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Preconceptional Counselling in Active Rheumatoid Arthritis (PreCARA)

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: NCT01345071
Recruitment Status : Recruiting
First Posted : April 29, 2011
Last Update Posted : April 28, 2016
Sponsor:
Collaborators:
Erasmus Medical Center
Dutch Arthritis Association
Information provided by (Responsible Party):
J.M.W. Hazes, Erasmus Medical Center

Tracking Information
First Submitted Date April 13, 2011
First Posted Date April 29, 2011
Last Update Posted Date April 28, 2016
Study Start Date September 2011
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 26, 2016)
DAS28(3)CRP at all study points [ Time Frame: Every 3 months from baseline till 6 months after delivery ]
Original Primary Outcome Measures
 (submitted: April 28, 2011)
number of pregnancies [ Time Frame: 2 years ]
Percentage of women that become pregnant during 2 year period of time, with accurate controlled disease activity of RA.
Change History
Current Secondary Outcome Measures
 (submitted: April 26, 2016)
  • Time to pregnancy [ Time Frame: At baseline and every 3 months till pregnant ]
    Patient is asked whether is she is pregnant. Pregnancy is defined as positive pregnancy test or ultrasound.
  • Number of miscarriages [ Time Frame: After conception, every 3 months ]
    Patients normally report miscarriages spontaneously at the next visit after miscarriage or contact the research nurse themselves to report this. If not, and patient is not pregnant anymore, reason for ending of pregnancy will be asked.
  • Complications during pregnancy [ Time Frame: Every 3 months during pregnancy and first visit after delivery ]
    Complications are: hypertensive disorders, pre-eclampsia, diabetes, mode of delivery, hospitalization
  • Gestational age of child [ Time Frame: First visit after delivery ]
  • Birth weight of child [ Time Frame: First visit after delivery ]
  • Congenital malformations [ Time Frame: First visit after delivery ]
  • Growth of child and tempo of growth during first year [ Time Frame: One year after birth ]
  • Maternal serum levels of anti-TNF [ Time Frame: Every three months during pregnancy ]
  • Levels of anti-TNF in cord blood [ Time Frame: Collected at birth ]
  • Levels of anti-TNF in child [ Time Frame: Every six weeks after birth ]
    Only if anti-TNF in cord blood was above reference value, blood will be drawn from the newborn every six weeks, till anti-TNF-levels are below reference value
Original Secondary Outcome Measures
 (submitted: April 28, 2011)
health of newborn exposed to TNFalfa inhibitors [ Time Frame: 3 years ]
Development (growth and health) of newborns exposed to TNFalfa in utero / early in pregnancy.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Preconceptional Counselling in Active Rheumatoid Arthritis
Official Title PreConceptional Counselling in Active Rheumatoid Arthritis
Brief Summary The first objective of the study is to evaluate a treat to target treatment strategy in women with moderate to high disease activity of RA and a pregnancy wish, from pre-pregnancy. The treatment strategy is based on deliberate treatment decisions to lower disease activity, including the continuation or start of biological treatment (in particular anti-Tumor Necrosis Factor [anti-TNF]), based on a standard care protocol in the Erasmus MC. The second objective is to evaluate the safety of the use of anti-TNF during pregnancy among women with a rheumatic disease that require the use of anti-TNF before or during pregnancy.
Detailed Description

Rheumatoid Arthritis (RA) is an auto-inflammatory disease that particularly involves chronic inflammation of the joints.The disease is in essence a systemically active one that can affect almost any organ. Pregnancy can spontaneously reduce the activity of RA. This phenomenon has been investigated in the PARA-study (Pregnancy-induced Amelioration of Rheumatoid Arthritis study), a nationwide prospective cohort study initiated and coordinated by the department of Rheumatology, Erasmus University Medical Center, Rotterdam the Netherlands.

The PARA-study reconfirmed previous data that RA improved during pregnancy. However, it also showed that this improvement was less pronounced than previously thought since > 50% of RA-patients still had active disease during third trimester of pregnancy. It also demonstrated that active RA was associated with lower birth weight and that children of mothers with active RA demonstrated rapid catch up growth in weight. Lower birth weight as well as rapid catch up growth in weight have been shown to be associated with a less favorable cardiovascular profile in early adulthood. Finally, it showed that time to pregnancy is prolonged in RA-patients with active disease. Also the use of prednisone > 7,5 mg daily or the use of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) were associated with a prolonged time to pregnancy. These latter associations were independent of disease activity.

The findings of the PARA-study implicate that one should strive for low disease activity in women with RA and a pregnancy wish, but that in the meantime NSAIDs and doses of prednisone exceeding 7.5 mg daily should be avoided. Since common drugs to treat RA, like methotrexate, are incompatible with pregnancy, lowering disease activity in pregnant RA-patients or with a pregnancy wish becomes a real challenge for the patient and the treating physician. This all underscores the importance of new treatment modalities for RA-patients with a pregnancy wish.

In the last decade new treatment options for RA, the so-called biologicals, became available. During pregnancy the most experience has been gained with biologicals belonging to the class of anti-TNF therapy. In the USA, anti-TNF has been approved for use during pregnancy as a FDA (Food and Drug Administration) class B (i.e. Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate, but well-controlled, studies of pregnant women have not been conducted). Registry studies show that anti-TNF use seems to be safe during pregnancy in humans also. Furthermore, anti-TNF therapy has been used intentionally preconceptionally to improve the chance of pregnancies in women with recurrent spontaneous abortions. Since no randomized controlled trials can be done during pregnancy, circumstantial evidence has led to decision making in daily practice. In case of high disease activity use of anti-TNF to control disease activity outweighs the risk of potential harm to the foetus.

Most anti-TNF medications are monoclonal antibodies of the IgG class. For that reason these antibodies are, from around week 14 of gestation, actively transported across the placenta. When used into third trimester of pregnancy, higher levels of these TNF-alpha antibodies are reached in the fetal circulation compared to the maternal circulation, making the newborn more prone for infections. Vaccination of newborns with live inactivated vaccines are therefore contraindicated till anti-TNF alpha antibody levels are not detectable anymore. It is often advised to stop anti-TNF in the first trimester of pregnancy. The rationale behind this approach is that RA improves during pregnancy anyway and that it is safe to taper off medication. In addition it is thought that with discontinuation of anti-TNFearly during pregnancy no placental transfer of anti-TNF antibodies will take place. However, currently no scientific evidence is available to support both assumptions.

An alternative approach is to prescribe Certolizumab during pregnancy or in women with a pregnancy wish. Certolizumab is a pegylated antibody against TNF-alpha. Since it lacks an Fc-tail it is not transported across the placenta and only trace amounts can be detected in the newborn. In the Erasmus MC a protocol was recently developed to standardize care for patients (already pregnant or with a pregnancy wish) that in theory might benefit from treatment with anti-TNF therapy. This protocol is being evaluated in the Pre-CARA study.

The Pre-CARA study is a continuation of the previous PARA study, but focuses on RA patients with high disease activity and a pregnancy wish. The first objective is to evaluate a treat to target treatment strategy in women with moderate to high disease activity of RA and a pregnancy wish, from pre-pregnancy till six months after delivery. The treatment strategy is based on deliberate treatment decisions to lower disease activity, including the continuation or start of biological treatment (anti-TNF), based on a standard care protocol in the Erasmus MC. The second objective is to evaluate the safety of the use of anti-TNF during in women with any chronic arthritide who require the use of this medication preconceptionally and/or during pregnancy.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Blood of mother before, during and after pregnancy; cordblood of newborn; blood of newborn if anti-TNF in cord blood was above reference level.
Sampling Method Non-Probability Sample
Study Population

For first objective: Women with high disease activity of RA and a pregnancy wish.

For second objective: Women with a rheumatic disease that requires the use of anti-TNF before or during pregnancy

Condition
  • Rheumatoid Arthritis
  • Pregnancy
Intervention Not Provided
Study Groups/Cohorts RA patients
RA patients with active disease or current use of anti-TNF. Treatment is according to treat to target principles.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: April 26, 2016)
150
Original Estimated Enrollment
 (submitted: April 28, 2011)
40
Estimated Study Completion Date May 2025
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion criteria for first objective (150 subjects)

  • Rheumatoid Arthritis according to 2010 ACR/EULAR criteria
  • active pregnancy wish
  • either DAS28(3)CRP > 3.2 or the current use of anti-TNF

Inclusion criteria for second objective (no limit on number of subjects needed, recruitment will end when 150 RA patients have been included)

  • rheumatic disease that requires the use of anti-TNF before or during pregnancy
  • active pregnancy wish

Exclusion criteria:

- none

Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Marieke van Wier, PhD +31 10 7032181 m.vanwier@erasmusmc.nl
Contact: Radboud Dolhain, PhD MD r.dolhain@erasmusmc.nl
Listed Location Countries Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number NCT01345071
Other Study ID Numbers ErasmusMC-MEC-2011-032
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Undecided
Plan Description: This will be discussed in the research group
Responsible Party J.M.W. Hazes, Erasmus Medical Center
Study Sponsor J.M.W. Hazes
Collaborators
  • Erasmus Medical Center
  • Dutch Arthritis Association
Investigators
Principal Investigator: Radboud Dolhain, PhD MD Staff Rheumatologist
PRS Account Erasmus Medical Center
Verification Date April 2016