Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD who can undergo MRI and behavioral testing

Healthy males or females without known medical or metabolic disorder (control group) who can undergo MRI and behavioral testing

Female carriers of ornithine transcarbamylase deficiency (OTCD) or males with late onset presentation of OTCD or participants with CPS-1 who have had a recent hyperammonemic episode who can undergo MRI and behavioral testing

Males and females with ASSD and ASLD who can undergo MRI and behavioral testing

Urea Cycle Disorders

Behavioral

Children's Research Institute

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Concentration based on area under curve on 1H MRS and quantitated by LCModel. A metabolite's tissue concentration is related to the integrated amplitude of the MRS signal it produces. Integrated amplitude is the area under the MRS signal curve. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocols used selects 257 averages. This means, 257 free induction decays. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point.
Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM).

Measure of white matter integrity in OTCD Patients and Controls in frontal white matter. Fractional anisotropy values fall on a scale of 0 to 1, with 0 meaning that the diffusion of water is isotropic and unrestricted, or equally restricted, in all directions and with 1 meaning that diffusion occurs along only one axis and is fully restricted along all other directions. Scores closer to 1 are associated with intact white matter while scores closer to 0 are associated with white matter damage.

correlation of the findings from neuroimaging with cognitive functioning that assesses executive function

Data will be kept on UCD website and released after study completion

Children's National Research Institute

Boston Children’s Hospital

Ornithine Phenylacetate is administered intravenously, through a peripheral venous catheter. Each infusion should will be administered over a period of 120 hours.

Initial infusion of study drug at 0.139 g/h for the first 12 hours (approximately 3.33 g/24h) and maintained at this rate for up to 120 hours.

Maximum Dose Level 3.33 g/24h

Initial infusion of study drug at a dose of 0.139 g/h for the first 12 hours (approximately 3.33 g/24h); dose increased to 0.277 g/h for the remaining 108 hours (approximately 6.65 g/24h) for a total treatment period of up to 120 hours.

Maximum Dose Level 6.65 g/24h

Initial infusion of study drug at a dose of 0.139 g/h for the first 12 hours (approximately 3.33 g/24h); dose increased to 0.277 g/h for the next 12 hours; dose then increased to 0.416 g/h (approximately 10 g/24h) and maintained at this rate for the remaining 96 hours for a total treatment period of up to 120 hours.

Maximum Dose Level 10 g/24h

Study drug infused at a dose of 20g/24h from initiation of infusion for up to 120 hours.

Maximum Dose Level 20g/24h

Total

Sex: Female, Male

Race (NIH/OMB)

Region of Enrollment

To evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury

Study drug infused at a dose of 20g/24h from initiation of infusion for a maximum time of up to 120 hours.

Number of Participants That do Not Tolerate the Administered Dose and Had Grade 3 or 4 Treatment Emergent Adverse Events as a Measure of Safety and Tolerability

To evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with impaired and intact renal function using urinary phenylacetylglutamine (PAGN) as a surrogate marker

Measurement of OCR-002 Plasma Concentration

To evaluate the effect of OCR-002 on ammonia levels in patients with acute liver failure/severe acute liver injury

Initial infusion of study drug at a dose of 0.139 g/h for the first 12 hours (approximately 3.33 g/24h); dose increased to 0.277 g/h for the remaining 108 hours (approximately 6.65 g/24h) for a total treatment period of 120 hours.

Initial infusion of study drug at a dose of 0.139 g/h for the first 12 hours (approximately 3.33 g/24h); dose increased to 0.277 g/h for the next 12 hours; dose then increased to 0.416 g/h (approximately 10 g/24h) and maintained at this rate for the remaining 96 hours for a total treatment period of 120 hours.

Study drug infused at a dose of 20g/24h from initiation of infusion for a maximum time of 120 hours.

Change in Ammonia

The West Haven Criteria (WHC) for Hepatic Encephalopathy measures the severity of encephalopathy and patient's level of consciousness. The scale ranges from 0 to 4; a minimum score of 0 represents a better outcome, and a maximum total score of 4 represents a worse outcome. A score of 0 corresponds to normal consciousness and behavior and normal neurological examination. A score of 1 corresponds to mild lack of awareness, shortened attention span, and impaired addition or subtraction; mild asterixis or tremor. A score of 2 corresponds to lethargy, disorientated or inappropriate behavior, obvious asterixis; slurred speech. A score of 3 corresponds to somnolent but arousable, gross disorientation or bizarre behavior, muscle rigidity and clonus; hyperreflexia. A score of 4 corresponds to coma and decerebrate posturing.

Neurological Function Measured by the West Haven Criteria (WHC) for Hepatic Encephalopathy

The orientation log focuses on orientation to place, time, and circumstance. There are 10 items on the orientation log, which are scored 0-3. A spontaneous correct response is awarded 3 points. A spontaneous response that is lacking or incorrect, but a correct response is provided following a logical cue is awarded 2 points. A score of 1 is given if spontaneous and cued responses are lacking or incorrect, but a correct response is provided in a recognition format. A score of 0 is given if the spontaneous, cued, or recognition format does not generate a correct answer. Scores from the 10 items are summed and the final score ranges from 0 to 30.

Neurological Function Measured by the Orientation Log (O-log)

Overall Study

William M. Lee, MD

Acute Liver Failure

Acute Liver Injury

Up to 36 patients will be enrolled into 2 groups [~18 with minimal renal dysfunction (Cohort 1) & ~18 w/ comprised renal function (Cohort 2)] and receive OCR-002 infusion for at least 72 hrs. OCR-002 will be administered in the vein and pharmacokinetics (pk) assessed for all subjects who receive the infusion.
The first 24 enrolled subjects received OCR-002 at 3 ascending dose levels (DLs 1-3) with a maximum target infusion rate equivalent to 10g/24h.
The remaining 12 patients (~6 Cohort 1 & ~6 Cohort 2) will be enrolled and receive identical quantities of OCR-002 at 20g/24hr continuously for 5 days (Dose Level 4).

Ornithine Phenylacetate

University of California, San Francisco

Yale University School of Medicine

Emory University

Northwestern University

University of Kansas Medical Center

University of Michigan Medical Center

The Ohio State University

Medical University of South Carolina

University of Texas Southwestern Medical Center

Virginia Commonwealth University

University of Washington

Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury

A Phase 2a Study to Evaluate the Safety and Tolerability of OCR-002 (Ornithine Phenylacetate) in the Treatment of Patients With Acute Liver Failure/Severe Acute Liver Injury

De-identified data for the overall study will be shared once the study is completed.

ornithine/opuch

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Safety Study of Ornithine Phenylacetate to Treat Patients With Acute Liver Failure/Severe Acute Liver Injury

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