Intravenous Immunoglobulin and Prednisolone for RPL After ART. (RPL)

• ClinicalTrials.gov Identifier: NCT04701034
• Recruitment Status: Recruiting
• First Posted: January 8, 2021
• Last Update Posted: July 23, 2021
• Sponsor: Caroline Nørgaard-Pedersen
• Collaborators: Clinical Immunological Department, Aalborg University Hospital; Svend Andersen Fonden; The Pharmacy of Aalborg University Hospital; GCP department of Aalborg University Hospital; Beckett Foundation; L.F. Foghts Foundation
• Information provided by (Responsible Party): Caroline Nørgaard-Pedersen, Aalborg University Hospital

Study Description

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 volume of the immune system, capillary permeability, and immune cell activity.

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 is definitely effective in patients with unexplained RPL after ART (defined as IVF or ICSI treatment). Potentially, this study will be able to establish a new treatment to women with unexplained RPL after ART, who otherwise have a poor prognosis.

Condition or disease	Intervention/treatment	Phase
Habitual Abortion; Recurrent Pregnancy Loss; Fertility Disorders; Miscarriage	Drug: Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring); Drug: Prednisolone Tablets; Drug: Human Albumin Solution; Drug: Placebo	Phase 2

Detailed Description:

In a randomized, double-blinded, placebo-controlled trial, this study aims to investigate whether treatment with prednisolone and intravenous immunoglobulin (IVIg) before and in early pregnancy improves the chance of a live birth in women undergoing treatment with artificial reproductive technologies (ART) (defined as IVF or ICSI or FER treatment) after previous recurrent pregnancy loss (RPL) after ART.

If an improved live birth rate can be confirmed, the treatment will be the first documented treatment supplement for women undergoing ART treatment. A treatment with such effect is highly desirable, and in addition to increased birth rate, it will potentially improve quality of life and reduce detrimental anxiety and stress symptoms associated with RPL and ART treatment, since the number of treatments and the number of losses will be reduced.

Potential study participants will be identified among patients who are referred to The Center for Recurrent Pregnancy Loss of Western Denmark (in the following called The RPL Center), located at Aalborg University Hospital (AaUH).

At the first appointment at The RPL Center, a list of standard health information important for the RPL examination will be collected together with the RPL Center's standard blood sample.

Treatment: The participants will be randomly allocated 1:1 to active immunomodulatory treatment versus placebo treatment (see Arms and Interventions). Study treatment starts on the patient's first day of her menstrual cycle in which her fertility clinic plan to transfer an embryo/blastocyst(s) and continue until a negative pregnancy test, the time of biochemical pregnancy loss/miscarriage or pregnancy week 8+0, whichever comes first.

Approximately 14 days after ET, the patient will have a pregnancy test. If positive, the patient will have plasma-hCG measured twice with 1-2 days interval at her local hospital. With adequate increment of plasma-hCG, the patient will be booked for her last 3 infusions in gestational week 5, 6, and 7, and continue tablet intake. If she is not pregnant, study medication will not continue.

On the day of the first infusion treatment and again approximately four weeks later (the day of her third infusion treatment during pregnancy), a study specific blood sample will be taken for our research biobank. In participants who do not achieve pregnancy or have a miscarriage before gestational week 6 (and therefore do not come for the third infusion), we will ask these participants to come for the second blood sample too. The blood samples will be analysed by the Department of Clinical Immunology at AaUH. In addition, a group of 37 healthy female blood donors in reproductive age with no prior known pregnancy losses will have one blood sample collected in their luteal phase and analyzed according to the same protocol and will serve as a reference group to the two study groups.

An immediate analysis of the blood sample will quantify NK-cells, B-cells, and T-cell subsets by flow cytometry. Also, a TruCulture analysis for activity of leucocyte subsets will be carried out in 25 patients. The research/future biobank will store frozen serum and plasma for analysis of immune markers including smaller extracellular vesicles.

If the participant is still pregnant after her last infusion of study medicine before week 8+0, she will be offered routine monitoring at The RPL Center at AaUH, at her local fertility clinic, and her local hospital. She will receive a questionnaire 2 weeks after her nuchal scan and 2 weeks after her due date for collection of data regarding her pregnancy, delivery, and perinatal outcome.

Study-relevant data will be collected from medical records, birth records, questionnaires, and the research biobank.

Adverse events will be recorded on all participants from the day of admission and until 6 months after last infusion treatment or until birth of her child if she becomes pregnant. Both adverse events in the participant and her child will be recorded. To support compliance and meticulous reporting of side effects, all participants receive a folder with a list of all known side effects to prednisolone, IVIg and albumin, a diary with boxes to tick of every day the tablet(s) is taken, and a table in which side effects can continuously be noted. According to the child, negative perinatal outcomes (low birth weight, preterm birth, stillbirth) and malformations will be recorded after birth.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: 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.
• Primary Purpose: Treatment
• Official Title: Does Intravenous Immunoglobulin and Prednisolone Treatment Improve Success Rate in Women With Recurrent Pregnancy Loss After Assisted Reproductive Technology Treatment?
• Actual Study Start Date: February 6, 2021
• Estimated Primary Completion Date: June 1, 2023
• Estimated Study Completion Date: August 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Active treatment group; Intravenous immunoglobulin and prednisolone. See study description	Drug: Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring); Privigen 100 mg/ml (CLS Behring); Infusion of approximately 0.4 ml/kg body weight. Administration is planned at the time of embryo/blastocyst transfer (5 days before to 2 days after ET) and if she becomes pregnant, the infusion is repeated in the same dose in gestational week 5, 6, and 7. Patients with pre-pregnancy weight ≤70 kg will receive 25 g Privigen (250 ml), patients with weight 70-85 kg will receive 30 g Privigen (300 ml), and patients with weight ≥85 kg will receive 35 g Privigen (350 ml) at each infusion, which will approximate 0.4 g IVIg per kg body weight.; Other Name: IVIg; Drug: Prednisolone Tablets; Prednisolone DAK, tablets, 5mg. 1 tablet daily from first day of menstrual cycle and until embryo/blastocyst transfer. On the day of embryo/blastocyst transfer, she will double her dose to 2 tablets daily until negative pregnancy test, pregnancy week 8+0 or the time of biochemical loss/miscarriage, whichever comes first.
Placebo Comparator: Passive treatment group; Human albumin infusion and placebotablet. See study description	Drug: Human Albumin Solution; Human albumin, 5%, (CLS Behring). 0.4 ml/kg body weight. Administration is planned at the time of embryo/blastocyst transfer (5 days before to 2 days after ET) and if she becomes pregnant, the infusion is repeated in the same dose in gestational week 5, 6, and 7.; Other Name: Albumin infusion; Drug: Placebo; The Placebo tablets contain 85 mg of lactose monohydrate, 85 mg potato starch, 8.1 mg, talc 3 mg gelatine, and 0.9 mg magnesium stearate. 1 tablet daily from first day of menstrual cycle and until embryo/blastocyst transfer. On the day of embryo/blastocyst transfer, she will double her dose to 2 tablets daily until negative pregnancy test, pregnancy week 8+0 or the time of biochemical loss/miscarriage, whichever comes first.

Outcome Measures

Primary Outcome Measures :

1. A normal live fetus at nuchal scan [ Time Frame: 12 week after embryo transfer ]

   The frequency of patients with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively.

   The primary analyses will be undertaken as:

   1. An intention-to-treat (ITT) analysis, including all patients 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.
   2. 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.
2. Live birth rate [ Time Frame: At delivery ]
   Number of patients with a liveborn (sign of life immediately af delivery >24 weeks) among all patients - both PP and ITT.

Secondary Outcome Measures :

1. Maternal adverse reactions [ Time Frame: 9 months after embryo transfer. ]
   Number of patients with adverse reactions including headache, skin rash, and fever that might be associated to study medicine among all patients included (intention to treat).
2. Miscarriage rate [ Time Frame: Before 24 weeks of gestation ]
   Number of patients with a miscarriage (defined as any loss before 24 weeks of gestation) among the number of patients becoming pregnant (defined as a rise in serum beta hCG concentration >25 UI/L per transfer)
3. Stillbirth rate [ Time Frame: 9 months after embryo transfer. ]
   Number of patients with a still birth (defined as fetal death at 24 weeks or more or no sign of life after delivery) among the number of patients becoming pregnant (defined as a rise in serum beta hCG concentration >25 UI/L per transfer)
4. Rate of congenital deformities [ Time Frame: 1 week after delivery ]
   Number of live-born babies with a of congenital deformity among all live-borns.
5. Rate of preterm birth [ Time Frame: 1 week after delivery ]
   Number of live-born before 37+0 weeks of gestation among all live-borns.
6. Rate of low birth weight (BW) [ Time Frame: 1 week after delivery ]
   Number of live-born with a BW <2500 g among all live-borns.
7. Rate of preeclampsia [ Time Frame: 1 week after delivery ]
   Number pregnant patients >24 weeks with hypertension (systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP) greater than or equal to 90 mm Hg) and proteinuria (>0.3 g per day or urine albumine/creatinine ratio≥ 300 mg/g) among all pregnant patients >24 weeks.
8. Rate of gestational hypertension [ Time Frame: 1 week after delivery ]
   Number pregnant patients >24 weeks with hypertension (i.e. systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP)) among all pregnant patients >24 weeks.
9. Rate of abnormal embryonic/fetal karyotype [ Time Frame: Before 24 weeks of gestation ]
   Number of miscarriages with a abnormal embryonic/fetal karyotype among all miscarriages having a karyotype test.
10. The effect of study medicine on immune cells (explorative study) [ Time Frame: The first blood sample taken the day for 1 infusion (which is the same week as embryo transfer) and the second blood sample is taken 4 weeks after embryo transfer. ]
    NK-cell count, B-cell count and T-cell count, including T-cell subsets (Th1, Th2, Th17 and Treg) and Th1/Th2 ratio measured from blood samples taken at time of embryo transfer and again 4 weeks later to access immune balance before and after treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 41 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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

Exclusion Criteria:

1. BMI ≥35
2. Age ≥41
3. Significant uterine malformation(s)
4. Known parental balanced chromosomal translocations
5. ≥2 previous pregnancies with fetuses with known abnormal karyotype
6. Patients with IgA deficiency, IgA-autoantibodies or hyperprolinaemia

7. 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.
8. 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.
9. Patients with a clinical or biochemical profile indicating need for heparin or levothyroxine treatment during pregnancy
10. Previous treatment with IVIg
11. Allergy to prednisolone and/or IVIg
12. AMH <4 pmol/L. If transfer of donor egg is planned for her IVF cycle, the AMH value will not be an exclusion criterion.

Contacts and Locations

Contacts

Contact: Caroline Noergaard-Pedersen; +45 97663037; c.noergaardpedersen@rn.dk

Contact: Ole B Christiansen; +45 97663064; olbc@rn.dk

Locations

Denmark

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

Aalborg, Denmark, 9000

Contact: Caroline Nørgaard-Pedersen, D.M. c.noergaardpedersen@rn.dk

Contact: Ole Bjarne Christiansen, dr.med. olbc@rn.dk

Sponsors and Collaborators

Caroline Nørgaard-Pedersen

Clinical Immunological Department, Aalborg University Hospital

Svend Andersen Fonden

The Pharmacy of Aalborg University Hospital

GCP department of Aalborg University Hospital

Beckett Foundation

L.F. Foghts Foundation

Investigators

• Principal Investigator: Ole B Christiansen; Aalborg University Hospital, Denmark

More Information

• Responsible Party: Caroline Nørgaard-Pedersen, Investigator, data manager, dr.med, Aalborg University Hospital
• ClinicalTrials.gov Identifier: NCT04701034
• Other Study ID Numbers: CNPOBC2020; 2020-000256-35 ( EudraCT Number )
• First Posted: January 8, 2021
• Last Update Posted: July 23, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: The data that will be shared includes (due to the danish regulation) an overview of the data results with means, medians and standard deviations on numbers reported in manuscripts (text, tables, figures, and appendices). If allowed, individual data on these variables will be shared after deidentification together with data dictionary upon request. Sharing will be done after publication and will be available up to 5 years after study end. Study protocol will be available. 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (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.

• 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

Keywords provided by Caroline Nørgaard-Pedersen, Aalborg University Hospital:

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

Additional relevant MeSH terms:

Abortion, Spontaneous; Fetal Death; Abortion, Habitual; Pregnancy Complications; Death; Pathologic Processes; Prednisolone; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunologic Factors