Clinical trial NCT03380546: Acarbose and Prandial Insulin for the Treatment of Gestational Diabetes Mellitus.
Official title: Non-inferiority Between Acarbose and Prandial Insulin for the Treatment of Gestational Diabetes Mellitus: a Randomized Multicenter and Prospective Trial. ACARB-GDM Study.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Gestational Diabetes Mellitus in Pregnancy
Keywords: Diabetes
Pregnancy
Gestational
Acarbose
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-12-21
Enrollment: 341
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Caring for women with gestational diabetes mellitus (GDM) is very time-consuming. Therapeutic strategy includes dietary and lifestyle measures and additional insulin therapy for 15 to 40% of the women with GDM if the glycemic targets are not achieved after a period of 1 to 2 weeks of diet. Insulin therapy is imperfect for the following main reasons: need for education (i.e. subcutaneous administration, dose titration), hypoglycemia and weight gain, limited acceptance and high cost. Psychosocial deprivation is associated with more cases of GDM and health accessibility may be unequal.

Glucosidase inhibitors (acarbose) reduce intestinal absorption of starch and reduce the rate of complex carbohydrate digestion. It mainly lowers postprandial glucose values and is used in type 2 diabetes for a long time. Less than 2% of a dose is absorbed as active drug in adults, with 34% of the metabolites found in the systemic circulation. Doses of up to 9 and 32 times the human dose were not teratogenic in pregnant rats or rabbits. Limited but reassuring data during pregnancy are available. Acarbose was well tolerated (little gestational weight gain, no hypoglycemia) with digestive discomfort in some women, balanced by treatment satisfaction as compared with insulin injections. Our hypothesis is that treatment aiming to control postprandial glucose values with acarbose as compared with prandial insulin injection will be as efficient and safe, but more convenient and less expensive.

Detailed description: Phase III study. Prospective, multicenter, non-inferiority, randomized, open-labelled and controlled study with two arms.

1. In the 37 participating hospitals: selection of women with GDM who have unmet post prandial glycemic targets between 14 and 37 (+6 days) weeks of amenorrhea after at least 7 days of dietary and lifestyle measures. They may be treated with basal insulin to control pre prandial glucose values.
2. Explanation of protocol, with signature of consent in case of acceptation.
3. Randomization

   . Experimental group: The women will receive acarbose with a progressive increase of dose according to post prandial glucose values and digestive tolerance, with a maximal dose of 3 x 100 mg / day. The progressive titration of acarbose reduces gastro-intestinal side effects.

   Patients who have not reached the glycemic targets at this highest tolerated dose for at least one meal will receive instead prandial insulin therapy for each meal, whereas acarbose will be stopped. Failure to reach post-prandial target will be defined as 3 or more post-prandial glycaemic values ≥ 1.20 g/L for a given meal in a week (3 values out of 7) after the two weeks of dose adjustment.

   · Control group: The women will receive prandial insulin according to usual practice (routine care according to French recommendations): before each meal, with dose titration according to post prandial values.

   Basal insulin may be necessary in both arms to control pre-prandial glucose values.

   At delivery:

   - Maternal blood samples : 14 ml of blood will be collected at the same time as the sample routinely collected just before delivery for irregular agglutinin test measurement, when the women are perfused.

   - Cord fluid : 7 ml will be collected at the same as cord fluid pH is routinely measured just after delivery. There will be 5 aliquots to prepare.

   The aliquots previously labelled and stowed in the specific boxes for the study will be stored locally and will be transported to the "Centre de Ressources Biologiques"(CRB) of the Jean Verdier Hospital.
4. Routine monitoring of the women with GDM in both arms, up to delivery. No use of other oral hypoglycemic agents during pregnancy.
5. Last consultation three months after delivery.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Singleton pregnancy
* GDM diagnosed during pregnancy according to IADPSG criteria
* Self-monitoring of blood glucose
* After at least 7 days of dietary and lifestyle measures, unreached post-prandial glucose control
* 14-37 (+ 6 days) amenorrhea weeks at the time of randomization
* Signed informed consent

Exclusion Criteria:

* Prandial insulin use before randomization during this pregnancy
* Use of other oral hypoglycemic agents during this pregnancy
* Multiple pregnancy
* Known hepatic insufficiency
* Long time corticosteroid treatment
* Pre-existing diabetes in pregnancy
* Overt diabetes diagnosed during pregnancy (IADPSG criteria)
* Lack of Social Insurance
* Insufficient understanding
* Participant in another investigational drug study at inclusion visit
* Contraindications of acarbose
* Fetal malformation diagnosed by previous fetal ultrasound

Primary outcomes:
measure: Composite endpoint: birth weight ≥ 90th percentile for gestational age (large for gestational age: LGA) and/or neonatal hypoglycemia and/or shoulder dystocia and/or birth injury.
timeFrame: At delivery
Secondary outcomes:
measure: GLUCOSE CONTROL: Capillary glucose levels
timeFrame: From two weeks after inclusion : 14 and 37 (+6 days) weeks of amenorrhea to delivery
measure: GLUCOSE CONTROL: HbA1c
timeFrame: At delivery
measure: GLUCOSE CONTROL: Need for and dose/day of basal and prandial insulin in both arms
timeFrame: At delivery
measure: Neonatal complications : Birth weight and height,
timeFrame: At delivery
measure: Neonatal complications : Small for gestational age infant
timeFrame: At delivery
measure: Maternal complications : Preeclampsia
timeFrame: From two weeks after inclusion to delivery
measure: Maternal complications : Pregnancy-induced hypertension
timeFrame: From two weeks after inclusion : 14 and 37 (+6 days) weeks of amenorrhea to delivery
measure: Neonatal complications : Preterm delivery
timeFrame: At delivery
measure: Neonatal complications : Low Apgar score
timeFrame: At delivery
measure: Neonatal complications : Neonatal respiratory distress syndrome
timeFrame: At delivery
measure: Neonatal complications : Intrauterine fetal or neonatal death;
timeFrame: From two weeks after inclusion to delivery
measure: Acceptance/satisfaction of two strategies : -Quality of life -Satisfaction questionnaires
timeFrame: At delivery
measure: Side effects of drugs : Maternal hypoglycemia
timeFrame: during the 7 months of treatment
measure: Gastro-intestinal side effects
timeFrame: from two weeks after inclusion : 14 to 36 weeks of gestation to delivery
measure: Results of oral glucose tolerance test and HbA1c measurement
timeFrame: 3 months after delivery
measure: Infant anthropometrics.
timeFrame: At month 1, month 2 and month 3
measure: Conservation of serum and plasma; cord fluid. The samples may be used for further analyses ancillary studies and which could be beneficial for GDM care based on evolution in scientific knowledge.
timeFrame: within 10 years after the end of the study
Other outcomes:
Locations:
city: Bondy
country: France
facility: Jean Verdier Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Emmanuel COSSON, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193.
citation: Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000 Oct 19;343(16):1134-8. doi: 10.1056/NEJM200010193431601.
citation: Holt RI, Lambert KD. The use of oral hypoglycaemic agents in pregnancy. Diabet Med. 2014 Mar;31(3):282-91. doi: 10.1111/dme.12376.
citation: Zarate A, Ochoa R, Hernandez M, Basurto L. [Effectiveness of acarbose in the control of glucose tolerance worsening in pregnancy]. Ginecol Obstet Mex. 2000 Jan;68:42-5. Spanish.
citation: Platt J, O'Brien W. Title Acarbose therapy for gestational diabetes: a retrospective cohort study (abstract). Review AJOG 2003;189:S107