Intravenous Immunoglobulin and Prednisolone for RPL After ART. (RPL)
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|ClinicalTrials.gov Identifier: NCT04701034|
Recruitment Status : Recruiting
First Posted : January 8, 2021
Last Update Posted : July 23, 2021
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|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||74 participants|
|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.|
|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|
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
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.
- 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:
- 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.
- 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.
- 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.
- 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).
- 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)
- 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)
- Rate of congenital deformities [ Time Frame: 1 week after delivery ]Number of live-born babies with a of congenital deformity among all live-borns.
- Rate of preterm birth [ Time Frame: 1 week after delivery ]Number of live-born before 37+0 weeks of gestation among all live-borns.
- 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.
- 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.
- 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.
- 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.
- 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
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
|Contact: Caroline Noergaard-Pedersen||+45 firstname.lastname@example.org|
|Contact: Ole B Christiansen||+45 email@example.com|
|• 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. firstname.lastname@example.org|
|Contact: Ole Bjarne Christiansen, dr.med. email@example.com|
|Principal Investigator:||Ole B Christiansen||Aalborg University Hospital, Denmark|