Clinical trial NCT04444245: Ovarian Rejuvenation Using Platelet Rich Plasma (PRP) & Autologous Tissue Stromal Vascular Fraction (tSVF) and Cell Enriched tSVF
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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Ovarian Failure
Perimenopausal Disorder
Hormone Disturbance
Lead sponsor: Black Tie Medical, Inc.
Sponsor class: INDUSTRY
First posted: 2020-06-23
Enrollment: 100
Sex: FEMALE
Minimum age (years): 35
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Patient Safety For Procedure
timeFrame: 30 days
Secondary outcomes:
measure: Menstrual Resumption
timeFrame: baseline through 18 months
measure: Hormonal Response
timeFrame: Baseline, 3 months, 6 months, 12 months, 18 months
measure: Ovarian Morphology
timeFrame: Baseline, 6 month, 12 month, 18 month
measure: Bone Density and Body Composition
timeFrame: Baseline, 12 and/or 18 months
Other outcomes:
measure: Health Related Quality of Life
timeFrame: Baseline, 6 months, 12 months
Locations:
city: Colchester
country: United States
facility: Fanny Island Campus Medical Building
state: Vermont
Study officials:
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