Effects of Insulin Glargine and Lixisenatide on the Brain

NCT03881995 | Terminated Phase 4

• 2 other identifiers: 808/2018AMG12018-003557-21
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

1. 1.Background During the last years, the brain has been identified as a major insulin-sensitive organ . The investigators and also other scientists identified hypothalamus, fusiform gyrus and prefrontal cortex as major insulin-sensitivity brain areas in humans . Brain insulin action regulates important physiological functions in humans such as food intake, body weight regulation, and cognition. Furthermore, animal studies suggest that insulin action specifically in the brain is involved in the control of peripheral glucose metabolism via regulation of the sensitivity to insulin in the rest of the body. Recently, the investigators were able to replicate these findings in humans: The investigators measured whole-body insulin sensitivity in combination with the well-established experimental delivery of human insulin to the brain via an intranasal approach. Peripheral insulin sensitivity was profoundly improved by brain insulin action in lean but not in obese healthy volunteers. What determines the effectiveness of this brain-derived pathway is still unknown. Furthermore, insulin resistance of the brain is linked to neurodegenerative diseases possibly explaining the elevated risk for such diseases in patients with type 2 diabetes.
2. 2.Rationale Based on the close interplay between hypothalamic insulin and GLP-1 signalling, the investigators hypothesize that the antidiabetic therapy with insulin glargine/lixisenatide combination (iGlarLixi) induces improved hypothalamic and prefrontal insulin sensitivity compared to a therapy with insulin glargine alone. This could underlay iGlarLixi's beneficial effects on body weight and whole-body glucose homeostasis.
3. 3.Objective To assess whether treatment with iGlarLixi versus insulin glargine changes brain regional insulin sensitivity and thereby glucose metabolism, eating behaviour, and cognition in patients with type 2 diabetes insufficiently controlled with oral antidiabetic drugs (OAD).

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Brain insulin sensitivity

  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.

  Change from baseline brain insulin sensitivity at 12 weeks

Secondary Outcomes (16)

• Processing of food pictures

  Change from baseline processing of food pictures at 12 weeks

• Cognitive function

  Change from baseline participant's speed of response and the accuracy of pointing at 12 weeks

• Cognitive function

  Change from baseline reaction time and movement time at 12 weeks

• Cognitive function

  Change from baseline latency, probability of false alarms and sensitivity at 12 weeks

• Cognitive function

  Change from errors made by the participant, the number of trials required to locate the pattern(s) correctly, memory scores and stages completed baseline at 12 weeks

Other Outcomes (2)

• Hypoglycemia

  1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks after randomisation

• Hypoglycemia time of day

  1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks after randomisation

Study Arms (2)

iGlarLixi

ACTIVE COMPARATOR

Subjects will receive premixed Insulin glargine + lixisenatide once daily for 12 weeks

Drug: IGlarLixi

Insulin glargine

ACTIVE COMPARATOR

Subjects will receive Insulin glargine once daily for 12 weeks

Drug: Insulin Glargine 100 UNT/ML

Interventions

IGlarLixi DRUG

Dose titration will be done based on the subjects fasting blood glucose

iGlarLixi

Insulin Glargine 100 UNT/ML DRUG

Dose titration will be done based on the subjects fasting blood glucose

Insulin glargine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• University Hospital Tuebingen: lead

Study Sites (1)

University of Tuebingen, Department of Internal Medicine IV

Tübingen, 72076, Germany

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2019
• First Posted: March 20, 2019
• Study Start: March 18, 2019
• Primary Completion: June 29, 2020
• Study Completion: June 29, 2020
• Last Updated: July 10, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)