Rejuvenation of Premature Ovarian Failure With Stem Cells (ROSE-1)
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|ClinicalTrials.gov Identifier: NCT02696889|
Recruitment Status : Active, not recruiting
First Posted : March 2, 2016
Last Update Posted : May 28, 2020
|First Submitted Date ICMJE||February 16, 2016|
|First Posted Date ICMJE||March 2, 2016|
|Last Update Posted Date||May 28, 2020|
|Actual Study Start Date ICMJE||February 6, 2016|
|Estimated Primary Completion Date||May 6, 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Improved diagnostic hormonal levels [ Time Frame: 18 months ]
Reduction of 50% in FSH values; increase in AMH and Estradiol levels (30%)
|Original Primary Outcome Measures ICMJE
||Positive Pregnancy Test [ Time Frame: 12 months ]
Following the ROSE Protocol, subjects will be instructed to resume normal unprotected sexual intercourse as soon as possible and to continue for 12 months with monitoring of pregnancy test or until clinical pregnancy is confirmed.
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Rejuvenation of Premature Ovarian Failure With Stem Cells|
|Official Title ICMJE||Autologous Stem Cell Therapy for Premature Ovarian Insufficiency and Low Ovarian Reserve|
|Brief Summary||The ROSE-1 study is designed to determine the efficacy of bone marrow derived stem cell therapy on ovarian function recovery in subjects with idiopathic and other types of premature or primary ovarian failure (POF or POI) and low ovarian reserves.|
Premature ovarian insufficiency (POI), formerly referred to as premature ovarian failure (POF), is defined as hypergonadotropic ovarian insufficiency occurring prior to age 40 (1). It is surprisingly common and affects approximately 1% of women below the age of 40 (2, 3). The incidence is 10% to 28% in women with primary amenorrhea and 4% to 18% in women with secondary amenorrhea (2). The clinical manifestations include amenorrhea and abnormally high levels of luteinizing (LH) and follicle stimulating hormone (FSH) and low levels of Anti Mullerian Hormone (AMH). The etiology of POI is unknown in most cases. It can be caused by a combination of inherited conditions such as immune disorders, environmental toxins and iatrogenic injury (2, 3). The majority of patients with POI are considered to have idiopathic premature ovarian insufficiency because usually no cause can be identified (3). POI has been shown to be associated with an increased incidence of other conditions, including Alzheimer's, cardiovascular and immune system diseases, metabolic syndrome, osteoporosis, diabetes and cancer of reproductive organs. POI is characterized by loss of secondary follicles, arrested folliculogenesis, decreased estrogen production, and infertility (3). The mechanism of ovarian insufficiency is most likely accelerated follicular atresia but detailed pathogenesis is yet to be fully understood (2).
In women younger than 40, at least two menopausal FSH levels (≥40 IU/L) will be sufficient for the diagnosis of POI. It is not essential to have amenorrhea for the diagnosis of POI. Subjects with oligomenorrhea or low ovarian reserve and elevated FSH, referred to as transitional ovarian insufficiency (TOI), or at least 4 months amenorrhea together with FSH levels exceeding 40 IU/liter, and are included in this category. Spontaneous menstrual cycles can sometimes be seen after the diagnosis of POI as well. Resumption of normal ovarian function, albeit temporary, in patients with normal karyotypes has been documented in 10 to 20% of patients; thus, spontaneous resumption of fertility is possible (1).
No therapeutic intervention has proven effective in restoring fertility in patients with POI. Currently, egg donation remains the only reliable method to establish a pregnancy in women with POI (2, 3). Even though this approach is attainable, resulting children will not be genetically related to the recipient mother. Furthermore, egg donation is not ethically acceptable to many couples. Various attempts at ovarian stimulation patients with POI are usually unsuccessful because they are poor responders. Therefore, the diagnosis of POI can cause great physical and mental suffering among these patients. Thus, there is critical need to develop novel effective approaches for the treatment of POI.
Throughout life, there is an ongoing physiological level of atresia of oocytes. A decreased germ cell endowment combined with an increased rate of germ cell destruction can explain POI (1). The current concept that the ovary has a static ovarian reserve is entirely at odds with the germ cell dynamics. Current research supports the concept that the ovary continues to produce new germ cells into adult life, however, whether this occurs in humans is not universally accepted. Recent research suggests that diminished ovarian reserve is a result of the aging of the niche rather than a defect in the germ cells (4-6). Anti-mullerian hormone has been used as a reliable biomarker for ovarian reserve in humans and the circulating AMH levels change with age as follows:
20-25: 1.23-11.51 ng/mL 26-30: 1.03-11.10 ng/mL 31-35: 0.66-8.75 ng/mL 36-40: 0.42-8.34 ng/mL 41-46: 0.26-5.81 ng/mL 47-54: <0.82 ng/mL Emerging evidence suggests that bone marrow-derived mesenchymal stem cells (BMSCs) could restore the structure and function of injured tissues (7). During embryologic development, cells of the mesodermal layer give rise to multiple mesenchymal tissue types including bone, cartilage, tendon, muscle, and fat and marrow stroma (8). These precursor cells, also present in the postnatal organism, are referred to as mesenchymal stem cells. These stem cells have been shown to retain their developmental potential following extensive sub-cultivation in vitro. Implantation of culture-expanded mesenchymal stem cells has been demonstrated to effect tissue regeneration in a variety of animal models and depends on local factors to stimulate differentiation into the appropriate phenotype (8).
Recent studies suggest that stem cell therapy holds promise in treatment of variety of diseases including reproductive dysfunction. In a recent investigation by Ghadami et al (2012) in our lab at Augusta University in Georgia, BMSC treated animals resumed ovarian function (9). In another investigation by Lui et al (2014), granulosa cell apoptosis induced by cisplatin was reduced when BMSCs were migrated to granulosa cells in vitro. In this study, chemotherapy-induced POI rats were injected with BMSCs. The BMSCs treatment group's antral follicle count and estradiol levels increased after 30 days, compared with untreated POI group (10). In a recent clinical trial in Egypt, Edessy et al (2014) evaluated the therapeutic potential of autologous mesenchymal bone marrow stem cells transplantation in women with POI. Ten patients with POI were selected and their ovaries were injected with autologous BMSC at time of laparoscopy. The results revealed resumption of menstruation in one case after 3 months; two cases showed focal secretory changes after having atrophic endometrium (11). According to these results, BMSC seem to have the ability to revive prematurely failed ovaries both in their hormonal and follicular development abilities.
Furthermore, in this clinical trial, while at Augusta University, Georgia, USA, we have successfully initiated two cases so far (8/10/2017). Both patients have tolerated the procedure very well with no reported side effects or complications. Our first patient resumed menses after 6 months post stem cell injection and she demonstrated decreasing levels of serum FSH and increasing serum Estradiol levels (from undetectable levels pre-procedure, as well as the one week, one month and 3 months' time points assessments to 96pg/ml at the 6 months' time point (latest data available so far). She also reported amelioration of her post-menopausal symptoms including a decrease in hot flashes frequency and severity, decreased vaginal dryness and improved sleeping patterns. The second patient will be finished with the post-procedure follow up period on 2/21/2018.
Stem cell therapy has been shown to be beneficial and effective in various disease processes. The safety of the stem cell therapy has been assessed in multiple clinical trials. Although, autologous mesenchymal stem cell therapy for premature ovarian insufficiency is a novel approach, the safety and success of such stem cell therapy has been demonstrated in many other disease processes including graft versus host disease, acute myocardial infarction, acute respiratory distress syndrome (ARDS) and many other diseases (12-14). There are additional ongoing trials (Pilot -Phase III) to further assess risk and safety of stem cell based therapies (15-17). This interventional pilot clinical study will investigate the use of stem cell therapy to restore steroidogenesis, folliculogenesis, menstruation, and fertility in participants.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Procedure: ROSE-1 Protocol
A bone marrow aspiration will be performed under anesthesia in preparation for a diagnostic laparoscopy for full evaluation of the pelvic anatomy. Following laparoscopy, injection of BMSCs into the right ovary will occur.
|Study Arms ICMJE||Experimental: ROSE-1 Protocol
Patients with POF, POI or Low Ovarian Reserve choosing to enroll will be provided informed consent for Rejuvenation of Premature Ovarian Failure With Stem Cells (ROSE-1). They will undergo diagnosis and screening confirming diagnosis including History and Physical Exams, Labs and Diagnostic Procedures. Following final approval and under anesthesia, bone marrow aspiration with separation of the bone marrow derived stem cell fraction will be performed. Diagnostic laparoscopy will allow for assessment of pelvic anatomy and subsequent injection of the bone marrow derived stem cells into the right ovary.
Intervention: Procedure: ROSE-1 Protocol
|Publications *||Igboeli P, El Andaloussi A, Sheikh U, Takala H, ElSharoud A, McHugh A, Gavrilova-Jordan L, Levy S, Al-Hendy A. Intraovarian injection of autologous human mesenchymal stem cells increases estrogen production and reduces menopausal symptoms in women with premature ovarian failure: two case reports and a review of the literature. J Med Case Rep. 2020 Jul 18;14(1):108. doi: 10.1186/s13256-020-02426-5.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||May 6, 2022|
|Estimated Primary Completion Date||May 6, 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
If subject is planning to pursue pregnancy: Presence of at least unilateral tubal patency (with any clinically acceptable methods).
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02696889|
|Other Study ID Numbers ICMJE||2018-0277|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Ayman Al-Hendy, University of Illinois at Chicago|
|Study Sponsor ICMJE||University of Illinois at Chicago|
|Collaborators ICMJE||Not Provided|
|PRS Account||University of Illinois at Chicago|
|Verification Date||May 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP