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

Primary Purpose

Hyperlipidemias

Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Teduglutide + Normal Saline
Teduglutide + L-NMMA
Placebo + L-NMMA
Sponsored by
University Health Network, Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hyperlipidemias

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Tornto General Hospital, UHN

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

Teduglutide + Normal Saline

Teduglutide + L-NMMA

Placebo + L-NMMA

Arm Description

Teguglutide + (L-NMMA control)

Tedulgutide + L-NMMA

(Teduglutide control) + L-NMMA

Outcomes

Primary Outcome Measures

Plasma Lipid Levels
Lipid levels in plasma and lipoprotein fractions are measured following treatments

Secondary Outcome Measures

Blood Flow
Mesenteric blood flow rates are measured with ultrasound following treatments

Full Information

First Posted
May 11, 2018
Last Updated
March 26, 2020
Sponsor
University Health Network, Toronto
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1. Study Identification

Unique Protocol Identification Number
NCT03534661
Brief Title
L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release
Acronym
LNMMA
Official Title
Role of a Nitric Oxide Synthase Inhibitor on GLP-2 Mediated Intestinal Lipoprotein Release
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 27, 2017 (Actual)
Primary Completion Date
March 20, 2019 (Actual)
Study Completion Date
March 20, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Health Network, Toronto

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperlipidemias

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 2, Phase 3
Interventional Study Model
Crossover Assignment
Model Description
Each participant receives 3 randomized treatments.
Masking
Participant
Masking Description
Single-blinded for participants
Allocation
Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Teduglutide + Normal Saline
Arm Type
Placebo Comparator
Arm Description
Teguglutide + (L-NMMA control)
Arm Title
Teduglutide + L-NMMA
Arm Type
Active Comparator
Arm Description
Tedulgutide + L-NMMA
Arm Title
Placebo + L-NMMA
Arm Type
Placebo Comparator
Arm Description
(Teduglutide control) + L-NMMA
Intervention Type
Drug
Intervention Name(s)
Teduglutide + Normal Saline
Other Intervention Name(s)
L-NMMA control
Intervention Description
Teduglutide 0.05 mg/kg subcutaneous injection; Normal Saline intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Teduglutide + L-NMMA
Other Intervention Name(s)
active treatments
Intervention Description
Teduglutide 0.05 mg/kg subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Placebo + L-NMMA
Other Intervention Name(s)
Teduglutide control
Intervention Description
Placebo subcutaneous injection; L-NMMA 10 mg/kg intravenous infusion
Primary Outcome Measure Information:
Title
Plasma Lipid Levels
Description
Lipid levels in plasma and lipoprotein fractions are measured following treatments
Time Frame
10.5 hours
Secondary Outcome Measure Information:
Title
Blood Flow
Description
Mesenteric blood flow rates are measured with ultrasound following treatments
Time Frame
3 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
Facility Information:
Facility Name
Tornto General Hospital, UHN
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1L7
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No

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L-NMMA on GLP-2 Mediated Intestinal Lipoprotein Release

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