A Study of the Safety, Blood Levels and Biological Effects of GBT440 in Healthy Subjects and Subjects With Sickle Cell Disease

A Phase I Randomised, Placebo-controlled, Double-blind, Single and Multiple Ascending Dose Study of the Tolerability and Pharmacokinetics of GBT440 in Healthy Subjects and Patients With Sickle Cell Disease

The purpose of this study is to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of GBT440 compared with placebo in healthy subjects and subjects with sickle cell disease (SCD).

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Healthy Subjects
• Intervention / Treatment: Drug: GBT440; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 133
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guy's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male or female of non-child bearing potential; 18 to 55 years old; are non-smokers and have not used nicotine products within 3 months prior to screening.
• Male or female, 18 to 60 years old, with sickle cell disease (hemoglobin SS, HbS/β0thalassemia, HbS/β+thalassemia, or HbSC) not requiring chronic blood transfusion therapy; without hospitalization in 30 days before screening or receiving blood transfusion within 30 days before screening; subjects are allowed concomitant use of hydroxyurea if the dose has been stable for the 3 months prior to screening.

Exclusion Criteria:

• Subjects who have a clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders.
• Subjects who consume more than 14 (female subjects) or 21 (male subjects) units of alcohol a week.
• Subjects who have used any investigational product in any clinical trial within 30 days of screening
• Subjects with sickle cell disease who smoke >10 cigarettes per day; have hemoglobin level <6 g/dL or >10.4 g/dL (> ULN (appropriately corrected for gender) for Cohort 15) at screening; have aspartate aminotransferase (AST) >4x upper limit of normal or alanine aminotransferase (ALT), or alkaline phosphatase (ALK) >3x upper limit of normal reference range (ULN) at screening; have moderate or severe renal dysfunction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GBT440; Subjects randomized 6:2 to receive daily oral dosing of GBT440 or placebo for 1 day (single dose) and up to 118 days (multiple dose)	Drug: GBT440; GBT440 will be administered as oral capsules
Placebo Comparator: Placebo; Subjects randomized 6:2 to receive daily oral dosing of GBT440 or placebo for 1 day (single dose) and up to 118 days (multiple dose)	Drug: Placebo; Matching placebo will be administered as oral capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety, as assessed by frequency and severity of adverse events (AEs), and changes in vital signs, 12-lead electrocardiograms (ECGs), and laboratory assessments as compared to baseline	30 - 118 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Blood and plasma area under the concentration time curve (AUC) of GBT440	30 - 118 days
Blood and plasma maximum concentration (Cmax) of GBT440	30 - 118 days
Blood and plasma time to maximum concentration (Tmax) of GBT440	30 - 118 days
Percentage of hemoglobin occupied or modified by GBT440	30 days
Change from baseline in heart rate and pulse oximetry following exercise testing in healthy volunteers	30 days

Other Outcome Measures

Outcome Measure	Time Frame
Percentage of sickled cells under ex vivo conditions	30 - 90 days
Effect of GBT440 on hemolysis as measured by LDH, direct bilirubin, hemoglobin, and reticulocyte count	30 - 118 days
Change from baseline in pain as measured by visual analog scale	30 days
Change from baseline in fatigue as measured by questionnaire	30 - 118 days
Exercise capacity as measured by 6-minute walk test	30 - 90 days

Collaborators and Investigators

• Sponsor: Global Blood Therapeutics
• Investigators: Study Director: Josh Lehrer-Graiwer, MD, Global Blood Therapeutics; Principal Investigator: Timothy Mant, FRCP FFPM, Guy's Hospital

Publications and helpful links

General Publications

• Howard J, Hemmaway CJ, Telfer P, Layton DM, Porter J, Awogbade M, Mant T, Gretler DD, Dufu K, Hutchaleelaha A, Patel M, Siu V, Dixon S, Landsman N, Tonda M, Lehrer-Graiwer J. A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease. Blood. 2019 Apr 25;133(17):1865-1875. doi: 10.1182/blood-2018-08-868893. Epub 2019 Jan 17.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): May 1, 2017

Study Registration Dates

• First Submitted: November 4, 2014
• First Submitted That Met QC Criteria: November 4, 2014
• First Posted (Estimate): November 6, 2014

Study Record Updates

• Last Update Posted (Actual): February 15, 2018
• Last Update Submitted That Met QC Criteria: February 13, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: GBT440-001; 2014-003555-62 (EudraCT Number)