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

Official title

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

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.

Interventions

• Drug Rituximab (Arm A)
  Total 4 infusions (4 g) of Rituximab
• Drug Rituximab (Arm B)
  2 infusions (2 g) of Rituximab

Primary outcome measures

• Egg retrieval in response to controlled ovarian hyperstimulation [Time frame: 4 to 6 months after rituximab/placebo treatment.]

Secondary outcome measures (11)

• 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).]

Eligibility criteria

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)

\-

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Sweden · 2 centers

• Department of Obstetrics and Gynecology, Karolinska University Hospital — Stockholm
• Karolinska University Hospital — Stockholm

Identifiers

NCT: NCT07509840 · The REFINE study

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗