| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
| Female and male subjects with type 2 diabetes |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 |
| • Objective: To assess whether treatment with insulin glargine + lixisenatide (iGlarLixi) versus insulin glargine changes regional brain insulin sensitivity and thereby glucose metabolism, eating behaviour, and cognition in patients with type 2 diabetes insufficiently controlled with oral antidiabetic drugs (OAD). |
|
| E.2.2 | Secondary objectives of the trial |
o Effect of 12 weeks treatment with iGlarLixi or Glargine on resting state brain activity and on brain response to food pictures and control pictures as assessed by functional magnetic resonance imaging. Food intake and food preference will be monitored during an ad libitum buffet.
o Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by
established neurocognitive tests (CANTAB[Cambridge Neuropsychological Test Automated
Battery]containing Motor Screening Task (MOT),Reaction Time (RTI) Paired Associates Learning
(PAL), Spatial Working Memory (SWM), PatternRecognition Memory (PRM), Delayed Matching
to Sample (DMS), Rapid Visual InformationProcessing (RVP) tests).
o Effect of 12 weeks treatment with iGlarLixi or Glargine on glycemic control (HbA1c change
from baseline to week 12).
o Effect of 12 weeks treatment with iGlarLixi or Glargine on body weight and body fat distribution
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects meeting all of the following criteria will be considered
for admission to the trial:
• Must be between 18 and 65 years at the time of signing
the informed consent.
• BMI 25-45 kg/m²
• Understand and voluntarily sign an informed consent
document prior to any study related
assessments/procedures.
• Ability to adhere to the study visit schedule and other
protocol requirements.
• Patients with type 2 diabetes mellitus diagnosed for at
least 1 year before the screening visit (visit 1) treated for
at least 3 months prior to visit 1 with only metformin or
metformin and a sodium glucose co-transporter 2
inhibitor, and patients who are not adequately controlled
with this treatment.
• Females of childbearing potential (FCBP) must agree
to utilize a highly effective forms of contraception
(Pearl index < 1) or practice complete abstinence
from heterosexual contact while participating in
the study (including dose interruptions), and for
at least 28 days after study treatment
discontinuation and must agree to pregnancy
testing during this timeframe
to abstain from breastfeeding during study
participation and 28 days after study drug
discontinuation.
• Males must agree
to use a latex condom during any sexual contact
with FCBP while participating in the study and for
28 days following discontinuation from this study,
even if he has undergone a successful vasectomy
to refrain from donating semen or sperm while
participating in this study and for 28 days after
discontinuation from this study treatment.
• All subjects must agree to refrain from donating blood
while on study drug and for 28 days after discontinuation
from this study treatment.
• All subjects must agree not to share medication. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following criteria will not be included in the trial:
• HbA1c at screening visit less than 7.5% or more than 12% for patients previously treated with metformin alone or with metformin and a second oral anti-diabetic treatment.• Women during pregnancy and lactation.• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal products. This includes iGlarLixi, insulin glargine, and human nasal insulin.
• Use of oral glucose-lowering agents other than those stated in the inclusion criteria or any injectable glucoselowering
agents during 3 months before screening • History of discontinuation of a previous treatment with a GLP-1 receptor agonist (GLP-1 RA) due to safety/tolerability issue or lack of efficacy. • Patient who has previously participated in any clinical trial with lixisenatide or the insulin glargine +lixisenatide fixed ratio combination or has previously received lixisenatide.
• Any contraindication to metformin use, according to local labeling. • Use of weight loss drugs within 3 months prior to screening visit. • Within the last 6 months prior to screening visit: myocardial infarction, unstable angina, or heart failure
requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures to be
performed during the study period. • History of stroke. • History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery. • Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes). • Uncontrolled or inadequately controlled hypertension (systolic blood pressure above 160 mmHg or diastolic blood pressure above 90 mmHg) at screening visit. • At screening visit, Body Mass Index (BMI) less than or equal to 25 or above 45 kg/m². • At screening visit ALT or AST more than 3 ULN. • At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L). • Exclusion Criteria for randomization at the end of the screening period: o HbA1c less than 7.5% or above 12%. o Amylase and/or lipase more than 3 ULN. o Calcitonin above or equal to 20 pg/mL (5.9pmol/L). • Participation in other clinical trials or observation period of competing trials up to 30 days prior to this study. • Known malformation of the central nervous system• Persons working nightshift• Treatment with drugs with central nervous actions or systemic steroid therapy • Any relevant (according to investigator’s judgment) cardiovascular disease, e.g. myocardial infarction, acute coronary syndrome, unstable angina pectoris,PTCA, heart failure (NYHA II-IV), planned coronary,carotid or peripheral artery revascularisation procedures to be performed during the study period.
• Indication of liver disease, as per medical history or defined by serum levels of either Alanine,Aminotransferase (ALT [SGPT]), Aspartate Aminotransferase (AST [SGOT]), or Alkaline Phosphatase above 3 x upper limit of normal (ULN) as determined during screening.• Alcohol abuse, defined as more than 20 gr/day • Impaired renal function, defined as estimated Glomerular Filtration Rate (eGFR) ≤ 60 ml/min (MDRD formula) as determined during screening. • Known structural and functional urogenital abnormalitiesthat that predispose for urogenital infections. • Subjects with a haemoglobin (Hb) between 14 and 18g/dl (for males) and Hb between 12 and 16 g/dl (forfemales) at screening.• Bariatric surgery within the past two years and other
gastrointestinal surgeries that induce chronic malabsorption within the last 5 years. • Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years.• Treatment with anti-obesity drugs 3 months prior to
informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight. • Known autoimmune disease (except autoimmune disease of the thyroid gland) or chronic inflammatory condition.• Claustrophobia • Any other clinically significant major organ system disease at screening such as relevant gastrointestinal,neurologic, psychiatric, endocrine (i.e. pancreatic),hematologic, malignant, infection or other major
systemic diseases making implementation of the protocol or interpretation of the study results difficult.
Presence of any contraindication for the conduct of an MRI investigation. Any other clinical condition, Refusal to get informed of unexpected detected pathological MRI findings • History of diabetic ketoacidosis • Severe gastric or bowel disease (including
gastroparesis)[..]for further details please check the prtocol-Section Exclusion Criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| o Effect of 12 weeks treatment with iGlarLixi or Glargine on brain insulin sensitivity assessed by functional magnetic resonance imaging (fMRI) as change in regional cerebral blood flow (rCBF) from before to 30 minutes after nasal insulin spray application. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Visit 2 and visit 7 ( week 0 and 12) |
|
| E.5.2 | Secondary end point(s) |
o Effect of 12 weeks treatment with iGlarLixi or Glargine on resting state brain activity and on brain response to food pictures and control pictures as assessed by functional magnetic resonance imaging. Food intake and food preference will be monitored during an ad libitum buffet.
o Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established neurocognitive tests (HVLT [Hopkins Verbal Learning Test]; TMT-A&B [Trail Making Test-A&B], MMSE ; MOCA + Digit Symbol Substitution Test [SDMT ]; CANTAB [Cambridge Neuropsychological Test Automated Battery] Tests).
o Effect of 12 weeks treatment with iGlarLixi or Glargine on glycemic control (HbA1c change from baseline to week 12 ).
o Effect of 12 weeks treatment with iGlarLixi or Glargine on body weight and body fat distribution
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Effect of 12 weeks treatment with iGlarLixi or Glargine on resting state brain activity and on brain response to food pictures: Week 0 and Week 12 (Visit 0 and Visit 7)
Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established neurocognitive tests: Week 0 and Week 12 (Visit 0 and Visit 7)
Effect of 12 weeks treatment with iGlarLixi or Glargine on glycemic control (HbA1c change from baseline to week 12 ): Week 0 and Week 12 (Visit 0 and Visit 7)
Effect of 12 weeks treatment with iGlarLixi or Glargine on body weight and body fat distribution: Week 0 and Week 12 (Visit 0 and Visit 7) |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
• Serious Aadverse Drug Reactions (SADR)/not justifiable toxicity
• Substantial changes in risk-benefit considerations
• New insights from other trials
• Insufficient recruitment rate
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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