Ornithine Transcarbamylase Deficiency
Conditions
Brief summary
Determine the safety, tolerability and pharmacokinetics of single doses of ARCT-810 in clinically stable patients (stable on standard of care treatment, e.g. diet ± ammonia scavengers) with ornithine transcarbamylase deficiency (OTCD).
Detailed description
This is a single ascending dose study of ARCT-810 in which approximately 12 (up to a maximum of 20) clinically stable patients with ornithine transcarbamylase deficiency (OTCD) are planned to be enrolled. Each study subject's participation length is approximately 8 weeks, from screening through last study visit. The study comprises an up to 4-week screening period, and a 4-week diet run-in period, to occur concurrently, followed by a 1-day dosing period and a 28-day post-treatment period. Study participants will be allocated to one of the three single-dose treatment groups (also referred to as cohorts), to test different doses of ARCT-810. Four subjects will be enrolled in each group. Within each cohort, subjects will be randomized 3:1 to receive ARCT-810 or placebo as an IV infusion.
Interventions
BIOLOGICALARCT-810
ARCT-810 is an investigational medicinal product comprising Ornithine Transcarbamylase (OTC) mRNA formulated in a lipid nanoparticle (LNP) under development.
OTHERPlacebo
The placebo for this study is 0.9% sterile saline.
Sponsors
Arcturus Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double Blinded, Placebo Controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adequate cognitive ability to consent and recall symptoms over a 1-week time period 2. Males and females ≥18 years of age with documented diagnosis of ornithine transcarbamylase deficiency (OTCD) confirmed with genetic testing, or willing to consent to OTC gene sequencing and deletion/duplication testing 3. Subject's ornithine transcarbamylase deficiency (OTCD) is stable as evidenced by 1. no clinical symptoms of hyperammonemia AND 2. an ammonia level \<100 µmol/L (170 µg/dL) at the screening evaluation Subjects must remain free from symptoms of hyperammonemia throughout the screening period. 4. If using nitrogen ammonia scavenger therapy, must be on a stable regimen (no change in dose or frequency) for ≥ 28 days prior to providing informed consent and throughout the screening period 5. Must have maintained a stable protein-restricted diet (+/- amino acid supplementation) for at least 28 days prior to providing informed consent and continue to maintain a stable diet for the duration of the study 6. Good general health other than OTCD, in the opinion of the Investigator 7. Willing to refrain from strenuous exercise/activity and alcohol for 72 hours before study visits 8. Willingness to comply with procedures and visits 9. Willingness to follow contraception guidelines
Exclusion criteria
1. History of clinically significant disease(s), in the opinion of the Investigator 2. Clinically significant screening laboratory values 3. Uncontrolled diabetes 4. Clinically significant anemia 5. Subjects who develop infection during screening must be asymptomatic for at least 7 days prior to dosing 6. Unwillingness to comply with study requirements 7. History of positive HIV, hepatitis C, or chronic hepatitis B 8. Uncontrolled hypertension 9. Malignancy within 5 years prior to study 10. Treatment with another investigational drug, biological agent, or device within 30 days of screening, or 5 half-lives of investigational drug 11. Treatment with any oligonucleotide or mRNA within 6 months of screening, with exceptions for some vaccinations and investigational treatments 12. History of gene therapy, hepatocyte or mesenchymal stem cell transplantation 13. Prior organ transplant 14. History of severe allergic reaction to a liposomal product 15. Recent history of, or current, drug or alcohol abuse 16. Dependence on inhaled (smoked or vaped) or oral cannabis products 17. Systemic corticosteroids within 6 weeks prior to screening 18. Blood donation of 50 to 499 mL within 30 days of screening or of .499 mL within 60 days of screening 19. Other conditions, in the opinion of the Investigator, that would make the subject unsuitable for participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence, severity and dose-relationship of adverse events (AEs) | 4 weeks | Safety and tolerability of ARCT-810 assessed by determining the incidence, severity and dose-relationship of AEs by dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in area under the curve after single dose of ARCT-810 | Up to 4 weeks | Area under the plasma concentration versus time curve (AUC) from time zero to the last quantifiable time point |
| Maximum observed plasma concentration (Cmax) after single dose of ARCT-810 | Up to 4 weeks | The maximum observed plasma concentration (Cmax) |
| Time at which Cmax occurred after single dose of ARCT-810 | Up to 4 weeks | The time at which Cmax occurred (Tmax) |
| AUC0-inf after single dose of ARCT-810 | Up to 4 weeks | AUC from time zero extrapolated to infinity |
| AUCExtrap after single dose of ARCT-810 | Up to 4 weeks | The relative portion of AUC0-inf extrapolated beyond AUC0-t |
| T1/2 after single dose of ARCT-810 | Up to 4 weeks | Terminal half-life |
| MRT0-inf after single dose of ARCT-810 | Up to 4 weeks | The mean residence time extrapolated to infinity |
| CL after single dose of ARCT-810 | Up to 4 weeks | Total body clearance, calculated as dose divided by AUC0-inf |
| Vss after single dose of ARCT-810 | Up to 4 weeks | Volume of distribution |
Countries
United States
Outcome results
None listed