Healthy, Out-Of-Hospital Cardiac Arrest
Conditions
Keywords
Healthy participants, intranasal insulin
Brief summary
This study is to determine the safety and tolerability of regular insulin (Humulin R) when given intranasally (as drops in nostrils). Healthy participants will be enrolled to determine the maximum tolerated dose of intranasal insulin.
Detailed description
This is being studied because intranasal insulin may be a way to prevent the brain injury that occurs after a cardiac arrest. Cardiac arrest is a life-threatening condition in which the heart suddenly stops beating and there is no blood flow to the body. If cardiac arrest is not treated immediately, it causes sudden death. Even when immediate treatment gets the heart beating again, many victims remain comatose and die later from brain injury. Nasal insulin, given immediately after a cardiac arrest may prevent or reduce brain injury. Nasal insulin reduces brain injury in animal experiments, and has been used to try to improve brain degeneration in patients with Alzheimer's disease. However, cardiac arrest patients may need higher doses than patients with Alzheimer's disease, therefore, this study is to examine those higher doses.
Interventions
DRUGIntranasal insulin
This will be given intranasally at differing doses depending on study day. A total of 11 possible doses will be tested, ranging from 0 to 1000 U insulin. Each volunteer will come for 5 visits. On the first treatment day participants will receive placebo (sterile water) in each nostril followed by a 4-hour observation period. After this observation period participants will receive the initial dose of insulin squirted in each nostril followed by a a 4 hour observation period. Participants will have at least 7 days in between the other 4 visits. Subsequent visits will include increased doses of insulin (depending on how this is tolerated) and will take approximately 4 hours at these visits.
Sponsors
Robert Silbergleit
American Heart Association
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
For every 6 participants, iterations of a Bayesian model will be performed to associate the administered dose with the frequency of dose-limiting hypoglycemia or other adverse events. The model will adaptively reallocate the dose increments for the next 6 participants. To provide more precise and reproducible estimates of dose-limiting toxicity, the trial will modify the size of dose increments based on the developing model to allocate more administrations to areas of the model with greatest uncertainty, or to higher doses in the absence of dose-limiting hypoglycemia.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Good health based on medical history, physical exam, and routine laboratory testing. * Female participants must have negative urine pregnancy test or be surgically sterilized or postmenopausal. Criteria for menopause are surgical menopause (hysterectomy, oophorectomy) or age \> 45 years with the absence of menses for greater than 12 months. Tubal ligation with menses within the past 12 months is not considered to be surgical sterilization. * Body mass index (BMI) between 18 kilogram / square meter (kg/m2) and 35 kg/m2. * Willing and able to stay at the clinical research facility as required by the protocol * Willing and able to comply with the investigational nature of the study and able to communicate well with investigators * Ability to comprehend and willing to provide written informed consent in accordance with institutional and regulatory guidelines
Exclusion criteria
* Known allergy to insulin. * Preexisting diabetes. * Current or previous use of diabetes medication or insulin. * Any nasal disease or congestion that may interfere with intranasal drug absorption. * Baseline hypoglycemia (blood glucose ≤ 65 mg/dL) or hyperglycemia (blood glucose \> 200 mg/dL) as evident from the screening labs. * Active serious disease, such as liver disease, kidney disease, uncontrolled hypertension, clinically significant hypokalemia, and significant or unstable medical illness * Blood donation in excess of 500 milliliter (mL) within 60 days prior to the first dose of study medication. * Treated with an investigational drug within 30 days. * Individuals with inadequate venous access.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Severe Hypoglycemia | Within 4 hours of dosing during each of 5 visits | Results reflect the participants who experienced severe hypoglycemia generically at the time they received a dose of insulin, as defined by blood glucose \< 45 milligrams per deciliter (mg/dL). Severe hypoglycemia was considered a dose limiting toxicity (DLT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Glucose - Study Visit 1 (100 Units) | Baseline and up to 4 hours after drug administration (Study Visit 1, Day 1) | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 1 (200 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 1 (400 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 2 (400 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 2 (600 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 3 (600 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 3 (800 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 4 (800 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 4 (900 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Blood Glucose - Study Visit 5 (1000 Units) | Baseline, up to 4 hours after drug administration | Change in participant blood glucose from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. Higher numbers indicated a higher level of blood glucose. This procedure was followed at each study visit. |
| Change in Serum C-peptide Levels - Study Visit 1 (100 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study visit. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 1 (200 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study visit. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 1 (400 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study visit. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 2 (400 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 2 (600 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 3 (600 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 3 (800 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 4 (800 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 4 (900 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum C-peptide Levels - Study Visit 5 (1000 Units) | Baseline, up to 4 hours after drug administration | Change in participant C-peptide Levels from baseline as measured by blood draws taken at 15-minute and 30-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. C-peptide levels in the blood indicate how much insulin the pancreas is producing. Lower C-peptide levels suggest the body is producing little or no insulin, while higher C-peptide levels may indicate insulin resistance. |
| Change in Serum Insulin - Study Visit 1 (100 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 1 (200 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 1 (400 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 2 (400 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 2 (600 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 3 (600 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 3 (800 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 4 (800 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 4 (900 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
| Change in Serum Insulin - Study Visit 5 (1000 Units) | Baseline, up to 4 hours after drug administration | Serum insulin refers to the measurement of insulin levels in the blood. Change in participant serum insulin from baseline as measured by blood draws taken at 15-minute, 30-minute, and 60-minute intervals following administration of intra-nasal insulin. This procedure was followed at each study. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRobert Silbergleit, MD
University of Michigan
Participant flow
Pre-assignment details
The dosing schedule for each cohort was based on the occurrence of SAEs in the previous cohort. If no SAE occurred in any of the cohort's participants, then the dose escalation schedule for the next cohort was weighted towards higher doses and excluded a lower dose. One participant in Cohort 2 did not attend the final visit after Cohort 3 had already begun, so Cohort 3's dosing was not adjusted. Only Cohort 4 adaptively shifted to higher doses.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 49.7 years STANDARD_DEVIATION 16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 24 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 14 | 0 / 24 | 0 / 1 | 0 / 23 | 0 / 22 | 0 / 5 | 0 / 22 |
| other Total, other adverse events | 0 / 4 | 0 / 14 | 0 / 24 | 0 / 1 | 2 / 23 | 0 / 22 | 0 / 5 | 0 / 22 |
| serious Total, serious adverse events | 0 / 4 | 0 / 14 | 0 / 24 | 0 / 1 | 0 / 23 | 0 / 22 | 0 / 5 | 0 / 22 |
Outcome results
None listed