Clinical Trial to Determine Tolerable Dosis of Vorinostat in Patients With Mild Alzheimer Disease (VostatAD01)

Inclusion Criteria:

• written informed consent to participate in the study
• verified capacity to consent by a doctor not involved in the study
• mild Alzheimer's disease (NINCDS / ADRDA criteria and Mini-Mental State Examination (MMSE) 22-27)
• age (including) from 55 to 90 years
• subjects must be able to meet the requirements described in the study protocol
• outpatient living
• Informant lives with subject in the same household
• Rosen modified Hachinski ischemia score ≤4
• concerning only female patients: postmenopausal
• concerning only male patients: commitment to use a suitable contraceptive
• cerebral imaging study (CT or cMRI), which is consistent with a diagnosis of probable Alzheimer's disease (not older than 3 years)

Exclusion Criteria:

• other neurological and psychiatric diseases explaining cognitive deficits better than an AD diagnosis
• conspicuous MRI / CCT scan explaining the cognitive deficits better than an AD diagnosis
• severe physical, neurological or psychiatric disorders that interfere with the participation in the study
• history of malignant tumors except non- metastasizing basal cell carcinoma of the skin
• history of seizures
• dysphagia leading to the inability to swallow capsules
• untreated severe acute infections with clinical symptoms such as respiratory infections, pneumonia, bronchitis, acute diarrhea, influenza, untreated urinary tract infections
• in the family history, unexplained sudden cases of heart failure before the age of 50 years
• long QT syndrome in the family history
• evidence of QTc prolongation ≥480 ms at screening (Fridericia adjusted QT interval), of arrhythmias especially of severe uncontrolled ventricular arrhythmias or atrial fibrillation in ECG
• not sufficiently treated angina
• heart failure (NYHA III, IV)
• myocardial infarction
• known infection with HBV, HCV and / or HIV
• occurrence of venous thrombosis or embolism
• therapy with antidepressants begun in the last 12 weeks or dose modification of a pre-existing therapy with antidepressants
• antidiabetic treatment begun in the last 12 weeks or dose modification of pre-existing antidiabetic treatment
• long-term use of anti-inflammatory drugs except acetylsalicylic acid for cardiovascular prophylaxis
• current treatment or treatment within the past 12 weeks with HDAC inhibitors (eg valproate)
• taking medication that may increase the dose-dependent side effects myelosuppression or QTc interval prolongation.

These include, but are not limited to:

• Class Ia antiarrhythmic agents such as quinidine, procainamide, disopyramide
• Class III antiarrhythmic drugs such as amiodarone, sotalol, ibutilide
• Class Ic antiarrhythmics such as flecainide, propafenone
• penicillamine
• opioids such as methadone and pyrazolone derivatives such as metamizole and Propyphenazone
• doxorubicin, epirubicin
• macrolides and their analogues such as erythromycin, clarithromycin
• telithromycin
• oxazolidinones such as linezolid
• quinolones such as moxifloxacin, levofloxacin
• fluoxetine, maprotiline
• tricyclic and tetracyclic antidepressants
• chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone and clozapine
• antiemetics
• azole like ketoconazole, fluconazole, voriconazole
• aminocholine such as primaquine
• pentamidine such as quinine, chloroquine
• diaminopyrimidine such as pyrimethamine
• salbutamol and formoterol methotrexate
• azathioprine, cyclosporine Interferon gamma 1b
• alemtuzumab, basiliximab, efalizumab, natalizumab
• sunitinib, nilotinib, lapatinib
• mitoxantrone, Hydroxycarbamide, mercaptopurine
• taking of prescription and non-prescription drugs for cognitive enhancement (except cholinesterase inhibitors and memantine at a stable dose for at least 3 months before baseline)
• therapy with anticoagulants except acetylsalicylic acid
• HbA1c in screening more than 10% above the upper limit of normal
• magnesium, sodium, calcium and potassium levels outside the normal range (at screening and baseline)
• existing anemia with Hb <11 (at screening and baseline)
• existing thrombocytopenia; platelet ≤150.000 / ul, leukocytes ≤ 3.000 / ul, neutrophils absolutely ≤ 1.500 / ul (at screening and baseline)
• prothrombin or INR ≥ 1.5 above the laboratory limit of normal; PTT ≥ 1.5 x above the laboratory limit of normal (at screening and baseline)
• clinically relevant renal and / or hepatic impairment at screening and baseline (total bilirubin ≥ 1.5 x above the upper limit of the norm and / or GPT, AST ≥ 4x above the upper limit of the norm and / or creatinine ≥ 1.5x above the upper limit of the norm and / or creatinine clearance <60 ml / min)
• hematuria> 15 RBCs / mL at screening and baseline
• proteinuria at screening and baseline except in asymptomatic urinary tract infections
• participating in other clinical and therapeutic trials within the last 12 weeks

relevant only for dose confirmation:

• subjects with existing contraindications for performing an MRI if no MRI available from the period of 6 months prior to screening
• cardiac pacemaker
• metal objects in the body, which exclude a 1.5 or 3 T MRI
• claustrophobia