Intravenous Immunoglobulin and Prednisolone for RPL After ART.

NCT04701034 | Completed Phase 2 DMC

• 3 other identifiers: CNPOBC20202020-000256-35U1111-1273-8585
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Recurrent pregnancy loss (RPL) affects around 5 % of women in reproductive age. The underlying cause of RPL is most often unknown, probably multifactorial, and no treatment with documented effect on chance of live birth exists. In unexplained cases of RPL, primarily the immune system is hypothesized to play a pivotal, causative role, since autoantibodies and specific human leukocyte antigen (HLA) alleles as well as unbalanced distribution of leucocyte subsets, especially natural killer (NK) cells and T-helper (Th) cells, occurs more frequently in patients with unexplained RPL. For that reason, many treatment regimens used in autoimmune diseases have been tested on RPL patients, as for example prednisolone and intravenous immunoglobulin (IVIg). IVIg (Privigen) consist of a broad spectrum of structurally and functionally intact IgG antibodies. The mechanism of action is not fully elucidated, but certainly IVIg do help opsonise and neutralize foreign cells and pathogens. Prednisolone support this anti-inflammatory action by suppressing migration of polymorphonuclear leukocytes, and reducing the volume and activity of the immune system and the capillary permeability. A retrospective, observational pilot study suggested that a combination of prednisone and IVIg in first trimester improves the chance of a live birth in women with RPL after assisted reproductive technologies (ART) (Nyborg et al., 2014). A randomized controlled study is necessary for determining if this immunomodulatory treatment definitely is effective in patients with unexplained RPL after ART (defined as IVF or ICSI ad FER). Potentially, this study will be able to establish evidence for an effective treatment to women with unexplained RPL after ART, who otherwise have a poor prognosis.

Conditions

Habitual Abortion; Recurrent Pregnancy Loss; Fertility Disorders; Miscarriage

Keywords

Fertility treatment; In vitro fertilization; Intravenous immunoglobulin; Prednisolone; Recurrent pregnancy loss

Outcome Measures

Primary Outcomes (6)

• A normal live fetus at nuchal scan in ITT population

  The frequency of participants with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively. Here, the primary analyses will be undertaken as an intention-to-treat (ITT) analysis, including all participants who were allocated to either active or placebo treatment at the start of the ART cycle, even if they did not receive infusion with IVIg or albumin due to cancellation of embryo/blastocyst transfer.

  12 week after embryo transfer

• A normal live fetus at nuchal scan in PP population

  The frequency of participants with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively. Here, the primary analyses will be undertaken as a per-protocol (PP) analysis, including patients who were randomized and received the allocated infusion of study medicine at the time of embryo/blastocyst transfer and had this transfer performed.

  12 week after embryo transfer

• Live birth rate in ITT population

  The frequency of participants with a liveborn (sign of life immediately af delivery \>24 weeks) among all randomized participants

  At delivery

• Live birth rate in the PP population

  The frequency of participants with a liveborn (sign of life immediately af delivery \>24 weeks) among all participants who fulfill criteria for PP-analysis

  At delivery

• A normal live fetus at nuchal scan among participants who become pregnant after embryo transfer in the ITT population

  The frequency of participants in the ITT population with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively, and who become pregnant after embryo transfer.

  12 week after embryo transfer

• A normal live fetus at nuchal scan among participants who become pregnant after embryo transfer in the PP population

  The frequency of participants in the PP population with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively, and who become pregnant after embryo transfer.

  12 week after embryo transfer

Secondary Outcomes (13)

• Maternal adverse reactions

  9 months after embryo transfer.

• Negative pregnancy test

  9 months after embryo transfer.

• Miscarriage rate

  Before 24 weeks of gestation

• Rate of Abnormal karyotype in Miscarried fetuses

  Before 24 weeks of gestation

• Rate of Stillbirth rate

  9 months after embryo transfer.

Study Arms (2)

Active treatment group

ACTIVE COMPARATOR

Intravenous immunoglobulin(IVIg) and prednisolone. IVIG is administered at the time of embryo/blastocyst transfer (ET) (5 days before to 2 days after ET) and if the participant becomes pregnant, the infusion (same dose) is repeated in gestational week 5, 6, and 7. Participants with pre-pregnancy weight ≤70 kg will receive 25 g immunoglobulin (250 ml), participants with weight 70-85 kg will receive 30 g immunoglobulin (300 ml), and participants with weight ≥85 kg will receive 35 g immunoglobulin (350 ml) at each infusion, which will approximate 0.4 g IVIg per kg body weight. Prednisolone, tablets, 5mg. 1 tablet daily started within first 3 days of menstrual cycle and until ET. On the day of ET, the participant will double her dose to 2 tablets daily until a negative pregnancy test, the time of biochemical loss/miscarriage, or pregnancy week 8+0, whichever comes first. Gradual discontinuation four days with one tablet before completing cessation.

Drug: Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring); Drug: Prednisolone Tablets

Passive treatment group

PLACEBO COMPARATOR

Human albumin infusion and placebo tablets. Human albumin, 5%, (CLS Behring). Participants with pre-pregnancy weight ≤70 kg will receive 250 ml, participants with weight 70-85 kg will receive 300 ml, and participants with weight ≥85 kg will receive 350 ml at each infusion. Administration is planned at the time of ET (5 days before to 2 days after ET) and if the participant becomes pregnant, the infusion is repeated in the same volume in gestational week 5, 6, and 7. Placebo tablets: contain 85 mg of lactose monohydrate, 86 mg potato starch, 8.1 mg talc, 3 mg gelatine, and 0.9 mg magnesium stearate. 1 tablet daily started within first 3 days of menstrual cycle and until ET. On the day of ET, the participant will double her dose to 2 tablets daily until a negative pregnancy test, the time of biochemical loss/miscarriage, or pregnancy week 8+0, whichever comes first. Gradual discontinuation four days with one tablet before completing cessation.

Drug: Human Albumin Solution; Drug: Placebo tablet

Interventions

Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring) DRUG

infusion: Initial infusion rate of 0.3 ml/kg BW/hr in about 30 min. If well-tolerated, the infusion rate may gradually be increased to 4.8 ml/kg BW/hr. During the infusion, health care personnel are present to secure immediate action in case of serious AR. Blood pressure and pulse is monitored before, during and after the treatment. In case of anaphylaxis, the treatment is discontinued and the participant is excluded. The hospital ward possess adrenaline 0.1 % solutions ready in case of anaphylaxis.

Also known as: IVIg

Active treatment group

Prednisolone Tablets DRUG

5 mg before ET and 10 mg after ET until gestational week 8+0

Active treatment group

Human Albumin Solution DRUG

Infusion: Initial infusion rate of 0.3 ml/kg BW/hr in about 30 min. If well-tolerated, the infusion rate may gradually be increased to 4.8 ml/kg BW/hr. During the infusion, health care personnel are present to secure immediate action in case of serious AR. Blood pressure and pulse is monitored before, during and after the treatment. In case of anaphylaxis, the treatment is discontinued and the participant is excluded. The hospital ward possess adrenaline 0.1 % solutions ready in case of anaphylaxis.

Also known as: Albumin infusion

Passive treatment group

Placebo tablet DRUG

1 tablet before ET and 2 tablets after ET until gestational week 8+0

Passive treatment group

Eligibility Criteria

• Age: 18 Years - 41 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Women with ≥ 2 consecutive pregnancy losses (miscarriages or biochemical pregnancies) ≤ completed gestational week 10 after ART with the present partner or with an egg/semen donor\*
• The gestational week of the non-induced pregnancy losses will be based on the date of clinical signs of miscarriage or the fetus' crown-rump-length of a missed abortion measured on the ultrasonic scan detecting the pregnancy loss. If the participant plan to use egg donation in the study cycle, the previous two pregnancy losses must also have happened with the use of egg donation; however, it is not required to use the same egg donor in all three embryo transfers.

You may not qualify if:

• BMI ≥35
• Age ≥41
• Significant uterine malformation(s)
• Known parental balanced chromosomal translocations
• ≥2 previous pregnancies with fetuses with known abnormal karyotype
• Patients with IgA deficiency, IgA-autoantibodies or hyperprolinaemia
• Treatment with medication interacting with prednisolone
• CYP3A4-inhibitors (fx erythromycin, itraconazole, ritonavir, lopinavir), CYP3A4-inductors (fx phenobarbital, phenytoin og rifampicin), loop diuretics, thiazides, amphotericin B, beta2-agonists, antidiabetics, interleukin-2, somatotropins, anticholinergics and regular treatment with NSAIDs.
• Patients with moderate/severe hypertension, diabetes mellitus, heart insufficiency, severe mental disorders, Cushing syndrome, myasthenia gravis, ocular herpes simplex, pheochromocytoma, systemic sclerosis, and moderate/severe renal dysfunction.
• Patients with a clinical or biochemical profile indicating need for heparin or levothyroxine treatment during pregnancy
• Previous treatment with IVIg
• Allergy to prednisolone and/or IVIg

Sponsors & Collaborators

• Aalborg University Hospital: lead
• Svend Andersen Fonden: collaborator
• Beckett Foundation: collaborator
• L.F. Foghts Foundation: collaborator

Study Sites (1)

• The Centre for Recurrent Pregnancy Loss of Western Denmark, Department of Obstetrics and Gynaecology, Aalborg University Hospital

Aalborg, 9000, Denmark

Location

Related Publications (2)

• Norgaard-Pedersen C, Kesmodel US, Jorgensen MM, Christiansen O. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial. BMJ Open. 2025 Nov 19;15(11):e106024. doi: 10.1136/bmjopen-2025-106024.

  PMID: 41263919 DERIVED

• Norgaard-Pedersen C, Nielsen K, Steffensen R, Eriksen L, Jorgensen MM, Kesmodel US, Christiansen OB. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2022 Sep 22;12(9):e064780. doi: 10.1136/bmjopen-2022-064780.

  PMID: 36137638 DERIVED

MeSH Terms

Conditions

Abortion, Habitual; Abortion, Spontaneous

Interventions

Immunoglobulins, Intravenous; Prednisolone

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Ole B Christiansen

  Aalborg University Hospital, Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: None of the personnel with patient contact will have knowledge to the patient's allocation to active treatment or placebo group. Medicine will be handled at another location and sent to the RPL center masked with universal labels with only name of the patient and study ID number.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.med.

Study Record Dates

• First Submitted: January 5, 2021
• First Posted: January 8, 2021
• Study Start: January 28, 2021
• Primary Completion: April 18, 2024
• Study Completion: April 18, 2024
• Last Updated: November 24, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: After results have been published in a manuscript.
• Access Criteria: If allowed, individual data on these variables will be shared after deidentification together with data dictionary. Sharing will be done after publication and will be available up to 5 years after study has ended. Study protocol will be available too. Data will only be shared with researchers who provide a methodologically sound proposal according to CNP and OBC (the two primary investigators). Proposals should be directed to c.noergaardpedersen@rn.dk. To gain access, data requestors will need to sign a data access agreement.

Locations

DK (1)