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

Time frame: At gestational week (GW) 36

Population: Full Analysis Set (FAS) for pregnant subjects-all randomised subjects exposed to at least 1 dose of trial drug and pregnant during trial. IDet (N)=152 and NPH (N)=158. Missing values were imputed using Last observation carried forward (LOCF). For FAS, LOCF was made using the pregnancy visits, the early termination visit and the withdrawal visit.

Time frame: At gestational week (GW) 36

Population: Per Protocol Analysis Set (pregnant subjects): comprised all subjects from the FAS (pregnant subjects) except subjects who significantly violated the inclusion/exclusion criteria. Gestational age at delivery must be at least 32 completed weeks.

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.

Time frame: Visit P3 (GW 24)

Population: Full Analysis Set (FAS) for pregnant subjects-all randomised subjects exposed to at least 1 dose of trial drug and pregnant during trial. IDet (N)=152 \& NPH (N)=158. Missing values were imputed using Last observation carried forward (LOCF). For FAS, LOCF was made using the average values.

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.

Time frame: Visit P4 (GW 36)

Population: Full Analysis Set (FAS) for pregnant subjects-all randomised subjects exposed to at least 1 dose of trial drug and pregnant during trial. IDet (N)=152 \& NPH (N)=158. Missing values were imputed using Last observation carried forward (LOCF). For FAS, LOCF was made using the average values.

Time frame: During the pregnancy period [Visit P1 (GW 8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36)]

Population: Full Analysis Set (FAS) for pregnant subjects-all randomised subjects exposed to at least 1 dose of trial drug and pregnant during trial. IDet (N)=152 and NPH (N)=158. Missing values were imputed using Last observation carried forward (LOCF). For FAS, LOCF was made using the pregnancy visits, the early termination visit and the withdrawal visit.

Time frame: 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)

Population: Full Analysis Set (FAS) for pregnant subjects-all randomised subjects exposed to at least 1 dose of trial drug and pregnant during trial. IDet (N)=152 and NPH (N)=158. Missing values were imputed using Last observation carried forward (LOCF). For FAS, LOCF was made using the pregnancy visits, the early termination visit and the withdrawal visit.

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.

Time frame: From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Acceleration of nephropathy was summarised by treatment and missing data was imputed using LOCF.

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.

Time frame: From GW 8-12 (Visit P1) to Follow-Up (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Acceleration of retinopathy was summarised by treatment and missing data was imputed using LOCF.

Change in the body weight was summarised by treatment.

Time frame: Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing values were imputed using LOCF.

Change in the diastolic blood pressure was summarised by treatment.

Time frame: 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)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing values were imputed using LOCF.

Change in the pulse was summarised by treatment.

Time frame: Visit P1 (GW (8-12), Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing values were imputed using LOCF.

Change in the systolic blood pressure was summarised by treatment.

Time frame: 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)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing values were imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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.

Time frame: 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.

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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

Time frame: 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.

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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.

Time frame: 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.

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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).

Time frame: Visit P1 (GW 8-12), Follow-Up (FU) Visit (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Missing data was imputed using LOCF.

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.

Time frame: Follow-Up (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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.

Time frame: Participants were followed during the pregnancy period, an average of 9.6 months

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Non-Planned Caesarean Section is a procedure which takes place ≤8h prior to delivery. Planned Caesarean Section takes place \>8h prior to delivery.

Time frame: At Delivery Visit

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. This set in total contains 152 subjects in IDet and 158 subjects in NPH arm. The partcipant analysed for this outcome measure are the number of subjects at delivery visit.

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.

Time frame: Participants were followed during the pregnancy period, an average of 9.6 months

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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.

Time frame: Participants were followed during the pregnancy period, an average of 9.6 months

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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.

Time frame: Delivery Visit

Population: Safety analysis set (pregnant subjects): randomised subjects exposed to at least 1 dose of trial product and preg. during the trial. IDet (N)=152 (152 pregnancies) NPH (N)=158 subjects (160 pregnancies, 2 subjects had spontaneous abortion and became preg. again). Analysed subjects-no. of subjects with a preg. outcome at delivery visit.

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.

Time frame: Follow-Up (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): randomised subjects exposed to at least 1 dose of trial product and preg. during the trial. IDet (N)=152 (152 pregnancies) NPH (N)=158 subjects (160 pregnancies, 2 subjects had spontaneous abortion and became preg. again). Analysed subjects-no. of subjects with a preg. outcome at delivery visit.

Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T)

Time frame: At Delivery (End of Pregnancy)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T).

Time frame: At Delivery (End of Pregnancy)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Antibodies were measured in a subtraction radioimmunoassay and expressed as antibody bound tracer relative to the total amount of tracer (%B/T).

Time frame: At Delivery (End of Pregnancy)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Time frame: At Delivery

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. IDet in cord blood was analysed for subjects in the IDet Arm and only for 98 subjects, as for 72 subjects it was reported as below measuring range (\<25.00 pmol/L).

Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)

Time frame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)

Time frame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)

Time frame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

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.

Time frame: End of Pregnancy

Population: Safety analysis set (pregnant subjects): randomised subjects exposed to at least 1 dose of trial product and pregnant during the trial. IDet (N)=152 (152 pregnancies) NPH (N)=158 subjects (160 pregnancies, 2 subjects had spontaneous abortion and became pregnant again).

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.

Time frame: Foetuses/Newborns were followed during the pregnancy period, an average of 9.6 months and Follow-Up period (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial. Each pregnant woman analyzed had exactly one Foetus/Newborn that was analyzed for AEs.

Time frame: Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up (6 weeks after delivery)

Population: Safety analysis set (pregnant subjects): all randomised subjects who were exposed to at least one dose of trial product and who were pregnant during the trial.

Time frame: At both Visit P3 (GW 24) and Visit P4 (GW 36)

Population: FAS for pregnant subjects-all randomised subjects exposed to at least 1 dose of trial drug and pregnant during trial. IDet (N)=152 and NPH (N)=158. Missing values were imputed using LOCF which was made using pregnancy visits, early termination visit and withdrawal visit. Analysed subjects-subjects with valid HbA1c values at visit P3 and P4.