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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S
ClinicalTrials.gov Identifier:
NCT00474045
First received: May 15, 2007
Last updated: January 30, 2017
Last verified: January 2017
  Purpose
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).

Condition Intervention Phase
Diabetes Diabetes Mellitus, Type 1 Drug: insulin detemir Drug: NPH insulin Drug: insulin aspart Phase 3

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

Resource links provided by NLM:


Further study details as provided by Novo Nordisk A/S:

Primary Outcome Measures:
  • Glycosylated Haemoglobin (HbA1c) for Full Analysis Set (Pregnant Subjects) at GW 36 [ Time Frame: At gestational week (GW) 36 ]
  • Glycosylated Haemoglobin (HbA1c) for Per Protocol Analysis Set (Pregnant Subjects) at GW 36 [ Time Frame: At gestational week (GW) 36 ]

Secondary Outcome Measures:
  • Glycosylated Haemoglobin (HbA1c) During Pregnancy [ 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) ]
  • Subjects Reaching HbA1c at or Below 6.0% Both at GW 24 and GW 36 [ Time Frame: At both Visit P3 (GW 24) and Visit P4 (GW 36) ]
  • Fasting Plasma Glucose (FPG) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 - Number of Subjects With Adverse Events (AEs) [ Time Frame: 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.

  • Safety in Children - Number of Subjects (Foetuses and Newborns) With Adverse Events [ Time Frame: 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 - Hypoglycaemic Episodes [ Time Frame: 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.

  • Maternal Safety - Nocturnal Hypoglycaemic Episodes [ Time Frame: 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 Albumin Serum Level (Biochemistry) [ Time Frame: 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 Alanine Aminotransferase Serum Level (Biochemistry) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 Lactate Dehydrogenase Serum Level (Biochemistry) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 Total Protein Serum Level (Biochemistry) [ Time Frame: 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) [ Time Frame: 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 - Change in Leukocytes Level (Haematology) [ Time Frame: 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).

  • Maternal Safety - Change in Thrombocytes Level (Haematology) [ Time Frame: 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) [ Time Frame: 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 Albumin/Creatinine Ratio (Urinalysis) [ Time Frame: 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 Urine N (Creatinine) (Urinalysis) [ Time Frame: 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 [ 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. ]
    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 in Insulin Aspart Specific Antibodies [ 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. ]
    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.

  • Maternal Safety - Change in Insulin Detemir/Insulin Aspart Cross Reacting Antibodies [ 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. ]
    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

  • Pregnancy Outcome Safety - Level of Detemir Specific Antibodies (AB) in Umbilical Cord Blood [ Time Frame: 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 Aspart Specific Antibodies (AB) in Umbilical Cord Blood [ Time Frame: 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 Cross-Reacting Antibodies (AB) in Umbilical Cord Blood [ Time Frame: 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).

  • Ratio Between Detemir Specific Antibodies in Cord Blood and Maternal Antibodies [ Time Frame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36) ]
    Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)

  • Pregnancy Outcome Safety - Level of Insulin Detemir in Umbilical Cord Blood [ Time Frame: At Delivery ]
  • Maternal Safety - Change From Visit P1 in Body Weight During Pregnancy by Visit [ Time Frame: 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.

  • Maternal Safety - Change From Visit P1 in Systolic Blood Pressure During Pregnancy and at Follow-Up by Visit [ 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) ]
    Change in the systolic blood pressure was summarised by treatment.

  • Maternal Safety - Change From Visit P1 in Diastolic Blood Pressure During Pregnancy and at Follow-Up by Visit [ 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) ]
    Change in the diastolic blood pressure was summarised by treatment.

  • Maternal Safety - Change From Visit P1 in Pulse During Pregnancy and at Follow-Up [ 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) ]
    Change in the pulse was summarised by treatment.

  • Maternal Safety - Electrocardiogram (ECG) [ Time Frame: 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 Retinopathy in Any Eye [ Time Frame: 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 - Acceleration of Nephropathy [ Time Frame: 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.

  • Maternal Safety - Mode of Delivery [ Time Frame: 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 at Delivery [ Time Frame: 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 [ Time Frame: 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 - Total Daily Insulin Dose During Pregnancy [ Time Frame: Visit P2 (GW 14), Visit P3 (GW 24), Visit P4 (GW 36), Follow-Up (6 weeks after delivery) ]
  • Safety - Composite Pregnancy Outcome [ Time Frame: 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 [ Time Frame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36) ]
    Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)

  • Ratio Between Cross-reacting Antibodies in Cord Blood and Maternal Antibodies [ Time Frame: At Delivery (End of Pregnancy) and at Visit P4 (GW 36) ]
    Cord blood (at delivery) vs. Maternal Blood at Visit P4 (GW 36)


Enrollment: 470
Study Start Date: May 2007
Study Completion Date: August 2010
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: insulin detemir
Treat-to-target, dose titration, s.c. (under the skin) injection
Drug: insulin aspart
Treat-to-target, dose titration, s.c. (under the skin) injection
Active Comparator: Neutral Protamine Hagedorn (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
Drug: NPH insulin
Treat-to-target, dose titration, s.c. (under the skin) injection
Drug: insulin aspart
Treat-to-target, dose titration, s.c. (under the skin) injection

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00474045

  Show 100 Study Locations
Sponsors and Collaborators
Novo Nordisk A/S
Investigators
Study Director: Global Clinical Registry (GCR, 1452) Novo Nordisk A/S
  More Information

Additional Information:
Publications:
Responsible Party: Novo Nordisk A/S
ClinicalTrials.gov Identifier: NCT00474045     History of Changes
Other Study ID Numbers: NN304-1687
2006-004861-33 ( EudraCT Number )
Study First Received: May 15, 2007
Results First Received: August 5, 2011
Last Updated: January 30, 2017

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Insulin, Globin Zinc
Insulin degludec, insulin aspart drug combination
Isophane insulin, beef
Insulin
Insulin Aspart
Insulin, Long-Acting
Insulin Detemir
Insulin, Isophane
Isophane Insulin, Human
Protamines
Hypoglycemic Agents
Physiological Effects of Drugs
Heparin Antagonists
Molecular Mechanisms of Pharmacological Action
Coagulants

ClinicalTrials.gov processed this record on September 21, 2017