Clinical trial NCT02285088: A Study of the Safety, Blood Levels and Biological Effects of GBT440 in Healthy Subjects and Subjects With Sickle Cell Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Sickle Cell Disease
Lead sponsor: Global Blood Therapeutics
Sponsor class: INDUSTRY
First posted: 2014-11-06
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 30 - 118 days
Secondary outcomes:
measure: Blood and plasma area under the concentration time curve (AUC) of GBT440
timeFrame: 30 - 118 days
measure: Blood and plasma maximum concentration (Cmax) of GBT440
timeFrame: 30 - 118 days
measure: Blood and plasma time to maximum concentration (Tmax) of GBT440
timeFrame: 30 - 118 days
measure: Percentage of hemoglobin occupied or modified by GBT440
timeFrame: 30 days
measure: Change from baseline in heart rate and pulse oximetry following exercise testing in healthy volunteers
timeFrame: 30 days
Other outcomes:
measure: Percentage of sickled cells under ex vivo conditions
timeFrame: 30 - 90 days
measure: Effect of GBT440 on hemolysis as measured by LDH, direct bilirubin, hemoglobin, and reticulocyte count
timeFrame: 30 - 118 days
measure: Change from baseline in pain as measured by visual analog scale
timeFrame: 30 days
measure: Change from baseline in fatigue as measured by questionnaire
timeFrame: 30 - 118 days
measure: Exercise capacity as measured by 6-minute walk test
timeFrame: 30 - 90 days
Locations:
city: London
country: United Kingdom
facility: Guy's Hospital
Study officials:
affiliation: Global Blood Therapeutics
name: Josh Lehrer-Graiwer, MD
role: STUDY_DIRECTOR
affiliation: Guy's Hospital
name: Timothy Mant, FRCP FFPM
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.