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

University Health Network, Toronto

Status and phase: Completed; Phase 3; Phase 2

Conditions: Hyperlipidemias

Treatments: Drug: Placebo + L-NMMA; Drug: Teduglutide + L-NMMA; Drug: Teduglutide + Normal Saline

Study type: Interventional

Funder types: Other

Identifiers

NCT03534661

L-NMMA 13-6415

Details and patient eligibility

About

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.

Full 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.

Enrollment: 10 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts 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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

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10 participants in 3 patient groups, including a placebo group

Teduglutide + Normal Saline

Placebo Comparator group

Description:

Teguglutide + (L-NMMA control)

Treatment:

Drug: Teduglutide + Normal Saline

Teduglutide + L-NMMA

Active Comparator group

Description:

Tedulgutide + L-NMMA

Treatment:

Drug: Teduglutide + L-NMMA

Placebo + L-NMMA

Placebo Comparator group

Description:

(Teduglutide control) + L-NMMA

Treatment:

Drug: Placebo + L-NMMA