Clinical trial NCT04794413: Pimavanserin Treatment in TS
Official title: An Open Label, Proof-of-Principle, Pilot Study to Evaluate Pimavanserin for the Treatment of Motor and Behavioral Symptoms of Tourette Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Tourette Syndrome
Tardive Dyskinesia
Keywords: pimavanserin
Tourette Syndrome
tics
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: Andrew Billnitzer, MD
First posted: 2021-03-12
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is an open-label, proof-of-principle, 8-week treatment, pilot study for male and female patients aged 18 years and older with Tourette Syndrome. There were no control groups nor randomization.
Primary purpose: TREATMENT

Brief summary: This research study is determining if a drug called Pimavanserin if safe and effective in the treatment of the symptoms of Tourette Syndrome. Pimavanserin is an investigational drug for Tourette Syndrome, which means it has not been approved by the United States Food and Drug Administration (FDA) to treat Tourette Syndrome. Pimavanserin has been approved by the FDA as a treatment for hallucinations in Parkinson's Disease. It is currently marketed under the name NUPLAZID (pimavanserin) capsules by Acadia Pharmaceuticals.

Detailed description: Tourette Syndrome is typically treated with drugs that block or reduce the function of dopamine (a brain chemical involved in movement). However, many of these drugs have adverse effects including irreversible, involuntary movements, typically affecting the face, known as tardive dyskinesia. Newer drugs may have lower risk of tardive dyskinesia. However, many of these drugs are still in clinical trials or are very expensive when used off-label (without FDA approval) to treat Tourette Syndrome. Given these limitations, exploring the potential of other drugs is essential in helping patients.

Several studies have shown that serotonin, another chemical in the brain like dopamine, may also play a role in the symptoms of Tourette Syndrome. Serotonin is already the target of many drugs in the treatment of depression, anxiety and obsessive-compulsive disorder which frequently occur in patients with Tourette Syndrome. Pimavanserin is also a drug that works on serotonin system. This means it may be helpful in the treatment of Tourette Syndrome.

Eligibility criteria: Inclusion Criteria:

* Patients 18 years of age or older
* Patients meet the Diagnostic and Statistical Manuel of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for TS and, in the opinion of the investigator and patient, the patient's active tics are causing distress or impairment.
* Patient has a TTS of 20 or higher on the YGTSS at screening and baseline.
* Patient can swallow study medical whole.
* Patient is willing to adhere to the medication regimen and to comply with all study procedures.
* Patient is in good general health, as indicated by the medical and psychiatric history as well as physical and neurological examination.
* In the investigator's opinion, the patient has the ability to understand the nature of the study and its procedures, and the patient is expected to complete the study as designed.
* Patient has provided written informed consent according to local regulations.
* Females who are postmenarchal or greater than 12 years of age may be included if they have a negative urine pregnancy test at baseline or are sterile.
* Females who are postmenarchal or great than 12 years of age who male partners are potentially fertile (i.e. no vasectomy) must use highly effective birth control methods for the duration of the study (i.e. starting at screening) and for 30 days or 5 half-lives, whichever is longer after last dose of pimavanserin. The patient must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow-up evaluation as specified in this protocol.

Exclusion Criteria:

* Patient has a neurological disorder other than TS that could obscure the evaluation of tics.
* The patient's predominant movement disorder is stereotypy (coordinated movements that repeat continually and identically) associated with autism spectrum disorder.
* Patient has a confirmed diagnosis of bipolar disorder, schizophrenia, or another psychotic disorder.
* Patient has a DSM diagnosis at screening that, in the opinion of the investigator, makes the patient unsuitable for the study.
* Patient has received Comprehensive Behavioral Intervention for Tics for TS or Cognitive Behavioral Therapy for OCD within 4 weeks of screening.
* Patient has received treatment with deep brain stimulation, transmagnetic stimulation, or transcranial direct current stimulation within 4 weeks of the screening visit for reduction of tics.
* Stroke or other uncontrolled serious medical illness such as myocardial infarction within 6 months of baseline.
* Patient with unknown QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotics medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin, moxifloxacin).
* Patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.
* Patient has evidence of hepatic impairment.
* Patient has a known allergy to any of the components of pimavanserin.
* Patient has participated in an investigational drug or device study and received intervention within 30 days or 5 drug half-lives of baseline, whichever is longer.
* Patient is a pregnant or lactating female, or plans to be pregnant during the study.
* Patient has a history of or acknowledges alcohol-related disorder in the previous 12 months, as defined in the DSM-5.
* Patient has a positive urine drug screen test result or is unable to refrain from substance abuse throughout the study.

Primary outcomes:
measure: Evaluate the effect of pimavanserin on Tourette Syndrome
timeFrame: 10 weeks
Secondary outcomes:
measure: Evaluate the effect of pimavanserin on Tourette Syndrome
timeFrame: 10 weeks
measure: Evaluate the effect of pimavanserin on Tourette Syndrome
timeFrame: 10 weeks
measure: Evaluate the effect of pimavanserin on Tourette Syndrome
timeFrame: 10 weeks
measure: Evaluate the effect of pimavanserin on Tourette Syndrome
timeFrame: 10 weeks
measure: Evaluate the effect of pimavanserin on Tourette Syndrome
timeFrame: 10 weeks
Other outcomes:
Locations:
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
References:
citation: Jankovic J, Kurlan R. Tourette syndrome: evolving concepts. Mov Disord. 2011 May;26(6):1149-56. doi: 10.1002/mds.23618. Epub 2011 Apr 11.
citation: Thenganatt MA, Jankovic J. Recent Advances in Understanding and Managing Tourette Syndrome. F1000Res. 2016 Feb 9;5:F1000 Faculty Rev-152. doi: 10.12688/f1000research.7424.1. eCollection 2016.
citation: Billnitzer A, Jankovic J. Current Management of Tics and Tourette Syndrome: Behavioral, Pharmacologic, and Surgical Treatments. Neurotherapeutics. 2020 Oct;17(4):1681-1693. doi: 10.1007/s13311-020-00914-6.
citation: Robertson MM, Eapen V, Singer HS, Martino D, Scharf JM, Paschou P, Roessner V, Woods DW, Hariz M, Mathews CA, Crncec R, Leckman JF. Gilles de la Tourette syndrome. Nat Rev Dis Primers. 2017 Feb 2;3:16097. doi: 10.1038/nrdp.2016.97.
citation: Paschou P, Fernandez TV, Sharp F, Heiman GA, Hoekstra PJ. Genetic susceptibility and neurotransmitters in Tourette syndrome. Int Rev Neurobiol. 2013;112:155-77. doi: 10.1016/B978-0-12-411546-0.00006-8.
citation: Udvardi PT, Nespoli E, Rizzo F, Hengerer B, Ludolph AG. Nondopaminergic neurotransmission in the pathophysiology of Tourette syndrome. Int Rev Neurobiol. 2013;112:95-130. doi: 10.1016/B978-0-12-411546-0.00004-4.
citation: Forde NJ, Kanaan AS, Widomska J, Padmanabhuni SS, Nespoli E, Alexander J, Rodriguez Arranz JI, Fan S, Houssari R, Nawaz MS, Rizzo F, Pagliaroli L, Zilhao NR, Aranyi T, Barta C, Boeckers TM, Boomsma DI, Buisman WR, Buitelaar JK, Cath D, Dietrich A, Driessen N, Drineas P, Dunlap M, Gerasch S, Glennon J, Hengerer B, van den Heuvel OA, Jespersgaard C, Moller HE, Muller-Vahl KR, Openneer TJ, Poelmans G, Pouwels PJ, Scharf JM, Stefansson H, Tumer Z, Veltman DJ, van der Werf YD, Hoekstra PJ, Ludolph A, Paschou P. TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome. Front Neurosci. 2016 Aug 23;10:384. doi: 10.3389/fnins.2016.00384. eCollection 2016.
citation: Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J, Cohen DJ. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry. 1989 Jul;28(4):566-73. doi: 10.1097/00004583-198907000-00015.
citation: Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989 Nov;46(11):1006-11. doi: 10.1001/archpsyc.1989.01810110048007.
citation: Cavanna AE, Schrag A, Morley D, Orth M, Robertson MM, Joyce E, Critchley HD, Selai C. The Gilles de la Tourette syndrome-quality of life scale (GTS-QOL): development and validation. Neurology. 2008 Oct 28;71(18):1410-6. doi: 10.1212/01.wnl.0000327890.02893.61.
citation: Jeon S, Walkup JT, Woods DW, Peterson A, Piacentini J, Wilhelm S, Katsovich L, McGuire JF, Dziura J, Scahill L. Detecting a clinically meaningful change in tic severity in Tourette syndrome: a comparison of three methods. Contemp Clin Trials. 2013 Nov;36(2):414-20. doi: 10.1016/j.cct.2013.08.012. Epub 2013 Aug 31.
citation: Rothenberger A, Roessner V. Psychopharmacotherapy of Obsessive-Compulsive Symptoms within the Framework of Tourette Syndrome. Curr Neuropharmacol. 2019;17(8):703-709. doi: 10.2174/1570159X16666180828095131.
citation: McDougle CJ, Goodman WK, Leckman JF, Barr LC, Heninger GR, Price LH. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. J Clin Psychopharmacol. 1993 Oct;13(5):354-8.
citation: Leckman JF, Goodman WK, Anderson GM, Riddle MA, Chappell PB, McSwiggan-Hardin MT, McDougle CJ, Scahill LD, Ort SI, Pauls DL, et al. Cerebrospinal fluid biogenic amines in obsessive compulsive disorder, Tourette's syndrome, and healthy controls. Neuropsychopharmacology. 1995 Feb;12(1):73-86. doi: 10.1038/sj.npp.1380241.
citation: Comings DE. Blood serotonin and tryptophan in Tourette syndrome. Am J Med Genet. 1990 Aug;36(4):418-30. doi: 10.1002/ajmg.1320360410.
citation: Cath DC, Spinhoven P, Landman AD, van Kempen GM. Psychopathology and personality characteristics in relation to blood serotonin in Tourette's syndrome and obsessive-compulsive disorder. J Psychopharmacol. 2001 Jun;15(2):111-9. doi: 10.1177/026988110101500208.
citation: Higgins GA, Enderlin M, Haman M, Fletcher PJ. The 5-HT2A receptor antagonist M100,907 attenuates motor and 'impulsive-type' behaviours produced by NMDA receptor antagonism. Psychopharmacology (Berl). 2003 Nov;170(3):309-319. doi: 10.1007/s00213-003-1549-0. Epub 2003 Aug 7.
citation: Wong DF, Brasic JR, Singer HS, Schretlen DJ, Kuwabara H, Zhou Y, Nandi A, Maris MA, Alexander M, Ye W, Rousset O, Kumar A, Szabo Z, Gjedde A, Grace AA. Mechanisms of dopaminergic and serotonergic neurotransmission in Tourette syndrome: clues from an in vivo neurochemistry study with PET. Neuropsychopharmacology. 2008 May;33(6):1239-51. doi: 10.1038/sj.npp.1301528. Epub 2007 Nov 7.
citation: Haugbol S, Pinborg LH, Regeur L, Hansen ES, Bolwig TG, Nielsen FA, Svarer C, Skovgaard LT, Knudsen GM. Cerebral 5-HT2A receptor binding is increased in patients with Tourette's syndrome. Int J Neuropsychopharmacol. 2007 Apr;10(2):245-52. doi: 10.1017/S1461145706006559. Epub 2006 Feb 28.
citation: Steeves TD, Fox SH. Neurobiological basis of serotonin-dopamine antagonists in the treatment of Gilles de la Tourette syndrome. Prog Brain Res. 2008;172:495-513. doi: 10.1016/S0079-6123(08)00924-2.
citation: McCracken JT, Suddath R, Chang S, Thakur S, Piacentini J. Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette syndrome. J Child Adolesc Psychopharmacol. 2008 Oct;18(5):501-8. doi: 10.1089/cap.2007.135.
citation: Weisman H, Qureshi IA, Leckman JF, Scahill L, Bloch MH. Systematic review: pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2 adrenergic agonist agents. Neurosci Biobehav Rev. 2013 Jul;37(6):1162-71. doi: 10.1016/j.neubiorev.2012.09.008. Epub 2012 Oct 23.
citation: Porta M, Sassi M, Cavallazzi M, Fornari M, Brambilla A, Servello D. Tourette's syndrome and role of tetrabenazine: review and personal experience. Clin Drug Investig. 2008;28(7):443-59. doi: 10.2165/00044011-200828070-00006.
citation: Jankovic J, Jimenez-Shahed J, Budman C, Coffey B, Murphy T, Shprecher D, Stamler D. Deutetrabenazine in Tics Associated with Tourette Syndrome. Tremor Other Hyperkinet Mov (N Y). 2016 Nov 7;6:422. doi: 10.7916/D8M32W3H. eCollection 2016.
citation: Bonnier C, Nassogne MC, Evrard P. Ketanserin treatment of Tourette's syndrome in children. Am J Psychiatry. 1999 Jul;156(7):1122-3. doi: 10.1176/ajp.156.7.1122a. No abstract available.