Back to resultsSafety and Tolerability Study of SHP626 in Overweight and Obese Adults
Primary Purpose
Non-Alcoholic Steatohepatitis
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
SHP626
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Non-Alcoholic Steatohepatitis
Eligibility Criteria
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.
Sites / Locations
- New Orleans Center for Clinical Research
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
SHP626
Placebo
Arm Description
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
Three subjects per cohort will take a matched placebo
Outcomes
Primary Outcome Measures
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).
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).
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.
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]).
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.
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
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.
Mean Serum 7- Alpha-hydroxy-4-cholesten-3-one (C4) Concentration
Serum 7- alpha-hydroxy-4-cholesten-3-one (C4) concentrations were reported.
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.
Maximum Observed Plasma Concentration (Cmax) of Volixibat
Area Under the Plasma Concentration-Time Curve (AUC) of Volixibat (SHP626)
Full Information
NCT ID
NCT02287779
First Posted
November 6, 2014
Last Updated
March 14, 2019
Sponsor
Mirum Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02287779
Brief Title
Safety and Tolerability Study of SHP626 in Overweight and Obese Adults
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
January 19, 2015 (Actual)
Primary Completion Date
June 19, 2015 (Actual)
Study Completion Date
June 19, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mirum Pharmaceuticals, Inc.
4. Oversight
5. Study Description
Brief Summary
This study will investigate the safety and tolerability of daily dosing regimens of SHP626 in overweight and obese adults.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Alcoholic Steatohepatitis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
84 (Actual)
8. Arms, Groups, and Interventions
Arm Title
SHP626
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Three subjects per cohort will take a matched placebo
Intervention Type
Drug
Intervention Name(s)
SHP626
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Standard Hematology
Description
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).
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Fat Soluble Vitamins (Vitamin A, D, & E)
Description
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).
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Lipid Panel
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Thyroid Hormone Panel
Description
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]).
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Coagulation
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Standard Chemistry
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Urinalysis Parameters
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Electrocardiogram (12-lead)
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Treatment-emergent Adverse Events (STEAEs)
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Who Discontinued From the Study
Description
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.
Time Frame
From the start of the study drug administration up to 9 days after the last dose of study drug administration
Secondary Outcome Measure Information:
Title
Average Total Fecal Bile Acid (FBA) Concentration
Description
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.
Time Frame
Day -2 up to Day 14
Title
Mean Serum 7- Alpha-hydroxy-4-cholesten-3-one (C4) Concentration
Description
Serum 7- alpha-hydroxy-4-cholesten-3-one (C4) concentrations were reported.
Time Frame
Day -1 to Day 15
Title
Number of Participants With Stool Hardness Using Bristol Stool Chart
Description
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.
Time Frame
Day -2 to Day 14
Title
Maximum Observed Plasma Concentration (Cmax) of Volixibat
Time Frame
Day 1 to Day 14
Title
Area Under the Plasma Concentration-Time Curve (AUC) of Volixibat (SHP626)
Time Frame
Day 1 to Day 14
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Mirum
Official's Role
Study Director
Facility Information:
Facility Name
New Orleans Center for Clinical Research
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37920
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
29548345
Citation
Palmer M, Jennings L, Silberg DG, Bliss C, Martin P. A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis. BMC Pharmacol Toxicol. 2018 Mar 16;19(1):10. doi: 10.1186/s40360-018-0200-y.
Results Reference
derived
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Safety and Tolerability Study of SHP626 in Overweight and Obese Adults
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