| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ornithine transcarbamylase deficiency |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ornithine transcarbamylase deficiency |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 26.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013373 |
| E.1.2 | Term | Disorders of urea cycle metabolism |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess safety and tolerability of ARCT-810 in adult and adolescent (≥12 years) participants with OTC deficiency. |
|
| E.2.2 | Secondary objectives of the trial |
To assess in adult and adolescent (≥12 years) participants with OTC deficiency:
1. The pharmacokinetics (PK) of ARCT-810 with a single dose and multiple (up to 6) doses administered once every two weeks
2. The pharmacodynamic (PD) activity of ARCT-810 administered once every two weeks as determined by 13C ureagenesis assay and 24-hour plasma ammonia profile |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Must have adequate cognitive ability, in the opinion of the Investigator, to understand the investigational nature of the study and study requirements, to recall symptoms over a 1-week time period, and to give informed consent. Must be willing and able to comply with all the protocol requirements (...). Adolescent participants (<18 years) must sign an assent form and their parent or legal representative must sign an informed consent form.
2.Males and females aged 12 to 65 years inclusive, at Screening.
3.Documented clinical diagnosis of OTC deficiency by biochemical testing (...) or enzymatic testing (...), and/or molecular testing. Confirmation with genetic testing should be documented or may be performed at screening, and should include OTC gene sequencing and deletion/duplication testing. However, a negative genotype is not exclusionary, as 10-15% of documented OTC deficiency cases lack identifiable mutations by routine molecular testing (Jang 2018). Also, participants should have a history of symptomatic hyperammonemia or plasma ammonia > ULN.
4.No hospitalizations for metabolic decompensation within 3 months and no more than 2 hospitalizations for metabolic decompensation within 12 months prior to the first dose of Study Drug, and no clinical symptoms of hyperammonemia within 1 month prior to signing informed consent.
5.If using nitrogen ammonia scavenger therapy, must be on a stable regimen (no change in dose or dose frequency) for ≥ 28 days prior to signing informed consent.
6.Participant has, in the opinion of the Investigator, maintained a stable protein restricted diet (which may or may not include medical foods) and/or amino acid supplementation with no changes in calorie or protein goals and no changes in medical food and/or amino acid supplementation for at least 28 days prior to signing informed consent and participant is willing to remain on the same diet for the full duration of the study. Participants may have their diet adjusted for optimization by the study dietician at the Study Center during the screening period (Section 6.1).
7.Good general health, aside from OTC deficiency and its complications, as determined by no clinically significant abnormal findings on medical history (e.g., previous acute coronary syndrome within 6 months of Screening, or major surgery within 3 months of Screening), clinical laboratory test results (other than ammonia concentrations and other biomarkers), vital sign measurements, 12-lead ECG results, or physical examination at Screening that, in the opinion of the Investigator or Sponsor Medical monitor (or designee), would interfere with Study Drug administration, jeopardize the safety of the participant, or impact the validity of the study results. Screening plasma ammonia level should be within the participant’s historical range when clinically stable, in the judgment of the investigator.
8.BMI = 18.0 – 32.0 kg/m2, inclusive for adults, and >5th percentile for adolescents ≥12 to 17 years old.
9.Participants must refrain from strenuous exercise/activity (e.g., heavy lifting, weight training, intense aerobics classes etc.) and consuming alcohol for at least 72 hours prior to study visits.
10.Males are eligible to participate if they agree to the following requirements during the intervention period and for at least 60 days after the last dose of study drug, which corresponds to the time needed to minimize any potential reproductive safety risk of the study drug:(...)
11.Females are eligible to participate if they are not currently pregnant or breastfeeding nor planning to become pregnant or breastfeed during the study; and at least one of the following conditions applies:
a.Is not a woman of child-bearing potential (defined below)
b.Is a WOCBP and using highly effective contraceptive methods specified in protocol Section 6.3.1 during the study intervention period and for at least 60 days after the last dose of Study Drug. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study drug.
A woman is considered fertile following menarche and until becoming postmenopausal, unless permanently sterile.
Females are considered WOCBP unless they fall in one of the following categories:
•Documented surgically sterile (hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy)
•Postmenopausal defined as follows:
oNo menses for 12 months without an alternative medical cause.
oA high FSH level in the postmenopausal range must be used to confirm a postmenopausal state in women under 60 years of age and not using hormonal contraception or hormone replacement therapy (HRT).
oA female participant on HRT and whose menopausal status is in doubt will be required to use one of the non-estrogen hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status. |
|
| E.4 | Principal exclusion criteria |
1.Uncontrolled hypertension (Systolic BP > 160 and/or diastolic BP >100 mm Hg)
2.Any participant who develops symptoms of infection, including a temperature of 38.0 degrees Celsius (100.4 degrees Fahrenheit) or above during the screening period must be asymptomatic for at least 7 days prior to dosing on Day 1. Any participant who requires systemic antimicrobial treatment must have both discontinued antimicrobial therapy for at least 7 days and be symptom free for at least 7 days prior to dosing. The screening period may be extended, as necessary, for up to 14 days without need to repeat screening evaluations. In this instance the diet run-in period should also be extended. Participants who are not free of symptoms and/or antimicrobials for at least 7 days prior to Day 1 despite the aforementioned extension of the screening period may be rescreened once medication is complete, and their clinical condition is stable for at least 7 days.
3.Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Participants with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor medical monitor (or designee)
4.History of any OTC gene therapy, or history of liver-derived stem cell therapy in the past 3 years (recipients must demonstrate a return to baseline urea cycle activity according to the investigator).
5.History of any organ transplant or stem cell transplant.
6.History of severe allergic reaction (i.e., anaphylaxis, generalized urticaria, angioedema, or other significant reaction) to a liposomal or PEG containing product.
7.Abuse of medications, illicit drugs or alcohol within 1 year prior to screening, per the investigator.
8.Dependence on inhaled (smoked or vaped) or oral cannabis products, in the opinion of the investigator. Non-dependent cannabis users must agree to abstain from 2 days before each clinic visit through the time of the visit.
9.Blood donation of 50 to 499 mL within 30 days of Screening or of > 499 mL within 60 days of Screening
10.Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that, in the opinion of the Investigator or Sponsor Medical Monitor (or designee) would render a participant unsuitable for inclusion:
•ALT or AST > 2x ULN
•Total bilirubin > 1.5 mg/dL, unless due to documented Gilbert's syndrome in which case total bilirubin must be <3 mg/dL
•Platelet count < 100x109/L
•Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 calculated by Modification to Diet in Renal Disease [MDRD] study equation.
•Abnormal thyroid function tests
•Presence of human immunodeficiency virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody (unless there is history of cure, in which case confirmatory RNA testing must be negative).
11.Diabetes that is not, in the opinion of the investigator, adequately controlled (...).
12.Clinically significant anemia (...)
13.Changes in maintenance therapies (...) within 28 days prior to Day 1. Participants who require a change in maintenance therapy may be rescreened once they have been on a stable regimen for ≥ 28 days.
14.Treatment with oral or systemic corticosteroids within 28 days prior to Day 1 and prohibited during the study unless required to manage an IRR.
15.Treatment with another investigational drug, biological agent, or device within 30-days of screening, or 5 half-lives of investigational drug, whichever is longer.
16.Treatment with any oligonucleotide (including siRNA) or mRNA therapy within 6 months prior to Screening. Participants who have previously received only a single dose of an oligonucleotide or mRNA as part of a clinical study may be included if a duration ≥3 months has elapsed since dosing. Participants who received an mRNA vaccine (e.g. for COVID-19) may be included if the vaccination course was completed ≥28 days prior to the first dose of study drug.
17.Individuals who are Investigator site staff members, employees of Arcturus or the Clinical Research Organization directly involved in the conduct of the study, or site staff members otherwise supervised by the Investigator or immediate family members of any of the previously mentioned individuals.
18.Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the participant unsuitable for inclusion or could interfere with participating in or completing the Study (e.g., severe liver disease including cirrhosis, significant cardiac disease, and disorders of coagulation or complement activation). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the safety and tolerability of ARCT-810, as assessed by determining the incidence, severity, and dose-relationship of adverse events, changes in ECG, changes in vital signs and changes in the laboratory parameters by dose level. The safety results in participants dosed with ARCT-810 will be compared with those from participants dosed with placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Multiple timepoints throughout the study. |
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics
1. The plasma pharmacokinetics of ARCT-810 will be assessed based on the observed plasma concentrations of mRNA-1801 and ATX-95 at multiple timepoints throughout the study.
Pharmacodynamics
2. Within participant change from baseline in area under curve and peak plasma concentration for 13C-urea at Day 30 (Week 5), Day 72 (Week 11) and Day 78 (Week 12).
3. Within participant change from baseline in area under the curve and peak plasma ammonia for the 24-hour plasma ammonia profile at Day 72 (Week 11) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetics secondary endpoint:
Multiple timepoints throughout the study - Days 1-3, Day 8, Day 15, Day 29, Day 43, Day 57, Days 71-73, Day 78 and Day 113.
Pharmacodynamics secondary endpoint:
Change from baseline to Day 30 (Week 5), Day 72 (Week 11) and Day 78 (Week 12) for 13C-urea;
Change from baseline to Day 72 (Week 11) for 24-hour plasma ammonia profile. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of trial is defined as the last visit of the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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