Safety and Tolerability Study of Oral LGD-6972 for Type 2 Diabetes Mellitus

NCT02250222 | Completed Phase 1 DMC

• 1 other identifier: L6972-02
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 3

Brief Summary

Ligand Pharmaceuticals Incorporated is developing LGD-6972, a novel, orally-bioavailable addition to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The mechanism of action of LGD-6972 is to reduce the excess liver glucose production characteristic of type 2 diabetes mellitus that is a major contributor to hyperglycemia. This clinical trial will evaluate the safety and tolerability of escalating doses LGD-6972 administered daily over 2 weeks in both healthy subjects and subjects with type 2 diabetes mellitus.

Conditions

Type 2 Diabetes Mellitus

Outcome Measures

Primary Outcomes (1)

• Number of participants with one or more drug related adverse events or serious adverse events

  Safety and tolerability of repeat (14 days for normoglycemic healthy subjects (NHS) and 14 days for type 2 diabetes mellitus (T2DM) subjects) and sequential increasing oral doses of LGD-6972 in NHS and subjects withT2DM will be compared to NHS and T2DM subjects receiving placebo.

  At least 14 days after last dose

Secondary Outcomes (11)

• Pharmacokinetic (PK) profile (area under the concentration curve (AUC) of LGD-6972 after repeat oral doses in NHS and in subjects with T2DM

  14 days

• Change from baseline in fasting plasma glucose measured 24 hours after first dose and pre-dose Day 14 of treatment with LGD-6972 in NHS

  14 days

• Change from baseline in fasting plasma glucagon measured 24 hours after first dose and pre-dose Day 14 of treatment with LGD-6972 in NHS

  14 days

• Change from baseline in active and total glucagon-like-peptide (GLP-1) in fasting plasma measured 24 hours after first dose and pre-dose Day 14 of treatment with LGD-6972 in NHS

  14 days

• Change from baseline in fasting plasma glucose measured 24 hours after first dose and at Day 14 of treatment with LGD-6972 in subjects with T2DM

  14 days

Other Outcomes (4)

• Change from baseline in fasting plasma glucose measured during an oral glucose tolerance test (OGTT) on Day 14 of treatment with LGD-6972 at 0.5, 1, 1.5, 2, 3, and 4 hours post-glucose load in one dose group of subjects with T2DM

  14 days

• Change from baseline in fasting plasma glucagon measured during an OGTT on Day 14 of treatment with LGD-6972 at 0.5, 1, 1.5, 2, 3, and 4 hours post-glucose load in one dose group of subjects with T2DM

  14 days

• Change from baseline in fasting plasma insulin measured during an OGTT on Day 14 of treatment with LGD-6972 at 0.5, 1, 1.5, 2, 3, and 4 hours post-glucose load in one dose group of subjects with T2DM

  14 days

Study Arms (6)

Part 1: LGD-6972 15 mg

EXPERIMENTAL

15 mg LGD-6972 administered once daily (QD) for 14 days.

Drug: LGD-6972

Part 1: Placebo (Captisol ®)

PLACEBO COMPARATOR

Placebo administered once daily (QD) for 14 days.

Drug: Placebo (Captisol ®)

Part 2: LGD-6972 5 mg

EXPERIMENTAL

5 mg LGD-6972 administered orally QD for 14 days.

Drug: LGD-6972

Part 2: LGD-6972 10 mg

EXPERIMENTAL

10 mg LGD-6972 administered orally QD for 14 days.

Drug: LGD-6972

Part 2: LGD-6972 15 mg

EXPERIMENTAL

15 mg LGD-6972 administered orally QD for 14 days.

Drug: LGD-6972

Part 2: Placebo (Captisol ®)

PLACEBO COMPARATOR

Placebo administered orally QD for 14 days.

Drug: Placebo (Captisol ®)

Interventions

LGD-6972 DRUG

LGD-6972 sodium salt powder in Captisol ® (betadex \[β-cyclodextrin\] sulfobutylether sodium, NF)

Also known as: LGD-6972 sodium oral solution

Part 1: LGD-6972 15 mg; Part 2: LGD-6972 10 mg; Part 2: LGD-6972 15 mg; Part 2: LGD-6972 5 mg

Placebo (Captisol ®) DRUG

betadex \[β-cyclodextrin\] sulfobutylether sodium, NF

Also known as: SBECD

Part 1: Placebo (Captisol ®); Part 2: Placebo (Captisol ®)

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part 1
• Healthy, adult man or woman, 21 to 65 years of age. If the subject is a woman, she must be surgically sterile or naturally post-menopausal to be considered for enrollment.
• Willing and able to provide written informed consent.
• Not diabetic and has a fasting plasma glucose (FPG) between 70 mg/dL and 105 mg/dL, inclusive.
• Good health with no significant concomitant pathology based on medical history, physical examination, electrocardiogram (ECG), routine laboratory tests (chemistry, hematology, lipid profile, international normalized ratio, and urinalysis), and vital signs.
• Part 2
• Healthy, adult man or woman, 21 to 65 years of age. If the subject is a woman, she must be surgically sterile or naturally post-menopausal to be considered for enrollment.
• Willing and able to provide written informed consent.
• Has T2DM according to American Diabetes Association criteria.
• Has an HbA1c level between 6.5% and 10.5% at screening. One retest is permitted.
• Venous FPG is 125 mg/dL and 260 mg/dL at screening and either the Day -1 venous FPG or the Day 1 capillary blood glucose (CBG) is 115 mg/dL and 260 mg/dL. One retest is permitted.
• Has a body mass index between 20 and 45 kg/m2, inclusive.

You may not qualify if:

• Part 1
• Has a recent history of drug and/or alcohol abuse.
• Unwilling to comply with tobacco, nicotine, alcohol, and caffeine restrictions as specified in the protocol.
• Unwilling to comply with restrictions on strenuous exercise as specified in the protocol.
• Has history of clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurologic, psychiatric, immunologic, hematologic, gastrointestinal (including pancreatitis), or metabolic disease requiring medical treatment or has any medical problems that pose an increased risk during the study or that may compromise the integrity of the study data.
• Has liver transaminase levels (aspartate transaminase \[AST\] or alanine transaminase \[ALT\]) \>10% of the upper limit of normal (ULN), or has creatine kinase (CK) levels \>2 × ULN at screening or admission to clinic (Day -1).
• Has a plasma triglyceride level \>400 mg/dL. If triglyceride level is between 400 mg/dL and 500 mg/dL.
• Has a recent history of uncontrolled high blood pressure or has systolic blood pressure \<90 mmHg or \>140 mmHg or diastolic blood pressure \<60 mmHg or \>90 mmHg at screening.
• Is taking prescription or non-prescription drugs, vitamins, herbal, and dietary supplements, within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug, or is unwilling to refrain from taking any such medication until after the last protocol-specified blood sample. The use of acetaminophen, not to exceed a total daily dose of 1 g, is permitted up to 24 hours prior to admission to the investigational site and then prohibited until after the last protocol-specified blood sample. The use of stable hormone replacement medication by women, topical steroids, and stable thyroid medication is permitted.
• Part 2
• Has a history of hypoglycemic unawareness or recurrent hypoglycemia requiring assistance.
• Has liver transaminase levels (AST or ALT) \>10% × ULN, or has CK levels \>1.5 × ULN at screening or admission to clinic (Day -1).
• Has history of clinically significant cardiovascular, pulmonary, renal, endocrine (other than T2DM), hepatic, neurologic, psychiatric, immunologic, hematologic, gastrointestinal (including pancreatitis), or metabolic disease requiring medical treatment or has any medical problems that pose an increased risk during the study or that may compromise the integrity of the study data.
• Has a recent history of uncontrolled high blood pressure or has systolic blood pressure \<90 mmHg or \>140 mmHg or diastolic blood pressure \<60 mmHg or \>90 mmHg at screening. One retest of blood pressure within 24 hours is permissible at the discretion of the Investigator. Therapy for hypertension (beta blockers excluded) that has been stable for at least one month prior to screening is permitted. At the Investigator's discretion, one anti-hypertensive medication (angiotensin converting enzyme inhibitor, angiotensin receptor blocker, hydrochlorothiazide, or dihydropyridine calcium-channel blocker) may be initiated, or the dosage of a current antihypertensive medication up titrated, in a subject with blood pressure slightly above the eligibility criterion at screening. After at least 4 weeks of stable blood pressure treatment, if the subject's blood pressure has decreased to within the 140/90 mmHg limit, the subject will be fully reassessed for eligibility.
• Has received insulin for more than 6 consecutive days within 6 months prior to screening or has received insulin within 3 months prior to screening.

Sponsors & Collaborators

• Ligand Pharmaceuticals: lead

Study Sites (3)

Celerion, Inc

Tempe, Arizona, 85283, United States

Location

Clinical Pharmacology of Miami, Inc

Miami, Florida, 33014, United States

Location

Medpace Clinical Pharmacology

Cincinnati, Ohio, 45227, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

RVT-1502; SBE4-beta-cyclodextrin

Condition Hierarchy (Ancestors)

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

Study Officials

• Keith Marschke, Ph.D.

  Ligand Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 19, 2014
• First Posted: September 26, 2014
• Study Start: October 1, 2014
• Primary Completion: May 1, 2015
• Study Completion: June 1, 2015
• Last Updated: June 11, 2015

Record last verified: 2015-06

Locations

US (3)