rifaximin 550 milligrams (mg) orally twice daily for 3 months

Alzheimer's Disease

Rifaximin (Xifaxan, Salix Pharmaceuticals, Bridgewater, N.J.) (See Package Insert) is a drug that is approved by the FDA for use in humans for the treatment of Hepatic Encephalopathy, Traveler's Diarrhea and Irritable Bowel Syndrome. It is commercially available. It will be used in accordance with approved labeling as pertains to dosage and administration for Hepatic Encephalopathy, contraindications and warnings. However, it will be used investigationally in this trial as rifaximin is not FDA approved for the treatment of Alzheimer's Disease.

Rifaximin 550 milligrams (MG)

Duke University Medical Center

Trial of Rifaximin in Probable Alzheimer's Disease

Pilot, Single Center, Open, Trial of Rifaximin in Probable Alzheimer's Disease

Done at Baseline, 3 month and 5 month visits. ADAS-Cog is a widely used cognitive endpoint in AD clinical trials and changes on this scale, over time, are considered clinically meaningful. ADAS-11 range is 0-70 with higher scores indicating worse performance. Errors from 11 items are added to generate the total score.

Collected at every visit and follow-up phone visits. A rare side effect of Rifaximin is diarrhea caused by clostridium difficile. This is a very serious form of diarrhea that can be fatal if not treated. The investigators will be following the patients closely during treatment and for 2 months following treatment to see if the patient has any signs or symptoms of this diarrhea. If a patient does develop clostridium difficile diarrhea, they will be promptly treated.

Done at Baseline, 3 month and 5 month visits. When brain tissue is damaged, it releases substances (serum neuronal markers) into the blood, such as Neurofilament Light. The investigators will be looking for the amount of these serum neuronal markers to decrease after three months of Rifaximin treatment, indicating less brain tissue damage.

The investigators will be looking for changes in the amounts of the following pro-inflammatory markers:
Interleukin (IL) 1 beta, IL 2, IL 4, IL 5, IL 6, IL 8, IL 10, IL 13, Tumor necrosis factor - alpha

The study drug, Rifaximin, is an antibiotic. It changes the mixture of bacteria in the colon. The investigators will analyze the types of bacteria that are in the patient's colon. The microbiome variables the investigators will use standard FDR correction to examine nominal significance of change from baseline. The investigators will be assessing the Escherichia, shigella, pseudomonas, bacteroides, eubacterium and Faecalibacterium.

Assessed at every visit. The patients will be followed closely to see if they are tolerating the drug, Rifaximin. The of the number of side effects would indicate that the patient may not be tolerating the drug. Most of these side effects are minor and include headache, nausea, vomiting, tiredness. A potentially fatal side effect would be the development of clostridium difficile diarrhea. The investigators will be following the patients closely during treatment and for 2 months following treatment to see if the patient has any signs or symptoms of this diarrhea. If a patient does develop clostridium difficile diarrhea, they will be promptly treated.

Change from baseline global cognitive scores at month 3). Global cognitive performance will be assessed by a psychometrician using the (MMSE). It is a brief cognitive questionnaire with a maximum score of 30 points. MMSE range is 0-30 with lower scores indicating worse performance. The number of correct answers is added to generate the total score.

Safety will be measured through adverse events as reported by the subjects

Clinically significant deviations from the baseline on CBC will be considered an AE and clinically significant

Clinically significant deviations from baseline to month 3 in blood pressure.

Clinically significant deviations from baseline to month 3 in pulse.

Clinically significant deviations from the baseline on Chemistry values as defined as Creatine, blood urine nitrogen, electrolytes and sodium potassium chloride results will be considered an AE.

Clinically significant deviations from the baseline on LFT will be considered an AE.

Clinically significant deviations from the baseline on clinically significant and newly emergent C Difficile infection will be considered.

Duke University

Bausch Health Americas, Inc.

the intervention will consist of 3 phases: a one week run-in period, 24 weeks strict KD and 24 weeks Modified Atkins Diet.
Every day, 40 g of KetoCal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals and to ensure ketosis during the night (some patients drink some sips of the shake during the night). During this run-in period, patients will become familiar with their diet and, in particular, they will learn which foods are allowed and which are not.

During the run-in period, the dietician will discuss the diet and maintenance of an isocaloric diet with the patients. As such, the diet of the control group will not change from their normal dietary pattern, unless a patient is following an Atkins-like diet. In the latter case, the patient will be asked to change the diet to a normal Belgian diet.

Lymphedema

Ketogenic Dieting

Ketocal, a nutritionally complete ready-to-drink liquid, is foreseen to ensure adequate amounts of vitamins and minerals will be used. After 24 weeks a Modified Atkins diet will be started.

Ketogenic diet

Isocaloric diet

UZ Leuven

Ketogenic Diet: a Novel Metabolic Strategy to Treat Lymphedema Patients?

measured with QOL questionnaire, a scale from 0-10 on 16 items, how higher the score, how higher the QOL

measured with Lymph ICF (international classification of functioning, disability and Health), a scale from 0-10 on 29 items, total score ranged from 0-100, 0-4: indicate no problem; 5-24 a small problem; 26-49: moderate problem; 50-95: severe problem; 96-100: very severe problem

Universitaire Ziekenhuizen Leuven

After baseline assessment, patients will be randomized in one of the treatment groups.
Randomization is performed according to 'www.randomization.com'. This free generator randomizes each subject to a single treatment by using the method of randomly permuted blocks.
Assessments are performed by a person blinded to the treatment allocation groups.
Randomization will be stratified for baseline lymphedema volume (3-9.9%, 10.0-19.9% and ≥20%), affected limb (arm or leg) and gender (females or males). The staff members who perform the measurements are blinded for the allocation.

The staff members who perform the measurements are blinded for the allocation.

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

Hepatic Encephalopathy

Aarhus University Hospital

Quantitative Determination of Brain Water Content in Patients During and After Hepatic Encepalopathy

Quantitative Determination of Brain Water Content in Patients During and After Hepatic Encepalopathy Measured by MR

Gitte Dam

MD, PHD

University of Aarhus

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.

glutamine/edema

Trial of Rifaximin in Probable Alzheimer's Disease

Ketogenic Diet: a Novel Metabolic Strategy to Treat Lymphedema Patients?

Neuroimaging and Neuropsychological Outcomes in Urea Cycle Disorders

Quantitative Determination of Brain Water Content in Patients During and After Hepatic Encepalopathy

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

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