Immunomodulatory Therapy in Women With Autoimmune Premature Ovarian Insufficiency

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

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:

1. Reestablishment of spontaneous menstrual bleedings during the 12 months' study period
2. Ovulation during the 12 months' study period
3. 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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Diseases; Premature Ovarian Insufficiency
• Intervention / Treatment: Drug: Rituximab

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Angelica L Hirschberg, MD, PhD; Phone Number: +46 70 255 99 24; Email: angelica.linden-hirschberg@regionstockholm.se
• Study Contact Backup: Name: Sigridur Björnsdottir, MD, PhD; Phone Number: +46 70 255 99 24; Email: sigridur.bjornsdottir@regionstockholm.se

Study Locations

• Sweden
  • Stockholm, Sweden
    • Recruiting
    • Angelica Hirshberg
    • Contact: Angelica L Hirshberg, Md, PhD; Phone Number: +46702559924; Email: angelica.linden-hirschberg@regionstockholm.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 33 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Autoimmune premature ovarian insufficiency defined as presence of autoantibodies against 21-OH, SCC, 17-OH and/or NALP5 or other relevant autoantibodies
2. 18-35 yrs of age
3. Body mass index 19-30.
4. In fertile females, willingness to comply with effective contraceptive methods.
5. Ability to provide informed consent

Exclusion Criteria:

1. Documented hypersensitivity or intolerance to rituximab
2. Active, severe infection
3. Severe immunosuppression
4. Severe cardiac disease
5. Cancer
6. Benign tumours of the hypothalamus, pituitary, or ovary; ovarian enlargement or ovarian cyst
7. Vaginal bleeding of unknown aetiology
8. Hormone replacement therapy (HRT) within four weeks prior study entry.
9. Pregnant or lactating women
10. Concurrent treatment with other immunosuppressive drugs
11. Vaccination within 4 weeks of infusion of study medication
12. Severe psychiatric disorder
13. Patient with any condition or any circumstance that in the opinion of the investigator would make it unsafe to undergo treatment with Rituximab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Angelica Lindén Hirschberg
• Investigators: Study Chair: Olle Kämpe, MD, PhD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2019
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: October 9, 2022
• First Submitted That Met QC Criteria: October 15, 2022
• First Posted (Actual): October 19, 2022

Study Record Updates

• Last Update Posted (Actual): October 24, 2022
• Last Update Submitted That Met QC Criteria: October 20, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Autoimmune Diseases; Primary Ovarian Insufficiency; Menopause, Premature; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: KarolinskaUniversityHospital

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No