Clinical trial NCT00474045: Efficacy and Safety of Insulin Detemir Versus Neutral Protamine Hagedorn (NPH) Insulin in Pregnant Women With Type 1 Diabetes
Official title: A Randomised, Parallel-group, Open-labelled, Multinational Trial Comparing the Efficacy and Safety of Insulin Detemir (Levemir®) Versus Human Insulin (NPH Insulin), Used in Combination With Insulin Aspart as Bolus Insulin, in the Treatment of Pregnant Women With Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes
Diabetes Mellitus, Type 1
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2007-05-16
Enrollment: 470
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial is conducted in Africa, Europe, North and South America and Oceania. The aim of this trial is to compare the effect and safety on blood glucose control in pregnant women with type 1 diabetes of a modern insulin analogue (insulin detemir) and human insulin (NPH insulin) given as long-acting insulin in combination with a short-acting insulin (insulin aspart).


Eligibility criteria: Inclusion Criteria:

* Type 1 diabetes treated with insulin for at least 12 months
* Planning to become pregnant and have a screening HbA1c (glycosylated haemoglobin) lesser than or equal to 9.0%, or
* Pregnant with an intrauterine singleton living foetus, 8-12 weeks pregnant when joining the trial and a HbA1c lesser than or equal to 8.0% when pregnancy is confirmed

Exclusion Criteria:

* Known or suspected hypersensitivity to the trial product(s) or related products
* Untreated hyperthyroidism or hypothyroidism
* Known or suspected abuse of alcohol or narcotics
* Cardiac problems
* Impaired kidney function
* History of severe hyperemesis gravidarum
* Treatment with in-vitro fertilisation or other medical infertility treatment
* Impaired liver function
* Uncontrolled hypertension
* Proliferative retinopathy or maculopathy requiring acute treatment
* Known to be HIV (human immunodeficiency virus) positive, Hepatitis B or Hepatitis C positive
* Any concomitant medication contraindicated in pregnancy

Primary outcomes:
measure: Glycosylated Haemoglobin (HbA1c) for Full Analysis Set (Pregnant Subjects) at GW 36
timeFrame: At gestational week (GW) 36
measure: Glycosylated Haemoglobin (HbA1c) for Per Protocol Analysis Set (Pregnant Subjects) at GW 36
timeFrame: At gestational week (GW) 36
Secondary outcomes:
measure: Glycosylated Haemoglobin (HbA1c) During Pregnancy
timeFrame: During the pregnancy period [Visit P1 (GW 8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Delivery Visit (end of pregnancy)] and Follow-Up Visit ( 6 weeks after delivery)
measure: Subjects Reaching HbA1c at or Below 6.0% Both at GW 24 and GW 36
timeFrame: At both Visit P3 (GW 24) and Visit P4 (GW 36)
measure: Fasting Plasma Glucose (FPG)
timeFrame: During the pregnancy period [Visit P1 (GW 8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36)]
measure: 8-point Self-monitored Plasma Glucose (SMPG) Profile at GW 24
timeFrame: Visit P3 (GW 24)
measure: 8-point Self Monitored Plasma Glucose (SMPG) Profile at GW 36
timeFrame: Visit P4 (GW 36)
measure: Maternal Safety - Number of Subjects With Adverse Events (AEs)
timeFrame: Participants were followed during the pregnancy period, an average of 9.6 months
measure: Safety in Children - Number of Subjects (Foetuses and Newborns) With Adverse Events
timeFrame: Foetuses/Newborns were followed during the pregnancy period, an average of 9.6 months and Follow-Up period (6 weeks after delivery)
measure: Maternal Safety - Hypoglycaemic Episodes
timeFrame: Participants were followed during the pregnancy period, an average of 9.6 months
measure: Maternal Safety - Nocturnal Hypoglycaemic Episodes
timeFrame: Participants were followed during the pregnancy period, an average of 9.6 months
measure: Maternal Safety - Change in Albumin Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Alanine Aminotransferase Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Alkaline Phosphatase Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Creatinine Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Lactate Dehydrogenase Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Potassium Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Sodium Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Total Protein Serum Level (Biochemistry)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Haemoglobin Level (Haematology)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Leukocytes Level (Haematology)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Thrombocytes Level (Haematology)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Urine Albumin Level (Urinalysis)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Albumin/Creatinine Ratio (Urinalysis)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Urine N (Creatinine) (Urinalysis)
timeFrame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change in Insulin Detemir Specific Antibodies
timeFrame: Baseline, Visit P4 (GW 36). Baseline is Visit 2 (randomisation visit, within 3 weeks of screening) for subjects not pregnant at randomisation and Visit P1 (GW 8-12) for pregnant subjects at randomisation.
measure: Maternal Safety - Change in Insulin Aspart Specific Antibodies
timeFrame: Baseline, Visit P4 (GW 36). Baseline is Visit 2 (randomisation visit, within 3 weeks of screening) for subjects not pregnant at randomisation and Visit P1 (GW 8-12) for pregnant subjects at randomisation.
measure: Maternal Safety - Change in Insulin Detemir/Insulin Aspart Cross Reacting Antibodies
timeFrame: Baseline, Visit P4 (GW 36). Baseline is Visit 2 (randomisation visit, within 3 weeks of screening) for subjects not pregnant at randomisation and Visit P1 (GW 8-12) for pregnant subjects at randomisation.
measure: Pregnancy Outcome Safety - Level of Detemir Specific Antibodies (AB) in Umbilical Cord Blood
timeFrame: At Delivery (End of Pregnancy)
measure: Pregnancy Outcome Safety - Level of Aspart Specific Antibodies (AB) in Umbilical Cord Blood
timeFrame: At Delivery (End of Pregnancy)
measure: Pregnancy Outcome Safety - Level of Cross-Reacting Antibodies (AB) in Umbilical Cord Blood
timeFrame: At Delivery (End of Pregnancy)
measure: Ratio Between Detemir Specific Antibodies in Cord Blood and Maternal Antibodies
timeFrame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36)
measure: Pregnancy Outcome Safety - Level of Insulin Detemir in Umbilical Cord Blood
timeFrame: At Delivery
measure: Maternal Safety - Change From Visit P1 in Body Weight During Pregnancy by Visit
timeFrame: Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36)
measure: Maternal Safety - Change From Visit P1 in Systolic Blood Pressure During Pregnancy and at Follow-Up by Visit
timeFrame: Visit P1 (GW (8-12)), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change From Visit P1 in Diastolic Blood Pressure During Pregnancy and at Follow-Up by Visit
timeFrame: Visit P1 (GW (8-12)), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up (FU) Visit (6 weeks after delivery)
measure: Maternal Safety - Change From Visit P1 in Pulse During Pregnancy and at Follow-Up
timeFrame: Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up Visit (6 weeks after delivery)
measure: Maternal Safety - Electrocardiogram (ECG)
timeFrame: Follow-Up (6 weeks after delivery)
measure: Maternal Safety - Acceleration of Retinopathy in Any Eye
timeFrame: From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery)
measure: Maternal Safety - Acceleration of Nephropathy
timeFrame: From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery)
measure: Maternal Safety - Mode of Delivery
timeFrame: At Delivery Visit
measure: Pregnancy Outcome at Delivery
timeFrame: Delivery Visit
measure: Pregnancy Outcome at Follow-Up
timeFrame: Follow-Up (6 weeks after delivery)
measure: Safety - Total Daily Insulin Dose During Pregnancy
timeFrame: Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up (6 weeks after delivery)
measure: Safety - Composite Pregnancy Outcome
timeFrame: End of Pregnancy
measure: Ratio Between Aspart Specific Antibodies in Cord Blood and Maternal Antibodies
timeFrame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36)
measure: Ratio Between Cross-reacting Antibodies in Cord Blood and Maternal Antibodies
timeFrame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36)
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
facility: Novo Nordisk Investigational Site
city: Buenos Aires
country: Argentina
facility: Novo Nordisk Investigational Site
city: Buenos Aires
country: Argentina
facility: Novo Nordisk Investigational Site
city: Buenos Aires
country: Argentina
facility: Novo Nordisk Investigational Site
city: Mar del Plata
country: Argentina
facility: Novo Nordisk Investigational Site
city: Pcia de Cordoba
country: Argentina
facility: Novo Nordisk Investigational Site
city: Salta
country: Argentina
facility: Novo Nordisk Investigational Site
city: Broadmeadow
country: Australia
facility: Novo Nordisk Investigational Site
state: New South Wales
city: Camperdown
country: Australia
facility: Novo Nordisk Investigational Site
state: New South Wales
city: St Leonards
country: Australia
facility: Novo Nordisk Investigational Site
state: New South Wales
city: Elizabeth Vale
country: Australia
facility: Novo Nordisk Investigational Site
state: South Australia
city: Clayton
country: Australia
facility: Novo Nordisk Investigational Site
city: Garran
country: Australia
facility: Novo Nordisk Investigational Site
city: South Brisbane
country: Australia
facility: Novo Nordisk Investigational Site
city: Subiaco
country: Australia
facility: Novo Nordisk Investigational Site
city: Wollongong
country: Australia
facility: Novo Nordisk Investigational Site
city: Feldkirch
country: Austria
facility: Novo Nordisk Investigational Site
city: Innsbruck
country: Austria
facility: Novo Nordisk Investigational Site
city: Salzburg
country: Austria
facility: Novo Nordisk Investigational Site
city: Wien
country: Austria
facility: Novo Nordisk Investigational Site
city: Wien
country: Austria
facility: Novo Nordisk Investigational Site
city: Wien
country: Austria
facility: Novo Nordisk Investigational Site
city: Wien
country: Austria
facility: Novo Nordisk Investigational Site
city: Curitiba
country: Brazil
facility: Novo Nordisk Investigational Site
state: Parana
city: Porto Alegre
country: Brazil
facility: Novo Nordisk Investigational Site
city: Sao Paulo
country: Brazil
facility: Novo Nordisk Investigational Site
city: São Paulo
country: Brazil
facility: Novo Nordisk Investigational Site
city: Calgary
country: Canada
facility: Novo Nordisk Investigational Site
state: Alberta
city: Cambridge
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: London
country: Canada
facility: Novo Nordisk Investigational Site
state: Ontario
city: Edmonton
country: Canada
facility: Novo Nordisk Investigational Site
city: Montreal
country: Canada
facility: Novo Nordisk Investigational Site
city: Quebec
country: Canada
facility: Novo Nordisk Investigational Site
city: Toronto
country: Canada
facility: Novo Nordisk Investigational Site
city: Toronto
country: Canada
facility: Novo Nordisk Investigational Site
city: Vancouver
country: Canada
facility: Novo Nordisk Investigational Site
city: Winnipeg
country: Canada
facility: Novo Nordisk Investigational Site
city: Zagreb
country: Croatia
facility: Novo Nordisk Investigational Site
city: Aalborg
country: Denmark
facility: Novo Nordisk Investigational Site
city: Aarhus N
country: Denmark
facility: Novo Nordisk Investigational Site
city: København ø
country: Denmark
facility: Novo Nordisk Investigational Site
city: Helsinki
country: Finland
facility: Novo Nordisk Investigational Site
city: Amiens
country: France
facility: Novo Nordisk Investigational Site
city: Angers
country: France
facility: Novo Nordisk Investigational Site
city: Bondy
country: France
facility: Novo Nordisk Investigational Site
city: Lille
country: France
facility: Novo Nordisk Investigational Site
city: Marseille
country: France
facility: Novo Nordisk Investigational Site
city: MONTPELLIER cedex 5
country: France
facility: Novo Nordisk Investigational Site
city: Nimes
country: France
facility: Novo Nordisk Investigational Site
city: Strasbourg
country: France
facility: Novo Nordisk Investigational Site
city: TOULOUSE cedex 9
country: France
facility: Novo Nordisk Investigational Site
city: Valenciennes
country: France
facility: Novo Nordisk Investigational Site
city: Dublin 1
country: Ireland
facility: Novo Nordisk Investigational Site
city: Dublin 2
country: Ireland
facility: Novo Nordisk Investigational Site
city: Dublin 8
country: Ireland
facility: Novo Nordisk Investigational Site
city: Dublin
country: Ireland
facility: Novo Nordisk Investigational Site
city: Petach Tikva
country: Israel
facility: Novo Nordisk Investigational Site
city: Bergen
country: Norway
facility: Novo Nordisk Investigational Site
city: Trondheim
country: Norway
facility: Novo Nordisk Investigational Site
city: Tønsberg
country: Norway
facility: Novo Nordisk Investigational Site
city: Krakow
country: Poland
facility: Novo Nordisk Investigational Site
city: Lodz
country: Poland
facility: Novo Nordisk Investigational Site
city: Lublin
country: Poland
facility: Novo Nordisk Investigational Site
city: Olsztyn
country: Poland
facility: Novo Nordisk Investigational Site
city: Szczecin
country: Poland
facility: Novo Nordisk Investigational Site
city: Warszawa
country: Poland
facility: Novo Nordisk Investigational Site
city: Warszawa
country: Poland
facility: Novo Nordisk Investigational Site
city: Wroclaw
country: Poland
facility: Novo Nordisk Investigational Site
city: Zabrze
country: Poland
facility: Novo Nordisk Investigational Site
city: Moscow
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Moscow
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Novosibirsk
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Samara
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Tumen
country: Russian Federation
facility: Novo Nordisk Investigational Site
city: Port Elizabeth
country: South Africa
facility: Novo Nordisk Investigational Site
state: Eastern Cape
city: Port Elizabeth
country: South Africa
facility: Novo Nordisk Investigational Site
state: Eastern Cape
city: Pretoria
country: South Africa
facility: Novo Nordisk Investigational Site
state: Gauteng
city: Durban
country: South Africa
facility: Novo Nordisk Investigational Site
state: KwaZulu-Natal
city: Alcoy
country: Spain
facility: Novo Nordisk Investigational Site
city: Alicante
country: Spain
facility: Novo Nordisk Investigational Site
city: Barcelona
country: Spain
facility: Novo Nordisk Investigational Site
city: Madrid
country: Spain
facility: Novo Nordisk Investigational Site
city: Santander
country: Spain
facility: Novo Nordisk Investigational Site
city: Sevilla
country: Spain
facility: Novo Nordisk Investigational Site
city: Valencia
country: Spain
facility: Novo Nordisk Investigational Site
city: Belfast
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Birmingham
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Blackburn
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Bristol
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Edinburgh
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Exeter
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Leicester
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: London
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Middlesbrough
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Northampton
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Norwich
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Plymouth
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Southampton
country: United Kingdom
facility: Novo Nordisk Investigational Site
city: Watford
country: United Kingdom
facility: Novo Nordisk Investigational Site
Study officials:
affiliation: Novo Nordisk A/S
name: Global Clinical Registry (GCR, 1452)
role: STUDY_DIRECTOR
References:
citation: Mathiesen ER, Damm P, Jovanovic L, McCance DR, Thyregod C, Jensen AB, Hod M. Basal insulin analogues in diabetic pregnancy: a literature review and baseline results of a randomised, controlled trial in type 1 diabetes. Diabetes Metab Res Rev. 2011 Sep;27(6):543-51. doi: 10.1002/dmrr.1213.
citation: Mathiesen ER, Hod M, Ivanisevic M, Duran Garcia S, Brondsted L, Jovanovic L, Damm P, McCance DR; Detemir in Pregnancy Study Group. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care. 2012 Oct;35(10):2012-7. doi: 10.2337/dc11-2264. Epub 2012 Jul 30.
citation: Hod M, Mathiesen ER, Jovanovic L, McCance DR, Ivanisevic M, Duran-Garcia S, Brondsted L, Nazeri A, Damm P. A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine Hagedorn in type 1 diabetes. J Matern Fetal Neonatal Med. 2014 Jan;27(1):7-13. doi: 10.3109/14767058.2013.799650. Epub 2013 Jun 5.