| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049746 |
| E.1.2 | Term | Insulin-requiring type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate that clinically significant hypoglycemia (defined as blood glucose <54 mg/dL (3.0 mmol/L) or symptoms of severe hypoglycemia) is significantly less frequent following a double dose of insulin peglispro than following a double dose of insulin glargine within 84 hours of double dosing in patients with T2DM. |
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| E.2.2 | Secondary objectives of the trial |
1. Evaluate the PK of insulin peglispro and insulin glargine after the double dose.
2. Compare measures of glycemic control for the 84 hours following double doses of insulin peglispro and insulin glargine, including: incidence of hypoglycemia, mean nadir glucose, time to mean nadir glucose, mean duration in minutes (per patient) with glucose ≤70 mg/dL (3.9mmol/L) and fasting blood glucose.
3. Compare measures of glycemic control following a standard dose of insulin peglispro and a double dose of insulin peglispro, including: incidence of hypoglycemic events fasting blood glucose.
4. Compare the effects during the day following the standard dose of insulin peglispro and insulin glargine on, including: glucose area under the concentration-time curve (AUC), Glucose AUC excursion and beta cell function
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetic Evaluations – 06 Jan 2014
Where local regulations allow, a blood sample will be collected for pharmacogenetic analysis. It is a onetime collection, as noted in the Study Schedule. Samples will be stored and analysis may be performed on genetic variants thought to play a role in glucose and insulin regulation, beta cell function, characterization of patients’ responsiveness to insulin peglispro, or diabetes-related metabolic abnormalities.
Nonpharmacogenetic/Biomarker Evaluation – 06 Jan 2014
Samples will be collected for Nonpharmacogenetic biomarker research where local regulations allow. Blood and/or urine samples will be collected at the times specified in the Study Schedule. Samples may be used for research on diabetes progression and/or complications, mechanism of action of insulin peglispro, patients’ response to insulin peglispro, in case future analyses are warranted with regard to safety, or in validating diagnostic tools or assay(s) related to diabetes or related metabolic abnormalities or biomarker response to insulin peglispro.
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| E.3 | Principal inclusion criteria |
[1] Have T2DM, based on the World Health Organization (WHO) classification, for ≥1 year.
[2] Are 18-70 years of age, inclusive.
[3] Use any type of basal insulin (except degludec), including once-or twice-daily human insulin NPH, insulin detemir, or insulin glargine.
[4] Have HbA1c levels ≤9.0% according to central laboratory testing at Visit 1.
[5] Have BMI ≤40.0 kg/m2.
[6] Have been treated with stable doses of insulin for at least 30 days before Visit 1 with:
• Basal insulin with daily doses ±30% of mean during the last 4 weeks.
• Doses of a basal insulin must be between 0.3 U/kg/day and 1 unit/kg/day.
[7] If on metformin, TZDs, SGLT-2 inhibitors, or DPP4 inhibitors, must be on stable doses for the last 30 days.
[8] This inclusion criterion applies to all females of child-bearing potential:
• Are not breastfeeding.
• Test negative for pregnancy at Visits 1and 3 based on a serum pregnancy test.
• Intend not to become pregnant during the study.
• Have practiced reliable methods of birth control (for example, use of oral contraceptives or levonorgestrel, diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, intrauterine devices, partner with vasectomy, or abstinence) for at least 6 weeks before screening.
• Agree to continue to use reliable methods of birth control as determined by the investigator during the study (and for 2 weeks following the last dose of study drug).
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| E.4 | Principal exclusion criteria |
[14] Are using prandial, self-mixed, or premixed insulin. Patients using prandial
insulin may be switched to daily glargine if investigator judges that the patient
will still meet fasting glucose requirements for randomization.
[15] Are using insulin pump therapy.
[16] Have excessive insulin resistance: Defined as >1.0 U/kg/day as baseline
treatment.
[17] If being treated with SUs before Visit 1, then must have SUs washed out
between Visit 1 and Visit 2.
[18] Use any of these concomitant medications: morphine, codeine, antidiuretics,
glucagon-like peptide-1 (GLP-1) receptor agonists (for example, exenatide,
exenatide once weekly, lixisenatide or liraglutide), or pramlintide, used
concurrently or within 90 days before Visit 1 (screening).
[19] Have hypoglycemia unawareness, defined as confirmed by laboratory test
results or by historical episodes of hypoglycemia <54 mg/dL (3.0 mmol/L)
without symptoms.
[20] Have fasting hypertriglyceridemia >400 mg/dL (>4.5 mmol/L) at Visit 1, as
determined by the local laboratory.
[21] If currently taking prescription or over-the-counter medications to promote
weight loss, should discontinue use of the medication at Visit 1.
[22] Have had any episode of severe hypoglycemia (defined by requiring
assistance due to neurologically disabling hypoglycemia) within 6 months
before entry into the study.
[23] Have had 2 or more emergency room visits or hospitalizations due to poor
glucose control in the past 6 months.
[24] Have had a previous clinically significant episode of ketoacidosis as
determined by the investigator (ketone bodies at fasting and without acidosis
is acceptable) in the past 6 months. If the investigator is in doubt, C-peptide
should be measured, and patients should be excluded if confirmed as Cpeptide
negative (while having a fasting C-peptide in the normal range).
[25] Have 1 of the following concomitant diseases: clinically significant
hematologic, oncologic, renal, cardiac, hepatic, or gastrointestinal disease or
positive for human immunodeficiency virus (HIV), or have signs of active
hepatitis B or C as determined by the investigator, for participation.
[26] Have known history of cardiovascular disease (including angina, transient
ischemic attack [TIA], significant arrhythmia, stroke, myocardial infarction
[MI], or peripheral vascular disease), or history of coronary artery bypass
graft (CABG) or percutaneous coronary interventions (such as coronary
arterial stent insertion or coronary angioplasty).
[27] Have cardiac disease with functional status that is New York Heart
Association Class III or IV (per New York Heart Association Cardiac Disease
Classification) (Attachment 7).
[28] Have history of seizure disorder.
[29] Have history of renal transplantation, are currently receiving renal dialysis, or
have estimated Glomerular Filtration Rate (eGFR) <60 mL/min (Chronic
Kidney Disease Epidemiology Collaboration [CKD-EPI]).
[30] Have any known metabolic or lactic acidosis; have any condition associated
with hypoperfusion, hypoxemia, dehydration, or sepsis; or have had a
radiologic contrast study within 48 hours before study entry.
[31] Have obvious clinical signs or symptoms of liver disease (excluding
nonalcoholic fatty liver disease), acute or chronic hepatitis, nonalcoholic
steatohepatitis, or elevated liver enzyme measurements as indicated below:
total bilirubin 2× the upper limit of normal (ULN) as defined by the local
laboratory, or
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase
(SGPT) >2.5× ULN as defined by the local laboratory, or
aspartate aminotransferase (AST)/serum glutamic oxaloacetic
transaminase (SGOT) >2.5× ULN as defined by the local laboratory.
[32] Have active or untreated malignancy, have been in remission from clinically
significant malignancy (other than basal cell or squamous cell skin cancer) for
less than 5 years, or are at increased risk for developing cancer or a recurrence
of cancer in the opinion of the investigator.
[33] Have had a blood transfusion or severe blood loss within 3 months before
Visit 1 or have known hemoglobinopathy, hemolytic anemia, sickle cell
anemia, or any other traits of hemoglobin abnormalities known to interfere
with HbA1c measurement.
[34] Are receiving chronic systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, and inhaled
preparations) or have received such therapy within 8 weeks immediately
before Visit 1.
[35] Have diagnosed clinically significant diabetic autonomic neuropathy, in the
opinion of the investigator.
[36] Have had an organ transplant.
[37] Have any other condition (including known, recent drug or alcohol abuse or
psychiatric disorders [including eating disorders]) that precludes patients from
following and completing the protocol.
[38] Are smokers who cannot go without using tobacco products
[45] Have known history of proliferative retinopathy. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinically significant hypoglycemia is significantly less frequent following a double dose of insulin peglispro that for insulin glargine |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within 84 hours of double dose |
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| E.5.2 | Secondary end point(s) |
- Evaluation of PK of both insulin peglispro and insulin glargine
- Incidence of hypoglycemia (blood glucose ≤70 mg/dL (3.9mmol/L))
- Incidence of clinically significant hypoglycemia (blood glucose ≤54 mg/dL (3.0mmol/L))
- Mean nadir glucose
- Time to nadir glucose, which is ≤70 mg/dL (3.9mmol/L)
- Mean duration in minutes (per patient) with glucose ≤70 mg/dL (3.9mmol/L)
- Fasting blood glucose
- Incidence of hypoglycemic events, defined as ≤70 mg/dL (3.9mmol/L)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 84 hours following double dose for all secondary objectives
- within 12 and 84 hours from double dose (evaluate PK of insulin peglispro and insulin glargine, incidence of hypoglycemia)
- within 12 hours from double dose (incidence of clinically significant hypoglycemia)
- First, second and third days following the double dose (fasting blood glucose)
- window between the first inpatient standard dose and the second inpatient standard dose versus the incidence on the first, second, and third days following the double dose (incidence of hypoglycemia events)
- window between first inpatient standard dose and the second inpatient standard dose versus the first, second, and third days following the double dose (fasting blood glucose)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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