The REFINE study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karolinska University Hospital

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Decision date (initial)

2025-10-17

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of this trial is to investigate the efficacy of rituximab in enabling egg retrieval after controlled ovarian hyperstimulation in autoimmune POI 4 to 6 months after rituximab compared to placebo, as well as the whole group treated with rituximab at 4 to 6 and 12 months after the last treatment session compared to baseline.

Secondary objectives 6

1. To assess the occurrence of spontaneous menstrual bleeding during the 19-month study period.
2. To determine the incidence of ovulation during the study period, confirmed by increased serum progesterone levels (>10 nmol/L).
3. To evaluate changes in B-cell count, auto-antibody indices, and immunoglobulin levels (IgG) following treatment.
4. To measure changes in serum levels of follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) throughout the study period.
5. To assess changes in quality of life using validated instruments, including the Quality of Life in Addison´s disease (AddiQol), Psychological General Well-Being (PGWB), Short Form Health Survey (SF-36), and Menopause Rating Scale (MRS).
6. Safety objective: to evaluate the safety of the intervention by monitoring adverse events, hospital admissions, infections, allergic reactions and over stimulation in relation to the controlled ovarian hyperstimulation.

Conditions and MedDRA coding

Autoimmune Premature Ovarian Insufficiency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

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 method (such as intra uterine device (IUD), sexual abstinence, male or female condom with or without spermicide, cap, diaphragm or sponge with spermicide) during the 18-month study period

Exclusion criteria 16

1. Hypersensitivity to rituximab, any of the AxMPs, or any of the excipients (as detailed in the SmPC for the various IMPs)
2. Concurrent treatment with other immunosuppressive drugs
3. Any vaccination within 4 weeks of infusion of study medication
4. Severe psychiatric disorder
5. 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
6. Active, severe infection or JCV positivity
7. Severe immunosuppression
8. Severe cardiac disease
9. Cancer
10. Benign tumours of the hypothalamus, pituitary, or ovarian pathology
11. Vaginal bleeding of unknown etiology
12. Hormone replacement therapy within four weeks prior study entry
13. Pregnant or lactating women
14. Active hepatitis B infection
15. Active thrombolic disorder (contraindicated for Ovirelle)
16. Moderate or severe impairment of kidney or liver function (contraindicated for Orgalutran)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Egg retrieval (yes/no) in response to controlled ovarian hyperstimulation at 4 to 6 months post-rituximab treatment compared to placebo, as well as within the rituximab-treated group at 4 to 6 and 12 months after the last treatment session compared to baseline.

Secondary endpoints 6

1. Occurrence of spontaneous menstrual bleeding (yes/no) at any point during the 19-month study period.
2. Proportion of participants who achieve ovulation (defined as serum progesterone >10 nmol/L) at any time during the study period.
3. Changes in B-cell count, auto-antibody indices, and immunoglobulin (IgG) levels from baseline to the end of the study period.
4. Changes in serum follicle-stimulating hormone (FSH) and anti-Müllerian hormone (AMH) levels from baseline to the end of the study period.
5. Changes in quality of life scores, as measured by validated instruments (AddiQol, PGWB, SF-36, and MRS), from baseline to the end of the study period.
6. Safety endpoint: the incidence and severity of adverse events, hospital admissions, infections, allergic reactions and over stimulation in relation to the controlled ovarian hyperstimulation.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karolinska University Hospital

Sponsor organisation

Karolinska University Hospital

Address

Eugeniavagen 3

City

Solna

Postcode

171 64

Country

Sweden

Scientific contact point

Organisation

Karolinska University Hospital

Contact name

Angelica Lindén Hirschberg

Public contact point

Organisation

Karolinska University Hospital

Contact name

Angelica Lindén Hirschberg

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications