Metformin Use to Improve Pregnancy Outcome in Women With Type 1 Diabetes.

Metformin Use to Improve Pregnancy Outcome in Women With Type 1 Diabetes. A Randomized Double-blind Placebo-controlled Multicenter Study.

The study investigates whether additional metformin medication in combination with regular insulin treatment will decrease the need of insulin for women with diabetes mellitus type 1 during pregnancy.

Study Overview

• Status: Completed
• Conditions: Type1diabetes; Insulin Resistance; Diabetic Pregnancy
• Intervention / Treatment: Drug: metforminhydrochloride; Drug: Placebo Oral Tablet

Detailed Description

Insulin resistance during pregnancy of diabetes mellitus type 1 patients (DM1) increases the need for insulin and makes it more difficult to maintain normoglycemia. Fetal exposure to hyperglycemia induces macrosomia which increases fetal and neonatal morbidity and mortality. Further more obesity and excess weight gain during pregnancy enhances insulin resistance and it's an independent risk factor for fetal macrosomia.

Metformin is a medical treatment for type 2 diabetes (DM2) where consequential pathophysiology includes insulin resistance. It reduces hepatic glucose production and enhances the use of glucose in muscles relieving insulin resistance. Metformin has also found to inhibit weight gain effectively.

Metformin has approved to be safe and effective in patients with gestational diabetes (GDM). It has found to reduce weight gain and improve postprandial blood glucose levels during pregnancy and reduce neonatal birth trauma in GDM. However, there are no previous studies about the use of metformin in pregnant women with DM1.

Two hundred women with DM1 will be randomized to get placebo or metformin in addition to regular insulin treatment. The sample size has been estimated to demonstrate the difference of 15 % in the need to increase insulin dosages during the pregnancy between the study groups.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kati Tihtonen, PhD; Phone Number: +3583 311 67855; Email: kati.tihtonen@pshp.fi
• Study Contact Backup: Name: Elina Juuma, MD; Phone Number: +358142691811; Email: elina.juuma@fimnet.fi

Study Locations

• Finland
  • Helsinki, Finland
    • Helsinki University Hospital
  • Jyväskylä, Finland
    • Central Finland Health Care District
  • Oulu, Finland
    • Oulu University Hospital
  • Tampere, Finland
    • Tampere University Hospital
  • Turku, Finland
    • Turku University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• a pregnancy of a woman with type 1 diabetes.

Exclusion Criteria:

• multiple pregnancy, significant underlying disease (hearth disease, kidney transplant, IBD (inflammatory bowel disease ), SLE (systemic lupus erythematosus ), diseases with use of high dosage corticosteroids (severe asthma or rheumatic disease), severe complications of diabetes (nephropathy, neuropathy, gastroparesis or severe retinopathy), substance abuse, smoking, BMI <18, strong early pregnancy nausea (=hyperemesis)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: metforminhydrochloride; Metformin medication starts on 12-14 weeks of gestation. The starting dosage is 1 tablet (500 mg) x1 and it is increased gradually 1 tablet a week up to 2+2 tablets (2000mg) daily. Duration of the treatment is approximately until one week before delivery. Otherwise metformin treatment combined with regular insulin and follow-up during pregnancy follows the national guidelines.	Drug: metforminhydrochloride; metformin 500 mg tablets and insulin; Other Names: Metformin; A10BA02; Diformin
Placebo Comparator: Placebo Oral Tablet; Placebo tablets starts on 12-14 weeks of gestation. The starting dosage is 1 tablet x1 and it is increased gradually 1 tablet a week up to 2+2 tablets daily. Duration of the treatment is approximately until one week before delivery. Otherwise placebo treatment combined with regular insulin and follow-up during pregnancy follows the national guidelines.	Drug: Placebo Oral Tablet; Placebo tablets mimic metformin 500 mg tablets and insulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the insulin need during pregnancy	The insulin dosage (IU/ml) in two weeks sets	from 5-10 gestational weeks until the delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood glucose balance during pregnancy HbA1c	HbA1c (mmol/mol)	from gestational weeks 5 until the delivery
Blood glucose balance during pregnancy AVG, SD, CV	mean blood glucose (mmol/l) level, standard deviation (SD) and the coefficient of variation of the blood glucose levels	from gestational weeks 5 until the delivery
Change in the weight	Weight gain (g) during pregnancy	from gestational weeks 5 until the delivery
Change in the blood pressure	Blood pressure (mmHg)	from gestational weeks 5 until the delivery
Incidence of pre-eclampsia	Incidence of pre-eclampsia (%)	from gestational weeks 20 until the delivery
Incidence hepatogestosis	Incidence hepatogestosis (%)	from gestational weeks 20 until the delivery
Pregnancy complications	Incidence proteinuria (mg/mmol or mg/d)	from gestational weeks 5 until the delivery
macrosomia	estimated fetal weight in ultrasound (grams)	from gestational weeks 20 until the delivery
Pregnancy complications	incidence of miscarriage (intrauterine death before 22 weeks of gestation or fetal weigth under 500g) (%)	12-22 weeks of gestation
Pregnancy complications	incidence of intrauterine death (intrauterine death after 22 weeks of gestation or fetal weigth over 500g) (%)	22-40 weeks of gestation
Thigh fractional volume ultrasound	Fetal weight estimation (g) is specified by thigh fractional volume ultrasound program	from gestational weeks 20 until delivery
Rate of the caesarean sections	Rate of the caesarean sections (%)	The delivery
Labour	rate of spontaneous delivery (%)	The delivery
Rate of the operative vaginal deliveries	Rate of the operative vaginal deliveries (%)	The delivery
Rate of the shoulder dystocia	Rate of the shoulder dystocia (%)	The delivery
Labor complications	rate of induced delivery (%)	The delivery
Rate of the perineal tears	Rate of the perineal tears (%)	The delivery
Postpartum bleeding	postpartum bleeding (ml)	The delivery
Newborn variables (gestational age)	Rate of the premature deliveries (=deliveries before 37 weeks of gestation) (%)	After the delivery
Newborn variables	weight of the newborn (g)	After the delivery
Newborn outcome	Acidosis of the newborn (pH)	After the delivery
Newborn outcome (intensive care)	The need of NICU (neonatal intensive care unit) treatment (days)	After the delivery
Newborn outcome (hypoglycemia)	The occurrence of hypoglycemia (=plasma glucose under 2.6mmol/l or usage of iv glucose infusion) (%)	After the delivery
Newborn outcome (Erb's)	Incidence of the Erb's paresis (%)	After the delivery
Cost benefit calculations (sick leaves)	The need of sick leaves during pregnancy (days)	from gestational weeks 12 until delivery
Cost benefit calculations (visits to maternity outpatient clinic or internal medicine policlinic)	The need of polyclinical controls during pregnancy (number of visits/pregnancy)	14-40 weeks of gestation
Cost benefit calculations (hospitalization)	The need of hospitalization during pregnancy (days/pregnancy)	14-40 weeks of gestation
Cost benefit calculations (all outpatient visits after delivery )	The need of policlinical controls of the diabetic mother after the delivery (number of visits)	One year after the delivery
Cost benefit calculations (hospitalization after delivery, all departments)	The need of hospitalization of the diabetic mother after the delivery (days)	Up to one year after the delivery
Cost benefit calculations (all hospitalization of the child)	The need of hospitalization of the child (days)	Until the age of one year
Cost benefit calculations (all policlinical controls of the child)	The need of policlinical controls of the child (number of visits)	Until the age of one year
high sensitive-CRP	high sensitive-CRP (mg/l)	7-10, 26-28 and 34-36 weeks of gestation
lipids	cholesterol, high density lipoprotein, low density lipoprotein, triglyserids (mmol/l)	7-10, 26-28 and 34-36 weeks of gestation
Inflammatory markers	adiponectin, leptin, resistin, IL-6, TNF-α (pg/ml)	7-10, 26-28 and 34-36 weeks of gestation

Collaborators and Investigators

• Sponsor: Tampere University Hospital
• Collaborators: Turku University Hospital; Helsinki University Central Hospital; Oulu University Hospital; Central Finland Hospital District
• Investigators: Principal Investigator: Kati Tihtonen, PhD, Tampere University Hospital, Tampere University

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2019
• Primary Completion (Actual): December 19, 2022
• Study Completion (Actual): December 19, 2022

Study Registration Dates

• First Submitted: April 24, 2018
• First Submitted That Met QC Criteria: December 4, 2018
• First Posted (Actual): December 5, 2018

Study Record Updates

• Last Update Posted (Actual): June 7, 2023
• Last Update Submitted That Met QC Criteria: June 6, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: insulin resistance; metformin; insulin need; diabetic pregnancy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Hyperinsulinism; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin Resistance; Pregnancy in Diabetics; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: Diabetes2017; 2016-005031-32 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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