Autoimmune Prematur Ovarian InsuffiencePhase 3REFINENCT07509840
Immunomodulatory Therapy to Restore Ovarian Function and Improve Fertility in Women With Autoimmune Premature Ovarian Insufficiency
A Phase 3 study testing Rituximab (Arm A) and Rituximab (Arm B) in people with Autoimmune Prematur Ovarian Insuffience, run by Angelica Lindén Hirschberg at 2 sites in Sweden.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 38 years, women only
- Conditions the study is for
- Autoimmune Prematur Ovarian Insuffience
- What is being tested?
- Rituximab (Arm A) and Rituximab (Arm B)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 2 sitesSweden
- Study dates
- 12 Feb 2026to 31 Dec 2031
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 38 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 17Show fewer
- 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)
- -
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Sweden2 sites, 2 recruiting
- Recruiting
Department of Obstetrics and Gynecology, Karolinska University Hospital
Stockholm, 171 76
Angelica L Hirschberg, Professor, +46 8 517 733 26, angelica.linden-hirschberg@karolinska.se
Angelica Linden Hirschberg
- Recruiting
Karolinska University Hospital
Stockholm, 17176
Liselott Blomberg, +46812373782, liselott.blomberg@regionstockholm.se
Anna Cockin, anna.cockin@regionstockholm.se
About this study
Official title: 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.
- Conditions
- Autoimmune Prematur Ovarian Insuffience
- Being tested
- Rituximab (Arm A), Rituximab (Arm B)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Rituximab (Arm A)Drug
Total 4 infusions (4 g) of Rituximab
Rituximab (Arm B)Drug
2 infusions (2 g) of Rituximab
| Study group | Role | What they receive |
|---|---|---|
| Group A 2 infusions with placebo or Rituximab, and then 2 infusions of Rituximab | Active comparator | 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. Receives: Drug: Rituximab (Arm A) |
| Group B , 2 infusions (2 g) Rituximab | Active comparator | Group B a total of 2 infusions (2 g) with Rituximab, 2 weeks apart per occasion. Receives: Drug: Rituximab (Arm B) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 4 to 6 months after rituximab/placebo treatment.
Secondary outcomes (11)
Occurrence of spontaneous menstrual bleeding
Occurrence of spontaneous menstrual bleeding (yes/no) at any point during the 19-month study period.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: From baseline to the end of the study period (19 months).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Apr 2026
- Study start12 Feb 2026
- Primary completion31 Dec 2031 (estimated)
- Study completion31 Dec 2031 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Autoimmune Prematur Ovarian InsuffienceStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Angelica Lindén Hirschberg
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Angelica Lindén Hirschberg, Karolinska University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07509840
- Sponsor's protocol ID
- The REFINE study
- Acronym
- REFINE
- Status last verified
- Oct 2025
- First submitted
- 23 Mar 2026
- Last updated
- 3 Apr 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunomodulatory Therapy to Restore Ovarian Function and Improve Fertility in Women With Autoimmune Premature Ovarian Insufficiency - Double-blind, Placebo-contrelled, Randomized Study.
- ClinicalTrials.gov ID
- NCT07509840
- Acronym / sponsor ID
- REFINE / The REFINE study
- Conditions
- Autoimmune Prematur Ovarian Insuffience
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Angelica Lindén HirschbergUniversity, hospital or other
- Study start
- 12 Feb 2026 (actual)
- Primary completion
- 31 Dec 2031 (estimated)
- Study completion
- 31 Dec 2031 (estimated)
- First posted
- 3 Apr 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A 2 infusions with placebo or Rituximab, and then 2 infusions of Rituximab | Active comparator | Drug: Rituximab (Arm A)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. |
| Group B , 2 infusions (2 g) Rituximab | Active comparator | Drug: Rituximab (Arm B)Group B a total of 2 infusions (2 g) with Rituximab, 2 weeks apart per occasion. |
Who may qualify
- Ages
- 18 to 38 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rituximab (Arm A)Total 4 infusions (4 g) of Rituximab | Drug | Group A 2 infusions with placebo or Rituximab, and then 2 infusions of Rituximab |
| Rituximab (Arm B)2 infusions (2 g) of Rituximab | Drug | Group B , 2 infusions (2 g) Rituximab |
Primary outcome
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.
11 secondary outcomes
Occurrence of spontaneous menstrual bleeding
Time frame: 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.
Changes in serum follicle-stimulating hormone
Time frame: 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 B-cell count
Time frame: 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 immunoglobulin (IgG) levels
Time frame: 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 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 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 Menopause Rating Scale
Time frame: From baseline to the end of the study period (19 months).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2026.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Rituximab (Arm A) and Rituximab (Arm B) in people with Autoimmune Prematur Ovarian Insuffience, run by Angelica Lindén Hirschberg at 2 sites in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 3 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Angelica Lindén Hirschberg (+46812373326, angelica.linden-hirschberg@regionstockholm.se), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Egg retrieval in response to controlled ovarian hyperstimulation (time frame: 4 to 6 months after rituximab/placebo treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Apr 2026.