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Impact on Birth Weight of Two Therapeutic Strategies (Insulin Therapy From the Beginning of Pregnancy vs. Insulin Therapy Initiated According to Fetal Growth Evaluated by Ultrasonography Measurements) in Pregnant Women With Monogenic Diabetes (MODY2)

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ClinicalTrials.gov Identifier: NCT02556840
Recruitment Status : Recruiting
First Posted : September 22, 2015
Last Update Posted : March 19, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Maturity-onset diabetes of youth (MODY) are the most frequent monogenic diabetes with autosomic dominant inheritance (2% of diabetes). The MODY2 diabetes is related to a defect in the glucokinase (GCK) enzyme, the first limiting step of insulin secretion. An abnormal GCK leads to a delayed insulin secretion. Patients with GCK mutations have only mild raised fasting plasma glucose. Treatment is usually unnecessary since hyperglycemia is stable and MODY2 patients have no microvascular complications of diabetes. In contrast, pregnancy in MODY2 women is a challenging situation. A non-mutated fetus will produce excess insulin in response to raised maternal blood glucose leading to an accelerated growth and a higher risk of macrosomia. The mother of non-mutated fetus should therefore be treated to normalize her blood glucose levels. On contrary, a mutated fetus will produce a delayed insulin secretion (as his MODY2 mother) in response to maternal hyperglycemia. Consequently insulin therapy during pregnancy would reduce fetal insulin secretion and result in a low birth weight.

Moreover, insulin therapy exposes pregnant women to more labor induction, prematurity and cesarean deliveries. In these MODY2 women whose glucose set point is physiologically higher, glycemic goals are difficult to achieve while often requiring extensive insulin therapy. An optimal situation would consist in initiating insulin therapy only for women with non-mutated offsprings. Unfortunately no antenatal diagnosis of the GCK mutation on fetal cells is available yet. In literature, birth weight differences between mutated and non-mutated neonates may reach up to 700g. In clinical practice, two strategies are used but without standardized protocol on glycemic targets, delay and doses of insulin : 1) insulin at diagnosis of pregnancy 2) treatment based on fetal abdominal circumference and fetal weight measurements by ultrasonography (US) and initiated if fetal biometry is greater than the 75th percentile.

The purpose of the study is to evaluate for the first time these two management strategies through a prospective and standardized study. Hypothesis: US assessment would be sufficient to identify fetuses at risk of macrosomia and to initiate insulin treatment in mothers.


Condition or disease Intervention/treatment Phase
Maturity-Onset Diabetes of the Young Other: insulin therapy Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Impact of Two Standardized Clinical Care Protocols on Pregnancy Outcomes in Women With Monogenic Diabetes MODY2
Actual Study Start Date : April 25, 2016
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
Active Comparator: Insulin therapy from the beginning of pregnancy

Insulin therapy (Glargine/Lantus®, Détémir/Levemir® , Insulatard® , Umuline NPH® , Lispro/Humalog® , Asparte/Novorapid® or Actrapid ®) administered from the beginning of pregnancy according to maternal blood glucose (if fasting blood glucose > 0.95g/l or post-prandial blood glucose > 1.20g/l) as recommended by the national guidelines for gestational diabetes mellitus.

Insulin administered to patients either by subcutaneous injections or by pump.

Other: insulin therapy
Experimental: Insulin therapy initiated according to fetal growth

Insulin therapy (Glargine/Lantus®, Détémir/Levemir® , Insulatard® , Umuline NPH® , Lispro/Humalog® , Asparte/Novorapid® or Actrapid ®) initiated according to fetal growth evaluated by ultrasonography measurements. MODY2 women will not be treated with insulin until delivery, except when the fetal abdominal circumference exceeds ≥ the 75 percentile on one US or maternal fasting capillary blood glucose is ≥ 1,20 g/L or maternal post-prandial capillary blood glucose is ≥ 2,00 g/L.

Insulin administered to patients either by subcutaneous injections or by pump.

Other: insulin therapy



Primary Outcome Measures :
  1. Birth weight for gestational age [ Time Frame: at birth ]
    this end point will sustain two derived criteria: birth weight for gestational age as a quantitative criterion and birth weight considered as small (below the 10th percentile), normal, or large (above the 90th percentile).


Secondary Outcome Measures :
  1. Number of neonatal hypoglycaemia [ Time Frame: at birth ]
    defined as the presence of symptoms and/or the need for treatment with a glucose infusion, and/or a plasma or capillary glucose value ≤ 2 mmol/L within the first 24 hrs

  2. Number of hyperinsulinemia [ Time Frame: at birth ]
    defined by a C-peptide level >90th

  3. Neonatal leptin level [ Time Frame: at birth ]
  4. Number of fetal and neonatal complications [ Time Frame: at birth ]
    Major and minor complications, stillbirth, shoulder dystocia, birth trauma, admission to neonatal intensive care unit, jaundice, respiratory distress syndrome, 5-min Apgar score <7, Cord blood glucose pH<7.2 mmol/L.

  5. Composite obstetrical outcome [ Time Frame: at birth ]
    Gestational age at delivery, mode of delivery, elective cesarean delivery, emergency cesarean delivery, labor induction

  6. Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, before pregnancy ]
  7. Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, at weeks 14-16 of pregnancy ]
  8. Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, at weeks 25-27 of pregnancy ]
  9. Mean blood glucose levels [ Time Frame: before and 2 hours post prandial over one week, at weeks 36-38 of pregnancy ]
  10. Post-prandial hyperglycaemic peak (level and delay) [ Time Frame: at 22 weeks of pregnancy ]
  11. Post-prandial hyperglycaemic peak (level and delay) [ Time Frame: at 32 weeks of pregnancy ]
  12. HbA1c level [ Time Frame: pre-gestational and monthly during pregnancy ]
    according to the HPLC method

  13. Fructosamine level [ Time Frame: monthly during pregnancy ]
  14. Number of women requiring insulin treatment [ Time Frame: at 38 weeks of pregnancy ]
  15. Term of insulin therapy [ Time Frame: at 38 weeks of pregnancy ]
    in case of insulin therapy

  16. Type of insulin [ Time Frame: at 38 weeks of pregnancy ]
    in case of insulin therapy

  17. Number of injections [ Time Frame: at 38 weeks of pregnancy ]
    in case of insulin therapy

  18. Number of units/kg.day of insulin [ Time Frame: over one week at weeks 14/16, 25/27 and 36/38 ]
    in case of insulin therapy

  19. Weight gain during pregnancy [ Time Frame: at 38 weeks of pregnancy ]
  20. Number of pregnancy induced hypertension [ Time Frame: at delivery ]
    to evaluate maternal complications

  21. Number of preeclampsia [ Time Frame: at delivery ]
    to evaluate maternal complications

  22. Number of medical appointments [ Time Frame: at delivery ]
    to evaluate maternal complications

  23. Duration of hospital stay [ Time Frame: at delivery ]
    to evaluate maternal complications

  24. depression (Edinburgh Postnatal Depression Scale. [ Time Frame: at delivery ]
    to evaluate maternal complications

  25. Quality of Life (SF-36 questionary) [ Time Frame: at delivery ]
    to evaluate maternal complications

  26. Anxiety score (short form of the Spielberger State - Trait Anxiety Inventory [ Time Frame: at delivery ]
    to evaluate maternal complications



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Women diagnosed with a GCK mutation before pregnancy
  • Aged ≥ 18 years old
  • Pre-gestational BMI < 30kg/m²
  • Term of pregnancy < 14 WG , if delay overdue, to be validated by investigators
  • Written informed consent

Exclusion Criteria:

  • Twin pregnancy
  • Not able to understand and sign written informed consent
  • Not affiliated to the French Social Security

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): NCT02556840


Contacts
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Contact: Cécile Ciangura, MD, +33 1 42 17 80 51 cecile.ciangura@aphp.fr
Contact: Adèle Bellino, Master +33 1 58 41 11 95 adele.bellino@aphp.fr

Locations
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France
La Pitié Salpêtrière Hospital Recruiting
Paris, France, 75651
Contact: Cécile CIANGURA, MD    +33 1 42 17 80 51    cecile.ciangura@aphp.fr   
Contact: José TIMSIT, MD, PhD    +33 1 58 41 24 41    jose.timsit@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Study Director: Christine Bellanné-Chantelot, PharmaD, PhD Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02556840    
Other Study ID Numbers: 2015-A00261-48
First Posted: September 22, 2015    Key Record Dates
Last Update Posted: March 19, 2018
Last Verified: March 2018
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Monogenic diabetes
maturity-onset diabetes of the young
MODY
Pregnancy
Gestational diabetes
Glucokinase
Insulin therapy during pregnancy
Evaluation of fetal growth by ultrasonography measurements
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs