Immunomodulatory Therapy in Women With Autoimmune Premature Ovarian Insufficiency

Study Overview
=================
Brief Summary
-----------------
Title: Effects of immunomodulatory therapy on gonadal function in women with autoimmune premature ovarian insufficiency (POI) Trial objectives and purpose: To study if rituximab therapy can improve ovarian response to gonadotropin stimulation and menstrual function in women with autoimmune POI. Treatment: Controlled ovarian hyperstimulation before and four months after an infusion of 1-gram rituximab (Mabthera®) twice with two weeks interval. Follow-up period 12 months after infusion. Primary outcome: Number of antral follicles and the size of the largest follicle in response to ovarian stimulation. Secondary outcomes: Reestablishment of spontaneous menstrual bleedings during the 12 months' study period Ovulation during the 12 months' study period Change in B-cell count, autoantibody indices and immunoglobulin levels (IgG) after treatment Safety outcomes: All adverse events. Of particular relevance are any hospital admissions, infections and allergic reactions. Study population: Fifteen women with autoimmune POI defined as absence of menstruation > 6 months and elevated serum level of follicle stimulation hormone > 40 International units (IU)/L. Inclusion criteria: Autoimmune POI defined as presence of autoantibodies against 21-hydroxylase (OH), side chain cleavage enzyme (SCC), 17-OH and/or neuronal apoptosis inhibitory protein (NACHT) leucine-rich-repeat protein 5 (NALP5) or other relevant autoantibodies; 18-35 yrs of age; body mass index 19-30. Exclusion criteria: Hypersensitivity to rituximab; severe infection; severe immunosuppression; cardiac disease; cancer; benign tumours of the hypothalamus, pituitary, or ovary; ovarian enlargement or ovarian cyst; vaginal bleeding of unknown aetiology. Time plan: The study is expected to start the spring 2017. It is expected to be closed spring 2023.

Official Title
-----------------
Effects of Immunomodulatory Therapy on Gonadal Function in Women With Autoimmune Premature Ovarian Insufficiency

Conditions
-----------------
Autoimmune Diseases, Premature Ovarian Insufficiency

Intervention / Treatment
-----------------
* Drug: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Autoimmune premature ovarian insufficiency defined as presence of autoantibodies against 21-OH, SCC, 17-OH and/or NALP5 or other relevant autoantibodies 18-35 yrs of age Body mass index 19-30. In fertile females, willingness to comply with effective contraceptive methods. Ability to provide informed consent Exclusion Criteria: Documented hypersensitivity or intolerance to rituximab Active, severe infection Severe immunosuppression Severe cardiac disease Cancer Benign tumours of the hypothalamus, pituitary, or ovary; ovarian enlargement or ovarian cyst Vaginal bleeding of unknown aetiology Hormone replacement therapy (HRT) within four weeks prior study entry. Pregnant or lactating women Concurrent treatment with other immunosuppressive drugs Vaccination within 4 weeks of infusion of study medication Severe psychiatric disorder Patient with any condition or any circumstance that in the opinion of the investigator would make it unsafe to undergo treatment with Rituximab.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rituximab<br>Controlled ovarian hyperstimulation will be performed before and four months after two infusions of 1-gram rituximab (Mabthera®). | Drug: Rituximab<br>* 1 gram rituximab twice with two weeks interval<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of antral follicles in response to ovarian stimulation 4 months after last rituximab infusion. | Vaginal ultrasound measurement | 4 months | 
| The largest follicle in response to ovarian stimulation 4 months after last rituximab infusion. | Vaginal ultrasound measurement | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous menstrual bleedings during the 12 months' study period | Number of spontaneous menstrual bleedings | 12 months | 
| Ovulation during the 12 months' study period | Confirmed ovulation (y/n) | 12 months | 
| Immunoglobulin levels | Change in immunoglobulin levels (g/L) from baseline | 4 and 12 months |