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| ID | Type | Description | Link |
|---|---|---|---|
| FD-R-004772 | Other Grant/Funding Number | FDA |
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The overall study objectives are to determine whether carbidopa (Lodosyn®) is safe and well tolerated and to assess whether it can inhibit catecholamine-induced paroxysmal hypertension and normalize or reduce the exaggerated blood pressure variability in patients with familial dysautonomia (FD, also called hereditary sensory and autonomic neuropathy type III or Riley-Day syndrome). Funding Source- FDA OOPD.
The investigators propose to perform a double-blind randomized trial with a cross over design to compare high dose (600 mg/day) and low dose (300 mg per day) carbidopa blockade with placebo. Patients will be randomly assigned to a high-dose/low-dose/placebo sequence, lowdose/placebo/high-dose sequence or placebo/high-dose/low-dose sequence. Participants will remain on each treatment period for 28-days.
Aim 1: To evaluate the safety and tolerability of carbidopa in FD patients with particular emphasis on the orthostatic fall in blood pressure.
Aim 2: As proof of concept, examine the hemodynamic effects of carbidopa and determine its effects on norepinephrine production, BP variability and paroxysmal hypertension.
Aim 3: In a dose finding study, compare the effects of low (300 mg/day) and high (600 mg/day) dose carbidopa blockade vs. placebo on BP variability and paroxysmal hypertension.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Matching placebo |
|
| Low-Dose Carbidopa | Experimental |
| |
| High-Dose Carbidopa | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Carbidopa Low-Dose | Drug | 300 mg/day |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Reported Adverse Events Related to Study Drug | Adverse events defined as: a change in a patient's baseline condition including intercurrent illnesses irrespective of the relationship to carbidopa treatment. This will be monitored primarily with phone calls at weekly intervals. In addition, patients will be asked about adverse events while at the office. Patients will also fill a daily diary with a specific prompts to note any adverse events. | Up to 90 days |
| Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study. | Body mass measured in kg | Up to 90 days |
| Number of Participants With Abnormal Electrocardiographic Interval Patterns | Clinically significant changes in the intervals of characteristic electrocardiographic patterns | Up to 90 days |
| Average Systolic Blood Pressure Variability (Daytime) | Patients with FD undergo ambulatory BP monitoring while keeping a detailed log of their activities (sleep/meal-times/medications/posture/symptoms). Variability in blood pressure overtime will be measured by the standard deviation during awake hours | up to Week 14 |
| Highest Systolic Blood Pressure | Maximum blood pressure captured on 24-h ambulatory monitoring | Day 1 of treatment period |
| Systolic Blood Pressure | SBP measured in the seated position | up to Week 14 |
| Measure | Description | Time Frame |
|---|---|---|
| Severity of Hypotension During an Active Stand Test | Lowest blood pressure captured during 3 minutes of standing | up to Week 14 |
| Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug |
Not provided
Inclusion Criteria:
Male or female patients with familial dysautonomia (FD) age 10 or older
Unstable blood pressure, defined as:
Confirmed diagnosis of FD (genetic testing)
Providing written informed consent (or ascent) to participate in the trial
Ability to comply with the requirements of the study procedures.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Horacio C Kaufmann, MD | NYU School of Medicine | Principal Investigator |
| Lucy J Norcliffe-Kaufmann, PhD | NYU School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| NYU Langone Medical Center, Dyautonomia Center, Suite 9Q | New York | New York | 10016 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23553478 | Background | Norcliffe-Kaufmann L, Martinez J, Axelrod F, Kaufmann H. Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. Neurology. 2013 Apr 23;80(17):1611-7. doi: 10.1212/WNL.0b013e31828f18f0. Epub 2013 Apr 3. | |
| 22739220 | Background | Norcliffe-Kaufmann LJ, Axelrod FB, Kaufmann H. Cyclic vomiting associated with excessive dopamine in Riley-day syndrome. J Clin Gastroenterol. 2013 Feb;47(2):136-8. doi: 10.1097/MCG.0b013e3182582cbf. |
| Label | URL |
|---|---|
| New York University (NYU) Dysautonomia Center Research Site | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Low-Dose Carbidopa, Then Placebo, Then High-Dose Carbidopa | Patients received low-dose carbidopa (300 mg/day), matching placebo, then high-dose carbidopa (600 mg/day) in 3 separate 4-week treatment periods. Doses were divided 3x daily, administered 6 hours apart, with a 4-day dose de-escalation and washout period between dose changes. in 3 separate 4-week treatment periods. Doses were divided 3x daily, administered 6 hours apart, with a 4-day dose de-escalation and washout period between dose changes. |
| FG001 | High-Dose Carbidopa, Then Low-Dose Carbidopa, Then Placebo | Patients received high-dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), then matching placebo in 3 separate 4-week treatment periods. Doses were divided 3x daily, administered 6 hours apart, with a 4-day dose de-escalation and washout period between dose changes. in 3 separate 4-week treatment periods. Doses were divided 3x daily, administered 6 hours apart, with a 4-day dose de-escalation and washout period between dose changes. |
| FG002 | Placebo, Then High-Dose Carbidopa, Then Low-Dose Carbidopa | Patients received matching placebo, high-dose carbidopa (600 mg/day), then low-dose carbidopa (300 mg/day) in 3 separate 4-week treatment periods. Doses were divided 3x daily, administered 6 hours apart, with a 4-day dose de-escalation and washout period between dose changes. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Enrollment |
|
| ||||||||||||||||||
| First Intervention (28 Days) |
| |||||||||||||||||||
| Second Intervention (28 Days) |
| |||||||||||||||||||
| Third Intervention (28 Days) |
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | Low Dose Carbidopa, High Dose Carbidopa, Placebo | This is a 14-week study. Patients will receive, in random order, high dose carbidopa (600mg/day), low dose carbidopa (300 mg/day) or placebo. Between each crossover, there will be a titration down over 2-days followed by a 2-day washout. Carbidopa Low Dose Placebo: A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient. Carbidopa High Dose |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants Who Reported Adverse Events Related to Study Drug | Adverse events defined as: a change in a patient's baseline condition including intercurrent illnesses irrespective of the relationship to carbidopa treatment. This will be monitored primarily with phone calls at weekly intervals. In addition, patients will be asked about adverse events while at the office. Patients will also fill a daily diary with a specific prompts to note any adverse events. | Posted | Count of Participants | Participants | Up to 90 days |
|
1 year
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Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Low-Dose Carbidopa | 300 mg/day Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitaliztion | General disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Horacio C Kaufmann, MD | NYU Langone Health | 212-263-7225 | Horacio.Kaufmann@nyulangone.org |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 12, 2018 | Nov 5, 2020 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D004402 | Dysautonomia, Familial |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D054969 | Primary Dysautonomias |
| D001342 | Autonomic Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D009477 | Hereditary Sensory and Autonomic Neuropathies |
Not provided
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| ID | Term |
|---|---|
| D002230 | Carbidopa |
| D010110 | Oxymetholone |
| ID | Term |
|---|---|
| D008750 | Methyldopa |
| D004295 | Dihydroxyphenylalanine |
| D002395 | Catecholamines |
| D000588 | Amines |
Not provided
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| Placebo | Other | A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient. |
|
|
| Carbidopa High-Dose | Drug | 600 mg/day |
|
|
| Heart Rate |
Heart rate in the seated position |
| up to Week 14 |
| Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel | Clinically significant laboratory values include complete blood count (CMC) and metabolic panel related to treatment with carbidopa | Up to 90 days |
| Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters | Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa | Up to 90 days |
| Up to 90 days |
| Frequency of Worsening Symptoms Noted in the Patient's Diary | A tailored questionnaire to examine symptoms over the treatment period and the used of as needed medications. Each day will have a designated page. Since nausea/vomiting and hypertension occur together in FD we will use a diary consisting of a simplified version of the Rhodes Index 44 symptoms of nausea/retching, with items addressing vomiting/throwing up omitted, as most participants will have had anti-reflux surgery to prevent vomiting (fundoplication), graded on a 5-point scale (appendix 2). The diary will also include space to write down any adverse events on a daily basis. | Up to 90 Days |
| 24-h Urinary Norepinephrine Excretion | Norepinephrine concentration determined from a 24-hour urine sample in a bottle shielded from light containing preservative. Patients will be instructed to refrigerate their sample and bring it on the morning of their visit in a cool bag. | up to Week 14 |
| Coefficient of Systolic BP Variability (Daytime) | The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP. | up to Week 14 |
| Morning Surge in Systolic BP on Awakening From Sleep (24-h) | The morning surge will be calculated as the difference between the mean systolic blood pressure during the hour that included the lowest blood pressure during sleep and maximum value detected within 2-h of awakening from sleep | up to Week 14 |
| NYU Medical Center |
| New York |
| New York |
| 10016 |
| United States |
| 22129610 | Background | Norcliffe-Kaufmann L, Axelrod FB, Kaufmann H. Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome. J Hum Hypertens. 2013 Jan;27(1):51-5. doi: 10.1038/jhh.2011.107. Epub 2011 Dec 1. |
| 22045363 | Background | Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale. Clin Auton Res. 2012 Apr;22(2):79-90. doi: 10.1007/s10286-011-0146-2. Epub 2011 Nov 2. |
| 21098405 | Background | Norcliffe-Kaufmann L, Axelrod F, Kaufmann H. Afferent baroreflex failure in familial dysautonomia. Neurology. 2010 Nov 23;75(21):1904-11. doi: 10.1212/WNL.0b013e3181feb283. |
| 25323828 | Background | Palma JA, Norcliffe-Kaufmann L, Fuente-Mora C, Percival L, Mendoza-Santiesteban C, Kaufmann H. Current treatments in familial dysautonomia. Expert Opin Pharmacother. 2014 Dec;15(18):2653-71. doi: 10.1517/14656566.2014.970530. Epub 2014 Oct 17. |
| Familial dysautonomia medical information | View source |
| Patient Advocacy Group | View source |
| NOT COMPLETED |
|
|
| NOT COMPLETED |
|
|
| NOT COMPLETED |
|
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
300 mg/day
Other Names: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486
| OG002 | High-Dose Carbidopa | 600 mg/day Other Names: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486 |
|
|
| Primary | Number of Participants With Significant Changes in Body Mass That Resulted in Discontinuation From the Study. | Body mass measured in kg | Posted | Count of Participants | Participants | Up to 90 days |
|
|
|
| Primary | Number of Participants With Abnormal Electrocardiographic Interval Patterns | Clinically significant changes in the intervals of characteristic electrocardiographic patterns | Posted | Count of Participants | Participants | Up to 90 days |
|
|
|
| Primary | Average Systolic Blood Pressure Variability (Daytime) | Patients with FD undergo ambulatory BP monitoring while keeping a detailed log of their activities (sleep/meal-times/medications/posture/symptoms). Variability in blood pressure overtime will be measured by the standard deviation during awake hours | Posted | Mean | Standard Deviation | mmHg | up to Week 14 |
|
|
|
| Primary | Highest Systolic Blood Pressure | Maximum blood pressure captured on 24-h ambulatory monitoring | Posted | Mean | Standard Deviation | mmHg | Day 1 of treatment period |
|
|
|
| Primary | Systolic Blood Pressure | SBP measured in the seated position | Posted | Mean | Standard Deviation | mmHg | up to Week 14 |
|
|
|
| Primary | Heart Rate | Heart rate in the seated position | Posted | Mean | Standard Deviation | beats per minute (BPM) | up to Week 14 |
|
|
|
| Primary | Number of Participants Who Displayed Clinical Significant Laboratory Values on CBC or Metabolic Panel | Clinically significant laboratory values include complete blood count (CMC) and metabolic panel related to treatment with carbidopa | Posted | Count of Participants | Participants | Up to 90 days |
|
|
|
| Primary | Number of Participants Who Displayed Clinically Significant Values in Urine Safety Parameters | Clinically significant values on urinalysis, urine safety parameters related to treatment with carbidopa | Posted | Count of Participants | Participants | Up to 90 days |
|
|
|
| Secondary | Severity of Hypotension During an Active Stand Test | Lowest blood pressure captured during 3 minutes of standing | Posted | Mean | Standard Deviation | mmHg | up to Week 14 |
|
|
|
| Secondary | Number of Participants Who Reported Worsening of OH Symptoms or Dropped Out Because of Worsening OH While on Active Study Drug | Posted | Count of Participants | Participants | Up to 90 days |
|
|
|
| Secondary | Frequency of Worsening Symptoms Noted in the Patient's Diary | A tailored questionnaire to examine symptoms over the treatment period and the used of as needed medications. Each day will have a designated page. Since nausea/vomiting and hypertension occur together in FD we will use a diary consisting of a simplified version of the Rhodes Index 44 symptoms of nausea/retching, with items addressing vomiting/throwing up omitted, as most participants will have had anti-reflux surgery to prevent vomiting (fundoplication), graded on a 5-point scale (appendix 2). The diary will also include space to write down any adverse events on a daily basis. | Posted | Number | symptoms | Up to 90 Days |
|
|
|
| Secondary | 24-h Urinary Norepinephrine Excretion | Norepinephrine concentration determined from a 24-hour urine sample in a bottle shielded from light containing preservative. Patients will be instructed to refrigerate their sample and bring it on the morning of their visit in a cool bag. | Posted | Mean | Standard Deviation | pg/mL | up to Week 14 |
|
|
|
| Secondary | Coefficient of Systolic BP Variability (Daytime) | The measurement of blood pressure variability based on the standard deviation that also takes into account the underlying level of BP. | Posted | Mean | Standard Deviation | mmHg | up to Week 14 |
|
|
|
| Secondary | Morning Surge in Systolic BP on Awakening From Sleep (24-h) | The morning surge will be calculated as the difference between the mean systolic blood pressure during the hour that included the lowest blood pressure during sleep and maximum value detected within 2-h of awakening from sleep | Posted | Mean | Standard Deviation | mmHg | up to Week 14 |
|
|
|
| 1 |
| 16 |
| 1 |
| 16 |
| 4 |
| 16 |
| EG001 | High-Dose Carbidopa | 600 mg/day Other Name: Lodosyn ®, DL-α-methyl-α-hydrazino-3, 4-dihydroxyphenyl-propionic acid, HMD, MK-486 | 0 | 16 | 0 | 16 | 3 | 16 |
| EG002 | Placebo | A placebo containing an inert substance, in capsule form that does not contain an active drug ingredient. | 0 | 16 | 0 | 16 | 0 | 16 |
| Syncope | Vascular disorders | Non-systematic Assessment |
|
Not provided
Not provided
Not provided
| D009421 | Nervous System Malformations |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D011115 | Polyneuropathies |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D009930 |
| Organic Chemicals |
| D006834 | Hydrazines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D000732 | Androstanols |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |