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NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome

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.
 
ClinicalTrials.gov Identifier: NCT04977388
Recruitment Status : Recruiting
First Posted : July 26, 2021
Last Update Posted : July 26, 2021
Sponsor:
Information provided by (Responsible Party):
Stephen G. Kaler, MD, Nationwide Children's Hospital

Brief Summary:
The purpose of this study is to evaluate whether Northera (Droxidopa) is safe and effective in young adults with Menkes disease who survived the most severe complications of their illness or adults with occipital horn syndrome (OHS), who have trouble with intermittent low blood pressure and other symptoms of dysautonomia. The outcomes and information from this study may help adult survivors of Menkes disease and individuals with OHS lead more normal day-to-day lives.

Condition or disease Intervention/treatment Phase
Menkes Disease Occipital Horn Syndrome Drug: Droxidopa Other: Placebo Phase 1 Phase 2

Detailed Description:
This pilot clinical trial will evaluate the safety, tolerability, dosing, and preliminary efficacy of Northera (Droxidopa) treatment in young adults who survived the major neurodegenerative and neurocognitive effects of Menkes disease through early Copper Histidinate treatment. We hypothesize that Northera (Droxidopa) in Menkes disease survivors with symptoms of dysautonomia (e.g., syncope, dizziness, orthostatic hypotension, abnormal sinoatrial conduction, nocturnal bradycardia, and bowel or bladder dysfunction) from persistent deficiency of the copper-dependent enzyme, dopamine-β-hydroxylase, will be safe, and correct or improve blood neurochemical levels, raise systolic blood pressure, and produce symptomatic improvement and better overall quality of life. We will test this hypothesis in six to ten Menkes disease survivors or OHS patients in a double-blind placebo-controlled randomized crossover clinical trial.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Double-blind Placebo-controlled Randomized Crossover Clinical Trial
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Adults With Occipital Horn Syndrome: Double-blind Placebo-controlled Randomized Crossover Clinical Trial
Actual Study Start Date : July 12, 2021
Estimated Primary Completion Date : June 30, 2025
Estimated Study Completion Date : June 30, 2026


Arm Intervention/treatment
Active Comparator: Northera™ (Droxidopa) (Treatment A)
Northera (Droxidopa) (Treatment A) will be provided to adult subjects as a capsule with 100mg, 200mg, or 300mg of Northera (Droxidopa) contained within gelatin color capsules (sky blue and white, size 0) based on findings from the dose titration visit. These capsules are physically indistinguishable from the Treatment B (placebo) capsules. Frequency of administration (by mouth) will be twice daily for six weeks.
Drug: Droxidopa
Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.
Other Name: Northera

Placebo Comparator: Placebo (Treatment B)
Empty gelatin color capsules (sky blue and white, size 0) filled with cellulose microcrystalline and physically indistinguishable from Treatment A capsules. Frequency of administration (by mouth) will be twice daily for six weeks
Other: Placebo
Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5 tool [ Time Frame: Six week periods of Active drug versus Placebo ]
    Grade 1-5 with increasing severity from 1 to 5


Secondary Outcome Measures :
  1. Change in plasma catechol levels after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    Serial determinations of norepinephrine and dihydroxyphenylglycol

  2. Changes in systolic blood pressure after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    Serial BP measurements including at-home monitoring

  3. Changes in gastrointestinal symptoms after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    As reflected in the Irritable Bowel Syndrome-Diarrhea report

  4. Changes in Time standing duration after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    Measured in time seconds

  5. Changes in Up and Go test performance after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    Measured in time (seconds) needed to stand up from a chair, walk 3 m and return to a seated position on the chair.

  6. Changes in 6 minute walk test performance after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    Measured in distance (meters) walked in 6 minutes


Other Outcome Measures:
  1. Change in scores on the Orthostatic Hypotension Symptom Assessment questionnaire after Northera (Droxidopa) [ Time Frame: Six week periods of active drug versus placebo ]
    Scores range from zero to 10 with 0 meaning no symptoms and 10 meaning the worst possible symptoms



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult persons with Menkes disease who survived beyond the expected natural history, attained independent ambulation, attend (or attended) school, and reached adulthood after early CuHis treatment for three years or adults with Occipital Horn Syndrome, who manifest clinical signs and symptoms of dysautonomia, e.g., orthostatic hypotension: specifically, a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within three minutes after standing, and/or chronic diarrhea: production of loose stools with or without increased stool frequency for more than four weeks immediately preceding enrollment.
  2. History of at least thrice weekly occurrence of dizziness/feeling lightheaded while standing upright and/or thrice weekly episodes of diarrhea or an urgent need to defecate after food ingestion for more than four weeks immediately preceding enrollment.
  3. Documented mutation in ATP7A.
  4. Must sign and date an Informed Consent Form (ICF).
  5. Age ≥ 18 years of age.
  6. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen.
  7. Willingness to comply with all study visits and procedures.

Exclusion Criteria:

  1. Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated glomerular filtration rate <30 ml/min).
  2. History of hypertension, anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses.
  3. Any disease or condition that, in the opinion of the Investigator, has a high probability of precluding the subject from completing the study or where the subject cannot or will not appropriately comply with study requirements.
  4. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.

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): NCT04977388


Contacts
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Contact: Stephen G. Kaler, MD 614 722-5964 stephen.kaler@nationwidechildrens.org

Locations
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United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Stephen G Kaler, MD    614-722-5964      
Sponsors and Collaborators
Stephen G. Kaler, MD
Investigators
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Principal Investigator: Stephen G Kaler, MD Nationwide Children's Hospital
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Responsible Party: Stephen G. Kaler, MD, Professor, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT04977388    
Other Study ID Numbers: 00001113
First Posted: July 26, 2021    Key Record Dates
Last Update Posted: July 26, 2021
Last Verified: July 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Stephen G. Kaler, MD, Nationwide Children's Hospital:
Dysautonomia
Additional relevant MeSH terms:
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Primary Dysautonomias
Autonomic Nervous System Diseases
Menkes Kinky Hair Syndrome
Ehlers-Danlos Syndrome
Cutis Laxa
Syndrome
Disease
Pathologic Processes
Nervous System Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Metabolism, Inborn Errors
Metal Metabolism, Inborn Errors
Hair Diseases
Skin Diseases
Metabolic Diseases
Skin Diseases, Genetic
Connective Tissue Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases