Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000809639
Ethics application status
Approved
Date submitted
21/06/2023
Date registered
27/07/2023
Date last updated
25/04/2024
Date data sharing statement initially provided
27/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A Safety and Tolerability Study Evaluating CTX310 in Subjects With Refractory Dyslipidemias
Scientific title
A Phase 1 Open-label, Multicenter, First-in-human, Ascending Single-dose Study Evaluating the Safety and Tolerability of a Lipid Nanoparticle Formulation of CRISPR–Guide RNA–Cas9 Nuclease (CTX310) for In Vivo Editing of the Angiopoietin-like 3 (ANGPTL3) Gene in Subjects With Refractory Dyslipidemias
Secondary ID [1] 309491 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory Dyslipidemias 329760 0
Condition category
Condition code
Cardiovascular 326658 326658 0 0
Other cardiovascular diseases
Metabolic and Endocrine 327353 327353 0 0
Other metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single-arm, open-label, multicenter, ascending single-dose Phase 1 study. Subjects will receive a single dose of CTX310 via intravenous (IV) infusion. Planned ascending doses levels will be 0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 0.8 mg/kg. Participants will receive only one dose.
Intervention code [1] 325919 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334527 0
Incidence of Adverse Events (AEs), including treatment-emergent adverse events (TEAEs), AESIs (adverse event of special interest), dose-limiting toxicities (DLTs); clinically significant laboratory abnormalities; and clinically significant abnormal vital signs. Potential adverse reactions include infusion related reactions and abnormal liver changes. IRR will be evaluated with vital signs and nurse assessments (Heart rate and oxygen saturation monitored with finger pulse oximeter, blood pressure assessed with blood pressure cuff. Respiratory rate and monitoring for signs of infusion reaction (e.g. coughing, rash) will be evaluated with clinical observation. Liver function will be monitored with blood tests (ALP, ALT, AST, bilirubin, PT, PTT). Monitoring for other unanticipated adverse events will be performed with 12 lead ECG, blood and urine tests and physical examination.
Timepoint [1] 334527 0
AEs, TEAEs, AESIs, and DLTs will be monitored for up to 12 months post-intervention dose. Clinical observations and vital signs will be monitored at Screening, daily for the first 4 days following infusion, Weeks 1, 2, and 3, and Months 1, 2, 3, 6, 9 and 12 post-intervention dose. Laboratory assessments will be monitored at Screening, daily for the first 4 days following infusion, Weeks 1, 2, and 3, and Months 1, 3, 6, 9 and 12 post-intervention dose.
Secondary outcome [1] 421025 0
Pharmakokinetic exposure to CTX310 over time. Plasma samples will be collected at Screening, D1 (prior to infusion, within 5 minutes post-CTX310 infusion, and at 1, 2, and 7 hours after completion of CTX310 infusion), D2, D3, D4, D7, D14, D30, M3, M6, M12 to assess the levels of LNPs (ALC-0307 and ALC-0159) and Cas9 protein via LC-MS/MS and ELISA, respectively. Plasma levels over time will be summarized using descriptive statistics. Exploratory analysis based on an applicable PK model may be performed.
Timepoint [1] 421025 0
Screening, Days 1, 2, 3, 4, 7, 14, 30 and Months 3, 6, and 12 post-intervention dose.
Secondary outcome [2] 421026 0
Percentage change in ANGPTL3 concentration over time compared to baseline. Plasma ANGPTL3 levels will be assessed via ELISA. Samples will be collected at Screening, D14, D30, M3, M6, M9 and M12. Percentage change in ANGPTL3 concentration over time compared to baseline will be summarized using descriptive statistics.
Timepoint [2] 421026 0
Screening, Days 14, 30, and Months 3, 6, 9 and 12 post-intervention dose.
Secondary outcome [3] 424042 0
Percentage change in triglycerides (TG) over time compared to baseline. Blood tests will be used to assess percent change.
Timepoint [3] 424042 0
Screening, Days 14 and 30, and Months 2, 3, 6, 9 and 12 post-intervention dose.
Secondary outcome [4] 424043 0
Percentage change in apolipoprotein B (ApoB) concentrations over time compared to baseline. Blood tests will be used to assess percent change.
Timepoint [4] 424043 0
Screening, Days 14 and 30, and Months 2, 3, 6, 9 and 12 post-intervention dose.
Secondary outcome [5] 424044 0
Percentage change in high-density lipoprotein (HDL) concentrations over time compared to baseline. Blood tests will be used to assess percent change.
Timepoint [5] 424044 0
Screening, Days 14 and 30, and Months 2, 3, 6, 9 and 12 post-intervention dose.
Secondary outcome [6] 424045 0
Percentage change in non–HDL concentrations over time compared to baseline. Blood tests will be used to assess percent change.
Timepoint [6] 424045 0
Screening, Days 14 and 30, and Months 2, 3, 6, 9 and 12 post-intervention dose.

Eligibility
Key inclusion criteria
1. Subjects diagnosed with persistent dyslipidemia
2. Subjects must be refractory to the maximum tolerated doses of standard of care lines of treatment
3. Female subjects must be postmenopausal
4. Nonsterile male subjects and their female partners should agree to use an effective method of contraception through at least 12 months after CTX310 infusion
5. Adequate renal, liver and cardiac function
6. Willing to participate in a long-term follow-up study after completion of this study
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. No participants with Familial Chylomicronemia Syndrome (FCS)
2. Evidence of liver disease
3. History of alcohol or drug abuse
4. History of a significant coagulation disorder
5. Uncontrolled or untreated thyroid disease
6. Prior treatment with gene therapy/editing product
7. Active HIV, hepatitis B virus or hepatitis C virus infection
8. Any prior or current malignancy or myeloproliferative disorder or a significant immunodeficiency disorder

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/09/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
24
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
SA,WA
Recruitment hospital [1] 26481 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 42471 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 313688 0
Commercial sector/Industry
Name [1] 313688 0
CRISPR Therapeutics AG
Country [1] 313688 0
Switzerland
Primary sponsor type
Commercial sector/Industry
Name
CRISPR Therapeutics AG
Address
Baarerstrasse 14
ZUG V8 CH-6300
Country
Switzerland
Secondary sponsor category [1] 315488 0
Commercial sector/Industry
Name [1] 315488 0
MedPace
Address [1] 315488 0
5355 Medpace Way, Cincinnati, OH, 45227
Country [1] 315488 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312846 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 312846 0
https://www.rah.sa.gov.au/research/for-researchers/central-adelaide-local-health-network-human-research-ethics-committee
Ethics committee country [1] 312846 0
Australia
Date submitted for ethics approval [1] 312846 0
Approval date [1] 312846 0
29/09/2023
Ethics approval number [1] 312846 0

Summary
Brief summary
This study aims to evaluate the safety and tolerability of a single ascending dose of CTX310 in patients with refractory dyslipidemias and to determine the recommended Phase 2 dose.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126126 0
A/Prof David Sullivan
Address 126126 0
Head of Dept Chemical Pathology, Royal Prince Alfred Hospital, Sydney Local Health District and NSW Health Pathology. Missenden Rd Camperdown NSW 2050 Australia
Country 126126 0
Australia
Phone 126126 0
+61 295158832
Fax 126126 0
Email 126126 0
David.Sullivan1@health.nsw.gov.au
Contact person for public queries
Name 126127 0
Dr Sandeep Soni
Address 126127 0
Clinical Development, 105 W. First St, Boston, MA 02127
Country 126127 0
United States of America
Phone 126127 0
+1 8772144634
Fax 126127 0
Email 126127 0
sandeep.soni@crisprtx.com
Contact person for scientific queries
Name 126128 0
Dr Sandeep Soni
Address 126128 0
Clinical Development, 105 W. First St, Boston, MA 02127
Country 126128 0
United States of America
Phone 126128 0
+1 6504488044
Fax 126128 0
Email 126128 0
sandeep.soni@crisprtx.com

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


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.