A Phase II Double Blind, Placebo-Controlled, Parallel Group, Two-Cohort study of nilotinib to determine the safety and tolerability in participants with Parkinson’s Disease (PD).

As you may know, nilotinib is a marketed drug and approved by the Food and Drug Administration (FDA) for the treatment of certain types of leukemia. The drug is not currently indicated for treatment in Parkinson’s disease but there is preclinical data and a small open label clinical trial suggesting nilotinib may hold promise as a treatment for PD.

Nilotinib has a number of safety concerns specifically related to potential risk of cardiac and hematologic toxicity. The current study protocol was designed with tight adherence to the safety monitoring recommendations as described in the package insert. Please use the following link to view the nilotinib package insert.

https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tasigna.pdf

In addition, below is a summary of dosing instructions for commonly prescribed medications:
1) H2 blockers are allowed. However, these medicines should be taken 10 hours before or 2 hours after taking the study drug.
2) Antacid that contains aluminum hydroxide, magnesium hydroxide or simethicone are allowed. However, these medications should be taken about 2 hours before or about 2 hours after taking the study drug.
3) Use of grapefruit juice and grapefruit products will be prohibited (due to inhibition of CYP3A4)

The following medications are restricted or not allowed during subject participation in the study

If any disallowed medications are required and cannot be discontinued, study drug should be stopped and the subject should continue to be followed in the study off of study drug. Please notify the study team immediately regarding initiation of disallowed medications.


EXCLUSIONARY AND PRECAUTIONARY MEDICATIONS
NOTE: This list is not exhaustive but is designed to give examples of more commonly used drug classes.

Table 1. Exclusionary Medications: Known risk to prolong the QT interval

Antimicrobials
Erythromycin
Azithromycin (systemic)
Levofloxacin (systemic)
Sparfloxacin
Ciprofloxacin (systemic)
Clarithromycin
Telithromycin
Moxifloxacin
Fluconazole (systemic)

Antiprotozoal, Antimalarials, AntituberculosisPentamidine
Mefloquine
Chloroquine
Quinine
Delamanid
Bedaquiline
Mesoridazine

Antiarrhythmics
Dronedarone
Sotalol
Dofetilide
Ibutilide
Quinidine
Amiodarone
Disopyramide

Antiplatelet
Cilostazol

Antiemetics
Domperidone
Cisapride
Granisetron
Droperidol
Ondansetron//Granisetron
Propafenone
Procainamide
Flecainide

Others
Methadone
Sevoflurane
Anagrelide
Levomethadyl
Vilanterol
Propofol
Probucol
Halofantrine
Tacrolimus
Nicardipine

Antipsychotics (all have some risk)
Fluphenazine
Haloperidol
Pimozide
Chlorpromazine
Droperidol
Aripiprazole
Thioridazine
Sulpiride
Sertindole

Antidepressant
Citalopram/escitalopram*
Trimipramine
Clomipramine
Dosulepin
Mirtazapine
Trazodone
Venlafaxine
Lofepramine

Antineoplastics
Arsenic trioxide
Ceritinib
Dabrafenib
Dasatinib
Pazopanib
Bosutinib
Panobinostat
Lapatinib
Crizotinib
Bortezomib
Oxaliplatin
Ribociclib
Vandetanib
Osimertinib
Pazopanib
Romidepsin
Sunitinib
Tamoxifen
Toremifene
Vemurafenib

Hepatitis C Antivirals
Telaprevir
Boceprevir
Anticholinergic
Solifenacin

*stable regimen of Citalopram (<20mg) or escitalopram (<10mg) will be allowed provided that the baseline EKG did not demonstrate QT prolongation


Table 2. Exclusionary Medications: Strong CYP3A4 Inhibitors

Generic
Ketoconazole (systemic use)
Itraconazole
Posaconazole
Clarithromycin
Aprepitant
Domperidone
Atazanavir
Indinavir
Nefazodone
Nelfinavir
Ritonavir
Saquinavir
Telithromycin
Voriconazole

Brand
--
Onmel; Sporanox; Sporanox Pulsepak
Noxafil
Biaxin; Biaxin XL; Biaxin XL Pac; Prevpac; Omeclamox-Pak
Emend
--
Reyataz; Evotaz
Crixivan
--
Viracept
Norvir; Kaletra; Technivie; Viekira Pak; Viekira XR
Invirase
Ketek
Vfend


Table 3. Exclusionary Medications: Proton Pump Inhibitors

Generic
Dexlansoprazole
Esomeprazole
Lansoprazole

Omeprazole

Pantoprazole
Rabeprazole

Brand
Dexilant
Nexium; Vimovo
First-Lansoprazole; GoodSense Lansoprazole [OTC]; Heartburn Relief 24 Hour [OTC]; Heartburn Treatment 24 Hour [OTC]; Prevacid 24HR [OTC]; Prevacid SoluTab; Prevpac
First-Omeprazole; Omeclamox-Pak; Omeprazole+Syrspend SF Alka; Prilosec [OTC]; Yosprala; Zegrid
Protonix
Aciphex; AcipHex Sprinkle


Table 4. Exclusionary Medications: Strong CYP3A4 Inducers

Generic
Carbamazepine
Dexamethasone (systemic use)
Phenytoin
Phenobarbital
Rifampin
Rifabutin
St. John’s Wort

Brand
Carbatrol; Epitol; Equetro; TEGretol; TEGretol-XR
Dexamethasone Intensol; DexPak; DoubleDex
Dilantin; Dilantin Infatabs; Phenytek; Phenytoin Infatabs
Phenobarb; Donnatal; Donnatal Extentabs; Phenohytro
Rifadin; Rifamate; Rifater
Mycobutin
--


Table 5. Exclusionary Medications: P-glycoprotein Inhibitors

Generic
Amiodarone
Clarithromycin
Erythromycin (systemic use)
Ketoconazole (systemic use)
Quinidine
Saquinavir
Verapamil

Brand
Cordarone; Nexterone; Pacerone
Biaxin; Biaxin XL; Biaxin XL Pac; Prevpac; Omeclamox-Pak
EES; Ery-Tab; EryPed; Erythrocin; PCE
--
BioQuin Durules; Quinate; Nudexta
Invirase
Calan; Calan SR; Isoptin SR; Verelan; Tarka


Table 6. Exclusionary Medications: P-glycoprotein Inducers

Generic
Carbamazepine
Rifampin
St. John’s wort
Tipranavir

Brand
Carbatrol; Epitol; Equetro; TEGretol; TEGretol-XR
Rifadin; Rifamate; Rifater
--
Aptivus


Table 7. Exclusionary Medications: Anticoagulants

Generic Name
Warfarin
Dabigatran
Edoxaban
Rivaroxaban
Apixaban

Brand Name
Coumadin
Pradaxa
Savaysa
Xarelto
Eliquis


Table 8. Precautionary Medications: Drugs with possible or conditional risk of Torsades de Pointes

Anticholinergic
Tolterodine
Anticonvulsants
Ezogabine
Felbamate
Fosphenytoin
Antidepressants
Amitriptyline
Desipramine
Doxepin
Fluoxetine
Fluvoxamine
Imipramine
Maprotiline
Nortriptyline
Paroxetine
Sertraline
Antiemetics
Dolasetron
Promethazine
Tropisetron
Antihistamines
Diphenhydramine
Hydroxyzine
Antifungals
Amphotericin B
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Antimalarials
Artenimol + piperaquine
Hydroxychloroquine
Antiretrovirals
Atazanavir
Efavirenz
Nelfinavir
Rilpivirine
Ritonavir
Saquinavir
Antiviral
Foscarnet

Antibiotics
Garenoxacin
Gemifloxacin
Norfloxacin
Ofloxacin
Metronidazole
Sulfamethoxazole and Trimethoprim
Telavancin
Antineoplastics
Capecitabine
Degarelix
Eribulin
Lenvatinib
Leuprolide
Sorafenib
Vorinostat
Antipsychotics
Amisulpiride
Asenapine
Clozapine
Cyamemazine
Flupentixol
Iloperidone
Olanzapine
Paliperidone
Perphenazine
Pimavanserin**
Pipamperone
Quetiapine**
Risperidone
Ziprasidone
Zotepine
Beta-agonists
Albuterol
Arformoterol
Formoterol
Isoproterenol
Levalbuterol
Metaproterenol
Olodaterol
Salmetrol
Terbutaline
Calcium Channel Blockers
Isradipine

CNS Stimulants
Amphetamine
Dexmethylphenidate
Dextroamphetamine
Lisdexamfetamine
Methamphetamine
Methylphenidate
Phentermine
Contrast Media
Gadobenate
Iodinated ionic contrast media
Perflutren lipid microspheres
Diuretics
Bendroflumethiazide
Furosemide
Hydrochlorothiazide
Indapamide
Torsemide
GI Agents
Famotidine
Metoclpramide
Opioids
Buprenorphine
Hydrocodone
Miscellaneous
Alfuzosin
Apomorphine
Atomoxetine
Chloral hydrate
Fingolimod
Galantamine
Ivabradine
Lithium
Loperamide
Mifeprisfepristone
Mirabegron
Moxepril
Octreotide
Oxytocin
Pasireotide
Ranolazine
Tetrabenazine
Tiapride
Vardenafil
Tizanidine

**Pimavanserin and Quetiapine are also metabolized by CYP3A4. Therefore, low doses of quetiapine should be used when given with nilotinib (moderate inhibitor of CYP3A4). For pimavanserin, a dose of 17 mg once daily is recommended when given with a strong CYP3A4 inhibitor. For quetiapine, it is recommended to decrease the dose by one-sixth when given with a strong CYP3A4 inhibitor

Nilotinib AEs (adverse events) in CML population:
The percentages below were taken from a randomized trial of nilotinib 300mg BID in newly diagnosed Ph+ CML patients (N=279)—taken from the Tasigna 2017 package insert.
• The most common (>10%) non-hematologic adverse drug reactions were rash, pruritis, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain.
• Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (≤10% and>5%). These have been of mild to moderate severity, manageable and generally did not require dose reduction.
• The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (18%), neutropenia (15%) and anemia (8%).

Please click on the link to see the following information in regards to specific AEs:

NILO_PD adverse events summary