DiabetesPhase 1NCT02740829
Assessment of Intranasal Glucagon on Endogenous Glucose Production
A Phase 1 study testing Intranasal glucagon in people with Diabetes, run by University Health Network, Toronto.
Trial summary
Peripheral glucagon action increases hepatic glucose production. In rodents hypothalamic action of glucagon paradoxically suppresses glucose production. Intranasally administered peptides have been shown to preferentially enter the central nervous system. Read more about this study
- Who is it for?
- Ages 18 to 60 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Diabetes
- What is being tested?
- Intranasal glucagon
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 10 participants
- Where
- No sites listed yet
- Study dates
- Mar 2015to Mar 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 1. Men and women, aged 18 to 60 years 2. Body mass index 20 to 27 kg/m2 3. Hemoglobin in the normal range. 4. Normal glucose tolerance in response to a 75gram glucose
Who cannot join
- 1. Study participant with a history of hepatitis/hepatic disease that has been active within the previous two years.
- 2. Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis.
- 3. Any current or previous history of endocrine disease, dyslipidemia or malignancy 4. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal, genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic > 100 or systolic > 180 or systolic<100) or proliferative retinopathy 5. Use of immunosuppressive agents at any time during the study 6. Allergy to any study medication 7. Pregnancy or breastfeeding 8. Heavy smoker 9. Fasting blood glucose > 6.0 mmol/l or known diabetes. 10. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure.
- 11. Any nasal pathology. 12. Abnormal liver and thyroid function 13. Current addiction to alcohol or substances of abuse as determined by the investigator or of any mental illness.
- 14. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation 15. Taking any regular prescription or non-prescription medications at the time of the study. Occasional use of medications such as acetoaminophen or Tylenol 1 or any use of natural health products may be permitted at the discretion of the investigator.
- 16. Will not donate blood three months prior to and three months post study procedures
About this study
Official title: Evaluation of the Effects of Intranasal Glucagon on Endogenous Glucose Production in Humans
Peripheral glucagon action increases hepatic glucose production. In rodents hypothalamic action of glucagon paradoxically suppresses glucose production. Intranasally administered peptides have been shown to preferentially enter the central nervous system. We assessed the effects of intranasal glucagon on hepatic glucose production
Read the detailed description
Fifteen healthy, lean, non-diabetic males and females will undergo two studies each (single blinded crossover), in random order, 4-6 weeks apart.
Study A. Intranasal placebo administration with measurement of endogenous glucose production under pancreatic clamp conditions.
Study B. Intranasal glucagon (glucagon, Eli Lilly, Canada) administration with measurement of endogenous glucose production under pancreatic clamp conditions Each study participant will be admitted to the Metabolic Test Centre of the Toronto General Hospital the day before the study at 12pm. They will be provided with a standardized dinner (consisting of 7 Kcal/kg; 50% carbohydrate, 30% fat, and 20% protein) and will then be required to fast for 12 hr overnight (can have water but no other food or drinks).
At 7am (t=0) the next day, we will begin a primed, constant intravenous infusion of [6,6-2H2]glucose (D2 glucose; Cambridge Isotope Laboratories, MA; a stable isotope of glucose, the enrichment of which can be measured by GC/MS, allowing us to calculate endogenous glucose production rates). The infusion will continue for 8 hours.
At the same time (7am) a pancreatic clamp will be started for 8 hours in order to suppress pancreatic hormone secretion with somatostatin while providing basal infusions of pancreatic hormones and growth hormone by intravenous infusion. This method will permit us to study the effect of intranasal glucagon on hepatic glucose and TRL production without the confounding effects it may have on pancreatic hormone secretion. A simultaneous infusion of somatostatin (Sandostatin, Novartis Pharma, Miss, ON 30mcg/hr), insulin (Humulin R, Eli Lilly, Scarborough, ON, 0.05mU/kg/min), glucagon (Eli Lilly, Miss, ON 0.325ng/kg/min) and growth hormone (Humatrope, Eli Lilly, Mississauga, ON 3ng/kg/min) will be started and continued throughout the study. All hormones were diluted in 1 liter of normal saline and infused with a syringe pump (B. Braun Medical Inc., Bethlehem, PA). Autologous serum (3 mL), freshly prepared from the subject's blood, was added to the saline as carrier prior to hormone dilution.
A study nurse and/or doctor will be by the bedside throughout the clamp and will be monitoring the participant's blood glucose every 30 minutes after the onset of the clamp and every 10 minutes after administration of glucagon (if clinically indicated, sampling may be more frequent) to ensure participants do not develop hypo/hyperglycemia. Blood samples will be analysed with a glucometer for instant blood glucose readings. If intranasal glucagon reduces endogenous glucose production, a reduction in plasma glucose is likely. 20% dextrose will be administered if necessary to maintain euglycemia At 9 am (+120 minutes) intranasal placebo or glucagon will be administered. The glucagon (Eli Lily, Canada) and placebo (diluent) will be transferred to a metered nasal device (Pharmasystems, Markham, Ontario UPC: 063636 802721, Item 10271) immediately prior to use. This device dispenses 0.1ml (0.1mg) per puff. A maximum of 15 X0.1 ml puffs/vials (7 in 1 nostril and 8 in the other nostril) will be administered at rate of 2 (one in each nostril) every 60 seconds. This dose may be titrated down if necessary to reduce peripheral spillover.
Blood samples will be collected every 30 minutes after the start of the clamp and every 10 minutes after administration of intranasal glucagon or placebo (total of 400 ml). The blood samples will be collected into chilled sterile tubes containing 0.1% EDTA and preservative ( aprotinin, sodium azide) and processed as indicated below.
In order to match peripheral glucagon concentrations between study visits, a small dose of glucagon will likely need to be administered intravenously at 9am, during the placebo arm of the study. Based on the pharmacokinetics of glucagon, we are likely to administer 0.00625mg-0.025mg, although further dose titration may be necessary (maximum dose 0.1mg). Free fatty acids, triglycerides, insulin, glucagon, C-peptide, glucagon-like peptide-1 (GLP-1) and GIP,as well as glucose isotopic enrichment will be measured.
- Conditions
- Diabetes
- Being tested
- Intranasal glucagon, Intranasal placebo
- Medical subject headings
- Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intranasal glucagonDrug
Glucagon will be administered via a nasal dispenser
Intranasal placeboDrug
Placebo
| Study group | Role | What they receive |
|---|---|---|
| Intranasal placebo | Placebo comparator | placebo comparator Receives: Drug: Intranasal placebo |
| Intranasal glucagon | Experimental | active intervention Receives: Drug: Intranasal glucagon |
What is being measured
The primary outcome is the main question the study is designed to answer.
Endogenous glucose production following intranasal glucagon compared to placebo
Stable isotope infusion (D2 glucose) will enable assessment of endogenous glucose production by measuring glucose enrichment in plasma by gas chromatogaphy mass spectrometry. During steady state, rate of glucose appearance (Ra) = rate of glucose disappearance (Rd), where Ra = tracer infusion rate /plasma tracer enrichment. Endogenous glucose production (EGP) rate = Ra - glucose infusion rate
Measured: 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2016 (estimated)
- Study startMar 2015
- Primary completionJan 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for DiabetesStudies of the same condition, open and under way.
- More trials run by University Health Network, TorontoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Health Network, Toronto
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02740829
- Sponsor's protocol ID
- REB 14-8171-A
- Status last verified
- Apr 2016
- First submitted
- 8 Mar 2016
- Last updated
- 15 Apr 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Dash S, Xiao C, Stahel P, Koulajian K, Giacca A, Lewis GF. Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp. Diabetes Obes Metab. 2018 Feb;20(2):328-334. doi: 10.1111/dom.13069. Epub 2017 Sep 14.
PubMed 28730676
Study at a glance
From the registry record, last updated by the sponsor on 15 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Effects of Intranasal Glucagon on Endogenous Glucose Production in Humans
- ClinicalTrials.gov ID
- NCT02740829
- Acronym / sponsor ID
- REB 14-8171-A
- Conditions
- Diabetes
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University Health Network, TorontoUniversity, hospital or other
- Study start
- Mar 2015
- Primary completion
- Jan 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 15 Apr 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Peripheral glucagon action increases hepatic glucose production. In rodents hypothalamic action of glucagon paradoxically suppresses glucose production. Intranasally administered peptides have been shown to preferentially enter the central nervous system. We assessed the effects of intranasal glucagon on hepatic glucose production
Detailed description
Fifteen healthy, lean, non-diabetic males and females will undergo two studies each (single blinded crossover), in random order, 4-6 weeks apart.
Study A. Intranasal placebo administration with measurement of endogenous glucose production under pancreatic clamp conditions.
Study B. Intranasal glucagon (glucagon, Eli Lilly, Canada) administration with measurement of endogenous glucose production under pancreatic clamp conditions Each study participant will be admitted to the Metabolic Test Centre of the Toronto General Hospital the day before the study at 12pm. They will be provided with a standardized dinner (consisting of 7 Kcal/kg; 50% carbohydrate, 30% fat, and 20% protein) and will then be required to fast for 12 hr overnight (can have water but no other food or drinks).
At 7am (t=0) the next day, we will begin a primed, constant intravenous infusion of [6,6-2H2]glucose (D2 glucose; Cambridge Isotope Laboratories, MA; a stable isotope of glucose, the enrichment of which can be measured by GC/MS, allowing us to calculate endogenous glucose production rates). The infusion will continue for 8 hours.
At the same time (7am) a pancreatic clamp will be started for 8 hours in order to suppress pancreatic hormone secretion with somatostatin while providing basal infusions of pancreatic hormones and growth hormone by intravenous infusion. This method will permit us to study the effect of intranasal glucagon on hepatic glucose and TRL production without the confounding effects it may have on pancreatic hormone secretion. A simultaneous infusion of somatostatin (Sandostatin, Novartis Pharma, Miss, ON 30mcg/hr), insulin (Humulin R, Eli Lilly, Scarborough, ON, 0.05mU/kg/min), glucagon (Eli Lilly, Miss, ON 0.325ng/kg/min) and growth hormone (Humatrope, Eli Lilly, Mississauga, ON 3ng/kg/min) will be started and continued throughout the study. All hormones were diluted in 1 liter of normal saline and infused with a syringe pump (B. Braun Medical Inc., Bethlehem, PA). Autologous serum (3 mL), freshly prepared from the subject's blood, was added to the saline as carrier prior to hormone dilution.
A study nurse and/or doctor will be by the bedside throughout the clamp and will be monitoring the participant's blood glucose every 30 minutes after the onset of the clamp and every 10 minutes after administration of glucagon (if clinically indicated, sampling may be more frequent) to ensure participants do not develop hypo/hyperglycemia. Blood samples will be analysed with a glucometer for instant blood glucose readings. If intranasal glucagon reduces endogenous glucose production, a reduction in plasma glucose is likely. 20% dextrose will be administered if necessary to maintain euglycemia At 9 am (+120 minutes) intranasal placebo or glucagon will be administered. The glucagon (Eli Lily, Canada) and placebo (diluent) will be transferred to a metered nasal device (Pharmasystems, Markham, Ontario UPC: 063636 802721, Item 10271) immediately prior to use. This device dispenses 0.1ml (0.1mg) per puff. A maximum of 15 X0.1 ml puffs/vials (7 in 1 nostril and 8 in the other nostril) will be administered at rate of 2 (one in each nostril) every 60 seconds. This dose may be titrated down if necessary to reduce peripheral spillover.
Blood samples will be collected every 30 minutes after the start of the clamp and every 10 minutes after administration of intranasal glucagon or placebo (total of 400 ml). The blood samples will be collected into chilled sterile tubes containing 0.1% EDTA and preservative ( aprotinin, sodium azide) and processed as indicated below.
In order to match peripheral glucagon concentrations between study visits, a small dose of glucagon will likely need to be administered intravenously at 9am, during the placebo arm of the study. Based on the pharmacokinetics of glucagon, we are likely to administer 0.00625mg-0.025mg, although further dose titration may be necessary (maximum dose 0.1mg). Free fatty acids, triglycerides, insulin, glucagon, C-peptide, glucagon-like peptide-1 (GLP-1) and GIP,as well as glucose isotopic enrichment will be measured.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intranasal placebo | Placebo comparator | Drug: Intranasal placeboplacebo comparator |
| Intranasal glucagon | Experimental | Drug: Intranasal glucagonactive intervention |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- 1. Men and women, aged 18 to 60 years 2. Body mass index 20 to 27 kg/m2 3. Hemoglobin in the normal range. 4. Normal glucose tolerance in response to a 75gram glucose
Key exclusion criteria (6 listed)
- 1. Study participant with a history of hepatitis/hepatic disease that has been active within the previous two years.
- 2. Any current or previous history of biliary disease (including gall stones, biliary atresia and cholecystitis) or pancreatitis.
- 3. Any current or previous history of endocrine disease, dyslipidemia or malignancy 4. Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal, genitourinary, hematological systems, or has severe uncontrolled treated or untreated hyper/ hypotension (sitting diastolic > 100 or systolic > 180 or systolic<100) or proliferative retinopathy 5. Use of immunosuppressive agents at any time during the study 6. Allergy to any study medication 7. Pregnancy or breastfeeding 8. Heavy smoker 9. Fasting blood glucose > 6.0 mmol/l or known diabetes. 10. Any history of a MI or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on ECG, unstable angina, or decompensated heart failure.
- 11. Any nasal pathology. 12. Abnormal liver and thyroid function 13. Current addiction to alcohol or substances of abuse as determined by the investigator or of any mental illness.
- 14. Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation 15. Taking any regular prescription or non-prescription medications at the time of the study. Occasional use of medications such as acetoaminophen or Tylenol 1 or any use of natural health products may be permitted at the discretion of the investigator.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intranasal glucagonGlucagon will be administered via a nasal dispenser | Drug | Intranasal glucagon |
| Intranasal placeboPlacebo | Drug | Intranasal placebo |
Primary outcome
Endogenous glucose production following intranasal glucagon compared to placebo
Time frame: 6 hours
Stable isotope infusion (D2 glucose) will enable assessment of endogenous glucose production by measuring glucose enrichment in plasma by gas chromatogaphy mass spectrometry. During steady state, rate of glucose appearance (Ra) = rate of glucose disappearance (Rd), where Ra = tracer infusion rate /plasma tracer enrichment. Endogenous glucose production (EGP) rate = Ra - glucose infusion rate
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Apr 2016.
- Derived from this study: PubMed 28730676Dash S, Xiao C, Stahel P, Koulajian K, Giacca A, Lewis GF. Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp. Diabetes Obes Metab. 2018 Feb;20(2):328-334. doi: 10.1111/dom.13069. Epub 2017 Sep 14.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Intranasal glucagon in people with Diabetes, run by University Health Network, Toronto.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Endogenous glucose production following intranasal glucagon compared to placebo (time frame: 6 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02740829, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2016.