Diminished Ovarian Reserve (DOR)
Conditions
Keywords
Female fertility, Diminished ovarian reserve, Adipose stromal vascular fraction
Brief summary
A multi-center, prospective, randomised controlled clinical trial (1:1 treatment ratio), designed to investigate the efficacy and safety of autologous SVF in improving the pregnancy outcome of infertile patients with DOR.
Detailed description
A multi-center, large-scale, prospective, randomized controlled clinical trial will enroll 260 patients diagnosed with DOR based on the inclusion and exclusion criteria from Peking University Third Hospital, Shanghai Zhongshan Hospital, General Hospital of Ningxia Medical University and The Third Affiliated Hospital of Guangzhou Medical University. Eligible participants will be randomized to two groups at a ratio of 1:1- SVF protocol, and conventional protocol.The participation in this study will be approximately 2 years with a total of 5 visits and 3 follow-up phone calls.
Interventions
After lower abdominal liposuction (the liposuction volume is about 200 ml), the preparation and quality inspection of SVF will be completed by a laboratory with good manufacturing practice-approved facilities immediately. The adipose tissue will be cut into pieces of about 1mm3, and the equal volume of 0.1% collagenase I will be added to digest the adipose tissue. The digestion will be terminated after 40 minutes, followed by isolation, filtration, centrifugation, resuspension and dilution to obtain the SVF suspension. The test items, including bacteria, fungi, viruses and endotoxin, will be tested, and the expression of SVF surface markers, including CD45, CD34, CD31, CD11b, CD44, CD73, CD105 and CD90, will be detected by flow cytometry to ensure the quality of the SVF suspension. After about 4 hours of quality control and detection, the SVF suspension will be transported to the operating room on ice in a sealed incubator.
PROCEDUREOvarian injection
Under ultrasound guidance, the SVF suspension will be transplanted into the patient's bilateral ovaries by a reproductive endocrinologist. Briefly, both ovaries will be intramedullary injected on multiple sites using a 17-gauge single-lumen needle. A total of 1-2×107 cells from autologous adipose tissue will be injected into each ovary. Approximately 330±10µL of SVF suspension will be administered at each point, 1mL per ovary in total. Following the infusion procedure, the pelvis will be thoroughly examined via ultrasonography in order to check for total vascular integrity. Anaesthetic drugs will not be used during this procedure, but analgesics may be administered if necessary. After the injection, patients will be required to lie flat for 2h to monitor for any AEs.
PROCEDUREConventional ART treatment
Conventional assisted reproductive technology (ART) treatment including in vitro fertilisation and embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI) ; Standard assisted reproductive treatments.
If necessary, oral administration of hormones such as Fenbolone can be given for replacement therapy.
Sponsors
Peking University Third Hospital
Shanghai Zhongshan Hospital
General Hospital of Ningxia Medical University
The Third Affiliated Hospital of Guangzhou Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Because of the particularity of the therapeutic schedule, the evaluator, specifically the follow-up personnel who collect postoperative medical histories and the ultrasound evaluator, will be blinded in this trial to conceal the grouping results. However, blinding of participants and researchers is not possible.
Intervention model description
Eligible participants will be randomized to two groups at a ratio of 1:1- SVF protocol, and conventional protocol.
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 39 Years
Healthy volunteers
No
Inclusion criteria
* Women of childbearing age (20-39 years old) with fertility needs. * The following conditions must be met simultaneously: ① Basal FSH \> 10 IU/L (measured on days 2-4 of menstruation); ② Total number of bilateral AFC \< 5 (by transvaginal ultrasound, measured on days 2-4 of menstruation); ③ AMH \< 1.2 ng/mL. * Previous controlled ovarian stimulation resulted in no more than 3 retrieved oocytes and/or no viable embryos for transfer and/or more than 2 previous embryo transfer failures; or previous inability to enter the ovarian stimulation cycle due to FSH levels ≥ 20 IU/L. * The uterus and both ovaries are present, and the informed consent form is signed.
Exclusion criteria
* Suffering from autoimmune diseases or other endocrine disorders and the conditions are not under control; * Having a history of gynecological malignant tumors or radiotherapy and chemotherapy; having malignant tumors in the adnexal area, or having a mass with an unclear benign or malignant nature; having a family history of gynecological malignant tumors; * Having a history of venous thrombosis or pulmonary embolism; * Having a history of malignant tumors, acute or chronic infectious diseases, hematological diseases or other diseases that affect the removal of fat during surgery and ovarian injection; * Having serious diseases that are not suitable for pregnancy and have been judged by the investigator to potentially affect the efficacy or safety evaluation, such as circulatory system diseases, urinary system diseases, digestive system diseases, endocrine system diseases, respiratory system diseases, immune system diseases, mental or neurological diseases, etc.; * Using systemic glucocorticoids or other immunosuppressants continuously for ≥ 3 weeks within 6 months before administration, or using systemic glucocorticoids (prednisone ≥ 20mg/d or equivalent dose) or other immunosuppressants within 3 days before administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The cumulative clinical pregnancy rate within 6 months in women with DOR undergoing IVF | Within 6 months after treatment | This will be calculated as: cumulative clinical pregnancy rate (%)= number of participants obtain clinical pregnancy within 6 months / total number of participants×100%. Clinical pregnancy refers to the condition where ultrasound can detect one or more viable gestational sacs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum level of Anti-Mullerian hormone (AMH) | 1 month, 3 months, and 6 months after treatment | Independent sample t-test or non-parametric test will be used to compare and analyze AMH between the control group and the SVF group. |
| Antral follicles count (AFC) | 1 month, 3 months, and 6 months after treatment | Independent sample t-test or non-parametric test will be used to compare and analyze AFC between the control group and the SVF group. |
| Serum level of sex hormone (E2 and FSH) | 1 month, 3 months, and 6 months after treatment | Independent sample t-test or non-parametric test will be used to compare and analyze E2 and FSH between the control group and the SVF group. |
| Ovarian volume | 1 month, 3 months, and 6 months after treatment | Ovarian volume will be recorded before and after the intervention. Changes in ovarian volume between the control group and the SVF group will be analyzed and compared using paired sample t-test or independent sample t-test. A change in ovarian volume is considered significant at p\<0.05. |
| Menstrual status | Within 6 months after treatment | The frequency, duration and volume of menses within 6months after the intervention will be recorded to evaluate whether the patient's menstrual status improved. The number of sanitary napkins needed will be used to approximate the menstrual volume. We define the recovery of menstrual status as the resumption of menstrual cycles (at least two consecutive uterine bleeds at an interval of 3-6 weeks) without any hormonal treatment, and normal menstruation duration and volume. This will be calculated as: menstrual recovery rate (%)=number of participants with menstrual recovery/total number of participants×100%. |
| Pregnancy outcomes | Within 2 years after treatment | Live births or miscarriage of patients with successful pregnancy within 6months will be followed up. Live birth refers to the delivery of one or more viable fetus after 24 weeks of gestation. Miscarriage refers to a loss of pregnancy that occurs before 24 weeks of gestation. The rate of live birth will be calculated as: live birth rate (%)=number of participants with live births/total number of participants×100%. The rate of miscarriage will be calculated as: miscarriage rate (%)=number of participants with miscarriage/total number of participants×100%. |
| Health status of offspring | 1 year, 1 year and 6 months, and 2 years after treatment | The health status (survival, physiological and intellectual development) of the offspring will also be recorded at the following follow-up times: 1 year, 1 year and 6 months, and 2 years after the intervention. |
| Adverse events (AEs) | Within 2 years after treatment | The incidence of AEs will be calculated as: incidence of AEs (%)=number of participants with AEs/ total number of participants×100%. The gold standard for reporting AEs is the Common Terminology Criteria for Adverse Events version 5.0, which provides a standardized framework for evaluating the severity and impact of AE. Clinicians will interpret, diagnose and grade AEs using a scale from 1 to 5 over the duration of the trial: grade 1 (mild): asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; grade 2 (moderate): minimal, local or non-invasive intervention indicated, limiting age-appropriate instrumental activities of daily living (ADL); grade 3 (severe): severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self-care ADL; grade 4: life-threatening consequences, urgent intervention indicated; grade 5: death related to AE. |
Countries
China
Contacts
CONTACTRui Yang, M.D.
CONTACTYaodong Zhang, Bachelor
STUDY_DIRECTORRui Yang, M.D.
Peking University Third Hospital
Outcome results
None listed