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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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Hypoglycaemia is a well-known complication of insulin treated diabetes. The counterregulatory response to hypoglycaemia, with glucagon as the most important mediator, is initially diminished within a few years of onset of Type 1 diabetes and subsequently lost and thus increasing the risk of hypoglycaemia. Dipeptidyl Peptidase (DPP)-4 inhibitors augment the glucagon response to insulin-induced hypoglycaemia in type 2 diabetes. The investigators hypothesize that treatment with a DPP-4 inhibitor in patients with type 1 diabetes will recover the alpha cell response to hypoglycaemia.
The 16 type 1 patients will be randomised to one of two treatment sequences: DPP-4 inhibitor followed by placebo or placebo followed by a DPP-4 inhibitor. Each treatment period lasts 6 weeks, so all patients will receive treatment for 12 weeks in total. Induction of hypoglycaemia will take place at 0 weeks, 6 weeks and 12 weeks to determine the glucagon response.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sequence A (sitagliptin→placebo) | Other | Cross-over, both arms reveived the same intervention in different order. |
|
| Sequence B (placebo→sitagliptin) | Other | Cross-over, both arms reveived the same intervention in different order. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sitagliptin | Drug | 100 mg once daily for six weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Glucagon Response to Acute Hypoglycaemia | Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia | Change from initialisation phase to 40 minutes after onset of hypoglycaemia |
| Glucagon Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | 0, 10, 20 and 40 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | 0, 10, 20, 40 minutes |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Frits Holleman, MD,PhD | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Academic Medical Center | Amsterdam | North Holland | 1100DD | Netherlands |
Patients were excluded if they were found to have impaired awareness of hypoglycaemia, had a history of seizures, cardiac arrhythmia (or used beta-adrenoreceptor blockers) and/or acute infection in the 12 weeks before the study, or evidence of severe diabetes complications (autonomic neuropathy, nephropathy or proliferative retinopathy).
Participants came to the Academic Medical Center in Amsterdam for a screening visit to determine eligibility for the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence A (Sitagliptin→Placebo) | Cross-over, both arms reveived the same intervention in different order. Sitagliptin : 100 mg once daily for six weeks Placebo : placebo, once daily for six weeks |
| FG001 | Sequence B (Placebo→Sitagliptin) | Cross-over, both arms reveived the same intervention in different order. Sitagliptin : 100 mg once daily for six weeks Placebo : placebo, once daily for six weeks |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sequence A (Sitagliptin→Placebo) | Cross-over, both arms reveived the same intervention in different order. Sitagliptin : 100 mg once daily for six weeks Placebo : placebo, once daily for six weeks |
| BG001 | Sequence B (Placebo→Sitagliptin) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Glucagon Response to Acute Hypoglycaemia | Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia | Posted | Median | Inter-Quartile Range | pmol/L | Change from initialisation phase to 40 minutes after onset of hypoglycaemia |
|
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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 | Baseline |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Josefine E. Schopman | Academic Medical Center | +31 20 5669111 | j.e.schopman@amc.uva.nl |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D007003 | Hypoglycemia |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Placebo | Drug | placebo, once daily for six weeks |
|
| Epinephrine Response to Acute Hypoglycaemia |
Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. |
| 0, 10, 20, 40 minutes |
| Norepinephrine Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | 0, 10, 20, 40 minutes |
| Growth Hormone Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | 0, 10, 20, 40 minutes |
| Cortisol Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | 0, 10, 20, 40 minutes |
| Symptomatic Hormone Responses to Acute Hypoglycaemia. | The symptomatic responses to hypoglycaemia were assessed using a standard validated symptom questionnaire adapted for experimental hypoglycaemia (McCrimmon et al (2003) Diabet.Med. 20: 507-509). A 7-point Likert scale (1=symptom absent; 7=symptom experienced with great intensity) was used to score presence and intensity of autonomic and neuroglycopenic symptoms of hypoglycaemia. Symptom scores were obtained during the initialisation phase, at occurrence of autonomic reaction and again 30 minutes later. For analyses the scale was considered as a continuous variable. | Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia |
Cross-over, both arms reveived the same intervention in different order. Sitagliptin : 100 mg once daily for six weeks Placebo : placebo, once daily for six weeks |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
|
| Secondary | Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | Posted | Median | Inter-Quartile Range | pmol*minutes/L | 0, 10, 20, 40 minutes |
|
|
|
|
| Secondary | Epinephrine Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | Posted | Median | Inter-Quartile Range | nmol*minutes/L | 0, 10, 20, 40 minutes |
|
|
|
|
| Primary | Glucagon Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | Posted | Median | Inter-Quartile Range | pmol*minutes/L | 0, 10, 20 and 40 minutes |
|
|
|
|
| Secondary | Norepinephrine Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | Posted | Median | Inter-Quartile Range | nmol*minutes/L | 0, 10, 20, 40 minutes |
|
|
|
|
| Secondary | Growth Hormone Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | Posted | Median | Inter-Quartile Range | mU*minutes/L | 0, 10, 20, 40 minutes |
|
|
|
|
| Secondary | Cortisol Response to Acute Hypoglycaemia | Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method. | Posted | Median | Inter-Quartile Range | mU*minutes/L | 0, 10, 20, 40 minutes |
|
|
|
|
| Secondary | Symptomatic Hormone Responses to Acute Hypoglycaemia. | The symptomatic responses to hypoglycaemia were assessed using a standard validated symptom questionnaire adapted for experimental hypoglycaemia (McCrimmon et al (2003) Diabet.Med. 20: 507-509). A 7-point Likert scale (1=symptom absent; 7=symptom experienced with great intensity) was used to score presence and intensity of autonomic and neuroglycopenic symptoms of hypoglycaemia. Symptom scores were obtained during the initialisation phase, at occurrence of autonomic reaction and again 30 minutes later. For analyses the scale was considered as a continuous variable. | Posted | Median | Inter-Quartile Range | units on a scale | Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia |
|
|
|
| 0 |
| 16 |
| 0 |
| 16 |
| EG001 | Sitagliptin Treatment | 0 | 16 | 0 | 16 |
| EG002 | Placebo | 0 | 16 | 0 | 16 |
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| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D011719 |
| Pyrazines |
|
| GIP intact |
|
| GIP total |
|
The Friedman Test was used for ANOVA. |
| 0.98 |
GLP-1 Total |
| 95 |
| No |
| Superiority or Other |
| ANOVA | The Friedman Test was used for ANOVA. | 0.049 | GIP intact | 95 | No | Superiority or Other |
| ANOVA | The Friedman Test was used for ANOVA | 0.44 | GIP total | 95 | No | Superiority or Other |
Post Hoc testing
| <0.05 |
| 95 |
| No |
| Superiority or Other |
|