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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

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:

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.

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

NCT ID

NCT04977388

First Posted

July 9, 2021

Last Updated

January 7, 2023

Sponsor

Stephen G. Kaler, MD

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

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

Arm Title

Placebo (Treatment B)

Arm Type

Placebo Comparator

Arm Description

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

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

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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