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Diabetes Mellitus, Type 2Phase 4Lixibrain01NCT03881995

Effects of Insulin Glargine and Lixisenatide on the Brain

A Phase 4 study testing IGlarLixi and Insulin Glargine 100 UNT/ML in people with Diabetes Mellitus, Type 2, run by University Hospital Tuebingen at 1 site in Germany.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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 . Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Diabetes Mellitus, Type 2
What is being tested?
IGlarLixi and Insulin Glargine 100 UNT/ML
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1 participants
Where
1 siteGermany
Study dates
18 Mar 2019to 29 Jun 2020
Phase
Phase 4
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 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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 glucose-lowering 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.
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  • 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:
  • HbA1c less than 7.5% or above 12%.
  • Amylase and/or lipase more than 3 ULN.
  • Calcitonin above or equal to 20 pg/mL (5.9 pmol/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 abnormalities that that predispose for urogenital infections.
  • Subjects with a haemoglobin (Hb) between 14 and 18 g/dl (for males) and Hb between 12 and 16 g/dl (for females) 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, such as cardiac pacemakers, ferromagnetic haemostatic clips in the central nervous system, metallic splinters in the eye, ferromagnetic or electronically operated active devices like automatic cardioverter defibrillators, cochlear implants, insulin pumps and nerve stimulators, prosthetic heart valves etc.
  • Any other clinical condition that would jeopardize subjects' safety while participating in this clinical trial.
  • Refusal to get informed of unexpected detected pathological MRI findings
  • History of diabetic ketoacidosis
  • Severe gastric or bowel disease (including gastroparesis)

Trial locations and contacts

1 site in 1 country.

Germany1 site
  • University of Tuebingen, Department of Internal Medicine IV

    Tübingen, 72076

Other trials in Germany

About this study

Official title: Effect of Insulin Glargine and Lixisenatide Versus Insulin Glargine on Brain Insulin Sensitivity in Patients With Type 2 Diabetes

  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. GLP-1 receptor agonists have been shown to acutely modulate appetite- and reward-related brain areas in humans. Research in animals suggest a close interaction between insulin and GLP-1 action especially in homeostatic centers of the hypothalamus. In this context, it is important that GLP-1 sensitivity of the brain is still present in the insulin resistant human brain. The investigators therefore hypothesized that GLP-1 agonists are able to improve insulin sensitivity of the brain; this might be one mechanism how GLP-1 agonists lead to weight loss and improved glucose metabolism. This might also have beneficial implications for cognitive function. However, at present, there are no human studies examining the effect of a GLP-1 agonist on brain activity and especially insulin action in the brain in patients with type 2 diabetes mellitus (T2D). Furthermore, there is no study in humans examining the effect of newly initiated insulin therapy on brain activity and especially insulin action in the brain in patients with T2D.
  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. 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).
Being tested
IGlarLixi, Insulin Glargine 100 UNT/ML
Medical subject headings
Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IGlarLixiDrug

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

  • Insulin Glargine 100 UNT/MLDrug

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

Study groups in NCT03881995
Study groupRoleWhat they receive
iGlarLixiActive comparatorSubjects will receive premixed Insulin glargine + lixisenatide once daily for 12 weeks
Receives: Drug: IGlarLixi
Insulin glargineActive comparatorSubjects will receive Insulin glargine once daily for 12 weeks
Receives: Drug: Insulin Glargine 100 UNT/ML

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Change from baseline brain insulin sensitivity at 12 weeks

Secondary outcomes (16)
  1. Processing of food pictures

    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.

    Measured: Change from baseline processing of food pictures at 12 weeks

  2. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Motor Screening Task (MOT). Outcome measures: assess the participant's speed of response and the accuracy of pointing.

    It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

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

  3. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Reaction Time (RTI). Outcome measures: Reaction time and movement time for both the simple and five-choice variants.

    It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

    Measured: Change from baseline reaction time and movement time at 12 weeks

  4. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Rapid Visual Information Processing (RVP). Outcome measures: Latency (speed of response), probability of false alarms and sensitivity.

    It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

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

  5. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Paired Associates Learning (PAL). Outcome measures: Errors made by the participant, the number of trials required to locate the pattern(s) correctly, memory scores and stages completed.

    It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

    Measured: 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

  6. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Spatial Working Memory (SWM). Outcome measures: errors (selecting boxes that have already been found to be empty and revisiting boxes which have already been found to contain a token) and strategy.

    It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

    Measured: Change from baseline errors and strategy at 12 weeks

  7. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Pattern Recognition Memory (PRM). Outcome measures: Number and percentage of correct trials and latency (speed of participant's response) It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

    Measured: Change from baseline number and percentage of correct trials and latency at 12 weeks

  8. Cognitive function

    Effect of 12 weeks treatment with iGlarLixi or Glargine on cognitive function assessed by established Delayed Matching to Sample (DMS). Outcome measures: Latency (the participant's speed of response), the number of correct patterns selected and a statistical measure giving the probability of an error after a correct or incorrect response.

    It is part of Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess neurocognition. All CANTAB tests are evaluated together.

    Measured: Change from baseline latency, the number of correct patterns selected and a statistical measure giving the probability of an error after a correct or incorrect response at 12 weeks

  9. Glycemic control

    Effect of 12 weeks treatment with iGlarLixi or Glargine on glycemic control (HbA1c change from baseline to week 12.

    Measured: Change from baseline glycemic control at 12 weeks

  10. Liver fat content

    Will be assessed by liver MR-spectroscopy change from baseline to 12 weeks.Unit: [%]

    Measured: Change from baseline body fat distribution at 12 weeks

  11. Total adipose tissue (TAT)

    Will be assessed by whole body MRI as change from baseline to 12 weeks. Unit: [l]

    Measured: Change from baseline body fat distribution at 12 weeks

  12. Visceral adipose tissue (VAT)

    Will be assessed by whole body MRI as change from baseline to 12 weeks. Unit: [l]

    Measured: Change from baseline body fat distribution at 12 weeks

  13. Subcutaneous adipose tissue (SCAT)

    Will be assessed by whole body MRI as change from baseline to 12 weeks. Unit: [l]

    Measured: Change from baseline body fat distribution at 12 weeks

  14. Body fat

    Will be assessed by bioelectric impedance analysis (BIA) as change from baseline to 12 weeks. Unit: [%]

    Measured: Change from baseline body fat at 12 weeks

  15. Lean body mass

    Will be assessed by bioelectric impedance analysis (BIA) as change from baseline to 12 weeks. Unit: [kg]

    Measured: Change from baseline body fat at 12 weeks

  16. Body weight

    Will be assessed as change from baseline to 12 weeks. Unit [kg]

    Measured: Change from baseline body weight at 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Mar 2019
  2. Study start18 Mar 2019
  3. Primary completion29 Jun 2020
  4. Study completion29 Jun 2020

Why it stopped: insufficient recruitment

Resources

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 4
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03881995
Sponsor's protocol ID
808/2018AMG1
Other IDs
2018-003557-21, 2018
Acronym
Lixibrain01
Status last verified
May 2020
First submitted
19 Feb 2019
Last updated
10 Jul 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing IGlarLixi and Insulin Glargine 100 UNT/ML in people with Diabetes Mellitus, Type 2, run by University Hospital Tuebingen at 1 site in Germany.

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 13 inclusion and 41 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: stopped early, as of the sponsor's last update on 10 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

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 was stopped early (reason given: insufficient recruitment). Results are not available in the source record.

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?

Brain insulin sensitivity (time frame: Change from baseline brain insulin sensitivity at 12 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
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 10 Jul 2020.

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