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

Primary Purpose

Menkes Disease, Occipital Horn Syndrome

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Droxidopa
Placebo
Sponsored by
Stephen G. Kaler, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Menkes Disease focused on measuring Dysautonomia

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Nationwide Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Northera™ (Droxidopa) (Treatment A)

Placebo (Treatment B)

Arm Description

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.

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

Outcomes

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5 tool
Grade 1-5 with increasing severity from 1 to 5

Secondary Outcome Measures

Change in plasma catechol levels after Northera (Droxidopa)
Serial determinations of norepinephrine and dihydroxyphenylglycol
Changes in systolic blood pressure after Northera (Droxidopa)
Serial BP measurements including at-home monitoring
Changes in gastrointestinal symptoms after Northera (Droxidopa)
As reflected in the Irritable Bowel Syndrome-Diarrhea report
Changes in Time standing duration after Northera (Droxidopa)
Measured in time seconds
Changes in Up and Go test performance after Northera (Droxidopa)
Measured in time (seconds) needed to stand up from a chair, walk 3 m and return to a seated position on the chair.
Changes in 6 minute walk test performance after Northera (Droxidopa)
Measured in distance (meters) walked in 6 minutes

Full Information

First Posted
July 9, 2021
Last Updated
January 7, 2023
Sponsor
Stephen G. Kaler, MD
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1. Study Identification

Unique Protocol Identification Number
NCT04977388
Brief Title
NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 12, 2021 (Actual)
Primary Completion Date
June 30, 2025 (Anticipated)
Study Completion Date
June 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Stephen G. Kaler, MD

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Menkes Disease, Occipital Horn Syndrome
Keywords
Dysautonomia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Model Description
Double-blind Placebo-controlled Randomized Crossover Clinical Trial
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
6 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Northera™ (Droxidopa) (Treatment A)
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo (Treatment B)
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Droxidopa
Other Intervention Name(s)
Northera
Intervention Description
Subjects will self-administer capsules of Droxidopa by mouth twice daily for six weeks.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Subjects will self-administer capsules of placebo by mouth twice daily for six weeks.
Primary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5 tool
Description
Grade 1-5 with increasing severity from 1 to 5
Time Frame
Six week periods of Active drug versus Placebo
Secondary Outcome Measure Information:
Title
Change in plasma catechol levels after Northera (Droxidopa)
Description
Serial determinations of norepinephrine and dihydroxyphenylglycol
Time Frame
Six week periods of active drug versus placebo
Title
Changes in systolic blood pressure after Northera (Droxidopa)
Description
Serial BP measurements including at-home monitoring
Time Frame
Six week periods of active drug versus placebo
Title
Changes in gastrointestinal symptoms after Northera (Droxidopa)
Description
As reflected in the Irritable Bowel Syndrome-Diarrhea report
Time Frame
Six week periods of active drug versus placebo
Title
Changes in Time standing duration after Northera (Droxidopa)
Description
Measured in time seconds
Time Frame
Six week periods of active drug versus placebo
Title
Changes in Up and Go test performance after Northera (Droxidopa)
Description
Measured in time (seconds) needed to stand up from a chair, walk 3 m and return to a seated position on the chair.
Time Frame
Six week periods of active drug versus placebo
Title
Changes in 6 minute walk test performance after Northera (Droxidopa)
Description
Measured in distance (meters) walked in 6 minutes
Time Frame
Six week periods of active drug versus placebo
Other Pre-specified Outcome Measures:
Title
Change in scores on the Orthostatic Hypotension Symptom Assessment questionnaire after Northera (Droxidopa)
Description
Scores range from zero to 10 with 0 meaning no symptoms and 10 meaning the worst possible symptoms
Time Frame
Six week periods of active drug versus placebo

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. 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. Documented mutation in ATP7A. Must sign and date an Informed Consent Form (ICF). Age ≥ 18 years of age. Ability to adhere to the prescribed oral Northera (Droxidopa) regimen. Willingness to comply with all study visits and procedures. Exclusion Criteria: Pre-existing liver (e.g., hepatitis, biliary atresia, cirrhosis) or kidney disease (i.e., calculated glomerular filtration rate <30 ml/min). History of hypertension, anti-hypertensive therapy, heart failure (or decreased ejection fraction), cardiac arrhythmia, or bleeding diatheses. 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. Any alpha-1 adrenoreceptor agonist, beta-blocker, DOPA decarboxylase inhibitor, midodrine, ephedrine, or any triptan medication as a concomitant medication.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Stephen G. Kaler, MD
Phone
614 722-5964
Email
stephen.kaler@nationwidechildrens.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen G Kaler, MD
Organizational Affiliation
Nationwide Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stephen G Kaler, MD
Phone
614-722-5964

12. IPD Sharing Statement

Learn more about this trial

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

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