Safety and Tolerability Study of SHP626 in Overweight and Obese Adults

Study Overview
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Brief Summary
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This study will investigate the safety and tolerability of daily dosing regimens of SHP626 in overweight and obese adults.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase 1 Study to Assess the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Multiple Oral Doses of SHP626 in Overweight and Obese Adult Subjects

Conditions
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Non-Alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: SHP626
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males that comply with any applicable contraceptive requirements or females of non-childbearing potential No history of active or chronic disease other than that allowed by study (hypertension, hyperlipidemia and GERD or heartburn) Has a body mass index of 25-35 kg/m2 with a body weight of greater than 140lbs (assessed at screening) Exclusion Criteria: No history of alcohol or substance abuse, including use of tobacco No substantial changes in eating habits or exercise routine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHP626<br>9/12 subjects -1x daily dose of 20mg for 12 days 9/12 subjects-1x daily dose of 40mg for 12 days 9/12 subjects-1x daily dose of 80mg for 12 days 9/12 subjects-1x daily dose of 120mg for 12 days or dose lower than 80mg for 12 days 9/12 subjects-1x daily dose of 160mg for 12 days or dose lower than 80mg for 12 days 9/12 subjects-2x daily dose of SHP626 (dose TBD) for 12 days 9/12 subjects-2x daily dose of SHP626 (dose TBD; lower or higher than cohort 6) for 12 days 9/12 subjects-1x or 2x daily dose of SHP626 in an escalating titration (doses TBD). Initial 3 days of SHP626 followed by an increased dose of SHP626 for 3 days and finally a further increase in dose of SHP626 for 6 days 9/12 subjects will take a 1x or 2x daily dose of SHP626 in escalating titration (doses TBD; lower or higher dose than cohort 8). Initial 3 days of SHP626 followed by an increased dose of SHP626 for 3 days and finally a further increase in dose of SHP626 for 6 days | Drug: SHP626<br> <br> |
| Placebo Comparator: Placebo<br>Three subjects per cohort will take a matched placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Standard Hematology | TEAEs were defined as events that either had a start date on or after the first dose of investigational medicinal product (IMP) or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An adverse event (AE) that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Hematology parameters included evaluation of hemoglobin, hematocrit, red blood cells, platelets, white blood cell count; total and differential, neutrophils (absolute), eosinophils (absolute), monocytes (absolute), basophils (absolute) and lymphocytes (absolute). | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Fat Soluble Vitamins (Vitamin A, D, & E) | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Fat soluble vitamin included vitamin A (serum retinol), vitamin D (serum 25-hydroxycholecalciferol) and vitamin E (serum alfa-tocopherol). | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Lipid Panel | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Lipid panel parameters included evaluation of total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol and low-density lipoprotein (LDL) cholesterol. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Thyroid Hormone Panel | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Thyroid hormone panel parameters included evaluation of thyroid hormones (TSH [thyroid stimulating hormone]; T3 [triiodothyronine] and T4 [thyroxine]). | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Coagulation | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Coagulation included international normalized ratio, activated partial thromboplastin time and prothrombin time. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Standard Chemistry | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Standard chemistry parameters included evaluation of sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, chloride, thyrotropin, thyroxine, tri-iodothyronine, phosphorus, protein, bicarbonate or carbon dioxide, albumin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, urate, beta-human chorionic gonadotropin and follicle-stimulating hormone levels. Participant with TEAE related to standard chemistry were reported with hepatic enzyme increase. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Urinalysis Parameters | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Urinalysis parameters included evaluation of pH, glucose, protein, nitrites, leukocyte esterase, occult blood, ketones, bilirubin and specific gravity levels. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Vital signs parameter included evaluation of orthostatic blood pressure, respiratory rate and body temperature. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Electrocardiogram (12-lead) | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. Twelve lead electrocardiogram parameters [(heart rate (HR), PR, RR, QRS and QT intervals and information on T-wave morphology (normal/abnormal) and U-wave morphology (absent/normal or abnormal)] were assessed. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (STEAEs) | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Who Discontinued From the Study | TEAEs were defined as events that either had a start date on or after the first dose of IMP or has a start date before the date of the first dose of IMP, but increased in severity on or after the date of the first dose of IMP. An AE that occurred more than 9 days after the date of the last dose of double-blind IMP was not counted as a TEAE. | From the start of the study drug administration up to 9 days after the last dose of study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Total Fecal Bile Acid (FBA) Concentration | Stool samples for the determination of total FBA were collected in 48-hour windows from 48 hours before dosing on Day 1 through Day 14. The average of daily total FBA excretion is calculated before (Day -1 and Day -2) as the first pre dose of IMP and after (Day 1-12) as the first post-dose of IMP. The FBA is calculated as Total FBA (micromoles) = FBA (micromol per liter) * weight (grams) divided by 10^3. Participants with fecal bile acid concentration and their average pre-first dose and average post-first dose were reported. | Day -2 up to Day 14 | 
| Mean Serum 7- Alpha-hydroxy-4-cholesten-3-one (C4) Concentration | Serum 7- alpha-hydroxy-4-cholesten-3-one (C4) concentrations were reported. | Day -1 to Day 15 | 
| Number of Participants With Stool Hardness Using Bristol Stool Chart | Stool hardness was assessed after each evacuation using the bristol stool chart, a medical aid designed to classify the form of human feces into 7 categories where type 1 is the hardest and type 7 is the softest. | Day -2 to Day 14 | 
| Maximum Observed Plasma Concentration (Cmax) of Volixibat |  | Day 1 to Day 14 | 
| Area Under the Plasma Concentration-Time Curve (AUC) of Volixibat (SHP626) |  | Day 1 to Day 14 |