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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04701034
Recruitment Status : Recruiting
First Posted : January 8, 2021
Last Update Posted : July 23, 2021
Sponsor:
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

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

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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


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.




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



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04701034


Contacts
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Contact: Caroline Noergaard-Pedersen +45 97663037 c.noergaardpedersen@rn.dk
Contact: Ole B Christiansen +45 97663064 olbc@rn.dk

Locations
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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
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Principal Investigator: Ole B Christiansen Aalborg University Hospital, Denmark
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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    Key Record Dates
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.

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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:
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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