Type 1 Diabetes
Conditions
Keywords
Diabetes, Implantable Insulin Pump, Intraperitoneal Insulin Delivery
Brief summary
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.
Detailed description
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.
Interventions
DRUGMedtronic MiniMed Implantable Pump Human Recombinant Insulin
400 IU per ml - dosage based on the Investigators clinical judgement and the individual subject requirements.
DEVICEMedtronic MiniMed Implantable Pump System
The implantable pump system is intended to provide continuous intraperitoneal delivery of insulin in subjects with diabetes.
DRUGAventis HOE21PH U400
400 IU per ml - dosage based on the Investigators clinical judgement and the individual subject requirements.
Sponsors
Medtronic Diabetes
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes mellitus (American Diabetes Association definition) * HbA1c greater than or equal to 7.5% * Intensive insulin treatment for at least 3 months * Physical and intellectual ability to operate MIP system * Subject has been under the routine care of the investigator for at least two months prior to enrollment * Subject has a reliable support person (defined as a person who has daily contact with the subject and knows whom to contact in the event of an emergency). * Capability and willingness to perform self-monitoring of blood glucose at least four times daily for 9 months of the study and 7 times daily for 3 months of the study * Physical and intellectual ability to operate the MIP system and to comply with the data reporting requirements of the study. * Subject is willing to sign the informed consent form (approved by local Institutional Review Board and Medtronic MiniMed)
Exclusion criteria
* The subject's insulin usage exceeds 66 units per day. * Severe complications such as advanced autonomic neuropathy, legal blindness, or symptomatic cardiovascular disease as evidenced by a cardiovascular episode within the last six months * Reside at or plan to travel to elevations above 8000 feet during the study period (commercial airline travel is acceptable) * Subject who is pregnant, of childbearing potential or lactating and is neither surgically sterile, using contraceptives (devices, oral or implanted) nor other physician approved contraceptive * The subject has any major concomitant disease or any physical or psychological disorder within the last five years, which might be considered life threatening, or which might confound the collection or interpretation of the study data * The subject has previously enrolled in or participated in an investigational drug or device study within the preceding 4 weeks * The subject has any condition that precludes him/her from completing the study requirements * Has plans for activities which require them to go 25 feet below sea level
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c and Compared Between Groups | Baseline and 12 months | 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. |
| Incidence of Severe Hypoglycemia Events | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Daily Blood Glucose | average from baseline to 12 months | 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. |
| Mean Amplitude of Glycemic Excursions (MAGE) | average from baseline to 12 months | 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. |
| Low Blood Glucose Index (LBGI); | average from baseline to 12 months | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 52 |
| 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. | 48 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Physician Decision | 0 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Subcutaneous Insulin Arm (SC) | MiniMed Implantable Insulin Pump (MIP) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants | 52 Participants | 100 Participants |
| Age Continuous | 40.7 years STANDARD_DEVIATION 11.9 | 43.3 years STANDARD_DEVIATION 10.8 | 42 years STANDARD_DEVIATION 11.4 |
| Region of Enrollment United States | 48 participants | 52 participants | 100 participants |
| Sex: Female, Male Female | 31 Participants | 31 Participants | 62 Participants |
| Sex: Female, Male Male | 17 Participants | 21 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 53 | 27 / 54 |
| serious Total, serious adverse events | 9 / 53 | 7 / 54 |
Outcome results
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.
Time frame: Baseline and 12 months
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MiniMed Implantable Insulin Pump (MIP) | Change in HbA1c and Compared Between Groups | -0.3122449 percent HbA1c | Standard Deviation 0.8908406 |
| Subcutaneous Insulin Arm (SC) | Change in HbA1c and Compared Between Groups | 0.1191489 percent HbA1c | Standard Deviation 0.8691921 |
Comparison: Sample size calculations were performed on the primary endpoint: the average glycosylated hemoglobin (A1C). Sample size was estimated using a two-sample, one-sided t-test with a significance level of 0.05. The projected sample size of 50 subjects per treatment group provides 79% power to reject the null hypothesis in favor of the alternative hypothesis that the average A1C in both the MIP and SC groups are equivalent, assuming an effect size of 0.50% and a standard deviation of 1.0%.p-value: <0.05Mixed Models Analysis
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.
Time frame: 12 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MiniMed Implantable Insulin Pump (MIP) | Incidence of Severe Hypoglycemia Events | 2 events |
| Subcutaneous Insulin Arm (SC) | Incidence of Severe Hypoglycemia Events | 4 events |
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.
Time frame: average from baseline to 12 months
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MiniMed Implantable Insulin Pump (MIP) | Average Daily Blood Glucose | 186.77 mg/dL |
| Subcutaneous Insulin Arm (SC) | Average Daily Blood Glucose | 195.8 mg/dL |
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.
Time frame: average from baseline to 12 months
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MiniMed Implantable Insulin Pump (MIP) | Low Blood Glucose Index (LBGI); | 2.14 mg/dL |
| Subcutaneous Insulin Arm (SC) | Low Blood Glucose Index (LBGI); | 2.27 mg/dL |
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.
Time frame: average from baseline to 12 months
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MiniMed Implantable Insulin Pump (MIP) | Mean Amplitude of Glycemic Excursions (MAGE) | 136.27 mg/dL |
| Subcutaneous Insulin Arm (SC) | Mean Amplitude of Glycemic Excursions (MAGE) | 149.2 mg/dL |