, high platelet multiple >/= 4, e.g. (Emcyte II Pure PRP) Endovaginal ultrasound guided intra-ovarian placement into ovarian parenchyma, preferably both if accessible.

Blood draw, processing of PRP, white blood cell poor, high platelet multiple >/= 4, e.g. Emcyte PRP Lipoaspiration utilizing closed microcannula harvesting of small volume (Tulip tumescent fluid infiltrator and Tulip Harvester). Decanting of free lipid. Emulsification of adipose tissue into tSVF (Tulip Nanofat device). Blending of Nanofat with PRP at a 3:1 ratio. Endovaginal ultrasound guided intra-ovarian placement into ovary, preferably both if accessible.

Blood draw, processing of PRP, white blood cell poor, high platelet multiple >/= 4, e.g. Emcyte PRP tSVF preparation: Lipoaspiration utilizing closed microcannula harvesting of small volume (Tulip tumescent fluid infiltrator and Tulip Harvester). Decanting of free lipid. Emulsification of adipose tissue (Tulip Nanofat device). cSVF preparation: lipoaspiration as above. Isolation and Concentration of cellular stromal vascular fraction (cSVF) using a Healeon Medical CentriCyte 1000 centrifuge, incubator and shaker plate with sterile Liberase enzyme (Roche Medical) per manufacturer protocol. Quantification of viable nucleated cell count with flow cytometry. Addition of pellet of viable nucleated cells to tSVF. Blending of tSVF/cSVF emulsion with PRP at a 3:1 ratio. Endovaginal ultrasound guided intra-ovarian placement into ovary, preferably both if accessible. Intervention:

Specifically designed 23 gauge modified oocyte harvester needle for ultrasound guided placement

Outcomes

Primary Outcome Measures

Patient Safety For Procedure
Reporting of all Adverse Events, Severe Adverse Events

Secondary Outcome Measures

Menstrual Resumption
Journal documentation by subjects of menstrual frequency, duration
Hormonal Response
Concentrations of Follicular Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol, Anti-Mullerian Hormone. Percentage of patients with significant reductions in FSH and LH, increases in Estradiol and Anti-Mullerian Hormone will be tabulated. Changes in these directions will indicate improved hormonal status that has been shown to correlate with improved health status across a wide range of measures.
Ovarian Morphology
Endovaginal Sonography for Ovarian Volume
Bone Density and Body Composition
Evaluation of Bone density and Body Composition (fat /muscle proportions) by Single Photon Absorptiometry

Full Information

First Posted
June 2, 2020
Last Updated
July 18, 2022
Sponsor
Black Tie Medical, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04444245
Brief Title
Ovarian Rejuvenation Using Platelet Rich Plasma (PRP) & Autologous Tissue Stromal Vascular Fraction (tSVF) and Cell Enriched tSVF
Acronym
OVAR-REJUV
Official Title
Re-establishment of Ovarian Hormonal Function, Delay of Menopause, or Reversal of Early Menopause With High Density (HD PRP), tSVF + PRP, or Cell Enriched tSVF + PRP by Ultrasound Guided Ovarian Injection
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 15, 2022 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
August 15, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Black Tie Medical, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Trial of imaging guided intra-ovarian injection to improve ovarian function in clinical settings of Premature Ovarian Failure, Perimenopausal and /or early postmenopausal symptomatology and related hormonal deficiencies. The study will compare the effectiveness of autologous Platelet Rich Plasma alone versus Stromal Vascular Fraction (tSVF and/or cellular stromal vascular fraction (cSVF) in combination with Platelet Rich Plasma as regards efficacy and duration of ovarian reactivation in women with acquired Premature Ovarian Failure, Menopausal, and Perimenopausal women.
Detailed Description
Intra-ovarian placement of platelet rich plasma (PRP) has already been demonstrated in several series to return peri-menopausal and early post-menopausal hormone levels towards pre-menopausal levels and pre-menopausal cyclic behavior, even resulting in pregnancies and deliveries of healthy infants. The intent of this trial is to evaluate the utility of PRP to improve hormonal status and clinical symptomatology in peri-menopausal and early post-menopausal women, and in women with non-Turner's premature ovarian failure, by documenting the improvements in biochemical/hormonal parameters, bone density, and physical and mental health related quality of life, as well as comparing the duration and effectiveness of this PRP procedure with the intra-ovarian placement of biocellular physiologically active cellular and cytokine elements contained within the adipose tissue-derived Stromal Vascular Fraction (tSVF). It should be noted that rate of loss of bone density in women is maximal in the 12 months prior and 24 months following menopause. The absolute and relative percentage amounts of body fat and muscle change in adverse ways - with increasing fat and falling muscle bulk, with the most dramatic changes also occurring in the menopausal transition period. This study therefore provides the potential to document measurable cessation of bone density loss or reduction in rate of bone density loss compared to well established known patterns and historical controls as a result of the proposed relatively innocuous interventions. The same technology to be used for bone density evaluation, single photon absorptiometry, will also be used to quantify fat versus muscle body composition at baseline and 18 months. SVF can be further characterized as either cellular SVF or tissue SVF (cSVF or tSVF). Tissue SVF (tSVF) is obtained by a small volume manual closed syringe microcannula aspiration of subcutaneous fatty tissue (approximately 10+ teaspoons), followed by closed system decanting to remove the infranatant fluids followed by emulsification of the remnant to the required degree of homogeneity and reduced particulate size to permit injection through a conventional gauge needle bores. Tissue SVF is characterized by retention of a proportion of the non-cellular matrix of collagenous and fine vascular remnants, which together form a matrix that retains and provides structure to the biocellular elements that are embedded within. Cellular SVF (cSVF) begins with the same mini-aspiration, but is characterized by closed system centrifugation, followed enzymatic digestion to isolate./concentrate the cellular SVF (cSVF). Following enzyme neutralization and rinsing, the resultant concentrate of viable stem/stromal nucleated cells, are prepared for guided placement into the ovarian parenchymal tissue. A sample of each injectate is tested and quantified using standard laser flow cytometry, including viability and numbers of cells within each sample. The study includes use of PRP (Emcyte II Pure PRP, Florida, USA) PRP per manufacturer's instructions) alone as control in first treatment limb (ARM), which will volumetrically be the same as the other injectates, for guided placement documented within the ovaries. A comparative second ARM composed of PRP will be combined with emulsified tSVF (Sterile Tulip Nanofat Disposable, San Diego, California (CA), USA) . In a third ARM, PRP plus emulsified tSVF will be combined with both concentrated cSVF. This arm is to determine effects of higher cellular concentration than achieved in second ARM using the cellular concentrates achieve using the Centricyte 1000 (Healeon Medical Inc, Newbury Park, CA, USA). The primary outcomes for each of these optional procedures will be compared, and evaluated as to safety, clinical efficacy in enhancing return of ovarian function to determine the preferred methodology to achieve maximal outcomes. Baseline and monitored patient characteristics are as follows: Baseline status of all patients will determined utilizing relevant biochemical indices, including serum levels of Follicle Stimulating Hormone (FSH), Anti-Mullerian Hormone (AMH), Luteinizing Hormone (LH), Estradiol (E2), and Progesterone (PRG). These will be repeated at 30 and 90 days, and then every 3 months for an additional 15 months, total follow up 18 months. Comprehensive Blood Panel (SMA 12), Complete blood count (CBC), lipid profiles and clotting indices will be obtained at baseline and repeated (without clotting indices) at 12 months. As bone density begins to decline at a significant rate in the peri-menopausal period, a bone density determination with single photon absorptiometry will be obtained at baseline, and again at 12 and/or 18 months. Body composition fat/muscle proportions will be evaluated with the same technology at the same sitting. Physical and mental health related quality of life will be evaluated with the quality of life surveys at baseline, 6 and 12 months. Ovarian volume will be assessed at baseline by endovaginal sonography, along with the size and number of follicles present, and then every 6 months. Journal recording of menstrual cycles - frequency/interval, days, and duration. In ARM 1, PRP alone will be placed within the ovaries. In ARM 2, PRP will be combined with tSVF. In ARM 3, tSVF will be combined with both cSVF and PRP. Matched volumes of injectate will be used in each ARM to avoid question of potential interference to ovarian parenchyma impacting the outcome due to volume variable effects. The primary outcomes for each of these arms will be compared, informing us of a preferred methodology for further evaluation, and ultimately, clinical practice. Autologous Platelet Rich Plasma is an established treatment modality which utilizes FDA approved methodologies and kits, and has developed into a mature treatment modality for a variety of orthopedic and soft tissue pathologies. As noted, its safety and utility in ovarian rejuvenation and reversal of infertility has already been established in peer reviewed, case series. Safety of use of certain allogeneic human mesenchymal stem cells (hMSC) has been proposed and limitedly tested for efficacy in some prior studies. The products tested have variable protocols in isolating and documenting content and cellular viabilities. Autologous stem-stromal cells (contained within cSVF) have been reported safe and effective in many applications/studies and in clinical trials currently underway in other body systems and pathologies. These cells are easily obtained and isolated/concentrated in a closed system from patient's adipose derived stromal vascular fraction (tSVF). This is important as such tissues are the patient's own, genetically unique cells and, in theory, potentially safer than the allogeneic human mesenchymal stem cells (hMSCs) which are potentially genetically foreign and bear the risk of contamination in processing and delivery. A combined approach may allow the implementation of a suitably larger number of cells, growth factors, exosomes/microvesicles without the need for culture expansion. Contents of the cSVF contains a heterogeneous population of undesignated (stem-like) and supportive cells (stromal). This combination of adult, autologous cells, along with stromal cells are felt to offer important therapeutic and regenerative qualities based cellular differentiation features and the paracrine (secretory communication signals and responses to niche) in varying degrees. It is believed that such signaling may constitute the body's own mechanism for homeostasis and regeneration. Interaction of these complex biochemical signals, are proposed to further recruit or activate reparative processes with interaction with the native host cells and tissues. Furthermore, this reparative process may become important specific host activities and needs in the location into which the therapeutic combination is placed. The precise mechanisms underlying these reparative processes are under intensive investigations. In all cases, the platelet and biocellular materials for intra-ovarian injection will be placed under conventional imaging guidance utilizing endovaginal sonography. Specially designed modified needles will be utilized to accurate deliver the biological products to the targeted intra-ovarian parenchymal tissues. The methodology required is very similar overall to oocyte retrieval in infertility treatments, which are performed worldwide, with minimal risk of adverse effects millions of times every year. The procedures are known to result in minimal discomfort,with patient preparation varying from none to mild supportive anxiolysis. Post procedure pain, if any, can be effectively managed with acetaminophen. Patients are observed post procedure for 60-120 minutes, and then discharged with suitable post-procedure written instructions to periodically return for clinical and laboratory follow up per protocol outlined in the outcomes analysis. The goal of this study seeks to compare the duration of hormonal, clinical, and quality of life improvement among the 3 arms of the study. For the minority of study participants in whom ovaries are not readily accessible by endovaginal ultrasound, a subset of patients may require use of laparoscopic guidance. In all such cases, the interventions will take place in hospital settings, with the Investigator preparing the injectate and gynecologic or other suitable specialist surgeons performing the laparoscopic procedure utilizing standard procedures as the guidance.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ovarian Failure, Perimenopausal Disorder, Hormone Disturbance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ARM 1 Platelet Rich Plasma
Arm Type
Experimental
Arm Description
Blood draw, processing of PRP, white blood cell poor, high platelet multiple >/= 4, e.g. (Emcyte II Pure PRP) Endovaginal ultrasound guided intra-ovarian placement into ovarian parenchyma, preferably both if accessible.
Arm Title
ARM 2 emulsified tSVF and PRP
Arm Type
Experimental
Arm Description
Blood draw, processing of PRP, white blood cell poor, high platelet multiple >/= 4, e.g. Emcyte PRP Lipoaspiration utilizing closed microcannula harvesting of small volume (Tulip tumescent fluid infiltrator and Tulip Harvester). Decanting of free lipid. Emulsification of adipose tissue into tSVF (Tulip Nanofat device). Blending of Nanofat with PRP at a 3:1 ratio. Endovaginal ultrasound guided intra-ovarian placement into ovary, preferably both if accessible.
Arm Title
ARM 3 emulsified tSVF and PRP, enriched with cSVF
Arm Type
Experimental
Arm Description
Blood draw, processing of PRP, white blood cell poor, high platelet multiple >/= 4, e.g. Emcyte PRP tSVF preparation: Lipoaspiration utilizing closed microcannula harvesting of small volume (Tulip tumescent fluid infiltrator and Tulip Harvester). Decanting of free lipid. Emulsification of adipose tissue (Tulip Nanofat device). cSVF preparation: lipoaspiration as above. Isolation and Concentration of cellular stromal vascular fraction (cSVF) using a Healeon Medical CentriCyte 1000 centrifuge, incubator and shaker plate with sterile Liberase enzyme (Roche Medical) per manufacturer protocol. Quantification of viable nucleated cell count with flow cytometry. Addition of pellet of viable nucleated cells to tSVF. Blending of tSVF/cSVF emulsion with PRP at a 3:1 ratio. Endovaginal ultrasound guided intra-ovarian placement into ovary, preferably both if accessible. Intervention:
Arm Title
ARM 4 Intra-ovarian guided placement
Arm Type
Experimental
Arm Description
Specifically designed 23 gauge modified oocyte harvester needle for ultrasound guided placement
Intervention Type
Procedure
Intervention Name(s)
lipoaspiration harvest tSVF
Intervention Description
Use of disposable, sterile microcannula lipoharvest to acquire tSVF
Intervention Type
Procedure
Intervention Name(s)
Platelet Rich Plasma
Intervention Description
Standard venipuncture, concentration of PRP in FDA approved device (Emcyte II)
Intervention Type
Procedure
Intervention Name(s)
Endovaginal Ultrasound
Intervention Description
Endovaginal Ultrasound guidance to intra-ovarian placement, bilaterally
Intervention Type
Device
Intervention Name(s)
Cellular Isolation cSVF
Intervention Description
Digestion of tSVF with Liberase, isolation & concentration of cSVF in Centricyte 1000
Intervention Type
Drug
Intervention Name(s)
Normal Saline (NS) .9% 10 mL Injection
Intervention Description
10 cc Sterile Normal Saline for Injection
Intervention Type
Device
Intervention Name(s)
emulsification tSVF
Intervention Description
Harvested tSVF emulsification with sterile, disposable Nanofat screen device
Primary Outcome Measure Information:
Title
Patient Safety For Procedure
Description
Reporting of all Adverse Events, Severe Adverse Events
Time Frame
30 days
Secondary Outcome Measure Information:
Title
Menstrual Resumption
Description
Journal documentation by subjects of menstrual frequency, duration
Time Frame
baseline through 18 months
Title
Hormonal Response
Description
Concentrations of Follicular Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol, Anti-Mullerian Hormone. Percentage of patients with significant reductions in FSH and LH, increases in Estradiol and Anti-Mullerian Hormone will be tabulated. Changes in these directions will indicate improved hormonal status that has been shown to correlate with improved health status across a wide range of measures.
Time Frame
Baseline, 3 months, 6 months, 12 months, 18 months
Title
Ovarian Morphology
Description
Endovaginal Sonography for Ovarian Volume
Time Frame
Baseline, 6 month, 12 month, 18 month
Title
Bone Density and Body Composition
Description
Evaluation of Bone density and Body Composition (fat /muscle proportions) by Single Photon Absorptiometry
Time Frame
Baseline, 12 and/or 18 months
Other Pre-specified Outcome Measures:
Title
Health Related Quality of Life
Description
Utian Menopausal Quality of Life (UQoL )Instrument and the SF-36v2 physical and mental health quality of life surveys. These are norm based clinically validated and widely accepted measurement tools. Improving scores would indicate increased subject satisfaction with general physical and mental health for the SF-36v2 survey, and reduced menopausal-specific symptomatology for the Utian Menopausal Quality of Life survey.
Time Frame
Baseline, 6 months, 12 months

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Ovaries must be present.
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Symptomatology or hormonal derangement for at least 6 months Stopped Hormonal Replacement Therapy (HRT) for at least 3 months prior to intervention Stopped Botanotherapy / Danazol for 3 months Willing to comply with study requirements, including avoiding HRT, Botanotherapy, Danazol for at least 12 months post intervention. Women over the age of 35 Presence of at least one ovary Agree to report any pregnancy to the research staff immediately. Willing and able to comply with study requirements. Exclusion Criteria: Current or previous Immune Globulin A (IgA) deficiency Current or previous premature ovarian failure due to a genetic origin, such as Turner's Syndrome or chromosomal abnormality Current or previous injuries or adhesions to the pelvis or ovaries Current and ongoing pregnancy Current and ongoing anticoagulant use Known bleeding diathesis Current and ongoing major Mental health disorder that precludes participation in the study Current and ongoing active substance abuse or dependence Prior or current ovarian malignancy, or known genetic mutation Current and ongoing chronic pelvic pain other than dyspareunia or vulval/vaginal integument disorders History of endometriosis Current diagnosis of cancer or active cancer within last 24 months Ovarian inaccessibility determined by endovaginal sonography Current or previous premature ovarian failure Active, untreated Endocrinologic disorders (uncompensated thyroid dysfunction, insulin dependant diabetes (type 1, type2) Body Mass Index (BMI) >30 kg/m2 Systemic autoimmune disorder Know Polycystic Ovarian Syndrome Unwilling to terminate ovarian pharmaceuticals or exogenous hormone treatments 3 months prior to entering study, and to avoid exogenous hormones for duration of study
Facility Information:
Facility Name
Fanny Island Campus Medical Building
City
Colchester
State/Province
Vermont
ZIP/Postal Code
05446
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
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Ovarian Rejuvenation Using Platelet Rich Plasma (PRP) & Autologous Tissue Stromal Vascular Fraction (tSVF) and Cell Enriched tSVF

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