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

March 29, 2026 updated by: Angelica Lindén Hirschberg

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

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
40

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Sweden
      • Stockholm, Sweden, 171 76
        • Recruiting
        • Department of Obstetrics and Gynecology, Karolinska University Hospital
        • Contact:
        • Principal Investigator:
          • Angelica Linden Hirschberg
      • Stockholm, Sweden, 17176

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
4 to 6 months after rituximab/placebo treatment.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
19-month study period from baseline to end of study.
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.
During 19 months from baseline to end of study.
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.
From baseline to the end of the study period (19 months).
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.
From baseline to the end of the study period (19 months).
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.
From baseline to the end of the study period (19 month).
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.
From baseline to the end of the study period (19 months)
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.
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
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.
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
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.
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
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.
From baseline to the end of the study period (19 months).
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.
From baseline to the end of the study period (19 months).

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Angelica Lindén Hirschberg

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 12, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2031

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2031

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 23, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 29, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 3, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 3, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 29, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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