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Nitric Oxide Supplementation on Neurocognitive Functions in Patients With ASLD

This study is currently recruiting participants.
Verified February 2017 by Sandesh Chakravarthy Sreenath Nagamani, Baylor College of Medicine
Sponsor:
ClinicalTrials.gov Identifier:
NCT03064048
First Posted: February 24, 2017
Last Update Posted: February 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Rare Diseases Clinical Research Network
Neogenis Laboratories
Information provided by (Responsible Party):
Sandesh Chakravarthy Sreenath Nagamani, Baylor College of Medicine
  Purpose
This is a study involving a dietary supplement. Patients with argininosuccinate lyase deficiency (ASLD) will be randomly assigned to receive either a nitric oxide dietary supplement or placebo for 24 weeks, and then crossed-over to receive the other treatment for 24 weeks. The investigators will assess the effects of the supplement in domains of general cognition, memory, executive functioning, and fine motor functioning in individuals with ASLD.

Condition Intervention
Argininosuccinate Lyase Deficiency Urea Cycle Disorder Urea Cycle Disorders, Inborn Argininosuccinic Aciduria Dietary Supplement: Neo-ASA Dietary Supplement: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Active Comparator: Nitric oxide supplement Active Comparator will l not contain nitric oxide supplement.

Placebo Comparator: Placebo Placebo will not contain nitric oxide supplement.

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
Randomization for treatment assignment is by the providing Institution's Investigational Pharmacy Services.
Primary Purpose: Treatment
Official Title: Effect of Nitric Oxide (NO) Supplementation on Neurocognitive Measures in Argininosuccinate Lyase Deficiency (ASLD)

Resource links provided by NLM:


Further study details as provided by Sandesh Chakravarthy Sreenath Nagamani, Baylor College of Medicine:

Primary Outcome Measures:
  • Delis-Kaplan Executive Function System - Tower subtest [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo

  • Stanford-Binet - 4th Edition: Bead Memory and Sentence Memory subtests [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo

  • Grip Strength [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo

  • Grooved Pegboard [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo

  • Wechsler Intelligence Scale for Children OR Wechsler Adult Intelligence Scale - 4th Edition (in subjects > 16 years of age) [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo

  • Tower of London Test [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo

  • Conners Continuous Performance Test - 3rd Edition Conners Continuous Performance Test - 3rd Edition [ Time Frame: 24 weeks ]
    Change in the scores from baseline to 24 weeks with drug vs placebo


Estimated Enrollment: 16
Anticipated Study Start Date: April 15, 2017
Estimated Study Completion Date: December 31, 2023
Estimated Primary Completion Date: January 31, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Neo-ASA
During this arm the participant will receive a lozenge with nitric oxide as a dietary supplement twice daily.
Dietary Supplement: Neo-ASA
Dietary supplement with nitric oxide in the form of a lozenge called Neo-ASA.
Placebo Comparator: Placebo
During this arm the participant will receive a lozenge which will not contain nitric oxide as a dietary supplement twice daily.
Dietary Supplement: Placebo
Dietary supplement with no nitric oxide in the form of a lozenge to look and taste like the dietary supplement Neo-ASA

Detailed Description:

Argininosuccinate lyase deficiency (ASLD; also known as argininosuccinic aciduria) is the second most common urea cycle disorder (UCD) and accounts for 15-20% of all disorders of ureagenesis. Individuals with ASLD can have unique clinical and physiologic characteristics as compared to other UCDs. Previous work from the members of the UCDC have shown that in spite of having fewer episodes of hyperammonemia as compared to those with proximal blockade of the urea cycle, individuals with ASLD can develop intellectual and learning disabilities. Neurocognitive deficits have been observed even in individuals without any documented hyperammonemia. Furthermore, hepatic abnormalities including hepatomegaly, hepatic injury, fibrosis and even frank cirrhosis, and vascular issues like hypertension are well known in the disorder. Previous work from the members of the UCDC has demonstrated a tissue- and molecular-specific role for ASL in the generation of NO. ASL is not only required for the synthesis of L-arginine, the substrate for the synthesis of NO, but is also an integral member of a complex that is critical for synthesis of NO from arginine. Loss of ASL can thus lead to systemic and tissue-specific NO deficiencies, which could potentially contribute to the complex phenotype including the neurocognitive deficits. A rational therapeutic option would hence be to use a NOS-independent NO supplement.

The purpose of this study is to determine whether a dietary NO supplement, Neo-ASA, would improve general cognition, memory, executive functioning, fine motor functioning, and attention in individuals with ASLD. In this single-center trial, double-blind, randomized, placebo-controlled, crossover study, individuals with ASLD will be assigned to receive a medication containing NO dietary supplement for 24 weeks and a placebo for 24 weeks. General cognition, memory, executive functioning, and fine motor functioning will be assessed and compared at the end of treatment with placebo and Neo-ASA.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age > 6 and <50 years
  2. Diagnosis of ASLD confirmed by biochemical OR enzymatic OR genetic testing
  3. Has a history of compliance with diet and treatment
  4. Negative pregnancy test and ability to use birth control method for the entire duration of the study (if the subject is of child-bearing potential)
  5. Males who enroll in the study (and their partners) should argee to use an acceptable form of birth control for the entire duration of the study

Exclusion Criteria:

  1. Clinical or laboratory abnormality of Grade 3 or greater according to the CTCAE (or for conditions not covered by the CTCAE, a severe or life-threatening toxicity) at enrollment which, in the view of the investigator compromises safety. (Elevated plasma levels of aspartate and alanine aminotransferases, or low serum potassium will not be considered as exclusion criteria as these are phenotypic manifestations of ASLD.)
  2. Known hypersensitivity to Neo-ASA or nitrite
  3. Individuals currently being administered other investigational agents
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03064048


Contacts
Contact: Mary A Mullins, RN 832-822-4263 mullins@bcm.edu
Contact: Sandesh C Nagamani, M.D. nagamani@bcm.edu

Locations
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Mary A Mullins, RN    823-822-4263    mullins@bcm.edu   
Principal Investigator: Sandesh C Nagamani, M.D.         
Principal Investigator: Brendan Lee, M.D., PhD         
Sponsors and Collaborators
Baylor College of Medicine
Rare Diseases Clinical Research Network
Neogenis Laboratories
Investigators
Principal Investigator: Sandesh C Nagamani, M.D. Baylor College of Medicine
Principal Investigator: Brendan Lee, M.D., PhD Baylor College of Medicine
  More Information

Publications:
Responsible Party: Sandesh Chakravarthy Sreenath Nagamani, Principal Investigator, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT03064048     History of Changes
Other Study ID Numbers: H-40143
First Submitted: February 10, 2017
First Posted: February 24, 2017
Last Update Posted: February 24, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: According to the policy of the National Institutes of Health (one of the study sponsors) research data may be put in a secure, limited-access database known as dbGaP. The data will include any genetic test results as well as other information about medical problems. There will be NO identifiers included (no name, data of birth, address, social security number, etc.). Access to this information is restricted by the National Institutes of Health. Only doctors and scientists who get approval from the National Institutes of Health can access this de-identified data.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sandesh Chakravarthy Sreenath Nagamani, Baylor College of Medicine:
Argininosuccinate Lyase Deficiency
Urea Cycle Disorder

Additional relevant MeSH terms:
Disease
Urea Cycle Disorders, Inborn
Argininosuccinic Aciduria
Pathologic Processes
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents