Immunomodulatory Therapy to Restore Ovarian Function and Improve Fertility in Women With Autoimmune Premature Ovarian Insufficiency (REFINE)

Immunomodulatory Therapy to Restore Ovarian Function and Improve Fertility in Women With Autoimmune Premature Ovarian Insufficiency - Double-blind, Placebo-contrelled, Randomized Study.

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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Prematur Ovarian Insuffience
• Intervention / Treatment: Drug: Rituximab (Arm A); Drug: Rituximab (Arm B)

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Angelica Lindén Hirschberg; Phone Number: +46812373326; Email: angelica.linden-hirschberg@regionstockholm.se

Study Locations

• Sweden
  • Stockholm, Sweden, 171 76
    • Recruiting
    • Department of Obstetrics and Gynecology, Karolinska University Hospital
    • Contact: Angelica L Hirschberg, Professor; Phone Number: +46 8 517 733 26; Email: angelica.linden-hirschberg@karolinska.se
    • Principal Investigator: Angelica Linden Hirschberg
  • Stockholm, Sweden, 17176
    • Recruiting
    • Karolinska University Hospital
    • Principal Investigator: Angelica Linden Hirschberg
    • Contact: Liselott Blomberg; Phone Number: +46812373782; Email: liselott.blomberg@regionstockholm.se
    • Contact: Anna Cockin; Email: anna.cockin@regionstockholm.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The subject has given their written consent to participate in the trial
2. 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)
3. 18-38 years of age
4. Body mass index between 19-30
5. 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:

1. Hypersensitivity to rituximab, any of the AxMPs, or any of the excipients (as detailed in the SmPC for the various IMPs)
2. Active, severe infection or JCV positivity
3. Active hepatitis B infection
4. Severe immunosuppression
5. Severe cardiac disease
6. Cancer
7. Benign tumours of the hypothalamus, pituitary, or ovarian pathology
8. Vaginal bleeding of unknown etiology
9. Hormone replacement therapy within four weeks prior study entry
10. Pregnant or lactating women
11. Concurrent treatment with other immunosuppressive drugs
12. Any vaccination within 4 weeks of infusion of study medication
13. Severe psychiatric disorder
14. 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
15. Active thrombolic disorder (contraindicated for Ovirelle)

16. Moderate or severe impairment of kidney or liver function (contraindicated for Orgalutran)

    -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A 2 infusions with placebo or Rituximab, and then 2 infusions of Rituximab; Randomized to 2 infusions of placebo or Rituximab (2g) with a 2-week interval between infusions 1 and 2 , and then 2 infusions of Rituximax (2g) ,after a 6-month interval between the first two and the last two infusions.	Drug: Rituximab (Arm A); Total 4 infusions (4 g) of Rituximab
Active Comparator: Group B , 2 infusions (2 g) Rituximab; Group B a total of 2 infusions (2 g) with Rituximab, 2 weeks apart per occasion.	Drug: Rituximab (Arm B); 2 infusions (2 g) of Rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Egg retrieval in response to controlled ovarian hyperstimulation	Egg retrieval (yes/no) in response to controlled ovarian hyperstimulation at 4 to 6 months after rituximab treatment compared to placebo.	4 to 6 months after rituximab/placebo treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of spontaneous menstrual bleeding	Occurrence of spontaneous menstrual bleeding (yes/no) at any point during the 19-month study period.	19-month study period from baseline to end of study.
Proportion of participants who achieve ovulation	Proportion of participants who achieve ovulation (defined as serum progesterone >10 nmol/L) at any time during the study period.	During 19 months from baseline to end of study.
Changes in serum follicle-stimulating hormone	Changes in serum follicle-stimulating hormone (FSH) IE/L levels from baseline to the end of the study period.	From baseline to the end of the study period (19 months).
Change in serum anti-Mullerian hormone	Changes in serum anti-Mullerian hormone (AMH) microgram/L levels from baseline to the end of the study period.	From baseline to the end of the study period (19 months).
Changes in B-cell count	Changes in B-cell count x109/L from baseline to end of study.	From baseline to the end of the study period (19 month).
Changes in autoantibody indices	Changes in autoantibody indices from baseline to the end of the study period.	From baseline to the end of the study period (19 months)
Changes in immunoglobulin (IgG) levels	Changes in immunoglobulin (IgG) g/L levels from baseline to the end of the study period.	From baseline to the end of the study period (19 months).
Changes in quality of life scores, as measured by the Addison's Disease Quality of Life questionnaire	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.	From baseline to the end of the study period (19 months).
Changes in quality life scores, as measured by the Psychological General Well-being questionnaire	Changes in quality life scores, as measured by the validated Psychological General Well-being (PGWB) from baseline to the end of the study period.	From baseline to the end of the study period (19 months).
Changes in quality of life scores, as measured by the Short Form Health Survey	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.	From baseline to the end of the study period (19 months).
Changes in quality of life scores as measured by the Menopause Rating Scale	Changes in qualit of life scores, as measured by the validated Menopause Rating Scale (MRS) from baseline to the end of the study period.	From baseline to the end of the study period (19 months).

Collaborators and Investigators

• Sponsor: Angelica Lindén Hirschberg

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031

Study Registration Dates

• First Submitted: March 23, 2026
• First Submitted That Met QC Criteria: March 29, 2026
• First Posted (Actual): April 3, 2026

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 29, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Antibodies, Monoclonal, Murine-Derived; Rituximab
• Other Study ID Numbers: The REFINE study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No