Rituximab (Arm A)
DrugTotal 4 infusions (4 g) of Rituximab
Recruiting
NCT Number: NCT07509840
Immunomodulatory Therapy to Restore Ovarian Function and Improve Fertility in Women With Autoimmune Premature Ovarian Insufficiency
Several autoimmune diseases such as Addison's disease are associated with failing ovarian function, known as premature ovarian insufficiency (POI), which can lead to early menopause and reduced fertility.The underlying cause of POI in these women is considered to be an immunological attack on the ovaries that causes them to not respond to hormonal stimulation from the brain. Hormone replacement effectively counteracts menopausal symptoms, but today there is no treatment to normalize or even improve fertility. As a patient with POI and an autoimmune diagnosis and the desire to become pregnant, you are asked to participate in the study. The aim of this study is to investigate whether immunomodulatory therapy can improve and ideally normalize ovarian function in women of childbearing age with autoimmune disease and proven POI. Patients with a male partner and a desire for children and who respond positively to the first ovarian stimulation will be offered in vitro fertilization (IVF) and will thus be allowed to complete the study. Other participating patients will undergo a total of three ovarian stimulations and treatment with first two infusions of the registered drug rituximab or placebo (inactive agent) and later two additional infusions where all patients receive rituximab. The first two infusions with rituximab or placebo are double-blind, which means that neither you nor the study staff know what you have received. Follow-up takes place up to 12 months after the last infusion.
Recruiting
Interested in participating?
Request InfoKey information
Conditions
Age range
18 year–38 year
Sex eligibility
Female
Study type
Interventional
Phase
Phase 3
Primary location
Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden
Loading trial locations.
Who can participate
Healthy volunteers accepted: No
Only the study team can determine whether someone qualifies for participation.
Inclusion criteria
- The subject has given their written consent to participate in the trial
- Autoimmune POI (FSH > 25 IU/L) including the presence of oligo/amenorrhea lasting at least 4 months, and elevated FSH levels (FSH > 25 IU/L) confirmed on two separate occasions, with measurements taken at least 4 weeks apart and Addison's disease or ab positivity for 21-hydroxylase or other relevant autoantibodies (SCC, 17-OH, NALP5)
- 18-38 years of age
- Body mass index between 19-30
- Willing to use effective non-hormonal contraceptive (such as intra uterine device (IUD), sexual abstinence, male or female condom with or without spermicide, cap, diaphragm or sponge with spermicide) method during the 18-month study period
Exclusion criteria
- Hypersensitivity to rituximab, any of the AxMPs, or any of the excipients (as detailed in the SmPC for the various IMPs)
- Active, severe infection or JCV positivity
- Active hepatitis B infection
- Severe immunosuppression
- Severe cardiac disease
- Cancer
- Benign tumours of the hypothalamus, pituitary, or ovarian pathology
- Vaginal bleeding of unknown etiology
- Hormone replacement therapy within four weeks prior study entry
- Pregnant or lactating women
- Concurrent treatment with other immunosuppressive drugs
- Any vaccination within 4 weeks of infusion of study medication
- Severe psychiatric disorder
- Any condition or any circumstance that in the opinion of the investigator would make it unsafe to undergo treatment with rituximab or controlled ovarian hyperstimulation
- Active thrombolic disorder (contraindicated for Ovirelle)
- Moderate or severe impairment of kidney or liver function (contraindicated for Orgalutran)
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Treatment and study plan
Rituximab (Arm B)
Drug2 infusions (2 g) of Rituximab
Primary outcomes
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Egg retrieval in response to controlled ovarian hyperstimulation
Time frame: 4 to 6 months after rituximab/placebo treatment.
Egg retrieval (yes/no) in response to controlled ovarian hyperstimulation at 4 to 6 months after rituximab treatment compared to placebo.
Secondary outcomes
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Occurrence of spontaneous menstrual bleeding
Time frame: 19-month study period from baseline to end of study.
Occurrence of spontaneous menstrual bleeding (yes/no) at any point during the 19-month study period.
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Proportion of participants who achieve ovulation
Time frame: During 19 months from baseline to end of study.
Proportion of participants who achieve ovulation (defined as serum progesterone >10 nmol/L) at any time during the study period.
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Changes in serum follicle-stimulating hormone
Time frame: From baseline to the end of the study period (19 months).
Changes in serum follicle-stimulating hormone (FSH) IE/L levels from baseline to the end of the study period.
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Change in serum anti-Mullerian hormone
Time frame: From baseline to the end of the study period (19 months).
Changes in serum anti-Mullerian hormone (AMH) microgram/L levels from baseline to the end of the study period.
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Changes in B-cell count
Time frame: From baseline to the end of the study period (19 month).
Changes in B-cell count x109/L from baseline to end of study.
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Changes in autoantibody indices
Time frame: From baseline to the end of the study period (19 months)
Changes in autoantibody indices from baseline to the end of the study period.
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Changes in immunoglobulin (IgG) levels
Time frame: From baseline to the end of the study period (19 months).
Changes in immunoglobulin (IgG) g/L levels from baseline to the end of the study period.
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Changes in quality of life scores, as measured by the Addison's Disease Quality of Life questionnaire
Time frame: From baseline to the end of the study period (19 months).
Changes in quality of life scores, as measured by the validated instrument Addison's Disease Quality of Life (AddiQol) from baseline to the end of the study period.
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Changes in quality life scores, as measured by the Psychological General Well-being questionnaire
Time frame: From baseline to the end of the study period (19 months).
Changes in quality life scores, as measured by the validated Psychological General Well-being (PGWB) from baseline to the end of the study period.
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Changes in quality of life scores, as measured by the Short Form Health Survey
Time frame: From baseline to the end of the study period (19 months).
Changes in quality of life scores as measured by the validated instrument Short Form Health Survey (SF-36) from baseline to the end of the study period.
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Changes in quality of life scores as measured by the Menopause Rating Scale
Time frame: From baseline to the end of the study period (19 months).
Changes in qualit of life scores, as measured by the validated Menopause Rating Scale (MRS) from baseline to the end of the study period.
Study contacts
Contact information is provided by the study sponsor or research team.
Sponsors and collaborators
Lead sponsor
Angelica Lindén Hirschberg
Other
Registry information
Official study title
Immunomodulatory Therapy to Restore Ovarian Function and Improve Fertility in Women With Autoimmune Premature Ovarian Insufficiency - Double-blind, Placebo-contrelled, Randomized Study.
Acronym: REFINE
Important dates
- Study start
- 2026
- Primary completion
- 2031
- Study completion
- 2031
- First posted
- Apr 3, 2026
- Registry last updated
- Apr 3, 2026
OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.
View the official ClinicalTrials.gov record (opens in a new tab)This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.