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Alzheimer DiseasePhase 1VostatAD01NCT03056495

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

A Phase 1 study testing N-hydroxy-N'-phenyl-octanediamide (Vorinostat) in people with Alzheimer Disease, run by German Center for Neurodegenerative Diseases (DZNE) at 2 sites in Germany.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This Clinical Trial is an open, non-randomized Phase Ib study to determine the maximal tolerable dose (MTD) of Vorinostat in Alzheimer disease (AD) patients between (including) 55 and 90 years with mild symptoms. Read more about this study

Who is it for?
Ages 55 to 90 years
Conditions the study is for
Alzheimer Disease
What is being tested?
N-hydroxy-N'-phenyl-octanediamide (Vorinostat)
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
2 sitesGermany
Study dates
28 Sep 2017to 4 Mar 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 1 country.

Germany2 sites

  • German Center for Neurodegenerative Diseases

    Bonn, 53127

  • University Medical Center Göttingen, Department of Psychiatry and Psychotherapy

    Göttingen, 37075

Other trials in Germany

About this study

Official title: Multicenter, Open-label Phase Ib Dose-escalation and Dose-confirmational Study for the Tolerability and Safety of N-hydroxy-N'-Phenyl-octanediamide (Vorinostat) in Patients With Mild Alzheimer's Disease

This Clinical Trial is an open, non-randomized Phase Ib study to determine the maximal tolerable dose (MTD) of Vorinostat in Alzheimer disease (AD) patients between (including) 55 and 90 years with mild symptoms. The MTD in this study is defined as the dose that leads to maximum toxicity with Common Toxicity Criteria (CTC) grade 1 symptoms.The safety and tolerability of Vorinostat in this group of study participants should be tested.

Read the detailed description

The MTD of Vorinostat in the treatment of Alzheimer's patients is to be determined by using an open, non-randomized, multicentric dose-finding study with adaptive design. This Clinical Trial will take place in 2 parts.

The first part will be performed as a dose escalation part in cohorts of three subjects. Possible dosages will be: one, two, three or four capsules (100 mg per capsule) once per day. The first cohort receives a dose of 100 mg per day. After the treatment, a Vorinostat-free follow-up phase will take place. For the following cohorts, dose increases, a repetition of the previous dose or a dose reduction are possible.

After the dose escalation with a determination of the MTD, a dosage confirmation is carried out with additional subjects. The subjects are given a dose of Vorinostat of MTD over 4 weeks followed by a Vorinostat-free follow-up phase.

Being tested
N-hydroxy-N'-phenyl-octanediamide (Vorinostat)
Medical subject headings
Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • N-hydroxy-N'-phenyl-octanediamide (Vorinostat)Drug

    Also called Vorinostat

    N-hydroxy-N'-phenyl-octanediamide capsules once a day, three weeks of treatment; dose escalation with different dosages per cohort; One cohort of three subjects

Study groups in NCT03056495
Study groupRoleWhat they receive
Investigational drugExperimentalN-hydroxy-N'-phenyl-octanediamide (Vorinostat) capsules once a day, three weeks of treatment; dose escalation with different dosages per cohort; One cohort of three subjects
Receives: Drug: N-hydroxy-N'-phenyl-octanediamide (Vorinostat)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Determination of the maximum-tolerated dose (MTD) in elderly subjects during dose escalation

    A MTD is defined as the highest dose with no > grade 1 toxicity according to Common Toxicity Criteria (CTC).

    The dose-limiting toxicity (DLT) is defined as the dose, which leads with a 30% chance of toxicity to CTC Grade 2 or higher and / or leads to corrected QT interval (QTc)≥480ms and/or increase of QTc >= 50ms compared to baseline

    Measured: 12 months

Secondary outcomes (3)

  1. Incidence of treatment - Emergent Adverse Events (Safety)

    The analysis of safety assessments will include the following data collected for each subject:

    • Adverse Events (AEs) in the context of Drug Exposure (days)

    Measured: during dose escalation and during 4 weeks treatment with MTD every week

  2. Quantification of Vorinostat concentration in blood - pharmacokinetics

    Blood and plasma area under the concentration time curve of Vorinostat from time zero to 8 hours postdose.

    The pharmacokinetic study will investigate the correlation between dose administered and concentration of Vorinostat in blood.

    Measured: d21 by 4 weeks treatment with MTD

  3. association of alterations in the genome-wide transcriptome profile with the dose administered, toxicity and treatment response - pharmacodynamics

    The genome-wide transcriptome profile will be determined as a pharmacodynamic surrogate parameter. Alterations between baseline and after dose administered will be compared. The pharmacodynamic study will investigate the correlation between dose administered, alterations in the genome-wide transcriptome profile as well as treatment responses (memory performance) and toxicities.

    Measured: d21 by 4 weeks treatment with MTD

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Feb 2017
  2. Study start28 Sep 2017
  3. Primary completion4 Mar 2024
  4. Study completion4 Mar 2024

Why it stopped: Insufficient Recruitment

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Basic science
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03056495
Sponsor's protocol ID
VostatAD01
Other IDs
2014-005311-17, 2014
Acronym
VostatAD01
Status last verified
Jul 2019
First submitted
27 Dec 2016
Last updated
10 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.

    PubMed 34389161

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing N-hydroxy-N'-phenyl-octanediamide (Vorinostat) in people with Alzheimer Disease, run by German Center for Neurodegenerative Diseases (DZNE) at 2 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 60 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 10 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Insufficient Recruitment). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determination of the maximum-tolerated dose (MTD) in elderly subjects during dose escalation (time frame: 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03056495, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2024.

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