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THE SAFETY, TOLERABILITY AND EFFICACY OF DRONABINOL, A SYNTHETIC
ENDOCANNABINOID RECEPTOR AGONIST, FOR THE TREATMENT OF NAUSEA
AND VOMITING IN PATIENTS WITH FAMILIAL DYSAUTONOMIA
Medical Marijuana Research Grant Program RFA #1353
Colorado Department of Public Health & Environment
Application Submission Checklist
 Cover letter signed by the authorized official of applicant agency
 Attachment A: Applicant Information Form
 Copy of letter of intent
 Attachment B: Budged template
 Detailed sub-contractor budget using budget template
 Application Executive Summary
 Description of Key Personnel
 Research plan
 Attachment C: W-9 form
 Biosketches of key personnel
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New York, October 10, 2014
From: Dysautonomia Center - New York University School of Medicine
To: Colorado Department of Public Health & Environment
Re: Medical Marijuana Research Grant Program RFA #1353
Dear Colorado Department of Public Health Staff,
We are submitting our project “THE SAFETY, TOLERABILITY AND EFFICACY OF DRONABINOL, A
SYNTHETIC ENDOCANNABINOID RECEPTOR AGONIST, FOR THE TREATMENT OF NAUSEA AND
VOMITING IN PATIENTS WITH FAMILIAL DYSAUTONOMIA” to be considered for the Colorado Medical
Marijuana Research Grant Program.
Familial dysautonomia is a hereditary autonomic neuropathy in which patients experience several symptoms,
including decreased temperature and pain sensation, gait ataxia, behavioral problems and hyperdopaminergic
retching and hypertensive crises. Current treatments for these symptoms are not effective enough and have severe
adverse effects. Given that marijuana has been previously used to treat nausea and vomiting in patients with cancer
and HIV, our primary aim in this trial is to use dronabinol (a tetrahydrocannabinol) to treat these retching,
hypertensive crises in patients with familial dysautonomia.
Our Dysautonomia Center has proven expertise in research and clinical care of patients with disorders of the
autonomic nervous system. We have conducted previous randomized clinical trials in this population, whose results
have been already published in high impact journals.
The potential application of marijuana derivatives in patients with dysautonomia is an exciting new field, as most of
these patients suffer from debilitating, difficult to treat symptoms, including retching and vomiting crises. Although
familial dysautonomia is a rare condition, the potentiality of extrapolating our results to other rare diseases with
similar debilitating symptoms –many of them orphan disorders- opens exciting possibilities for these patients.
We are confident that you will find the project, the budget and the expertise of our personnel suitable to consider
funding our proposal. We believe our contribution will improve the therapeutic management of familial
dysautonomia and, potentially, of other rare disorders and will be of interest to the Colorado Department of Public
Health.
Sincerely,
____________________________________
Principal Investigator
Horacio Kaufmann, MD FAAN ([email protected])
Director, Dysautonomia Center
Professor of Neurology, Pediatrics and Medicine
New York University School of Medicine
____________________________________
Authorized official
Justin Schrefer ([email protected])
Sponsored Programs Administration (SPA)
New York University Medical Center
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THE SAFETY, TOLERABILITY AND EFFICACY OF DRONABINOL, A SYNTHETIC
ENDOCANNABINOID RECEPTOR AGONIST, FOR THE TREATMENT OF NAUSEA
AND VOMITING IN PATIENTS WITH FAMILIAL DYSAUTONOMIA
EXECUTIVE SUMMARY
This is a pilot clinical trial of dronabinol to treat disabling attacks of nausea and vomiting
in patients with familial dysautonomia (FD, also known as Riley Day syndrome or hereditary
sensory and autonomic neuropathy type III). FD is a rare autosomal recessive disease in which
the growth and development of selective nerves is impaired. Patients with FD suffer recurrent
uncontrollable nausea and vomiting crises accompanied by skin flushing, tachycardia and arterial
hypertension. Current treatments of nausea are ineffective or have intolerable side sides. Our
long-term goal is to treat nausea effectively and without side effects, a therapeutic intervention
that would markedly improve the quality of life of patients with FD.
Dronabinol is synthetic delta-9-tetrahydrocannabinol (THC) and also a naturally occurring
component of Cannabis sativa L. (Marijuana). Dronabinol is an orally active endocannabinoid
receptor agonist, which has complex effects on the central nervous system (CNS) and other
organs. Dronabinol is an FDA-approved medication for the treatment of nausea and vomiting
induced by chemotherapy or related to human immunodeficiency virus (HIV) infection. We
reasoned that dronabinol could have a similar antiemetic effect in patients with FD.
Our aim is to conduct a pilot trial to assess the safety, tolerability and efficacy of
dronabinol for the treatment of nausea in patients with FD. The pilot trial will recruit 25 patients
with FD who complain of severe nausea that affects their quality of life. The trial will be divided
into two consecutive, but independent parts. Part 1, will address the safety and tolerability of
dronabinol in patients with FD using an open-label dose titration phase followed by 4-weeks of
open-label treatment. Part 2 will address the efficacy of dronabinol for the treatment of nausea
in patients with FD using a randomized, placebo controlled, double blind, 12-week cross over
design.
We hope to demonstrate that dronabinol is a safe, well-tolerated drug that blocks the
peripheral formation of dopamine and thus prevents dopamine-induced nausea and vomiting
attacks in patients with FD. If dronabinol results to be effective in patients with familial
dysautonomia, it may also be potentially useful in patients with other types of autonomic
dysfunction or other rare diseases in Colorado and the rest of the world.
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DESCRIPTION OF KEY PERSONNEL
Principal Investigator:
 Horacio Kaufmann, MD FAAN
Dr. Kaufmann is Professor of Neurology, Medicine and Pediatrics and the director of the
Dysautonomia Center at New York University. His research and clinical activities are dedicated
to the study and treatment of patients with disorders of the autonomic nervous system, a subject
that has been the focus of his research and academic career over the last 25 years. He has
extensive experience as the PI of national and international clinical trials for the treatment of
autonomic disorders. His research work in hereditary sensory and autonomic neuropathies (type
III, i.e., familial dysautonomia) has involved determining autonomic responses to stress and
arousal. Dr. Kaufmann has successfully completed clinical trials to devising appropriate
pharmacological strategies to blunt emotionally induced catecholamine release and prevent
hypertensive crises in patients with afferent baroreflex failure. His experience and expertise and
the patient population we care for will allow us to accomplish the aims of this project.
Sub-investigators:
 Jose-Alberto Palma, MD PhD
Dr. Palma received his medical degree from the University of Navarra, Spain. He completed
his residency training in neurology at the University Clinic of Navarra. In July 2013, he joined
the NYU Dysautonomia Center. Since then, he has been treating patients suffering from familial
dysautonomia and other autonomic disorders. His work over the past years has focused on the
autonomic dysfunction, and the cardiac autonomic impairment that occurs in neurodegenerative
disorders. He have a demonstrated record of accomplished and productive research in an area of
increasing relevance (autonomic dysfunction in sleep and neurodegenerative disorders), and his
education in this field have prepared him to be involved on this proposed project.
 Lucy Norcliffe-Kaufmann, PhD
Dr. Norcliffe-Kaufmann has a background in cardiovascular physiology with a focus on
neural regulation of autonomic control. She has 10 years experience in using neurophysiological
techniques to define the role of the autonomic nervous system in different diseases. After
completing a Post-Doctoral Fellowship at New York University (NYU) School of Medicine with
Professor Horacio Kaufmann, she joined the faculty in the Department of Physiology and
Neuroscience. Her research work described enhanced vascular responsiveness to hypocapnia
makes certain people more prone to fainting than others. Her most recent work has focused on
the autonomic phenotype of familial dysautonomia, an extremely rare fatal autosomal recessive
hereditary disorder. I have been involved in several clinical trials in familial dysautonomia. She
is the Associate Director of the Dysautonomia Research Laboratory. She is currently involved in
an R01 project on heart failure a multi-center U54 consortium grant to study rare autonomic
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disorders, both of which were funded by the NIH. My specific role in this project will focus on
implementing, collecting and analyzing autonomic research data.
Clinical Research Coordinator:
 Jose Martinez, MS
Mr. Martinez has over 15-years experience in managing clinical research trials and conducting
studies on a variety of different patient populations (psychiatric, genetic and neurological
disorders). he was the Senior Clinical Research Manager in the Department of Psychiatry at
Mount Sinai School of Medicine for 7 years prior to joining Dr. Kaufmann at the Dysautonomia
Center NYU 6-years ago. He has 6 years of experience working with familial Dysautonomia
patient including managing clinical trials with this population. He has expertise in collecting,
managing and analyzing physiological data similar to that proposed in this project and have
published several peer reviewed articles.
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RESEARCH PLAN
A. BACKGROUND AND SIGNIFICANCE
1. Specific aims
Patients with familial dysautonomia (FD), also called Riley Day syndrome or hereditary sensory
and autonomic neuropathy type III, suffer recurrent attacks of uncontrollable nausea and
vomiting that can last several hours or days and are severely disabling. Hypertension,
tachycardia and skin blotching frequently accompany these attacks. Our long-term objective is to
develop an effective treatment for nausea and vomiting in patients with FD. Dronabinol is an
orally active synthetic nonselective endocannabinoid receptor agonist, which has complex effects
on the central nervous system (CNS) and other organs. Dronabinol was superior to placebo to
prevent chemotherapy-induced nausea and vomiting in patients with different types of cancer
and in patients with HIV, which led to its approval by the Food and Drug Administration (FDA).
The antiemetic effects of dronabinol are mediated by its action on CB1 and CB2 receptors.
CB1 receptors are concentrated in the central nervous system, particularly in the dorsal vagal
complex. The dorsal vagal complex includes the central vomiting center, which comprises the
area postrema (chemoreceptor trigger zone), the dorsal motor nucleus of the vagus, and the
nucleus of the tractus solitarius. Dronabinol exerts a direct antiemetic effect by inhibiting dorsal
vagal complex activity. Peripherally, CB1 receptors are also concentrated in the myenteric and
submucosal plexuses of the gut. Dronabinol inhibits substance P release, which ultimately
decreases activation of emetogenic neurokinin-1 receptors. In addition, dronabinol seems to
inhibit reverse peristalsis through a direct effect on the myenteric and submucosal plexuses.
Although dronabinol has been used for many years in patients with cancer and HIV, it has never
been used in patients with FD. The first specific aim of this proposal is to assess the safety and
tolerability of dronabinol in patients with FD. The second specific aim of this proposal is to
determine whether stimulation of endocannabinoid receptors with dronabinol will improve
recurrent nausea in patients with FD. Secondary aims are to determine whether stimulation of
endocannabinoid receptors with dronabinol will increase weight, and decrease anxiety.
Primary outcome measures:

Number of adverse effects.

Change in nausea scores.
Secondary outcome measures:

Change in weight.

Change in anxiety scores.
2. Background
Familial dysautonomia (FD) is a rare autosomal recessive disease caused by a mutation in the
long arm of chromosome 9 (q11)[1,2]. There are currently less than 600 patients with FD
worldwide. The autonomic phenotype of FD is unlike other degenerative disorders of the
autonomic nervous system. In Conrad Riley and Richard Day’s original description of FD[3], all
5 children suffered severe episodic vomiting attacks. Aspiration of vomitus is often listed as a
cause of death in autopsy reports of FD patients[4]. The danger of aspiration during vomiting has
been reduced with fundoplication, a surgical procedure that prevents gastroesophageal reflux. In
patients with fundoplication, vomiting is replaced by retching but the attacks of nausea occur as
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frequently. Episodes of nausea can be so frequent and severe that they interfere with daily life.
Dehydration from prolonged vomiting is a frequent cause of emergency room visits and
withdrawal from school. It may also result in agoraphobia. Current treatment of nausea in FD
involves benzodiazepines and clonidine, which are not always effective and leave the patient
extremely sedated and frequently severely hypotensive. Recently, treatment with carbidopa has
been reported to reduce hyperdopaminergic-vomiting crises [5], but some patients do not
respond to it. Therefore, treating nausea effectively and without excessive sedation would be a
major breakthrough for these patients that would markedly improve their quality of life and is
therefore the major long-term objective of this proposal. Dronabinol is an orally active synthetic
nonselective endocannabinoid receptor agonist, which, as other cannabinoids, has complex
effects on the central nervous system (CNS) and other organs[6]. In trials performed several
decades ago, dronabinol was superior to placebo to prevent chemotherapy-induced nausea and
vomiting in patients with different types of cancer, which led to its approval by the Food and
Drug Administration in 1985. Subsequently, the use of dronabinol as an appetite stimulant in
cancer and AIDS patients experiencing excessive weight loss was also approved[7].
Endocannabinoid system and symptoms relieved by treatment with cannabinoids: The
cannabinoid receptor 1 (CB1) was first identified in 1990[8]. It is expressed mainly in the brain,
but also in number of peripheral tissues, including the gastrointestinal tract[9]. A second
cannabinoid receptor, CB2, is expressed primarily in the cells of the immune and hematopoietic
systems[10], but also in brain[11] and liver[12], and bone[13]. Both CB1 and CB2 receptors are
G protein-coupled receptors; dronabinol has similar affinity for both[14].
Increases in appetite and weight are among some of the well-known effects of cannabis since
antiquity. After the discovery of the cannabinoid receptors and the introduction of selective
antagonists, the increase in food intake was linked to the CB1 receptor, but not to the CB2[15].
Also, CB1 receptor-deficient mice ate less than normal mice[16]. A double blind, placebo
controlled 6-week study involving 139 patients showed that smoked or ingested cannabis
improves appetite and leads to weight gain and improved mood and quality of life among
patients with AIDS[17]. Dronabinol seems to provide small, but significant, orexigenic effects in
patients with severe anorexia nervosa[18]. Suppression of nausea, retching and vomiting is
another well-known effect of THC. In fact, THC is often effective in cases resistant to other,
more conventional, medications[19,20]. A meta-analysis of 30 randomized comparisons of
cannabis (nabilone, dronabinol or levonantradol) with placebo or standard antiemetics involving
a total of 1366 patients concluded that cannabinoids are more effective than conventional
antiemetics, and patients prefer them because of their mood enhancing and relaxing effects[21].
Paradoxically, chronic marijuana use has been associated with vomiting crises, probably as a
result of desensitization of cannabinoid receptors[22].
Selection of dronabinol dose: Dronabinol ((6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3pentyl-6H-dibenzo[b,d]pyran-1-ol) is a synthetic delta-9-tetrahydrocannabinol and also a
naturally occurring component of Cannabis sativa L. (Marijuana). Dronabinol is light yellow
resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is
insoluble in water and is formulated in sesame oil. Dronabinol treatment of chemotherapyinduced nausea was evaluated in 454 patients with cancer. Dronabinol dosages ranged from 2.5
mg/day to 40 mg/day administered in equally divided doses every 4-6 hours. Escalating the
dronabinol dose above 7 mg/m2 increased the frequency of adverse effects, with no additional
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antiemetic benefit. The pharmacologic effects of dronabinol are dose-related and subject to
considerable interpatient variability. Therefore, dosage individualization is critical in achieving
the maximum clinical benefit. Regarding its antiemetic activity, most adult patients respond to 5
mg three times/day (15 mg/day). Dosage may be escalated based upon initial results. Therapy
should be initiated at the lowest recommended dosage (5 mg/day) and titrated to clinical
response. The pharmacologic effects of dronabinol are reversible upon treatment cessation. The
pediatric dosage for the treatment of nausea is the same as in adults. Because of the large
interindividual dose variation with dronabinol, a 4-week titration period will be used in this trial,
during which doses will be adjusted to an appropriate level for each participant according to
bodyweight and adverse events. Once the optimized dose has been identified, patients will
undergo a 3(+1)-week washout period. Then, after the washout period, they will enter a 12-week
double-blind treatment period on their individualized dose of study medication.
3. Plans to submit a manuscript of research findings
Once the clinical trial is concluded and the statistical analyses are performed, we will present the
data in international meetings on autonomic and neurological disorders. We will also prepare a
manuscript to be submitted to a high impact journal. This has been the usual procedure in our
Center, whose personnel has a documented and prolific history of scientific publication,
including clinical trials.
4. References
1. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, et al. (2001) Tissue-specific expression of a splicing
mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68: 598-605.
2. Anderson SL, Coli R, Daly IW, Kichula EA, Rork MJ, et al. (2001) Familial dysautonomia is caused by
mutations of the IKAP gene. Am J Hum Genet 68: 753-758.
3. Riley CM, Day RL, et al. (1949) Central autonomic dysfunction with defective lacrimation; report of five cases.
Pediatrics 3: 468-478.
4. Pearson J, Brandeis L, Goldstein M (1979) Tyrosine hydroxylase immunoreactivity in familial dysautonomia.
Science 206: 71-72.
5. Norcliffe-Kaufmann L, Martinez J, Axelrod F, Kaufmann H (2013) Hyperdopaminergic crises in familial
dysautonomia: a randomized trial of carbidopa. Neurology 80: 1611-1617.
6. Volkow ND, Baler RD, Compton WM, Weiss SR (2014) Adverse health effects of marijuana use. N Engl J Med
370: 2219-2227.
7. Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, et al. (1991) Recent clinical experience with
dronabinol. Pharmacol Biochem Behav 40: 695-700.
8. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and
functional expression of the cloned cDNA. Nature 346: 561-564.
9. Croci T, Manara L, Aureggi G, Guagnini F, Rinaldi-Carmona M, et al. (1998) In vitro functional evidence of
neuronal cannabinoid CB1 receptors in human ileum. Br J Pharmacol 125: 1393-1395.
10. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for
cannabinoids. Nature 365: 61-65.
11. Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, et al. (2006) Discovery of the presence and functional
expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci 1074: 514-536.
12. Julien B, Grenard P, Teixeira-Clerc F, Van Nhieu JT, Li L, et al. (2005) Antifibrogenic role of the cannabinoid
receptor CB2 in the liver. Gastroenterology 128: 742-755.
13. Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, et al. (2006) Peripheral cannabinoid receptor, CB2, regulates
bone mass. Proc Natl Acad Sci U S A 103: 696-701.
14. Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological
strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367: 3353-3363.
15. Williams CM, Kirkham TC (2002) Observational analysis of feeding induced by Delta9-THC and anandamide.
Physiol Behav 76: 241-250.
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16. Wiley JL, Burston JJ, Leggett DC, Alekseeva OO, Razdan RK, et al. (2005) CB1 cannabinoid receptor-mediated
modulation of food intake in mice. Br J Pharmacol 145: 293-300.
17. D'Souza G, Matson PA, Grady CD, Nahvi S, Merenstein D, et al. (2012) Medicinal and recreational marijuana
use among HIV-infected women in the Women's Interagency HIV Study (WIHS) cohort, 1994-2010. J Acquir
Immune Defic Syndr 61: 618-626.
18. Andries A, Frystyk J, Flyvbjerg A, Stoving RK (2014) Dronabinol in severe, enduring anorexia nervosa: a
randomized controlled trial. Int J Eat Disord 47: 18-23.
19. Martin BR, Wiley JL (2004) Mechanism of action of cannabinoids: how it may lead to treatment of cachexia,
emesis, and pain. J Support Oncol 2: 305-314; discussion 314-306.
20. Hall W, Christie M, Currow D (2005) Cannabinoids and cancer: causation, remediation, and palliation. Lancet
Oncol 6: 35-42.
21. Tramer MR, Carroll D, Campbell FA, Reynolds DJ, Moore RA, et al. (2001) Cannabinoids for control of
chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323: 16-21.
22. Allen JH, de Moore GM, Heddle R, Twartz JC (2004) Cannabinoid hyperemesis: cyclical hyperemesis in
association with chronic cannabis abuse. Gut 53: 1566-1570.
23. Goldstein DS, Holmes C, Kaufmann H, Freeman R (2004) Clinical pharmacokinetics of the norepinephrine
precursor L-threo-DOPS in primary chronic autonomic failure. Clin Auton Res 14: 363-368.
B. CAPACITY/PROGRAM INFRASTRUCTURE
The Dysautonomia Center at NYU has the entire necessary infrastructure to perform all the
procedures outlined in this protocol. We have a documented history of accomplished research,
including randomized clinical trials in patients with autonomic disorders, whose results have
been published in high impact journals (Neurology.2013;80:1611-7 and Lancet
Neurol. 2014;13:268-75). The NYU Dysautonomia Center is the global reference center for
patients with Familial Dysautonomia; we currently manage an approximate population of 300
patients with this disorder, in addition to patient with other forms of dysautonomia. We have a
dedicated state of the art laboratory to conduct comprehensive autonomic evaluations, which
includes a tilt table, continuous electrocardiographic and beat-to-beat blood pressure (Finopres
and Finometer) monitoring. All physiological signals are sampled using a computer-based data
acquisiton and analysis system (PowerLab 16SP hardware and LabChart 7 software,
ADInstruments). We have several analysis programs for processing autonomic data, including
using spectral anlaysis software packages, as well as statistical software (Prism/GraphPad and
SPSS) to analyze data. We have a dedicated medical engineering specialist who maintains and
services equipment in the laboratory. We have 6 validated ambulatory blood pressure units with
a dedicated data management program. We have developed patient diaries to record activities,
posture, symptoms, mealtimes, medications and sleep/wake cycles. In addition to the autonomic
laboratory, we also have the necessary equipment to perform complete neurological evaluations.
We routinely perform plasma catecholamines determinations. We have several fully networked,
portable, securely encrypted computers dedicated to analysing, recording and capturing research
data. NYU IT services provides access to RedCap, a secure, web-based application for building
and managing online databases for clinical research trials. This extensive equipment is available
for this proposal.
C. RESEARCH DESIGN AND METHODS
1. Overview
This pilot trial will recruit patients with familial dysautonomia (FD) who complain of severe
nausea and vomiting that affects their quality of life. The trial will be divided into two
consecutive, but independent parts. Part 1 will address the safety and tolerability of dronabinol
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in patients with FD using an open-label dose titration phase. Part 2 will address the efficacy of
dronabinol for the treatment of nausea in patients with FD using a randomized, placebocontrolled, double-blind, 12-week cross-over design.
Figure 1. Study design. This is a 12-week randomized placebo-controlled, double blind, crossover, pilot study
with an initial 4-week dose titration phase.
2. Plans to obtain authorizations
Institutional Review Board: Under review (submitted August 2014)
FDA Investigational New Drug Application: Under review (submitted October 2014)
DEA authorization: Dr. Horacio Kaufmann is a DEA-authorized physician,
3. Subjects and procedures
A sufficient number of subjects will be screened and randomized to allow 25 patients to receive
at least one dose of double-blind study medication Patients with familial dysautonomia, between
the ages of 16 and 60, who are registered at the Dysautonomia Center and complain of severe
nausea and/or vomiting will be recruited to participate in this trial.
Inclusion criteria
1.
Male or female patients aged 16-60.
2.
Confirmed diagnosis of familial dysautonomia by genetic testing.
3.
Symptoms of severe nausea.
4.
Written informed consent or ascent to participate in the pilot trial and understanding that
they can withdraw consent or accent at anytime without affecting their future care.
5.
Ability to comply with the requirements of the study procedures, including taking blood
pressure measurements at home.
Exclusion criteria
1.
Patients with a history of hypersensitivity to any cannabinoid or sesame oil.
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2.
Cannabinoid use in the previous 4 weeks (a urinary cannabinoid test will be performed
before study entry).
3.
Patients with a history of substance abuse, including alcohol abuse or dependence, or
marijuana.
4.
Seizure disorder with at least one epileptic seizure in the last 10 years.
5.
Patients with history of psychiatric disorders, including mania, depression or
schizophrenia.
6.
Patients that require driving, operating machinery, or engaging in hazardous activities.
7.
Patients taking carbidopa or any other medications though, in the investigator’s opinion,
to be unsafe when used with dronabinol.
8.
Patients with cognitive impairment or pervasive developmental disorders, or patients who
are unable to clearly identify and rate their symptoms of nausea.
9.
Women who are pregnant or lactating.
10.
Patients who have a significant abnormality on clinical examination that may, in the
investigator’s opinion, jeopardize their health by participating in this pilot trial.
4. Recruitment
Patients with FD will be recruited from those that we are currently following at the
Dysautonomia Center. The Center currently follows 338 patients with familial dysautonomia.
Patients will be enrolled into the study after discussing and signing informed consent (currently
under review by New York University Institutional Review Board). The subject and families will
be given time to read the consent form and raise questions: if satisfied by the responses will be
asked to sign consent or ascent (depending on the age of the participant) before entering the
study. The original signed form will be kept within the study files, and the patient and family
will be given a copy. We plan to enroll a total of 25 patients. Patients with familial dysautonomia
are seen at frequent intervals at the Center. We expect that we would be able to enroll 1-2
patients a month. In 30 months we will be able to complete the trial and analysis of the data.
Children above the age of 16 are eligible to participate in this trial providing that signed
permission from both parents (or a guardian with legal responsibility for the care and custody of
the child) is obtained and that all children are capable of signing their own assent.
5. Procedures, interventions, randomizations, and measurements at each visit
Part 1
Screening (Visit 1)
Patients with FD who complain of severe nausea will be screened and enrolled (Visit 1) into Part
1 of the pilot trial. Assessments to be conducted by the investigator will include:

Assignment of patient identification number

Administration of informed consent

Review of inclusion and exclusion criteria

Demographics and medical history

Review of concomitants medications

Physical and neurological examinations

Nausea scores

Addiction research center inventory (ARCI) score

Anxiety scores (STAI-I and STAI-T)

Pregnancy test (if applicable)
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








Vital signs (temperature, RR), weight and height
Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing
Blood samples for hematology and biochemistry
Urinalysis
Marijuana metabolites in urine
12-lead electrocardiogram
24-hour urinary catecholamine excretion
24-hour blood pressure monitor
Plasma catecholamine levels after 10-min supine.
The investigator will review the screening laboratory test results and EKG reports prior to Visit
2. Screening assessments may be performed up to 14 days before Visit 2.
Dose titration (Visit 2)
The dose-titration period should be initiated within a maximum of 15 days from the date of the
screening visit (Visit 1).
At the beginning of the open-label titration visit the investigator will conduct the following
procedures:

Review of concomitant medication

Vital signs (temperature, RR), and weight.

Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing
Then, a dose of dronabinol will be administered. Dose titration will begin with an initial
dronabinol dose of 2.5 mg twice a day. Patients will be administered the first dose of open-label
dronabinol on site at the beginning of the visit, preferably in the morning (around 9 am). The
patient should remain on site to monitor the effects of the medication. Then, after 2 hours after
dose administration the following procedures should be performed:

Review of adverse effects

Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing.

ARCI score
If there are no adverse effects or these are mild, the patient will be discharged with a bottle of 2.5
mg dronabinol capsules and will be instructed to increase the medication dose as follows:
Table 1. Number of capsules to be prescribed according to weight of participants at baseline
< 60 kg
> 60 kg
Days 1-5
Days 6-10
Days 11-15
Days 16-20
1 twice a day
(5 mg/day)
1 twice a day
(5 mg/day)
2 twice a day
(10 mg/day)
2 twice a day
(10 mg/day)
3 twice a day
(15 mg/day)
3 twice a day
(15 mg/day)
4 twice a day
(20 mg/day)
4 twice a day
(20 mg/day)
From day 21 until the
end of the open-label
phase
4 twice a day
(20 mg/day)
4 three times a day
(30 mg/day)
If the patient has intolerable side effects at dose tested, the patient will return to the lower dose
level with which they were previously treated, if applicable and should remain at that dose until
the end of the open label dose titration (Visit 3).
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Safety assessment (Visit 3)
Patients will return to the Center 2 weeks after having started the titration for a safety
assessment. The following procedures will be conducted:

Review of adverse effects

Vital signs (temperature, RR), and weight

Blood samples for hematology and biochemistry

12-lead EKG

Urinalysis

Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing

ARCI score
If there are no adverse effects, patients will continue until the end of the open-label treatment
(Visit 4), increasing the medication dose as described.
End of titration phase (Visit 4)
After completing the 4-week titration phase, patients will be seen at the Center to monitor safety
parameters and to obtain open-label efficacy measures. The following parameters will be
assessed:

Review of concomitant medications

Review of AEs

Physical and neurological examinations

Nausea scores

ARCI score

STAI questionnaire

Vital signs (temperature, RR) and weight

Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing

Blood samples for hematology and biochemistry

Urinalysis

12-lead electrocardiogram

Plasma catecholamine levels after 10-min supine

24-hour catecholamines in urine

24-hour blood pressure monitor
Before proceeding to Part 2 of the trial (placebo-controlled double-blind cross over phase) there
will be a complete review of safety data from Part 1.
Part 2
Once Part 1 is completed, study medication will be withdrawn and the patient will begin a
washout period from the study drug for a period of at least 21 days (but no more than 28 weeks)
to ensure appropriate elimination of dronabinol and its metabolites.
Randomization (Visit 5)
After the washout period, patients will return to the Center for the randomization visit. Patients
will be randomized in a double-blind fashion, to receive either dronabinol or matching placebo.
The same assessments performed in Visit 4 will be conducted prior to randomization. Subjects
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randomized to receive placebo will receive an identical capsule. To prevent un-blinding because
of observed efficacy, adverse events or changes in nausea scores, the Center will have a
designated treating investigator and an examining investigator. The treating investigator will
assess the patient’s clinical response and laboratory findings of safety parameters and make all
clinical treatment decisions. He or she will have the capacity to remove any patient from the
study at anytime for safety concerns. The examining investigators will monitor the nausea
severity and improvement scales, the ARCI scores, the BP results, and catecholamine levels in
urine and plasma. Approximately equal numbers of patients will be randomized to receiving
dronabinol or placebo. We will use a permuted block randomization scheme to assign patients to
placebo or dronabinol. Sealed number randomization envelopes will be kept by the
investigational pharmacy at NYU School of Medicine (NYUSoM). The randomization envelope
will be opened and the patient’s treatment will be recorded in the study database.
Patients will be dispensed their initial bottle of study medication (dronabinol or matching
placebo capsules) and they will have to take their first dose at the Center. Then, 2 hours after
dose administration the following procedures should be performed:

Blood pressure and heart rate, after 5-min supine, sitting, and after 3-min standing.

Review of adverse effects

ARCI score
If there are no adverse effects, patients will be reminded on how to take their study medication
until the next visit (visit 6), which will be scheduled 4 weeks later.
End of first part of double blind (Visit 6)
During visit 5, patients will undergo the same procedures outlined in Visit 4. At the end of Visit
6, study medication will be withdrawn and the patient will begin a washout period from study the
drug for a period of at least 3 weeks (but no more than 4 weeks) to ensure appropriate
elimination of dronabinol and its metabolites.
Cross-over visit (Visit 7)
At the beginning of visit 6, patients will undergo the same procedures outlined in Visit 5. Then,
patients will be crossed over to the opposite arm of the study (i.e., patients that received
dronabinol will be given placebo, and patients that received placebo will be given dronabinol)
Then, 2 hours after dose administration, the following procedures should be performed:

Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing.

Review of adverse effects

ARCI score
If there are no adverse effects, patients will be reminded on how to take their study medication
until the next visit (visit 8), which will be scheduled 4 weeks later.
End of study visit (Visit 8)
Patients will return to the Center for an End of Study visit (visit 8). The same assessment that in
Visit 5 will be conducted:
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Safety follow-up (visit 9)
Patients will be contacted 2 weeks after the End of Study (Visit 7 or early termination) to follow
up on and record any AEs that were ongoing at the end of their previous visit. If performed at the
center, the following procedures will be carried out:

Blood pressure and heart rate, after 10-min supine, sitting, and after 3-min standing.

Review of adverse effects

Blood samples for hematology and biochemistry

Urine sample for urinalysis
The follow-up visit may be conducted without an on-site visit; however a response from the
patient should be obtained. This response may be obtained by a phone call with the patient and
appropriately documented in the source notes. In the event that the patient is unreachable by
phone, all reasonable efforts should be made and documented before considering the patient lost
to follow-up.
Early termination/Unscheduled visit
If at any time during the study a patient requests to withdraw from treatment, they should return
to the Center for an Early Termination Visit. At the early termination visit the same procedures
outlined in Visit 8 will be conducted. A patient may return for an unscheduled visit at any time at
the investigator’s discretion. If at any time during the double-blind treatment period a patient
develops intolerable side effects believed to be related to the study medication, but wishes to
remain in the study, they should return for an unscheduled visit.
6. Statistical considerations:
Sample size and power calculations: The primary outcome will be the number of adverse events
and the secondary efficacy outcome measures will be nausea scores and catecholamine levels. A
sample size of 16 patients will provide 80% power to detect a significant difference in group
means of dronabinol vs. placebo in nausea scores and dopamine levels with a = 0.05 (two-tailed).
Assuming a 10-20% dropout rate from the dose titration and open-label treatment phase, we
predict that the number of patients we need to enroll in the study will be at least 23.
Statistical analysis: Number of adverse events (measure of safety and tolerability) as well as
nausea scores and catecholamine levels (measures of efficacy) will be compared both between
interventions (baseline vs. end of titration vs. randomized trials) and between randomized groups
(dronabinol vs. placebo). This study designs calls for a two-way repeated-measures ANOVA
followed, if significant, by the pairwise multiple comparison procedure with Bonferroni
correction. To address safety and tolerability, analysis of adverse events will be subdivided into
three procedures and conducted separately for the events judged as possibly, probably or
definitely related to the study drug. Parametric procedures will be used whenever possible but
will be substituted with the non-parametric analogs if prerequisites for the parametric tests are
not met. All analyses will be performed using SigmaPlot 11 statistical software (Systat Software,
Inc.). Results with a p= 0.05 shall be considered statistically significant
7. Data and safety monitoring
All necessary safety information will be reported to the FDA in accordance with 312.32 IND
safety reports as outlined in Title 21 Food and Drugs. This study will involve approximately 25
human subjects. All subjects will be age 16 or older, able to give informed consent or assent,
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non-smokers, free of drugs that may affect dopamine transmission, free of clinically significant
pulmonary, renal, hematopoietic, liver and cardiac disease other than familial dysautonomia, as
indicated. Every effort will be made to enroll 50% women. Patients will be selected based on
genetic diagnosis of familial dysautonomia. The research material obtained in this proposal will
be recording data obtained specifically for research purposes. A secure database of patient
information will be maintained.
A. Potential risks: All human studies will be performed by trained personnel in a quiet room,
within the Dysautonomia Center. The monitoring procedures, including 12-lead
electrocardiogram and blood pressure with a sphygmomanometer are non-invasive and should
produce only minor discomfort. Risks associated with peripheral venous blood sampling are
mostly related to pain and bruising on the insertion site and will be explained on the consent
form. Adverse events information has been collected from well-controlled clinical trials
conducted in the US involving 474 patients exposed to dronabinol. Studies of AIDS-related
weight loss included 157 patients receiving dronabunol 2.5 mg BID and 67 receiving placebo.
Studies of different durations were combined by considering the first occurrence of events during
the first 28 days. Studies of nausea and vomiting included 317 patients with cancer receiving
dronabinol and 68 receiving placebo. A cannabinoid dose-related “high” (i.e., easy laughing,
elation, and heightened awareness) was reported in 24% of patient receiving dronabinol as an
antiemetic and in 8% receiving it as appetite stimulant. The most frequently reported AE
experiences in patients taking dronabinol involved the central nervous system in 33% of subjects.
Around 25% of patients reported a minor central nervous system AE during the first 2 weeks and
4% reported such an event each week for the next 6 weeks thereafter.
Drug abuse, dependence and overdosage: Dronabinol is one of the psychoactive compounds
present in cannabis, can be abused, and is controlled under the Controlled Substances Act. Both
psychological and physiological dependence have been noted in healthy individuals receiving
dronabinol, but addiction is uncommon and has only been seen after prolonged high dose
administration. Signs and symptoms following MILD dronabinol intoxication include
drowsiness, euphoria, heightened sensory awareness, altered time perception, red eye, dry mouth
and tachycardia. Those following MODERATE intoxication include memory impairment,
depersonalization, mood alteracion, urinary retention, and constipation. Those following
SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and
orthostatic hypotension. Apprehensive patients may experience panic reactions and seizures may
occur in patients with existing seizure disorders. The estimated lethal dose of IV dronabinol is 30
mg/kg (2100 mg in a 70 kg person). Patients experiencing depressive, hallucinatory or psychotic
reactions will be placed in a quiet are and offered reassurance. Benzondiazepines may be used
for treatment of extreme agitation. Orthostatic hypotension usually responds to supine position
and IV fluids. Anti-hypotensive medications may be also used. A potentially serious oral
ingestion, if recent, will be managed with supportive measures and immediate gastric lavage. In
unconscious patients, the airway will be maintained and activated charcoal (30-100 in adults, 1-2
g/kg in infants) will be administered via a nasogastric tube. Intravenous fluids will be
administered judiciously and an adequate airway maintained. Electrocardiographic monitoring
will be instituted and the patient carefully observed for the development of arrhythmias. If
required, appropriate antiarrhythmic therapy will be given.
16
D. Protection against risks
To minimize any potential risk, a physician and a research nurse will be present and monitor all
procedures involving the administration of medicines. Careful and continuous monitoring of vital
signs, blood chemistries, 12-lead echocardiograms and adverse events will help minimize
potential risks. Confidentiality will be maintained for the identity of participants in this study,
except as necessary for oversight by the Secretary of the Department of Health and Human
Services or his designated representative.
8. Documentation of adverse effects
The principal investigator, together with the treating investigator, will be responsible for
ensuring both data integrity and ensuring that patients who participate in the study will be
properly cared for, and that all adverse events are noted, followed, and reported to the IRB (if
appropriate). The PI and treating investigator will review the records of all study participants
following the participation of each subject to ensure patient safety and integrity. Any adverse
event rated moderate or severe will be immediately reported to the IRB. All adverse events will
be reported to the IRB on an annual basis. All necessary information will be reported to the FDA
in accordance with the guidelines outlined for a treatment IND.
D. LABORATORY TESTING
Catecholamines: Blood samples will be obtained for the measurement of dopamine,
norepinephrine and epinephrine concentrations. A 12-guage catheter with a heparin lock will be
inserted into a peripheral antecubital vein for blood sampling 30 minutes before the sample is
drawn. After at least 10 minutes of supine rest, bloods will be collected, spun and the plasma
separated and stored in a -70°C freezer for future assay. Prior to arriving for a study visit,
patients will be asked to collect a 24-hour urine sample in a bottle without preservative. Patients
will be instructed to refrigerate their sample and bring it on the morning of their visit in a cool
bag. Catecholamines will be measured using high-pressure liquid chromatography as previously
described [23].
Marijuana metabolites in urine: Urine testing, one of the most common screening methods, is
an accurate and reliable way to detect marijuana use that occurred within the past 72 hours.
Urine testing will be performed by Quest Diagnostics at one of their four Substance Abuse and
Mental Health Services Administration (SAMHSA)-certified laboratories. Quest Diagnostics
participates in rigorous laboratory proficiency testing. Their drug testing labs hold and maintain
Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), SAMHSA and CAP
certification as well as applicable New York State licensures.
17