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Trial registered on ANZCTR


Registration number
ACTRN12620001324909
Ethics application status
Approved
Date submitted
29/10/2020
Date registered
7/12/2020
Date last updated
7/04/2021
Date data sharing statement initially provided
7/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A Single and Multiple Dose Study to Determine the Safety and Tolerability of GBT021601 in Healthy Adult Volunteers
Scientific title
A Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Ascending Dose (SAD/MAD) Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Food Effect of GBT021601, a Hemoglobin S Polymerization Inhibitor, in Healthy Participants
Secondary ID [1] 302483 0
GBT021601-011
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sickle Cell Disease 319319 0
Condition category
Condition code
Blood 317291 317291 0 0
Haematological diseases
Human Genetics and Inherited Disorders 317335 317335 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Part A:
Part A of the study consists of 8 cohorts of 8 participants each. Participants in each cohort will receive a single oral dose of either placebo or 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or one of two more currently undecided dose levels of GBT021601 (dose levels to be determined by Safety Review Committee). One cohort will receive a dose previously found to be well tolerated following the ingestion of a high-fat meal (the meal will consist of two eggs fried in butter, two strips of bacon, two slices of white toast with butter, 2 hash browns and 240 mL of whole milk). All doses will be administered by a study nurse

Part B:
Part B of the study consists of 6 cohorts of 10 participants each. Participants in each cohort will receive a daily dose of either placebo or GBT021601 (at dose levels that are to be determined by the Safety Review Committee) for 14 days. The initial dose will be a higher 'loading dose' followed by 'maintenance doses'. All doses will be administered by a study nurse.
Intervention code [1] 318777 0
Treatment: Drugs
Comparator / control treatment
Placebo

The Placebo Capsules are composed of Microcrystalline cellulose and the placebo tablets are composed of microcrystalline cellulose, croscarmellose sodium, Magnesium Stearate and Opadry II Pink Coating System.
Control group
Placebo

Outcomes
Primary outcome [1] 325347 0
Part A:
To evaluate the safety and tolerability of single ascending doses of GBT021601 in healthy participants as assessed by the collection of safety data, such as adverse events, clinical laboratory tests, vital signs, Physical Exams and various ECGs.
Timepoint [1] 325347 0
Daily assessments during the inpatient period (up to 7 days post dose) and during the follow up period, up to Day 98 (9 visits 4-14 days apart)
Primary outcome [2] 325348 0
Part B:
To evaluate the safety and tolerability of multiple ascending doses of GBT021601 in healthy participants as assessed by the collection of safety data, such as adverse events, clinical laboratory tests, vital signs, physical exams and various ECGs.
Timepoint [2] 325348 0
Daily assessments during the inpatient period (up to 21 days post dose) and during the follow up period, up to Day 99 (8 visits 4-14 days apart).
Secondary outcome [1] 387586 0
Part A:
To evaluate the Pharmacokinetic (PK) properties (Cmax, tmax, AUC, AUC0-oo, AUC0-t, AUC0-24, %AUC extrapolated from last quantifiable time point to infinity, t½, CL/F and Vz/F) of single ascending doses of GBT021601 and its metabolites, if applicable, in healthy participants.

Timepoint [1] 387586 0
Plasma and whole blood concentrations of GBT021601 and its metabolites will be measured at the following timepoints:
Day 1/ Predose, 0.25hr, 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr and 12hr postdose, Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 70, Day 84 and Day 98.
Secondary outcome [2] 387589 0
Part A:
To obtain preliminary information on the effect of food on GBT021601 in healthy participants.

Preliminary information will include PK exposures in order to evaluate if there are any changes due to the effect of food.

The following Pharmacokinetic (PK) properties will be assessed:
Cmax, tmax, AUC, AUC0-oo, AUC0-t, AUC0-24, %AUC extrapolated from last quantifiable time point to infinity, t½, CL/F and Vz/F
Timepoint [2] 387589 0
Daily assessments during the inpatient period (up to 7 days post dose) and during the follow up period, up to Day 98 (9 visits 4-14 days apart).
Data will be compared between two cohorts at the same dose level where one has ingested a high-fat meal prior to dosing. All study procedures will remain the same.
Secondary outcome [3] 387590 0
Part B:
To evaluate whether GBT021601 has an effect on electrocardiogram (ECG) parameters, including concentration-QTc (C-QTc) analysis following multiple doses of GBT021601.
Timepoint [3] 387590 0
Assessed through:
12-lead ECG's at Day 3, Day 5, Day 7, Day 10, Day 14, Day 17, Day 21 and Day 99.
Cardio-dynamic Holter ECG Assessment on Day 1/Pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr, 12hr and 24hr post-dose and Day 14/Pre-dose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr, 12hr and 24hr post-dose.
Secondary outcome [4] 387591 0
Part B:
To evaluate the Pharmacokinetic (PK) properties (Cmax on Days 1 and 15, tmax on Days 1 and 15, AUC0-t on Day 15, AUC0-t on Days 1 and 15, t½ after last dose, CL/F Vz/F, Aeu,ss and CLr calculated as Aeu,ss/AUCt) of multiple ascending doses of GBT021601, and its metabolites, if applicable, in healthy participants.

Timepoint [4] 387591 0
Plasma and whole blood concentrations of GBT021601 and its metabolites will be measured at the following timepoints:
Day 1/ Predose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr and 12hr postdose, Day 2, Day 6, Day 7, Day 12, Day 13, Day 14/predose, 0.5hr, 1hr, 2hr, 3hr, 4hr, 6hr, 8hr and 12hr postdose, Day 15, Day 16, Day 17, Day 18, Day 19, Day 20, Day 21, Day 25, Day 29, Day 36, Day 43, Day 57, Day 71, Day 85 and Day 99.

Urine PK samples will be collected on Day 14/ Predose and at the following collection intervals: 0 to 6 hours, 6 to 12 hours, 12 to 24 hours postdose.

Eligibility
Key inclusion criteria
1. Healthy males or females between 18 and 55 years inclusive at screening.
2. No clinically significant findings as assessed by review of medical and surgical history,
vital signs assessments, 12-lead ECG, physical examination, and clinical laboratory
evaluations conducted at screening and on day of admission. In the event of clinically
significant abnormalities, a single repeat measurement/test may be performed at the
discretion of the investigator to confirm eligibility based upon initial vital signs, ECG, or
clinical laboratory tests.
3. Body mass index (BMI) between 18.0 and 30.0 kg/m^2 inclusive, and body weight more than or equal to50 kg at screening and Day -1. BMI = weight (kg)/(height[m])^2
4. Females must be of non-childbearing potential (eg, postmenopausal [defined as
amenorrhoeic for at least one year with a follicle stimulating hormone level >40 IU/L] or
surgically sterile by hysterectomy, bilateral tubal ligation, bilateral salpingectomy, or
bilateral oophorectomy [documentation required]).
5. Males who are not surgically sterile with partners of childbearing potential must agree to
use a highly effective method of birth control during the study and for 120 days following
study drug dose. A highly effective method of contraception is defined as one that results
in a low documented failure rate when used consistently and correctly such as: condom
plus use of an intrauterine device; intrauterine system or hormonal method of
contraception (oral, injected, implanted, or transdermal) for your female partner; or
sexual abstinence.
6. Males must agree to not donate sperm during the study and for 120 days following study
drug dosing.
7. Participants must be able to communicate effectively in English with the study personnel.
8. Participants must be nonsmokers, defined as having abstained from tobacco- or nicotine- containing products (eg, cigarettes, cigars, chewing tobacco, snuff, nicotine patches, and electronic cigarettes) in the 6 months prior to screening.
9. Participants must be informed of the nature and risks of the study and give written
consent prior to screening.
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Positive pregnancy test or currently breastfeeding.
2. History or presence of clinically significant allergic diseases (except for untreated,
asymptomatic, seasonal allergies) at time of dosing, in the opinion of the investigator.
3. History or presence of conditions which, in the opinion of the investigator, are known to
interfere with the absorption, distribution, metabolism, or excretion of drugs, such as
previous surgery on the gastrointestinal tract (including removal of parts of the stomach,
bowel, liver, gall bladder, or pancreas). Participants who have had an appendectomy are
eligible for enrollment.
4. History or presence of conditions that may place the participant at increased safety risk as determined by the investigator.
5. History of surgery or major trauma within 12 weeks of screening, or surgery planned during the study.
6. Any signs and/or symptoms of acute illness, including COVID-19, at screening, Day -1, or Day 1.
7. Abnormal ECGs collected at screening or Day -1, including QT interval corrected for
heart rate (HR) using Fridericia’s formula (QTcF) >450 msec for males and >470 msec
for females, or any cardiac rhythm other than sinus rhythm that is interpreted by the
investigator to be clinically significant. An additional triplicate ECG may be performed
to confirm ECG abnormalities (ie, to confirm that a participant is eligible).
8. Known personal or family history of congenital long QT syndrome or known family
history of sudden death.
9. Resting bradycardia (HR <45 beats per minute [bpm]) or resting tachycardia
(HR >100 bpm) at screening or Day -1 based on vital signs measurements. A single
repeat measurement may be performed to confirm vital sign abnormalities (ie, to confirm
that a participant is eligible). Each of the readings must be not clinically significant to
qualify for enrollment into the study.
10. Hypertension, defined as resting systolic blood pressure (BP) >140 mmHg or resting
diastolic BP >90 mmHg at screening or Day -1. A single repeat measurement may be
performed to confirm vital sign abnormalities (ie, to confirm that a participant is eligible).
Each of the readings must be not clinically significant per the investigator’s discretion to
qualify for enrollment into the study.
11. History of alcohol abuse or use of drugs of abuse in the 12 months prior to the date of
consent. Excess alcohol is defined as more than 14 drinks/week for women and 21 drinks/week for men. A drink is defined as 360 mL of beer 150 mL of wine, or 45 mL of spirits.
12. Use of prescription medications within 14 days or 5 half-lives, whichever is longer, or
any over-the-counter (OTC) drugs, including herbal preparations or dietary supplements
within 7 days or 5 half-lives, whichever is longer, prior to Day -1 or requiring continued use during study participation. Occasional use of acetaminophen/paracetamol (e.g. up to 2g/day) is permitted up to 24 hours before the first dose.
13. Consumption of more than 400 mg of caffeine (approximately 4 cups of coffee) per day
within 30 days of screening or unwillingness to abstain from consumption of caffeine- or
xanthine-containing products (eg, tea, coffee, chocolate, cola, etc.) from 48 hours prior to
dosing (Day 1) through Day 7 (Part A) and from 48 hours prior to dosing and through
Day 21 (Part B).
14. Unwillingness to abstain from alcohol from 48 hours prior to dosing (Day 1) through
Day 29.
15. Consumption of grapefruit and/or grapefruit juice within 14 days prior to Day -1 and
unwillingness to abstain from consumption of grapefruit, grapefruit juice, or Seville
oranges through the end of the study (follow-up visit).
16. Unwillingness to abstain from any strenuous physical exercise (such as weight training or aerobics) from 72 hours prior to dosing (Day 1) through Day 7 for Part A and 72 hours prior to dosing (Day 1) through Day 21 (Part B). Participants are permitted to exercise following the screening visit.
17. Has received another investigational drug within 30 days or 5 half-lives, whichever is
longer, prior to screening, or is currently participating in another trial of an investigational drug (or medical device).
18. Prior exposure to GBT021601.
19. Donation or loss of more than 470 mL of blood within 90 days, or plasma/platelets within 2 weeks prior to Day -1.
20. Positive result for drugs of abuse, alcohol, or cotinine screen at screening or Day -1.
21. Positive screen for human immunodeficiency virus (HIV)-1 and HIV-2 antibodies,
hepatitis A virus immunoglobulin M (IgM) antibody, hepatitis B virus surface antigen, or
hepatitis C virus antibody at screening.
22. Poor venous access as determined by the investigator/site staff.
23. Unwilling or unable to consume standard meals (eg, high-fat meal for food effect cohort).
24. Involved in the planning or conduct of this study.
25. Any other condition or prior therapy that, in the investigator’s opinion, would confound
or interfere with the evaluation of safety, tolerability, or PK of the investigational product, interfere with study compliance, or preclude informed consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
124 healthy volunteers between 18-55 years will be enrolled in this study.

Due to the exploratory nature of this study, no formal power or sample size calculations were used to determine cohort size. A sufficient number of healthy volunteers will be screened to ensure at least 8 participants are enrolled and dosed in each cohort for Part A and 10 participants are enrolled and dosed in each cohort for Part B.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 17800 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 31657 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 306909 0
Commercial sector/Industry
Name [1] 306909 0
Global Blood Therapeutics, Inc.
Address [1] 306909 0
181 Oyster Point Blvd.
South San Francisco
CA 94080
Country [1] 306909 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Linear Clinical Research Ltd
Address
Level 1, B Block
Hospital Ave
Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 307466 0
Commercial sector/Industry
Name [1] 307466 0
Global Blood Therapeutics, Inc.
Address [1] 307466 0
181 Oyster Point Blvd.
South San Francisco
CA 94080
Country [1] 307466 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307059 0
Bellberry Limited
Ethics committee address [1] 307059 0
123 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [1] 307059 0
Australia
Date submitted for ethics approval [1] 307059 0
07/10/2020
Approval date [1] 307059 0
09/11/2020
Ethics approval number [1] 307059 0

Summary
Brief summary
The purpose of this study is to assess the safety and tolerability of GBT021601, as well as the pharmacokinetics (PK- how your body uses the drug) and whether ingesting food has an effect on how your body uses the drug.

GBT021601 will be tested in 124 healthy participants aged 18 to 55 years.
In Part A 64 participants will be administered a single dose of GBT021601 as oral tablets or capsules and followed up for 98 days for safety and PK assessments.
In Part B 60 participants will be administered multiple daily doses of GBT021601 as oral tablets or capsules over the course of 14 days and will be followed up for 99 days for safety and PK assessments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105886 0
Dr Andrew Redfern
Address 105886 0
Linear Clinical Research
Level 1, B Block
Hospital Avenue
Nedlands, WA 6009
Country 105886 0
Australia
Phone 105886 0
+61 8 63825100
Fax 105886 0
Email 105886 0
aredfern@linear.org.au
Contact person for public queries
Name 105887 0
Ms Mariama McNeil
Address 105887 0
Global Blood Therapeutics, Inc.
181 Oyster Point Blvd.
South San Francisco, CA 94080
Country 105887 0
United States of America
Phone 105887 0
+1 919 909 2809
Fax 105887 0
Email 105887 0
mmcneil@gbt.com
Contact person for scientific queries
Name 105888 0
Dr William Tappe
Address 105888 0
Global Blood Therapeutics, Inc.
181 Oyster Point Blvd.
South San Francisco, CA 94080
Country 105888 0
United States of America
Phone 105888 0
+1 650 825 4678
Fax 105888 0
Email 105888 0
wtappe@gbt.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available
What supporting documents are/will be available?
No other documents available
Summary results
No Results