Safety and Tolerability of PQ912 in Subjects With Early Alzheimer's Disease (SAPHIR)

Study Description

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Brief Summary:

The aim of this study is to evaluate the safety, tolerability and preliminary efficacy of PQ912 in subjects with Mild Cognitive Impairment (MCI) due to Alzheimers Disease (AD) or mild dementia due to AD.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: PQ912 oral; Other: Placebo	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	120 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Phase 2A Multicentre, Randomised, Double Blind, Placebo-Controlled, Parallel-Group Safety and Tolerability Study of PQ912 in Subjects With Early Alzheimer's Disease
Study Start Date :	March 2015
Actual Primary Completion Date :	April 2017
Actual Study Completion Date :	April 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: PQ912 oral; PQ912 will be administered orally twice daily for 12 weeks.	Drug: PQ912 oral
Placebo Comparator: Placebo; Placebo will be administered orally twice daily for 12 weeks.	Other: Placebo

Outcome Measures

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Primary Outcome Measures :

1. Frequency of adverse events and serious adverse events (the study is a Phase II safety trial) [ Time Frame: 12 weeks ]

Secondary Outcome Measures :

1. Exploratory clinical measures (measured by a questionnaire) [ Time Frame: 12 weeks ]
   Mini-Mental State Examination (MMSE) Letter Fluency Test (LFT) Category Fluency Test (CFT) Geriatric Depression Scale (GDS) Cogstate Neuropsychological Test Battery
2. Change from baseline of a panel of concept and AD-related biomarkers in Cerebrospinal fluid (CSF) (measured by Analysis of several biochemical assays) [ Time Frame: 12 weeks ]
   QC activity, total-tau, phospho-tau, Abeta pattern, pro-inflammatory panel
3. Change from baseline in brain functional connectivity (measured by Magnetic Resonance Imaging (MRI) analysis) [ Time Frame: 12 weeks ]
4. Change from baseline in functional connectivity and network Analysis in electroencephalography (EEG) [ Time Frame: 12 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	50 Years to 89 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Major Inclusion Criteria:

• Signed and dated written informed consent
• Male or surgically sterile or postmenopausal female aged ≥ 50 to ≤ 89 years. Male subjects with childbearing potential partners are willing to and should use condoms during treatment and until 28 days of the last dose of study medication.
• Diagnosis of MCI due to AD or mild dementia due to AD with amnestic presentation, according to AA-NIA (Alzheimer's Association (AA) and the National Institute on (Aging NIA) criteria [Albert et al 2011; McKhann et al 2011]
• Mini-Mental State Examination (MMSE) score of 21 to 30 inclusive at screening

• A positive AD signature showing one of the following (either a, b, c, OR d):

  1. Screening CSF sample with an A-beta 42 concentration of less than 638 ng/L AND total tau >375 ng/L, as assessed by central laboratory.
  2. Screening CSF sample with an A-beta 42 concentration of less than 638 ng/L AND p-tau > 52 ng/L, as assessed by central laboratory.
  3. Tau/A-beta ratio > 0.52, as assessed by central laboratory.
  4. A positive amyloid PET if available prior to screening.
• Treatment naïve, this means not having received any prior established specific treatment for MCI due to AD or mild dementia due to AD including no (prior) use of an acetylcholinesterase inhibitor or memantine. A maximum of two months of prior cumulative treatment with an acetylcholinesterase inhibitor or memantine is allowed if the acetylcholinesterase inhibitor or memantine was discontinued due to intolerance, and if this was done at least two months prior to baseline. Use of Souvenaid will be allowed if Souvenaid was discontinued at least twomonths prior to baseline, or if the subject is on stable dose for at least six months prior to baseline and is willing to continue during the study on the same dose and frequency.
• Outpatient with study partner capable of accompanying the subject on all clinic visits. In accordance to Swedish regulations availability of study partner is not applicable for Sweden.

Major Exclusion Criteria:

• Significant neurologic disease, other than AD, that may affect cognition.
• Atypical clinical presentations of MCI due to AD or mild dementia due to AD, such as the visual variant of AD (including posterior cortical atrophy) or the language variant (including logopenic aphasia).

• Concomitant disorders:

  • Severe hepatic (Child-Pugh C) and/or kidney failure (creatinine clearance (estimated Glomerular Filtration Rate - eGFR) ≤ 30 ml/min/1.73m2) and/or serum creatinine above 1.5 fold of Upper Limit Normal (ULN) and/or Alanine-Amino Transferase (AST) or Asparagine-Amino Transferase (ALT) above 3 fold ULN at baseline.
  • History of or screening visit brain MRI scan indicative of any other significant abnormality.
  • Current presence of a clinically important major psychiatric disorder (e.g. major depressive disorder) as defined by DSM-5 criteria, or symptom(s) (e.g. hallucinations) that could affect the subject's ability to complete the study.
  • . Current clinically important systemic illness that is likely to result in clinically relevant deterioration of the subject's condition or might affect the subject's safety during the study.
  • Other clinically important diseases or conditions or abnormalities of vital signs, physical examination, neurologic examination, laboratory results, or electrocardiogram (ECG) examination (e.g. atrial fibrillation) that could compromise the study or the safety of the subject.
  • Clinically important infection within 30 days prior to screening e.g. chronic persistent or acute infection, such as bronchitis or urinary tract infection.
  • Any known hypersensitivity to any of the excipients contained in the test article formulation.
  • Severe hepatic failure (Child-Pugh C) OR kidney failure (creatinine clearance (eGFR) ≤ 30 ml/min/1.73m2) OR serum creatinine above 1.5 fold of ULN OR AST or ALT above 3 fold of ULN at screening.´
• Concomitant Medication/Therapies:

The following therapies are not permitted for the given intervals prior to baseline and until End-of-treatment (EOT):

• Use of experimental medications for AD or any other investigational medications or devices for treatment of indications other than AD within 60 days prior to baseline.
• Treatment with Souvenaid, except if the use of Souvenaid was discontinued at least two months prior to baseline, or if the subject is on stable dose for at least six months prior to baseline and is willing to continue the use of Souvenaid during the study on the same dose and frequency.
• Concomitant treatment with St. John's Wort (a wash out phase of at least two weeks prior to baseline is required).
• Any concomitant treatment which impairs cognitive function and cannot be washed out at least four weeks prior to baseline.

Contacts and Locations

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Locations

Belgium
Ziekenhuis Netwerk Antwerpen / Geheugenkliniek
Hoboken, Belgium, 2660
Finland
Kliininen tutkimuskeskus
Kuopio, Finland, 70211
Oulu University Hospital
Oulu, Finland, 90220
CRST Oy
Turku, Finland, 20520
France
CHU Bordeaux Pellegrin (CMRR)
Bordeaux, France, 33076
CHU François Mitterand (Centre Mémoire Ressources Recherche (CMRR))
Dijon, France, 21079
CHRU de Lille / Hôpital Roger Salengro
Lille Cedex, France, 59037
Hôpital La Grave / Centre de Recherche Clinique
Toulouse Cedex 9, France, 31059
Germany
Charité - Universitätsmedizin Berlin
Berlin, Germany, 10450
Universitätsmedizin Göttingen / Klinik für Psychiatrie und Psychotherapie
Göttingen, Germany, 37075
Universitätsklinikum Halle (Saale) Klinik und Poliklinik für Psychiatrie, Psychotherapie und Psychosomatik
Halle (Saale), Germany, 06112
Arzneimittelforschung Leipzig GmbH
Leipzig, Germany, 04107
Universitätsklinikum Magdeburg / Institut für Kognitive Neurologie und Demenzforschung
Magdeburg, Germany, 39120
Klinikum rechts der Isar der TU München / Klinik für Psychiatrie und Psychotherapie
München, Germany, 81675
Universitätsklinikum Münster / Klinik für Allgemeine Neurologie
Münster, Germany, 48149
Universitätsmedizin Rostock / Zentrum für Nervenheilkunde/ Klinik für Psychosomatik und Psychotherapeutische Medizin
Rostock, Germany, 18147
Neurologische Universitätsklinik Ulm
Ulm, Germany, 89081
Netherlands
Alzheimer Research Center
Amsterdam, Netherlands, 1081 GM
Spain
Hospital de la Santa Creu i Sant Pau, Neurology Department, Memory Unit
Barcelona, Spain, 08025
Fundació ACE. Institut Català de Neurociències Aplicades
Barcelona, Spain, 08028
Complexo Hospitalario Universitario de Santiago (CHUS)
Santiago de Compostela, Spain, 15706
Hospital Universitario Virgen Macarena
Sevilla, Spain, 41009
Sweden
Verksamheten för neuropsykiatri Sahlgrenska universitetssjukhuset
Mölndal, Sweden, 43141

Sponsors and Collaborators

Probiodrug AG

Julius Clinical

VU University Medical Center

Investigators

Study Director:	Frank Weber, Dr.	Probiodrug AG
Study Chair:	Philip Scheltens, Prof. Dr.	VUmc Alzheimer Centre (p: +31 20 4440816)

More Information

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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Probiodrug AG
ClinicalTrials.gov Identifier:	NCT02389413 History of Changes
Other Study ID Numbers:	PBD01071; 2014-001967-11 ( EudraCT Number )
First Posted:	March 17, 2015
Last Update Posted:	June 1, 2017
Last Verified:	January 2017

Keywords provided by Probiodrug AG:

PQ912; Glutaminy Cyclase (QC); QC - Inhibitor

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases	Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders