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SAD Phase I Study (First-in-human) to Investigate Contraloid Acetate

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ClinicalTrials.gov Identifier: NCT03944460
Recruitment Status : Completed
First Posted : May 9, 2019
Last Update Posted : May 9, 2019
Sponsor:
Collaborators:
Helmholtz-Gemeinschaft Deutscher Forschungszentren, Germany
Medical University of Vienna
NeuroScios, Austria
Triskelion, The Netherlands
Fundación Teófilo Hernando, Spain
Information provided by (Responsible Party):
Prof. Dr. Dieter Willbold, Forschungszentrum Juelich

Tracking Information
First Submitted Date  ICMJE April 26, 2019
First Posted Date  ICMJE May 9, 2019
Last Update Posted Date May 9, 2019
Actual Study Start Date  ICMJE April 9, 2018
Actual Primary Completion Date July 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2019)
  • Assessment of safety and tolerability of Contraloid by monitoring vital signs, ECG, EEG, and lab values [ Time Frame: 8 days ]
    To evaluate the safety and tolerability of Contraloid acetate in healthy subjects by assessing the number, severity and type of adverse events, including changes in vital signs, physical examinations, laboratory safety tests and ECGs.
  • Assessment of pharmacokinetics of Contraloid: Area under curve (AUC) in plasma [ Time Frame: 72 hours ]
    Area under curve (AUC) in plasma
  • Assessment of pharmacokinetics of Contraloid: Cmax in plasma [ Time Frame: 72 hours ]
    Cmax in plasma
  • Assessment of pharmacokinetics of Contraloid: Tmax in plasma [ Time Frame: 72 hours ]
    Tmax in plasma
  • Assessment of pharmacokinetics of Contraloid: Terminal elimination half-life (t1/2) in plasma [ Time Frame: 72 hours ]
    Terminal elimination half-life (t1/2) in plasma
  • Assessment of pharmacokinetics of Contraloid: Apparent total clearance (Cl/F) in plasma [ Time Frame: 72 hours ]
    Apparent total clearance (Cl/F) in plasma
  • Assessment of pharmacokinetics of Contraloid: Volume of distribution (Vd) in plasma [ Time Frame: 72 hours ]
    Volume of distribution (Vd) in plasma
  • AUC0-24 of Contraloid does not exceed of 2.3 µg·h/mL [ Time Frame: 72 hours ]
    Additionally, the AUC0-24 values of Contraloid in plasma will be determined in order to ensure that the recommended AUC0-24 of Contraloid does not exceed of 2.3 µg·h/mL in any of the subjects.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE SAD Phase I Study (First-in-human) to Investigate Contraloid Acetate
Official Title  ICMJE A Randomized, Double-blind and Placebo-controlled Single Ascending-dose Phase I Study (First-in-human) to Investigate the Safety, Tolerability and Pharmacokinetics of Contraloid Acetate (in Healthy Subjects).
Brief Summary This is a single-center first-in-human single-ascending-dose clinical trial assessing the safety and tolerability of oral dosing of Contraloid acetate in healthy volunteers. The study drug Contraloid (alias RD2, alias PRI-002) is an orally available all-D-peptide, which was developed to directly destroy toxic and replicating A-beta oligomer prions, by disassembling them into A-beta monomers. The study drug is specifically designed for the curative or at least disease-modifying treatment of cognition, memory and behavior deficits in Alzheimer´s disease patients. The study drug is not designed to reduce brain plaque load or total A-beta in cerebrospinal fluid. The study drug is blood-brain-barrier penetrable [1] and has demonstrated target engagement in vitro and in vivo [2, 3]. Preclinical treatments in three different transgenic mouse models in three different laboratories yielded improved cognition and deceleration of neurodegeneration, even under truly non-preventive treatment conditions and even when applied orally [2-5]. The hereby obtained PRI-002 plasma levels have also been achieved in humans after single oral dosing.
Detailed Description

The investigation on the compound Contraloid acetate in a single-ascending-dose phase I study (first-in-human) has been performed in 40 healthy male participants, randomly assigned to the treatment. Main focus was on the evaluation of the outcome of the safety and tolerability; secondarily the pharmacokinetic characteristics of the compound were assessed. Five different ascending doses (4, 12, 36, 108, and 320 mg Contraloid) administered orally as a single dose, were tested in five cohorts on respectively six participants per cohort, additionally two participants of each cohort received placebo.

In order to maintain the highest level of security for the participants of this first-in-human study a staggered design was used. First, only two sentinels of each cohort were administered with the study drug or placebo (ratio 1:1). Only after assessing all available data by the data safety and monitoring board (DSMB), the rest of the cohort (5 study drug : 1 placebo) were allowed to be treated. This took place on two consecutive days, administering the study drug to three participants per each starting day. After DSMB permission the next higher dose level was started in the next cohort with the same scheme of administration.

During the screening period the informed consent was obtained and the evaluation of the inclusion and exclusion criteria, collection of demographic data and previous medical history, physical examination and health assessment, 12-lead ECG were performed. Additionally vital signs, haemogram, coagulation, biochemistry and urine analysis determination, as well as serology and testing of drug abuse were carried out.

On the first study day the participants received in fasting conditions the study drug after re-evaluation the inclusion/exclusion criteria. For monitoring the laboratory parameters and the pharmacokinetics of Contraloid blood draws were performed in a predetermined frequency. Physical conditions, vital signs, ECG and EEG, concomitant medication, adverse events were monitored closely. Sentinels stayed in the Phase-I Unit for 72 hours, and the remaining participants of the cohort for 24 hours. A follow-up was performed on Days 3, 4 and 8. The study was double-blinded and conducted under the EU regulations and Good Clinical Practice (GCP) and national Austrian law. Monitoring and PV was performed by the CRO NeuroScios, DM by Fundación Teófilo Hernando, Spain, bio-analytics by Triskelion, The Netherlands.

Contraloid (alias RD2, alias PRI-002) is an all-D-peptide, which was developed to directly destroy toxic and replicating A-beta oligomer prions by disassembling them into A-beta monomers. The study drug is specifically designed for the curative or at least disease-modifying treatment of cognition, memory and behavior deficits in Alzheimer´s disease patients. The study drug is not designed to reduce brain plaque load or total A-beta in cerebrospinal fluid. The study drug is blood-brain-barrier penetrable [1] and has demonstrated target engagement in vitro and in vivo [2, 3]. Preclinical treatments in three different transgenic mouse models in three different laboratories yielded improved cognition and deceleration of neurodegeneration, even under truly non-preventive treatment conditions and even when applied orally [2-5]. The hereby obtained PRI-002 plasma levels have also been achieved in humans after single oral dosing.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Randomized, double-blind, placebo-controlled, multi-cohort trial.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Alzheimer Dementia
  • Alzheimer Disease
Intervention  ICMJE Drug: Contraloid
Oral administration of capsules, drug substance or placebo without any excipients.
Other Name: PRI-002
Study Arms  ICMJE
  • Active Comparator: Contraloid 4 mg
    4 mg Contraloid/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Active Comparator: Contraloid 12 mg
    12 mg Contraloid/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Active Comparator: Contraloid 36 mg
    36 mg Contraloid/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Active Comparator: Contraloid 108 mg
    108 mg Contraloid/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Active Comparator: Contraloid 320 mg
    320 mg Contraloid/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Placebo Comparator: Placebo (for Contraloid) 4 mg
    4 mg placebo/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Placebo Comparator: Placebo (for Contraloid) 12 mg
    12 mg placebo/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Placebo Comparator: Placebo (for Contraloid) 36 mg
    36 mg placebo/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Placebo Comparator: Placebo (for Contraloid) 108 mg
    108 mg placebo/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
  • Placebo Comparator: Placebo (for Contraloid) 320 mg
    320 mg placebo/participant in a single oral dose with a staggered dose for sentinels followed by the rest of the cohort
    Intervention: Drug: Contraloid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 8, 2019)
40
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 27, 2018
Actual Primary Completion Date July 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • With clinical history and physical examination results within normality.
  • Electrocardiogram without clinically significant pathologic abnormalities and with QTc values lesser than 450 ms.
  • Normotensive as defined by Systolic Blood Pressure ≤ 150 mm Hg. Diastolic Blood Pressure ≤ 90 mm Hg.
  • BMI between 19.0 and 30.0 kg/m2.
  • Body weight between 55 and 85 kg, inclusive
  • Signed ICF

Exclusion Criteria:

  • Any chronic medical condition (such as type 1 diabetes) requiring chronic treatment that might increase the risk to the subject or confound the interpretation of safety observations.
  • Evidence of active infection requiring antibiotic therapy within 14 days prior to screening.
  • Medical history of vasculitis or any autoimmune disease excluding seasonal allergic rhinitis and childhood history of atopic dermatitis.
  • History of any treatment for cancer within the past 2 years, other than basal cell or squamous cell carcinoma of the skin.
  • Seropositive for human immunodeficiency virus (HIV).
  • History of acute/chronic hepatitis B or C and/or carriers of hepatitis B (seropositive for Hepatitis B surface antigen [HbsAg] or anti-Hepatitis C [HCV] antibody).
  • Clinically significant abnormalities in screening laboratory tests, including:

    • Absolute neutrophil count < 1.4 x109
    • Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.5 x the upper limit of normal (ULN)
    • Absolute lymphocyte count < 1.2 x 109
    • Lactate dehydrogenase (LDH) > 1.5 x ULN
    • Total bilirubin level: Out of normal range 0-1.5 mg/dL
    • eGFR < 60 mL/min
    • Hemoglobin (Hgb): out of normal range (male: 13,5-18,0 g/dL)
    • CK level higher than normal values (250U/L)
  • All prescription, over-the-counter and herbal medications are prohibited within 10 days prior to study dosing (with exception of calcium/vitamin D supplements, nasal steroids, ocular medications, and paracetamol ≤1000 mg/day at the discretion of the Investigator).
  • Use of an investigational drug within 2 months prior to dosing in this study.
  • Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs (e.g. small bowel disease, Crohn's disease, celiac disease, or liver disease.)
  • Psychiatric history of current or past psychosis, bi-polar disorder, clinical depression, or anxiety disorder requiring chronic medication within the past 5 years.
  • History of substance abuse, including alcohol
  • Smokers
  • History of substance or drug dependence, or positive urine drug screen at screening visit.
  • History of head injury.
  • Chronic kidney disease (defined as the presence of any degree of proteinuria on urine analysis and/or an eGFR of <60 ml/min using the MDRD formula).
  • Any reason or opinion of the investigator that would prevent the subject from participation in the study.
  • Inability to follow the instructions or an unwillingness to collaborate during the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03944460
Other Study ID Numbers  ICMJE EUDRA-CT: 2017-000396-93
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Only as far as covered by the EU GDPR and regulated by GCP
Responsible Party Prof. Dr. Dieter Willbold, Forschungszentrum Juelich
Study Sponsor  ICMJE Prof. Dr. Dieter Willbold
Collaborators  ICMJE
  • Helmholtz-Gemeinschaft Deutscher Forschungszentren, Germany
  • Medical University of Vienna
  • NeuroScios, Austria
  • Triskelion, The Netherlands
  • Fundación Teófilo Hernando, Spain
Investigators  ICMJE
Principal Investigator: Michael Wolzt, MD University of Vienna
PRS Account Forschungszentrum Juelich
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP