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Trial registered on ANZCTR


Registration number
ACTRN12618001988246
Ethics application status
Approved
Date submitted
29/11/2018
Date registered
12/12/2018
Date last updated
22/04/2020
Date data sharing statement initially provided
12/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Double-Blind, Randomized, Placebo-Controlled Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of CT-868 in Healthy Overweight/Obese Participants and in Patients with
Type 2 Diabetes Mellitus
Scientific title
A Double-Blind, Randomized, Placebo-Controlled Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of CT-868 in Healthy Overweight/Obese Participants and in Patients with
Type 2 Diabetes Mellitus
Secondary ID [1] 296678 0
Nil known
Universal Trial Number (UTN)
U1111-1224-4463
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obese 310522 0
Type 2 Diabetes Mellitus 310523 0
Condition category
Condition code
Diet and Nutrition 309234 309234 0 0
Obesity
Metabolic and Endocrine 309235 309235 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single ascending dose cohorts (Part 1): Completed
Administered doses of CT-868 or matched placebo: 0.1mg, 0.5mg, 1.5mg, 3.0mg, 5.0mg, 7.5mg and 11.0mg given by subcutaneous (SC) injection. Injection administered by staff in the study unit.
Multiple ascending dose cohorts (Part 2): Completed
Administered doses of CT-868 or matched placebo: 0.75mg, 1.5mg and 5mg given by SC injection once daily for 14 days. Injections administered by staff in the study unit.
Multiple dose in Type 2 diabetes (T2DM) (Part 3): Open to enrollment
Following instructions provided by the clinical site staff, participants will self-administer once daily SC injection(s) of CT-868 or matched placebo for 28 days. Dosing will commence at 1.0mg for seven days, and if the dose level is tolerated, be increased to 1.5mg for a further seven days and then be increased again, subject to tolerance, to 2.25mg for a further fourteen days. The total duration of study participation is 13 weeks comprising of the screening period, two inpatient stays in the clinical unit: initially for 6 nights and then for a further 3 nights, three outpatient visits and two follow-up visits.
Participants may only take part in one cohort for the study
Intervention code [1] 312991 0
Treatment: Drugs
Comparator / control treatment
Placebo for SC injection will be normal saline and will be administered in a total volume to match the doses for the active interventional treatment:CT-868. Participant treatment allocation is blinded
Control group
Placebo

Outcomes
Primary outcome [1] 308201 0
Safety and tolerability will be assessed by reporting of adverse events, clinical laboratory tests, physical examination, vital signs (systolic and diastolic blood pressures, respiratory rate, heart rate and body temperature) and 12-lead ECGs
Timepoint [1] 308201 0
During Part 1, subjects were confined to the study unit and assessed from Day 1 to Day 3 before being discharged. They returned for follow up on Day 8 and Day 31. At the end of each dosing cohort the safety review committee met to review all available safety information to determine whether to proceed to the next dose level. During Part 2, subjects were confined to the study unit and assessed from Day 1 to Day 14 before being discharged. Subjects returned for a follow up on Day 21 and Day 44. At the end of each dosing cohort a Safety Review Committee met to review all available safety information and to make a determination on whether to progress to the next dose level. During Part 3, subjects will be confined to the study unit and assessed from Day -2 to Day 5 before being discharged on Day 6. Subjects will return to the clinical unit for outpatient visits on Day 8. Day 15 and Day 22 and will return on Day 27 for a further 3 night confinement following which they will be discharged and be required to return for two further follow up visits on Day 35 and Day 58.
Secondary outcome [1] 354224 0
The following pharmacokinetic parameters will be measured in serum: Cmax, Tmax, AUC 0-last, kel, AUC 0-inf, t1/2, Tlag, CL/F, CL/Fss, Vz/F, apparent terminal rate constant, MRT accumulation index and Fluctuation ratio.
Timepoint [1] 354224 0
Part 1: PK samples will be collected:prior to dosing on Day 1 and at 1, 2, 3, 4, 6, 8, 12, 16, 20 24, 30,36 and 48, hours (± 10 minutes) post-dose with a final sample collected on Day 8 (± 1 day)
Part 2: PK samples will be collected: prior to dosing on Day 1 and at 2, 3, 4, 6, 8, 12, 24 (pre-dose), 48 (pre-dose), 60, (post-dose), 72 (pre-dose), and 96 hours (pre-dose) (± 10 minutes). Further samples for measurement of serum PK will be collected pre-dose on Days 7,8,11 and 14 (± 10 minutes) and post-dose on Days 7,12 and 14 as well as on Days 15,16 and 21.
Part 3 PK samples will be collected: prior to dosing on Day 1 and at 1,2,3,4,6,8,12,24,36, 48,72 and 96 hours post-dose ( ± 30 minutes) and pre-dose at Days 8,15,22 and 28. Further samples for measurement of serum PK will be collected at 1,2,3,4,6,8,12,24,36 and 48 post Day 28 dosing (± 30 minutes) with a final sample collected on Day 35
Secondary outcome [2] 354717 0
In Part 1 (SAD cohorts), Part 2 (MAD cohorts), and Part 3 (MD T2DM patient cohort) glycemic effect will be assessed: plasma glucose will be measured using a glucometer

.
Timepoint [2] 354717 0
Part 1: Plasma glucose levels will be measured by glucometer or another monitoring device, for eligibility at screening and repeated on Day -1 and pre-dose Day 1. Post-dose plasma glucose levels will be measured at 1,2,3,4,6,8,10,12,16,20,24 and 48 hours post-dose (± 10 minutes) with a final measurement being performed on Day 8.
Part 2: Plasma glucose levels will be measured by glucometer or another monitoring device, for eligibility at screening and repeated on Day -1 and pre-dose Day 1. Pre-dose plasma glucose levels will be measured on Days 2, 3, 4, 5, 6, 7, 8, 9, 10,11,12,13 and 14 and post-dose plasma glucose levels will be measured at 1,2,3,4,6,8,12, 16 and 24 hours post-dose (± 10 minutes) on Days 1 and 14. A final plasma glucose measurement will be performed on Day 21.
Part 3: Plasma glucose levels will be measured by glucometer or another monitoring device, for eligibility at screening and repeated on Day -1 and pre-dose Day 1. Pre-dose plasma glucose levels will be measured on Days 2, 3, 4, 5, 8, 15, 22, 28 and 29 and post-dose plasma glucose levels will be measured at 1,2,3,4,6,8,12, 16 and 24 hours post Day 1 dose (± 10 minutes) and repeated at 1,2,3,4,6,8,12 and 24 hours post Day 28 dose. A final plasma glucose measurement will be performed on Day 35.
Secondary outcome [3] 354748 0
In Part 1 (SAD cohorts from S2 onwards), Part 2 (MAD cohorts), and Part 3 (MD T2DM patient cohort):
- Glycemic endpoint: plasma glucose
- Cavg and AUC for the Pharmacodynamic (PD) endpoints (glucose, insulin, and C-peptide) during meal tolerance test (MTT)
This is a composite secondary outcome
Timepoint [3] 354748 0
Part 1 from the second cohort (S2) onwards: A Meal Tolerance Test will be performed on Day -1 and repeated on Day 2 with blood samples obtained for analysis at 60 minutes prior to MTT and at 20 and 40 minutes, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post test meal ingestion.
Part 2: A Meal Tolerance Test will be performed on Day -1 and repeated on Days 7 and 14 with blood samples obtained for analysis at 60 minutes prior to MTT and at 20 and 40 minutes, 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours post test meal ingestion
Part 3: A Meal Tolerance Test will be performed on Day -1 and repeated on Day 28 with blood samples obtained for analysis at 60 minutes prior to MTT and at 20 and 40 minutes, 1, 1.5, 2, 2.5, 3, 3.5, 4, 8 and 12 hours post test meal ingestion
Secondary outcome [4] 354751 0
In Part 2 (MAD cohorts) and Part 3 (MD T2DM patient cohort) only
• Waist circumference
Timepoint [4] 354751 0
Part 2: Waist circumference will measured using a tape measure at Screening and again on admission to the clinical unit and prior to dosing on Days 1 and 14.
Part 3: Waist circumference will measured using a tape measure at Screening and again on Days -2, 1, 8, 15,22 and 29.
Secondary outcome [5] 354754 0
In Part 1 (SAD cohorts from S2 onwards), Part 2 (MAD cohorts), and Part 3 (MD T2DM patient cohort): Exploratory Pharmacodynamic (PD) biomarkers
Timepoint [5] 354754 0
Part 1 from the second cohort (S2) onwards: A blood sample will be collected for analysis of exploratory PD biomarkers pre-dose and at 3 hours post dose on Day 1.
Part 2: A blood sample will be collected for analysis of exploratory PD biomarkers pre-dose and 3 hours post dose on Days 1, 3, 15 and 14
Part 3: A blood sample will be collected for analysis of exploratory PD biomarkers pre-dose and 3 hours post dose on Days 1, 3, 5, 15 and 28.
Secondary outcome [6] 354755 0
Part 3 (MD T2DM patient cohort) only: Liver fat as measured by MRI-PDFF replacing DEXA scan
Timepoint [6] 354755 0
MRI will be used to evaluate subjects at Screening and Day 28. Subject evaluation will include MRI-PDFF as a measure of liver fat, and body composition analysis (skeletal muscle, visceral fat, and subcutaneous fat at the L3 vertebral body level).

Eligibility
Key inclusion criteria
All study parts:
• Males and females aged 18-65 years (inclusive)
• Body mass index (BMI) 27-45 kg/m2
• No more than 5% weight loss within the preceding 3 months
• Normal blood pressure or well managed hypertension
• Females must be non-pregnant and non-lactating, and either surgically sterile
• Males must be surgically sterile, abstinent, or if engaged in sexual relations with a WOCBP, the participant and his partner must be surgically sterile or using an acceptable, highly effective contraceptive method from screening until study completion,
Part 1 only:
• Certified as healthy by comprehensive clinical assessment
Part 1 and 2:
• Fasting plasma glucose less than or equal to 100 mg/dL (6.0 mmol/L)
Part 2 and 3 only:
• Waist circumference greater than or equal to 102 cm (males) or greater than or equal to 88 cm (females)
Part 3 only:
• Confirmed diagnosis of T2DM
• If not antidiabetic medication naïve, participants must be on a stable dose metformin or a DPP-4 inhibitor or a combination of these for at least 3 months prior to study enrollment
• Fasting insulin greater than 10 uIU/mL (> 60pmol/L)
• HbA1c equal to or greater than 7.0% and equal to but not greater than 10.0%
• Non-Alcoholic Fatty Liver Disease (NAFLD) as defined by an MRI-PDFF with greater to or equal to 10% steatosis
• Normal lipid profile or well managed dyslipidemia
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Pregnant or lactating, or intending to become pregnant within 30 days after last dose of study drug
• Participation in a clinical trial within 30 days before randomization; use of any experimental therapy within 30 days or 5 half-lives prior to randomization, whichever is greater; or use of any biologic therapy within 12 weeks or 5 half-lives prior to randomization, whichever is greater. Participants who have received an experimental therapy that has no half-life, like a vaccine, should have completed that therapy at least 12 weeks prior to randomization
• Any non-experimental vaccine within 12 weeks of randomization, until 4 weeks after the last dose, except for seasonal influenza vaccination which is permitted
• Use of any weight loss agent within 12 weeks prior to screening
• Surgery or hospitalization during the 4 weeks prior to screening
• Within the last 2 years, unstable or clinically significant cardiovascular disease
Part 3 only:
• Use of glitazones, sulfonylureas, or injectables (glucagon-like peptide 1 [GLP-1] mimetics, insulin) in the 3 months prior to study enrollment
• Persistent hyperglycemia, defined as a glucose level >270 mg/dL, not controlled by a stable dose of an a-glucosidase inhibitor or metformin or a DPP-4 inhibitor or a combination of these and/or diet/exercise
• A diagnosis of clinically significant diabetic neuropathy, retinopathy, nephropathy or renal impairment

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)
sealed codebreak envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
simple randomisation using computer system
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
The people analysing the results/data
Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Study has been voluntarily discontinued by the Sponsor due to the limitations placed on its conduct by the evolving COVID-19 situation
Date of first participant enrolment
Anticipated
19/12/2018
Actual
19/12/2018
Date of last participant enrolment
Anticipated
10/08/2020
Actual
9/10/2019
Date of last data collection
Anticipated
10/10/2020
Actual
22/11/2019
Sample size
Target
103
Accrual to date
Final
87
Recruitment in Australia
Recruitment state(s)
SA,WA
Recruitment hospital [1] 12490 0
Nucleus Network - Melbourne
Recruitment hospital [2] 15982 0
Linear Clinical Research - Nedlands
Recruitment hospital [3] 15983 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 24869 0
3004 - Melbourne
Recruitment postcode(s) [2] 29473 0
6009 - Nedlands
Recruitment postcode(s) [3] 29474 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 301257 0
Commercial sector/Industry
Name [1] 301257 0
Carmot Therapeutics
Country [1] 301257 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Carmot Therapeutics
Address
Carmot Australia First Pty Ltd., Tower 1, Level 16, Collins Square, 727 Collins Street, Melbourne VIC 3008, Australia
Country
Australia
Secondary sponsor category [1] 300893 0
Commercial sector/Industry
Name [1] 300893 0
Clinical Network Services
Address [1] 300893 0
Level 2, 381 MacArthur Ave, Hamilton, QLD, 4007, Australia
Country [1] 300893 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301998 0
Alfred Health Ethics Committee
Ethics committee address [1] 301998 0
Ethics committee country [1] 301998 0
Australia
Date submitted for ethics approval [1] 301998 0
31/10/2018
Approval date [1] 301998 0
30/11/2018
Ethics approval number [1] 301998 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88806 0
Dr Jason Lickliter
Address 88806 0
Nucleus Network, Level 5, Burnet Building, AMREP, Precinct, 89 Commercial Road, Melbourne VIC 3004
Country 88806 0
Australia
Phone 88806 0
+61 3 9076 8900
Fax 88806 0
Email 88806 0
[email protected]
Contact person for public queries
Name 88807 0
Michael Elliott
Address 88807 0
Carmot Therapeutics, Inc.
740 Heinz Avenue
Berkeley, California 94710
Country 88807 0
United States of America
Phone 88807 0
+1 510 8256377
Fax 88807 0
Email 88807 0
[email protected]
Contact person for scientific queries
Name 88808 0
Michael Elliott
Address 88808 0
Carmot Therapeutics, Inc.
740 Heinz Avenue
Berkeley, California 94710
Country 88808 0
United States of America
Phone 88808 0
+1 510 8256377
Fax 88808 0
Email 88808 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Commercial information


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.