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The purpose of this study is to evaluate the effectiveness of insulin delivered in the peritoneum (abdomen)by an implantable pump in Type 1 diabetics.
Implantable insulin delivery pumps have been shown to reduce the occurrence of severe hypoglycemia in Type 1 DM subjects, as demonstrated in numerous European studies. Glycemic control is difficult to attain in subjects using exogenous insulin due to the risk of severe hypoglycemia. This study is aimed at comparing the efficacy of intraperitoneal (IP) insulin therapy to intensive subcutaneous insulin therapy over a period of 12 months.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MiniMed Implantable insulin Pump (MIP) | Experimental | The experimental group will receive intraperitoneally (IP) delivered insulin via the Medtronic MiniMed Implantable Pump (MIP). At the time of implant, the pump will be filled with Aventis HOE21PH U400 insulin and the subject will be treated with this insulin for the first 180 days post implant. During the refill procedure performed 180 days post implant, any insulin remaining in the pump will be removed and the pump will be refilled with Medtronic MiniMed Implantable Pump Human Recombinant Insulin. |
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| Subcutaneous insulin arm (SC) | No Intervention | The control group will remain on their current pre-study subcutaneous insulin therapy of either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used, or be required to change or modify their current diabetes therapy for the purpose of the study. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Medtronic MiniMed Implantable Pump Human Recombinant Insulin | Drug | 400 IU per ml - dosage based on the Investigators clinical judgement and the individual subject requirements. |
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| Measure | Description | Time Frame |
|---|---|---|
| Change in HbA1c and Compared Between Groups | To determine whether Intra Peritoneal insulin delivery via MIP results in glycemic control that is equal to or superior (i.e. not inferior to) control with SC therapy (Ho : μ (IP) -μ (SC) ≥ 0.50% A1C), a repeated measures analysis of variance, adjusting for baseline A1C using SAS Proc Mixed was used to compare average A1C trends over time between the two treatment groups (19). Type 3 Least Square (LS) means for each group were assessed. The Estimate statement within SAS proc mixed was used to estimate contrasts among the LS means and confidence intervals for the contrasts. | Baseline and 12 months |
| Incidence of Severe Hypoglycemia Events | The total number of severe hypoglycemia events, defined as a clinical episode of hypoglycemia (resulting in seizure or coma, requiring hospitalization, intravenous glucose or glucagon administration), or any hypoglycemia that requires assistance from another person, compared between the two study arms from Baseline to 12 months. | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Average Daily Blood Glucose | For each subject, a minimum of two blood glucose readings per day was required for calculation of the average daily mean. The overall mean of the mean for each subject for the measure time frame was then calculated. The mean of the results for all subjects in each group were then analyzed and compared between groups both at Baseline and 12 months. | average from baseline to 12 months |
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Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Scott W Lee, MD | Medtronic | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Sansum Medical Research Institute | Santa Barbara | California | 93105 | United States | ||
| University of Colorado Health Sciences Center |
All subjects trained on testing for Low Blood Glucose Index (LBGI) and a baseline collection of this data for all subjects was collected prior to a block randomization plan. The randomization visit occured 14 days prior to the study start, to allow for scheduling of the implantation surgery for those randomized to the MIP arm.
Centers were either university or clinic based endocrinology centers. The centers were required to recruit from their current patient population. This ensured that they had knowledge of the medical and behavioural history prior to enrollment. The experimental pumps were to be implanted and so the study could not be blinded.
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| ID | Title | Description |
|---|---|---|
| FG000 | MiniMed Implantable Insulin Pump (MIP) | The experimental group will receive intraperitoneally (IP) delivered insulin via the Medtronic MiniMed Implantable Pump (MIP). At the time of implant, the pump will be filled with Aventis HOE21PH U400 insulin and the subject will be treated with this insulin for the first 180 days post implant. During the refill procedure performed 180 days post implant, any insulin remaining in the pump will be removed and the pump will be refilled with Medtronic MiniMed Implantable Pump Human Recombinant Insulin. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Medtronic MiniMed Implantable Pump System | Device | The implantable pump system is intended to provide continuous intraperitoneal delivery of insulin in subjects with diabetes. |
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| Aventis HOE21PH U400 | Drug | 400 IU per ml - dosage based on the Investigators clinical judgement and the individual subject requirements. |
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| Mean Amplitude of Glycemic Excursions (MAGE) | MAGE was calculated by taking the arithmetic mean of BG excursions when both ascending and descending segments of the curve exceed one Standard Deviation of the average 24-hour BG value. MAGE was calculated for each subject using SMBG data from periods in which subjects had a minimum of 4 and maximum of 10 readings daily. The overall mean of the mean for each subject for the measure time frame was then calculated. The mean of the results for all subjects in each group were then analyzed and compared between groups both at Baseline and 12 months. | average from baseline to 12 months |
| Low Blood Glucose Index (LBGI); | 4 to 10 daily blood glucose readings (BG) were required for this measure. LBGI was calculated from BG values collected for 30 days prior to Visit 2 and 30 days following Visits 5 and 7. The continuous measure was compared between the two treatment groups for the three periods with a repeated measures ANOVA using proc mixed. Type 3 least square means for each group were assessed and estimate statements used to make comparisons among the LS means and create confidence intervals on the contrasts. | average from baseline to 12 months |
| Aurora |
| Colorado |
| 80010 |
| United States |
| Hellman & Rosen Endocrine Associates | North Kansas City | Missouri | 64116 | United States |
| Cleveland Clinic | Wooser | Ohio | 44195 | United States |
| Diabetes & Glandular Disease Clinic | San Antonio | Texas | 78229 | United States |
| FG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
| As Treated Data Analysis Set |
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| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | MiniMed Implantable Insulin Pump (MIP) | The experimental group will receive intraperitoneally (IP) delivered insulin via the Medtronic MiniMed Implantable Pump (MIP). At the time of implant, the pump will be filled with Aventis HOE21PH U400 insulin and the subject will be treated with this insulin for the first 180 days post implant. During the refill procedure performed 180 days post implant, any insulin remaining in the pump will be removed and the pump will be refilled with Medtronic MiniMed Implantable Pump Human Recombinant Insulin. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
| BG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | This set includes all subjects followed to Visit 5 (90 days, first insulin refill for MIP group). | Count of Participants | Participants |
| |||||||||||||||||
| Age Continuous | Results reported on the As-Treated Data Analysis set (n=100). This is the primary efficacy analysis set and will include all subjects randomized and followed, at least, to Visit 5. Missing data are treated as missing. There is no extrapolation or interpolation of missing values. | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in HbA1c and Compared Between Groups | To determine whether Intra Peritoneal insulin delivery via MIP results in glycemic control that is equal to or superior (i.e. not inferior to) control with SC therapy (Ho : μ (IP) -μ (SC) ≥ 0.50% A1C), a repeated measures analysis of variance, adjusting for baseline A1C using SAS Proc Mixed was used to compare average A1C trends over time between the two treatment groups (19). Type 3 Least Square (LS) means for each group were assessed. The Estimate statement within SAS proc mixed was used to estimate contrasts among the LS means and confidence intervals for the contrasts. | The primary efficacy analysis set is the As treated data set and includes all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. | Posted | Mean | Standard Deviation | percent HbA1c | Baseline and 12 months |
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| Primary | Incidence of Severe Hypoglycemia Events | The total number of severe hypoglycemia events, defined as a clinical episode of hypoglycemia (resulting in seizure or coma, requiring hospitalization, intravenous glucose or glucagon administration), or any hypoglycemia that requires assistance from another person, compared between the two study arms from Baseline to 12 months. | The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set for the purpose of analysis. | Posted | Number | events | 12 months |
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| Secondary | Average Daily Blood Glucose | For each subject, a minimum of two blood glucose readings per day was required for calculation of the average daily mean. The overall mean of the mean for each subject for the measure time frame was then calculated. The mean of the results for all subjects in each group were then analyzed and compared between groups both at Baseline and 12 months. | The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set for the purpose of analysis. | Posted | Mean | 95% Confidence Interval | mg/dL | average from baseline to 12 months |
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| Secondary | Mean Amplitude of Glycemic Excursions (MAGE) | MAGE was calculated by taking the arithmetic mean of BG excursions when both ascending and descending segments of the curve exceed one Standard Deviation of the average 24-hour BG value. MAGE was calculated for each subject using SMBG data from periods in which subjects had a minimum of 4 and maximum of 10 readings daily. The overall mean of the mean for each subject for the measure time frame was then calculated. The mean of the results for all subjects in each group were then analyzed and compared between groups both at Baseline and 12 months. | The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set for the purpose of analysis. | Posted | Mean | 95% Confidence Interval | mg/dL | average from baseline to 12 months |
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| Secondary | Low Blood Glucose Index (LBGI); | 4 to 10 daily blood glucose readings (BG) were required for this measure. LBGI was calculated from BG values collected for 30 days prior to Visit 2 and 30 days following Visits 5 and 7. The continuous measure was compared between the two treatment groups for the three periods with a repeated measures ANOVA using proc mixed. Type 3 least square means for each group were assessed and estimate statements used to make comparisons among the LS means and create confidence intervals on the contrasts. | The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set for the purpose of analysis. | Posted | Mean | 95% Confidence Interval | mg/dL | average from baseline to 12 months |
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Adverse event data collected from screening at 30 days prior to randomization until end of study phase at one year.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | MiniMed Implantable Insulin Pump (MIP) | The experimental group will receive intraperitoneally (IP) delivered insulin via the Medtronic MiniMed Implantable Pump (MIP). At the time of implant, the pump will be filled with Aventis HOE21PH U400 insulin and the subject will be treated with this insulin for the first 180 days post implant. During the refill procedure performed 180 days post implant, any insulin remaining in the pump will be removed and the pump will be refilled with Medtronic MiniMed Implantable Pump Human Recombinant Insulin. Results were analyzed for subjects that completed beyond V5, which was the end of the first 90 day period of IP insulin therapy. These were considered to be the "As Treated" group. All randomized subjects were assessed for safety risk. | 9 | 53 | 51 | 53 | ||
| EG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. All randomized subjects were assessed for safety risk. | 7 | 54 | 27 | 54 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (6.0) | Systematic Assessment |
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| Central Line Infection | Infections and infestations | MedDRA (6.0) | Systematic Assessment |
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| Diabetes Mellitus aggravated | Metabolism and nutrition disorders | MedDRA (6.0) | Systematic Assessment | Diabetes out of control |
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| Gastroenteritis | Infections and infestations | MedDRA (6.0) | Systematic Assessment |
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| Hyperglycemia | Metabolism and nutrition disorders | MedDRA (6.0) | Systematic Assessment |
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| Hypoglycemia | Metabolism and nutrition disorders | MedDRA (6.0) | Systematic Assessment |
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| Multiple Myeloma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (6.0) | Systematic Assessment |
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| Operation NOS | Surgical and medical procedures | MedDRA (6.0) | Systematic Assessment | Pump explanted for unknown reason |
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| Post procedual site infection | Surgical and medical procedures | MedDRA (6.0) | Systematic Assessment |
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| Road traffic Accident | Injury, poisoning and procedural complications | MedDRA (6.0) | Systematic Assessment |
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| Skin ulcer | Skin and subcutaneous tissue disorders | MedDRA (6.0) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hyperglycemia NOS | Metabolism and nutrition disorders | MedDRA (6.0) | Non-systematic Assessment |
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| Hypoglycemia NOS | Metabolism and nutrition disorders | MedDRA (6.0) | Non-systematic Assessment |
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| Nasopharygitis | Infections and infestations | MedDRA (6.0) | Non-systematic Assessment |
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| Seasonal allergy | Immune system disorders | MedDRA (6.0) | Non-systematic Assessment |
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| Upper respiratory tract infection NOS | Infections and infestations | MedDRA (6.0) | Non-systematic Assessment |
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| Urinary tract infection | Renal and urinary disorders | MedDRA (6.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John Shin | Sr. Clinical Research Manager | 818-576-4019 | john.shin@medtronic.com |
| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D007328 | Insulin |
| ID | Term |
|---|---|
| D011384 | Proinsulin |
| D061385 | Insulins |
| D010187 | Pancreatic Hormones |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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| >=65 years |
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| Male |
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| Yes |
| Non-Inferiority or Equivalence |
For the average A1C, the goal was to show non-inferiority of MIP compared to SC. The minimal clinically relevant increase in A1C (%) was set at 0.50%. The between-subjects standard deviation of A1C was assumed to be 1.0% based on previous studies. |
| OG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
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| OG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
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| OG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
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| OG001 | Subcutaneous Insulin Arm (SC) | The control group will remain on their pre-study subcutaneous insulin therapy either Multiple Daily Injections (MDI) or Continuous Subcutaneous Insulin Infusion (CSII - external insulin pump). The SC group will not be restricted to the type of insulin used. For consistency, results were analyzed for subjects that completed beyond V5. These were considered to be the "As Treated" group. The primary efficacy analysis set will include all subjects randomized and followed, at least, to Visit 5 (90 days, first insulin refill for MIP group). Missing data are treated as missing. There is no extrapolation or interpolation of missing values. This set is considered to be the As-Treated Data Analysis Set and is the primary data set used in the analysis. |
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