Safety and feasibility study of intra-ovarian injection of bone marrow mesenchymal stromal cells-derived extracellular vesicles in idiopathic premature ovarian failure patients: Clinical trial phase I
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Intervention groups
#1
Intervention group: The patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). , the injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 30 million cells) will be performed into one ovary of the patient (the accessible ovary).
Intervention group: The patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). , The injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 50 million cells) will be performed into one ovary of the patient (the accessible ovary).
Intervention group: The patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). , theThe injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 3050 million cells) will be performed into one ovary of the patient (the accessible ovary).
گروه مداخله: بیمار بیهوش شده و در وضعیت لیتوتومی قرار می گیرد، بعد از آمادگی و شستشوی واژن با سرم نرمال سالین، تحت گاید سونوگرافی ترانس واژینال (پروب واژینال Aloka-40000 کشور ژاپن) با استفاده از نیدل پانکچر (Reproline medical Gmbh, Rheinbach/Germany), تزریق 2ml وزیکولهای خارج سلولی مشتق شده از سلولهای بنیادی مزانشیمی (معادل 30 میلیون سلول) در یک تخمدان بیمار (تخمدان در دسترس) انجام خواهد شد.
گروه مداخله: بیمار بیهوش شده و در وضعیت لیتوتومی قرار می گیرد، بعد از آمادگی و شستشوی واژن با سرم نرمال سالین، تحت گاید سونوگرافی ترانس واژینال (پروب واژینال Aloka-40000 کشور ژاپن) با استفاده از نیدل پانکچر (Reproline medical Gmbh, Rheinbach/Germany), تزریق 2ml وزیکولهای خارج سلولی مشتق شده از سلولهای بنیادی مزانشیمی (معادل 50 میلیون سلول) در یک تخمدان بیمار (تخمدان در دسترس) انجام خواهد شد.
گروه مداخله: بیمار بیهوش شده و در وضعیت لیتوتومی قرار می گیرد، بعد از آمادگی و شستشوی واژن با سرم نرمال سالین، تحت گاید سونوگرافی ترانس واژینال (پروب واژینال Aloka-40000 کشور ژاپن) با استفاده از نیدل پانکچر (Reproline medical Gmbh, Rheinbach/Germany), تزریق 2ml وزیکولهای خارج سلولی مشتق شده از سلولهای بنیادی مزانشیمی (معادل 3050 میلیون سلول) در یک تخمدان بیمار (تخمدان در دسترس) انجام خواهد شد.
Protocol summary
Study aim
Investigating the effect of intraovarian injection of bone marrow-derived extracellular vesicles (MSC-EV) on serum levels of Follicle-Stimulating Hormone (FSH),Anti-Mullerian Hormone (AMH) levels, as well as the return of the menstrual cycle in infertile patients with premature ovarian failure, as well as the evaluation of its possible side effects.
Design
A before/after clinical trial (phase I) on 10 patients
Settings and conduct
For all patients in the infertility clinic of Royan Research Institute, first a basic visit will be done to obtain basic laboratory data, hormone levels and ultrasound examination of the ovaries, and then MSC-EV will be injected into the ovaries with a determined dose.
Participants/Inclusion and exclusion criteria
Infertile women who have been diagnosed with premature ovarian failure and have normal body mass index and normal genetic tests are invited to participate in this project. Patients with early amenorrhea and certain immunological and cardiovascular diseases, as well as a history of ovarian masses or abnormal serological tests will not be included in the study. If the patient has undergone hormone replacement therapy (HRT), the HRT will be stopped for at least two months and then the injection cycle will be started.
Intervention groups
Injection of bone marrow-derived extracellular vesicles with a dose equivalent to 3 times 10 million clonal mesenchymal stem cells in 2 ml will be performed for all patients.
Main outcome variables
Follow-up of patients in order to respond to treatment for 8 months based on evaluation of Follicle-Stimulating Hormone (FSH),Anti-Mullerian Hormone (AMH) levels, return of menstrual cycle, ovarian ultrasound and also check possible complications due to injection (fever, bacteremia, sepsis, Pelvic inflammatory disease, anaphylactic shock and hematoma from the first 24 hours and in the first week) will be done.
General information
Reason for update
Completion of the trial recruitment and follow-up process
Acronym
IRCT registration information
IRCT registration number:IRCT20080831001141N43
Registration date:2023-10-17, 1402/07/25
Registration timing:registered_while_recruiting
Last update:2026-06-10, 1405/03/20
Update count:2
Registration date
2023-10-17, 1402/07/25
Registrant information
Name
Kiandokht Kiani
Name of organization / entity
Royan Institute
Country
Iran (Islamic Republic of)
Phone
+98 21 2230 7960
Email address
kiandokht.kiani@royaninstitute.org
Recruitment status
Recruitment complete
Funding source
Expected recruitment start date
2023-02-20, 1401/12/01
Expected recruitment end date
2025-02-18, 1403/11/30
Actual recruitment start date
2023-02-20, 1401/12/01
Actual recruitment end date
2024-10-08, 1403/07/17
Trial completion date
2025-07-08, 1404/04/17
Scientific title
Safety and feasibility study of intra-ovarian injection of bone marrow mesenchymal stromal cells-derived extracellular vesicles in idiopathic premature ovarian failure patients: Clinical trial phase I
Public title
Investigating the effect of intraovarian injection of extracellular vesicles derived from bone marrow mesenchymal stromal cells in patients with premature ovarian failure.
Purpose
Treatment
Inclusion/Exclusion criteria
Inclusion criteria:
Women between 20-38 years old
Baseline serum level of follicle stimulating hormone (FSH) higher or equal to 25 IU/l at least twice with an interval of 3 or 4 months
At least one year has passed since secondary amenorrhea and premature ovarian failure (POF) diagnosis
Normal karyotype and fragile X messenger ribonucleoprotein 1 (FMR1) gene
Exclusion criteria:
Primary amenorrhea
Congenital anomaly of the ovary
Thyroid disease
Immune system diseases such as lupus and...
Previous and/or family history of ovarian tumor
Previous and/or family history of suffering from major diseases in the past and present such as cancer
Positive serological evidence regarding previous or current hepatitis B and C, Human T-lymphotropic virus 1, Human immunodeficiency virus (HIV), Syphilis
Disturbance in the normal range of laboratory tests as levels of Hemoglobin Subunit Alpha 1 (HbA1), Alanine transaminase (ALT), The aspartate aminotransferase (AST), the number of white blood cells (WBCs), The creatinine (Cr), International normalised ratio (INR) , Platelets (Plt), Hematocrit (Hct) tests.
History of specific systemic disease (rheumatology, endocrine, cardiovascular, etc.)
Severe endometriosis (stage III and IV)
Small and non-injectable ovaries
Lack of patient satisfaction
The patient's unwillingness to continue participating in the plan
Age
From 20 years old to 38 years old
Gender
Female
Phase
1
Groups that have been masked
No information
Sample size
Target sample size:
10
Actual sample size reached:
10
Randomization (investigator's opinion)
N/A
Randomization description
Blinding (investigator's opinion)
Not blinded
Blinding description
Placebo
Not used
Assignment
Single
Other design features
Secondary Ids
empty
Ethics committees
1
Ethics committee
Name of ethics committee
Ethics Committee of Royan Research Institute
Street address
Shahid Qassem Soleimani Highway, Bani Hashem Street, Bani Hashem Square, Hafez East Alley, Royan Alley, Royan Research Institute
City
Tehran
Province
Tehran
Postal code
1665659911
Approval date
2022-01-04, 1400/10/14
Ethics committee reference number
IR.ACECR.ROYAN.REC.1400.124
Health conditions studied
1
Description of health condition studied
Premature ovarian failure
ICD-10 code
E28.3
ICD-10 code description
Primary ovarian failure
Primary outcomes
1
Description
Ovary abscess
Timepoint
First 24 hours, first week and monthly up to 8 months after injection
Method of measurement
Evaluation of ovarian abscess or any other ovarian lesion formation up to 8 months after intraovarian injection of extracellular vesicles derived from bone marrow mesenchymal stromal cells (any adverse events through follow-up visits (first 24 hours and first week after transplantation, 1, 2, 3, 4, 5, 6, 7 and 8 months after injection) will be checked and recorded.
Baseline,1 week as well as one, two, three, four , five, six, seven and eight months after transplantation
Method of measurement
Laboratory test
2
Description
Serum anti-mullerian hormone (AMH) levels
Timepoint
Before the intervention (baseline) and also three, six and eight months after transplantation
Method of measurement
Laboratory test
3
Description
Menstruation recurrence rate
Timepoint
one, two, three, four , five, six, seven and eight months after transplantation
Method of measurement
Through monthly follow-up and asking the questions
Intervention groups
1
Description
Intervention group: The patient is anesthetized and placed in a lithotomy position, after preparing and washing the vagina with normal saline, under transvaginal ultrasound guidance (Aloka-40000 vaginal probe, Japan) using needle puncture (Reproline medical Gmbh, Rheinbach/Germany). , The injection of 2 ml of extracellular vesicles derived from MSCs (equivalent to 50 million cells) will be performed into one ovary of the patient (the accessible ovary).