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

Study Overview
=================
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).

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

Conditions
-----------------
Diabetes, Diabetes Mellitus, Type 1

Intervention / Treatment
-----------------
* Drug: insulin detemir
* Drug: NPH insulin
* Drug: insulin aspart


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin detemir<br>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 | Drug: insulin detemir<br>* Treat-to-target, dose titration, s.c. (under the skin) injection<br>Drug: insulin aspart<br>* Treat-to-target, dose titration, s.c. (under the skin) injection<br>|
| Active Comparator: Neutral Protamine Hagedorn (NPH) insulin<br>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 | Drug: NPH insulin<br>* Treat-to-target, dose titration, s.c. (under the skin) injection<br>Drug: insulin aspart<br>* Treat-to-target, dose titration, s.c. (under the skin) injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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)] | 
| 8-point Self-monitored Plasma Glucose (SMPG) Profile at 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. | Visit P3 (GW 24) | 
| 8-point Self Monitored Plasma Glucose (SMPG) Profile at 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. | Visit P4 (GW 36) | 
| Maternal Safety - Number of Subjects With Adverse Events (AEs) | 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. | Participants were followed during the pregnancy period, an average of 9.6 months | 
| Safety in Children - Number of Subjects (Foetuses and Newborns) With Adverse Events | 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. | Foetuses/Newborns were followed during the pregnancy period, an average of 9.6 months and Follow-Up period (6 weeks after delivery) | 
| Maternal Safety - Hypoglycaemic Episodes | 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. | Participants were followed during the pregnancy period, an average of 9.6 months | 
| Maternal Safety - Nocturnal Hypoglycaemic Episodes | 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. | Participants were followed during the pregnancy period, an average of 9.6 months | 
| Maternal Safety - Change in Albumin Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Alanine Aminotransferase Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Alkaline Phosphatase Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Creatinine Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Lactate Dehydrogenase Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Potassium Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Sodium Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Total Protein Serum Level (Biochemistry) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Haemoglobin Level (Haematology) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Leukocytes Level (Haematology) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Thrombocytes Level (Haematology) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Urine Albumin Level (Urinalysis) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Albumin/Creatinine Ratio (Urinalysis) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Urine N (Creatinine) (Urinalysis) | 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). | Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery) | 
| Maternal Safety - Change in Insulin Detemir Specific Antibodies | 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. | 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. | 
| Maternal Safety - Change in Insulin Aspart Specific Antibodies | 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. | 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. | 
| Maternal Safety - Change in Insulin Detemir/Insulin Aspart Cross Reacting Antibodies | 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 | 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. | 
| Pregnancy Outcome Safety - Level of Detemir Specific Antibodies (AB) in Umbilical Cord Blood | Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T). | At Delivery (End of Pregnancy) | 
| Pregnancy Outcome Safety - Level of Aspart Specific Antibodies (AB) in Umbilical Cord Blood | Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T) | At Delivery (End of Pregnancy) | 
| Pregnancy Outcome Safety - Level of Cross-Reacting Antibodies (AB) in Umbilical Cord Blood | Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T). | At Delivery (End of Pregnancy) | 
| Ratio Between Detemir Specific Antibodies in Cord Blood and Maternal Antibodies | Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36) | At Delivery (End of Pregnancy) and at Visit P4 (GW 36) | 
| Pregnancy Outcome Safety - Level of Insulin Detemir in Umbilical Cord Blood |  | At Delivery | 
| Maternal Safety - Change From Visit P1 in Body Weight During Pregnancy by Visit | Change in the body weight was summarised by treatment. | Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36) | 
| Maternal Safety - Change From Visit P1 in Systolic Blood Pressure During Pregnancy and at Follow-Up by Visit | Change in the systolic blood pressure was summarised by treatment. | 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) | 
| Maternal Safety - Change From Visit P1 in Diastolic Blood Pressure During Pregnancy and at Follow-Up by Visit | Change in the diastolic blood pressure was summarised by treatment. | 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) | 
| Maternal Safety - Change From Visit P1 in Pulse During Pregnancy and at Follow-Up | Change in the pulse was summarised by treatment. | Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up Visit (6 weeks after delivery) | 
| Maternal Safety - Electrocardiogram (ECG) | 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. | Follow-Up (6 weeks after delivery) | 
| Maternal Safety - Acceleration of Retinopathy in Any Eye | 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. | From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery) | 
| Maternal Safety - Acceleration of Nephropathy | 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. | From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery) | 
| Maternal Safety - Mode of Delivery | Non-Planned Caesarean Section is a procedure which takes place ≤8h prior to delivery. Planned Caesarean Section takes place >8h prior to delivery. | At Delivery Visit | 
| Pregnancy Outcome at Delivery | 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. | Delivery Visit | 
| Pregnancy Outcome at Follow-Up | 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. | Follow-Up (6 weeks after delivery) | 
| 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) | 
| Safety - Composite Pregnancy Outcome | 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. | End of Pregnancy | 
| Ratio Between Aspart Specific Antibodies in Cord Blood and Maternal Antibodies | Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36) | At Delivery (End of Pregnancy) and at Visit P4 (GW 36) | 
| Ratio Between Cross-reacting Antibodies in Cord Blood and Maternal Antibodies | Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36) | At Delivery (End of Pregnancy) and at Visit P4 (GW 36) |