Nilotinib in Huntington's Disease

Status unconfirmed · Phase 1

Conditions studied: Huntington Disease

In brief

Based on strong pre-clinical evidence of the effects of Nilotinib on neurodegenerative pathologies, including autophagic clearance of neurotoxic proteins, neurotransmitters (dopamine and glutamate), immunity and behavior, the investigators conducted an open label pilot clinical trial in mid-to-advanced PD with dementia (PDD) and Dementia with Lewy Bodies (DLB) (stage 3-4) patients. Participants (N=12) were randomized 1:1 to once daily oral dose of 150mg and 300mg Nilotinib for 6 months. The investigators data suggests that Nilotinib penetrates the brain and inhibits CSF Abelson (Abl) activity via reduction of phosphorylated Abl in agreement with pre-clinical data. Several studies suggest that CSF alpha-Synuclein and Abeta42 are decreased and CSF total Tau and p-Tau are increased in PD and DLB. The investigators data shows attenuation of loss of CSF alpha-Synuclein and Abeta40/42 with 300mg (50% of the CML dose) compared to 150mg Nilotinib after 6 months treatment. CSF homovanillic acid (HVA), which is a by-product of dopamine metabolism, is significantly increased; and CSF total Tau and p-Tau are significantly reduced (N=5, P\<0.05) with 300mg Nilotinib between baseline and 6 months treatment. Despite the reduction of L-Dopa replacement therapies in our study, the Unified Parkinson's Disease Rating Scale (UDPRS) I-IV scores improved with 150mg (3.5 points) and 300mg (11 points) from baseline to 6 months and worsened (13.7 points and 11.4 points) after 3 months withdrawal of 150mg and 300mg, respectively. Other non-motor functions e.g. constipation was resolved in all patients and cognition was also improved (3.5 points) using both the Mini-Mental Status Exam (MMSE) or the Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog) between baseline and 6 months. MMSE scores returned to baseline after 3 months of Nilotinib withdrawal. These data are very compelling to evaluate the effects of Nilotinib in an open label proof-of-concept study in patients with HD.

Key facts

Study ID: NCT03764215
Run by: Georgetown University
People needed: 10
Starts: 2018-11-15
Expected to finish: 2020-11-30
Last updated by the study team: 2020-02-20

Who can join

Age: 25 and older, up to 90. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

Written informed consent
Capable of providing informed consent and complying with study procedures. Subjects who are unable to provide consent may use a Legally Authorized Representative (LAR).
Patients between the age of 25-90 years, medically stable
Clinical diagnosis of HD with either a confirmed family history or positive CAG repeat (CAG≥35)
MoCA ≥ 22
Able to perform the TMT-B in ≤240 seconds
Total Functional Capacity 7-12
Stable concomitant medical and/or psychiatric illnesses, in the judgement of the PI.
QTc interval 350-460 ms, inclusive
Participants must be willing to undergo LP at baseline and 3 months after treatment

You may not qualify if…

Patients with hypokalemia, hypomagnesaemia, or long QT syndrome- QTc≥461 ms
Concomitant drugs known to prolong the QTc interval and history of any cardiovascular disease, including myocardial infarction or cardiac failure, angina, arrhythmia
History or presence of cardiac conditions including:
Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke)
Congestive heart failure
First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances
Any history of Torsade de Pointes
Treatment with any of the following drugs at the time of screening or the preceding 30 days, and/or planned use over the course of the trial:
Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine)
Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, Trazodone, etc.)
Strong CYP3A4 inhibitors (including grapefruit juice). The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) must be avoided. Grapefruit products may also increase serum concentrations of Nilotinib. Should treatment with any of these agents be required, therapy with Nilotinib should be interrupted.
Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin, xarelto, etc.
St. John's Wort and the concomitant use of strong other CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) must be avoided since these agents may reduce the concentration of Nilotinib.
Abnormal liver function defined as AST and/or ALT > 100% the upper limit of the normal
Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal
History of HIV, clinically significant chronic hepatitis, or other active infection
Females must not be lactating, pregnant or with possible pregnancy
Medical history of liver or pancreatic disease
Clinical signs indicating syndromes other than idiopathic PD, including corticobasal degeneration, supranuclear gaze palsy, multiple system atrophy, chronic traumatic encephalopathy, signs of frontal dementia, history of stroke, head injury or encephalitis, cerebellar signs, early severe autonomic involvement, Babinski sign
.Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or DSM-IV criteria for any active major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse
Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving an investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, gastrointestinal, endocrine, metabolic, renal or other systemic disease or laboratory abnormality
Active neoplastic disease, history of cancer five years prior to screening, including breast cancer (history of skin melanoma or stable prostate cancer are not exclusionary)
Contraindications to LP: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets < 100,000, use of Coumadin/warfarin, or history of a bleeding disorder
Must not be on any immunosuppressant medications (e.g. IVig)
Must not be enrolled as an active participant in another clinical study

Where it is running

Georgetown University Medical Center — Washington D.C., District of Columbia, United States (enrolling)

Full record on ClinicalTrials.gov

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