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Nilotinib in Huntington's Disease (Tasigna HD)

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ClinicalTrials.gov Identifier: NCT03764215
Recruitment Status : Recruiting
First Posted : December 5, 2018
Last Update Posted : December 5, 2018
Sponsor:
Information provided by (Responsible Party):
Karen E. Anderson, MD, Georgetown University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Huntington Disease Drug: Nilotinib 150 MG Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Ten (10) participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If this dose is tolerated another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.
Masking: None (Open Label)
Masking Description: We propose to perform an open label, Phase Ib, proof of concept study to evaluate the impact of low doses of Nilotinib treatment on safety, tolerability and biomarkers in participants with HD. We propose an adaptive design based on safety and tolerability of 150mg Nilotinib treatment for 3 months. We will first enroll 10 participants who will receive an oral dose of 150mg Nilotinib once daily (group 1) for 3 months. If these participants tolerate 150mg dose of Nilotinib, an additional 10 new HD participants (group 2) will be enrolled to evaluate the effects of 300 mg dose of Nilotinib for 3 months. We will then compare baseline with the effects of 3-months Nilotinib treatment within each group and between groups (1 and 2). Participants (group 1 and 2) will return for a follow up visit one month after the termination of 3-months treatment with Nilotinib and results will compared to baseline visits and end of study visits.
Primary Purpose: Treatment
Official Title: An Open Label, Phase Ib Study to Evaluate the Impact of Low Doses of Nilotinib Treatment on Safety, Tolerability and Biomarkers in Huntington's Disease
Actual Study Start Date : November 15, 2018
Estimated Primary Completion Date : November 30, 2019
Estimated Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Nilotinib

Arm Intervention/treatment
Experimental: Group 1
Ten (10) participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If Nilotinib 150 mg per mouth daily dose is tolerated by the 1st group of 10 participants for 3 months, another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.
Drug: Nilotinib 150 MG
10 participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If this dose is tolerated another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.




Primary Outcome Measures :
  1. Number of participants experiencing any Adverse events and Serious Adverse Events [ Time Frame: 3 months ]
    will be measured using the occurrence of adverse events (AEs) and serious adverse events (SAEs) deemed to be possibly, probably, or definitely related to the study drug. AEs of interest are defined as QTc prolongation, myelosuppression, hepatotoxicity and pancreatitis as listed in Table 1. These AEs will be tracked over the course of the trial and reviewed by the data and safety monitoring board (DSMB) at scheduled meetings and in real time. SAEs and AEs are known to be related to drug use at 800mg daily in cancer. A small safety trial using lower oral daily doses of 150 mg and 300 mg Nilotinib in 12 PD patients showed one cardiac SAE over a six-month treatment period. Based on preliminary clinical data, investigator's brochure (IB) and scheduled EKGs and lab tests, SAEs and AEs will be evaluated real-time and on case-by-case basis.

  2. CSF levels of biomarkers linked to Disease symptoms Chorea and behavioral symptoms [ Time Frame: 3 months ]
    Prior studies from our group showed that Nilotinib treatment increases the CSF levels of HVA, suggesting alteration of dopamine level. We will evaluate the effects of potential changes of dopamine levels on Chorea and behavioral symptoms in HD participants. We will use an adaptive study design that will allow examination of the effects of 150mg Nilotinib once daily in 10 HD participants. If participants in this group do not exhibit worsening chorea or behavioral changes, then 300mg Niloitnib will be given to a new group of 10 additional participants. These potential AEs will be tracked over the course of the trial and reviewed by the DSMB at scheduled meetings and in real time.

  3. Number of participants tolerating the drug by the ability of remaining on treatment [ Time Frame: 3 months ]
    for a given participant will be defined as the ability of participants to remain on treatment. Overall tolerability of the drug will be defined as an acceptable number of up to 25% discontinuations.



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Ages Eligible for Study:   25 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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:

    1. Cardiovascular or cerebrovascular event (e.g. myocardial infarction, unstable angina, or stroke)
    2. Congestive heart failure
    3. First, second- or third-degree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances
    4. 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:

    1. Treatment with Class IA or III antiarrhythmic drugs (e.g. quinidine)
    2. Treatment with QT prolonging drugs (www.crediblemeds.org)- excluding Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. Citalopram, Escitalopram, Paroxetine, Sertraline, Duloxetine, Trazodone, etc.)
    3. 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.
    4. Anticoagulants, including Coumadin (warfarin), heparin, enoxaparin, daltiparin, xarelto, etc.
    5. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03764215


Contacts
Contact: Hope Heller 202-687-1366 hope.heller@gunet.georgetown.edu
Contact: Robin Kuprewicz, MA rk1028@georgetown.edu

Locations
United States, District of Columbia
Georgetown University Medical Center Recruiting
Washington, District of Columbia, United States, 20007
Contact: Hope Heller    202-687-1366    hope.heller@gunet.georgetown.edu   
Contact: Robin Kuprewicz, MA       rk1028@georgetown.edu   
Sponsors and Collaborators
Georgetown University

Additional Information:
Publications of Results:
Responsible Party: Karen E. Anderson, MD, Director, Huntington Disease Care, Education and Research Center at MedStar Georgetown University Hospital and Georgetown University Medical Center, Georgetown University
ClinicalTrials.gov Identifier: NCT03764215     History of Changes
Other Study ID Numbers: 2017-0440
First Posted: December 5, 2018    Key Record Dates
Last Update Posted: December 5, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Dementia
Huntington Disease
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Chorea
Dyskinesias
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Cognition Disorders
Neurocognitive Disorders
Mental Disorders