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

Phase 3RecruitingNCT07509840

Angelica Lindén Hirschberg40 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Autoimmune Prematur Ovarian Insuffience

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 38 Years

Medical Language ↔ Plain English

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) \-

Outcomes

Primary Outcomes

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.

Time frame: 4 to 6 months after rituximab/placebo treatment.

Secondary Outcomes

Occurrence of spontaneous menstrual bleeding

Occurrence of spontaneous menstrual bleeding (yes/no) at any point during the 19-month study period.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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

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.

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

Changes in quality life scores, as measured by the validated Psychological General Well-being (PGWB) from baseline to the end of the study period.

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

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.

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

Changes in qualit of life scores, as measured by the validated Menopause Rating Scale (MRS) from baseline to the end of the study period.

Time frame: From baseline to the end of the study period (19 months).

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

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts