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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 1 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 2 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. 3 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 4 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. 5 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 6 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 7 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. 8 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 9 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. 10 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) 11 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). 12 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 13 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: 14 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, 15 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