Clinical trial NCT04442347: Phase 1b Study to Assess Safety, Tolerability, and Pharmacokinetics of ARCT-810 in Stable Adult Subjects With Ornithine Transcarbamylase Deficiency
Official title: A Phase 1b Randomized, Double Blinded, Placebo Controlled, Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single Doses of ARCT-810 in Clinically Stable Patients With Ornithine Transcarbamylase Deficiency
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Ornithine Transcarbamylase Deficiency
Lead sponsor: Arcturus Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2020-06-22
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence, severity and dose-relationship of adverse events (AEs)
timeFrame: 4 weeks
Secondary outcomes:
measure: Change in area under the curve after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: Maximum observed plasma concentration (Cmax) after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: Time at which Cmax occurred after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: AUC0-inf after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: AUCExtrap after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: T1/2 after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: MRT0-inf after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: CL after single dose of ARCT-810
timeFrame: Up to 4 weeks
measure: Vss after single dose of ARCT-810
timeFrame: Up to 4 weeks
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Minneapolis
country: United States
facility: M Health Fairview Masonic Children's Hospital
state: Minnesota
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Waco
country: United States
facility: Baylor University
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Milwaukee
country: United States
facility: Children's Wisconsin - Milwaukee Hospital
state: Wisconsin
Study officials:
References: