Efficacy and Safety of Insulin Detemir Versus Neutral Protamine Hagedorn (NPH) Insulin in Pregnant Women With Type 1 Diabetes

Phase 3

Completed

Conditions: Diabetes
Diabetes Mellitus, Type 1

Interventions: Drug: insulin detemir
Drug: NPH insulin
Drug: insulin aspart

Registration Number: NCT00474045

Lead Sponsor: Novo Nordisk A/S

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 470

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Insulin detemir	insulin detemir	Individually adjusted insulin detemir injected subcutaneously as basal insulin + individually adjusted insulin aspart injected subcutaneously as bolus insulin from randomisation (gestational week 8-12) and continued until 6 weeks after delivery. If a subject was not pregnant at randomisation, treatment was given up to a maximum of 52 weeks. For subjects who became pregnant, randomised treatment was continued until 6 weeks after delivery. Subjects who were not pregnant at 52 weeks after randomisation were withdrawn
Neutral Protamine Hagedorn (NPH) insulin	NPH insulin	Individually adjusted NPH insulin injected subcutaneously as basal insulin + individually adjusted insulin aspart injected subcutaneously as bolus insulin from randomisation (gestational week 8-12) and continued until 6 weeks after delivery. If a subject was not pregnant at randomisation, treatment was given up to a maximum of 52 weeks. For subjects who became pregnant, randomised treatment was continued until 6 weeks after delivery. Subjects who were not pregnant at 52 weeks after randomisation were withdrawn
Insulin detemir	insulin aspart	Individually adjusted insulin detemir injected subcutaneously as basal insulin + individually adjusted insulin aspart injected subcutaneously as bolus insulin from randomisation (gestational week 8-12) and continued until 6 weeks after delivery. If a subject was not pregnant at randomisation, treatment was given up to a maximum of 52 weeks. For subjects who became pregnant, randomised treatment was continued until 6 weeks after delivery. Subjects who were not pregnant at 52 weeks after randomisation were withdrawn
Neutral Protamine Hagedorn (NPH) insulin	insulin aspart	Individually adjusted NPH insulin injected subcutaneously as basal insulin + individually adjusted insulin aspart injected subcutaneously as bolus insulin from randomisation (gestational week 8-12) and continued until 6 weeks after delivery. If a subject was not pregnant at randomisation, treatment was given up to a maximum of 52 weeks. For subjects who became pregnant, randomised treatment was continued until 6 weeks after delivery. Subjects who were not pregnant at 52 weeks after randomisation were withdrawn

Primary Outcome Measures

Name	Time	Method
Glycosylated Haemoglobin (HbA1c) for Full Analysis Set (Pregnant Subjects) at GW 36	At gestational week (GW) 36
Glycosylated Haemoglobin (HbA1c) for Per Protocol Analysis Set (Pregnant Subjects) at GW 36	At gestational week (GW) 36

Secondary Outcome Measures

Name	Time	Method
Maternal Safety - Hypoglycaemic Episodes	Participants were followed during the pregnancy period, an average of 9.6 months	All episodes include major, minor and symptoms only. Major episode : unable to self-treat. Minor: able to self-treat and plasma glucose (PG) \< 3.1 mmol/L. Symptoms only: able to self-treat and no PG measurement or PG glucose ≥3.1 mmol/L. Diurnal: Episode occurring between 06.00 - 00.00, both including.
Glycosylated Haemoglobin (HbA1c) During Pregnancy	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)
8-point Self-monitored Plasma Glucose (SMPG) Profile at GW 24	Visit P3 (GW 24)	8-point SMPG was recorded 3 times prior to each visit, and the average value for each of the 8-time points was applied when presenting and analysing the SMPG data. Visit reallocation was made for the early termination visit and for the withdrawal visit.
8-point Self Monitored Plasma Glucose (SMPG) Profile at GW 36	Visit P4 (GW 36)	8-point SMPG was recorded 3 times prior to each visit, and the average value for each of the 8-time points was applied when presenting and analysing the SMPG data. Visit reallocation was made for the early termination visit and for the withdrawal visit.
Maternal Safety - Change in Albumin Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in albumin level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Total Protein Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in total protein serum level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Haemoglobin Level (Haematology)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in haemoglobin level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Number of Subjects With Adverse Events (AEs)	Participants were followed during the pregnancy period, an average of 9.6 months	AE=any undesirable medical event occurring to a subject in a clinical trial, whether or not related to the trial product. Related AE=relationship of probable or possible. Serious adverse event (SAE) =any undesirable serious medical event as defined in protocol.
Maternal Safety - Change in Alanine Aminotransferase Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in alanine aminotransferase level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Alkaline Phosphatase Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in alkaline phosphatase level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Creatinine Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in creatinine serum level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Albumin/Creatinine Ratio (Urinalysis)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and calculated as an estimate of the mean change from Visit P1 in albumin/creatinine ratio at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Insulin Detemir/Insulin Aspart Cross Reacting Antibodies	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.	Change in concentrations values for insulin detemir/aspart cross-reacting antibodies from baseline to Visit P4 was calculated. The unit for measuring antibody levels is amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture (%B/T). Samples were taken before 1st dosing
Ratio Between Detemir Specific Antibodies in Cord Blood and Maternal Antibodies	At Delivery (End of Pregnancy) and at Visit P4 (GW 36)	Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)
Maternal Safety - Change in Leukocytes Level (Haematology)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in leukocytes level at Follow-Up Visit (6 weeks after delivery).
Pregnancy Outcome Safety - Level of Cross-Reacting Antibodies (AB) in Umbilical Cord Blood	At Delivery (End of Pregnancy)	Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T).
Maternal Safety - Change From Visit P1 in Body Weight During Pregnancy by Visit	Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36)	Change in the body weight was summarised by treatment.
Pregnancy Outcome at Delivery	Delivery Visit	Induced abortion means interruption of a living pregnancy \< 22 completed weeks. Early foetal death means death before 22 completed GWs. Stillbirth indicates death between at or after 22 GW and at or before delivery.
Pregnancy Outcome at Follow-Up	Follow-Up (6 weeks after delivery)	Induced abortion means interruption of a living pregnancy \< 22 completed weeks. Early foetal death means death before 22 completed GWs. Perinatal Death means death of a foetus/infant between ≥ 22 completed GWs and \< 1 completed week after delivery. Neonatal Death means death between at or after 7 completed days and before 28 completed days after delivery. Death During Follow-Up means death between at or after 28 days after delivery and at or before Follow-Up.
Safety - Composite Pregnancy Outcome	End of Pregnancy	Wt. corresponds to weight of live-born infants. Pre-term delivery: delivery before 37 completed GWs including abortions. Early foetal death: death before 22 completed GWs. Perinatal mortality: death of a foetus/infant between ≥ 22 completed GWs and \< 1 completed week after delivery. Neonatal mortality: post-partum after 7 completed days and before 28 completed days after delivery. Major-malformation: a life threatening structural anomaly or one likely to cause significant impairment of health or functional capacity and needs medical or surgical treatment.
Ratio Between Aspart Specific Antibodies in Cord Blood and Maternal Antibodies	At Delivery (End of Pregnancy) and at Visit P4 (GW 36)	Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)
Subjects Reaching HbA1c at or Below 6.0% Both at GW 24 and GW 36	At both Visit P3 (GW 24) and Visit P4 (GW 36)
Fasting Plasma Glucose (FPG)	During the pregnancy period [Visit P1 (GW 8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36)]
Safety in Children - Number of Subjects (Foetuses and Newborns) With Adverse Events	Foetuses/Newborns were followed during the pregnancy period, an average of 9.6 months and Follow-Up period (6 weeks after delivery)	AE=any undesirable medical event occurring to a subject in a clinical trial, whether or not related to the trial product. Related AE=relationship of probable or possible. SAE=any undesirable serious medical event as defined in protocol.
Maternal Safety - Nocturnal Hypoglycaemic Episodes	Participants were followed during the pregnancy period, an average of 9.6 months	A nocturnal episode is any episode occurring between 0.01 - 5.59, both including. It includes major, minor and symptoms only episodes. Major: unable to self-treat. Minor: able to self-treat and plasma glucose (PG) \< 3.1 mmol/L. Symptoms only: able to self-treat and no PG measurement or PG glucose ≥3.1 mmol/L.
Maternal Safety - Change in Lactate Dehydrogenase Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in lactate dehydrogenase serum level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Potassium Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in potassium serum level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Sodium Serum Level (Biochemistry)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in sodium serum level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Thrombocytes Level (Haematology)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and is calculated as an estimate of the mean change from Visit P1 in thrombocytes level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Urine Albumin Level (Urinalysis)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and calculated as an estimate of the mean change from Visit P1 in urine albumin level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Urine N (Creatinine) (Urinalysis)	Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)	This is the standard safety lab parameter and calculated as an estimate of the mean change from Visit P1 in Urine-N (creatinine) level at Follow-Up Visit (6 weeks after delivery).
Maternal Safety - Change in Insulin Detemir Specific Antibodies	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.	Change in concentrations of values for insulin detemir specific antibodies from baseline to Visit P4 was calculated. The unit for measuring antibody levels is amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture (%B/T). Samples were taken before 1st dosing.
Maternal Safety - Change From Visit P1 in Systolic Blood Pressure During Pregnancy and at Follow-Up by Visit	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)	Change in the systolic blood pressure was summarised by treatment.
Maternal Safety - Change in Insulin Aspart Specific Antibodies	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.	Change in concentrations values for insulin aspart specific antibodies from baseline to Visit P4 was calculated. The unit for measuring antibody levels is amount of tracer bound to the antibodies in the precipitate (B) expressed in percentage of the total amount of tracer (T) added to the mixture (%B/T). Samples were taken before 1st dosing.
Pregnancy Outcome Safety - Level of Detemir Specific Antibodies (AB) in Umbilical Cord Blood	At Delivery (End of Pregnancy)	Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T).
Pregnancy Outcome Safety - Level of Insulin Detemir in Umbilical Cord Blood	At Delivery
Maternal Safety - Change From Visit P1 in Pulse During Pregnancy and at Follow-Up	Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up Visit (6 weeks after delivery)	Change in the pulse was summarised by treatment.
Maternal Safety - Acceleration of Retinopathy in Any Eye	From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery)	Acceleration of Retinopathy is defined as worsening of fundoscopy/fundusphotography findings from GW 8-12 (Visit P1) to follow-up on one or both eyes.
Maternal Safety - Mode of Delivery	At Delivery Visit	Non-Planned Caesarean Section is a procedure which takes place ≤8h prior to delivery. Planned Caesarean Section takes place \>8h prior to delivery.
Pregnancy Outcome Safety - Level of Aspart Specific Antibodies (AB) in Umbilical Cord Blood	At Delivery (End of Pregnancy)	Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T)
Maternal Safety - Change From Visit P1 in Diastolic Blood Pressure During Pregnancy and at Follow-Up by Visit	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)	Change in the diastolic blood pressure was summarised by treatment.
Ratio Between Cross-reacting Antibodies in Cord Blood and Maternal Antibodies	At Delivery (End of Pregnancy) and at Visit P4 (GW 36)	Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)
Maternal Safety - Electrocardiogram (ECG)	Follow-Up (6 weeks after delivery)	The number of subjects having a electrocardiogram (ECG) that changed from 'Normal' or 'Abnormal, not clinically significant' (at Visit 1, 3 weeks before randomisation) to 'Abnormal, clinically significant' (at Follow-Up). 'Abnormal, Clinically significant' is an abnormality that suggests a disease and/or organ toxicity and is of a severity, which requires active management.
Maternal Safety - Acceleration of Nephropathy	From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery)	Acceleration of nephropathy was defined as a change from a low U-albumin:U-creatinine ratio ≤33.93 mg/mmol to a high U-albumin:U-creatinine ratio \> 33.93 mg/mmol from GW 8-12 (Visit P1) to the follow-up visit.
Safety - Total Daily Insulin Dose During Pregnancy	Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up (6 weeks after delivery)