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L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release (LNMMA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03534661
Recruitment Status : Completed
First Posted : May 23, 2018
Last Update Posted : March 27, 2020
Sponsor:
Information provided by (Responsible Party):
University Health Network, Toronto

Brief Summary:
The gut is able to retain some fat for many hours after a fatty meal. The gut hormone glucagon-like peptide-2 (GLP-2) is known to release these fat stores in the gut, but it is not known how GLP-2 achieves this. One possibility is that GLP-2 increases blood flow in the gut. NG-monomethyl-L-arginine (L-NMMA) is a substance that inhibits nitric oxide synthase (an enzyme that helps make nitric oxide which increases blood flow). This protocol examines whether blocking gut blood flow with L-NMMA is able to prevent GLP-2 from releasing gut lipid stores. Healthy participants will be treated with a combination of Teduglutide (a resistant form of GLP-2) and L-NMMA, and their respective controls. Blood lipid levels will be measured following treatments.

Condition or disease Intervention/treatment Phase
Hyperlipidemias Drug: Teduglutide + Normal Saline Drug: Teduglutide + L-NMMA Drug: Placebo + L-NMMA Phase 2 Phase 3

Detailed Description:

This is a single-blind, cross over, Phase 3b clinical study. The protocol aims to study 15 healthy, lean, non-diabetic males and females for three studies each, in random order, approximately four weeks apart, as follows.

Study A (L-NMMA + Teduglutide study): Volunteers will receive high-fat nutritional drink and seven hours later a subcutaneous injection of Teduglutide (0.05mg/kg of body weight, which is the FDA-approved route and daily dose for the treatment of short bowel syndrome).Thirty minutes prior to Teduglutide, the subject will receive an intravenous infusion of L-NMMA up to a maximum amount of 10 mg/kg, to inhibit nitric oxide synthesis. Lipid and lipoprotein levels will be measured at regular intervals for 3 hours following the injection of Teduglutide. Mesenteric blood flow will be measured at regular intervals by ultrasonography on some volunteers.

Study B (Teduglutide + normal saline): The design is identical to study A, except that, instead of L-NMMA, normal saline of the same volume will be infused.

Study C (Placebo + L-NMMA): The design is identical to study A, except that, instead of Teduglutide, a placebo will be injected subcutaneously.

Mesenteric Blood Flow measurement: Mesenteric blood flow will be measured at the bedside for some of the volunteers by ultrasonography in each study (A, B, C) before, during and after the administration of L-NMMA and Teduglutide. The first evaluation will begin 15 min before the start of the L-NMMA infusion and periodically afterwards.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Each participant receives 3 randomized treatments.
Masking: Single (Participant)
Masking Description: Single-blinded for participants
Primary Purpose: Basic Science
Official Title: Role of a Nitric Oxide Synthase Inhibitor on GLP-2 Mediated Intestinal Lipoprotein Release
Actual Study Start Date : September 27, 2017
Actual Primary Completion Date : March 20, 2019
Actual Study Completion Date : March 20, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Teduglutide

Arm Intervention/treatment
Placebo Comparator: Teduglutide + Normal Saline
Teguglutide + (L-NMMA control)
Drug: Teduglutide + Normal Saline
Teduglutide 0.05 mg/kg subcutaneous injection; Normal Saline intravenous infusion
Other Name: L-NMMA control

Active Comparator: Teduglutide + L-NMMA
Tedulgutide + L-NMMA
Drug: Teduglutide + L-NMMA
Teduglutide 0.05 mg/kg subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
Other Name: active treatments

Placebo Comparator: Placebo + L-NMMA
(Teduglutide control) + L-NMMA
Drug: Placebo + L-NMMA
Placebo subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
Other Name: Teduglutide control




Primary Outcome Measures :
  1. Plasma Lipid Levels [ Time Frame: 10.5 hours ]
    Lipid levels in plasma and lipoprotein fractions are measured following treatments


Secondary Outcome Measures :
  1. Blood Flow [ Time Frame: 3 hours ]
    Mesenteric blood flow rates are measured with ultrasound following treatments



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Men and women, aged 18 to 60 years
  • Body mass index 20 kg/m2 to 30 kg/m2
  • Hemoglobin above 130g/L.
  • Normal glucose tolerance in response to a 75g, 2-hr oral glucose tolerance test

Exclusion Criteria:

  • Subject has a history of hepatitis/hepatic disease that has been active within the previous two years.
  • Any significant active (over the past 12 months) disease of the gastrointestinal, pulmonary, neurological, renal (creatinine > 1.5 mg/dL), genitourinary, hematological systems, or has severe uncontrolled treated or untreated hypertension (sitting diastolic blood pressure > 100 or systolic > 180) or proliferative retinopathy
  • History of diabetes or oral glucose tolerance indicative of diabetes or impaired glucose tolerance.
  • Any history of a myocardial infarction or clinically significant, active, cardiovascular history including a history of arrhythmia's or conduction delays on electrocardiogram, unstable angina, or decompensated heart failure.
  • Any laboratory values: aspartate transaminase > 2x upper limit of normal; alanine aminotransferase > 2x upper limit of normal; thyroid-stimulating hormone > 6 miliunit/l
  • Current addiction to alcohol or substances of abuse as determined by the investigator.
  • Mental incapacity, unwillingness or language barrier precluding adequate understanding or cooperation
  • Taking any prescription or non-prescription medications at the time of the study
  • Having donated blood three months prior to and three months post study procedures
  • A pregnancy test will be performed 1 to 3 days prior to each study in all female research participants. Those who test positive for pregnancy will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03534661


Locations
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Canada, Ontario
Tornto General Hospital, UHN
Toronto, Ontario, Canada, M5G 1L7
Sponsors and Collaborators
University Health Network, Toronto
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Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT03534661    
Other Study ID Numbers: L-NMMA 13-6415
First Posted: May 23, 2018    Key Record Dates
Last Update Posted: March 27, 2020
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Teduglutide
omega-N-Methylarginine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents
Radiation-Protective Agents
Protective Agents
Physiological Effects of Drugs