MAD Phase I Study to Investigate Contraloid Acetate

Study Overview
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Brief Summary
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This is a single-center multiple-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 BBB penetrable [1] and has demonstrated target engagement in vitro and in vivo [2, 3]. 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
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The investigation on the compound Contraloid acetate in a multiple-ascending-dose phase I study has been performed in 24 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. Two different ascending doses (160 and 320 mg Contraloid) administered orally (for 14 days in the first cohort and for 28 days in the second cohort) as a single daily dose, were tested in two cohorts on respectively eight participants per cohort, additionally four participants of each cohort received placebo. In order to maintain the highest level of security for the participants of this study a staggered design was used. First, only four sentinels of each cohort were administered with the study drug or placebo (ratio 2:2). Only after assessing all available data by the data safety and monitoring board (DSMB), the rest of the cohort (6 study drug: 2 placebo) were allowed to be treated. This took place on two consecutive days, administering the study drug to four participants per each starting day. After DSMB permission the next dose level was started 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, concomitant medication, adverse events were monitored closely. Sentinels stayed in the Phase-I Unit for 7 days, and the remaining participants of the cohort for 24 hours. The participants returned daily for administration. On Day 14/28 (cohort 1/cohort 2) the participants were admitted to the phase 1 unit for another 24 h for PK-sampling. A follow-up was performed on Days 16/30, 17/31 and the End of Study Visit on Day 21/35. 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 Fundacion Teofilo Hernando, Spain, Bioanalytics by Nuvisan, Germany.It is a Part the Cloud Translational Research Funding award from the Alzheimer´s Association. 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 BBB penetrable [1] and has demonstrated target engagement in vitro and in vivo [2, 3]. 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.

Official Title
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Single-center, Randomized, Prospective, Double-blind, Placebo Controlled Phase Ib Study With an Adaptive Multiple Ascending Dose (MAD) Design to Investigate the Safety, Tolerability, Pharmacokinetics of Contraloid Acetate (Healthy Subjects)

Conditions
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Alzheimer Dementia, Alzheimer Disease

Intervention / Treatment
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* Drug: Contraloid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects willing and able to give their written consent to participate in the trial after having received information about the study design, the objectives of the project, the possible derivative risks, and their right to withdraw from the study at any time and for any reason. Healthy male and female subjects aged within: 18 to 45 years (limits included). 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. Women who were neither pregnant (negative urine pregnancy test) nor nursing and who were either: Surgically sterile (bilateral tubal ligation, hysterectomy) 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, female: 12,0 - 16,0 g/dL) CK level higher than 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled, multiple ascending dose, multi-cohort
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator: Contraloid 160 mg<br>160 mg Contraloid/participant administered orally (for 14 days in the first cohort and for 28 days in the second cohort) as a single daily dose. | Drug: Contraloid<br>* Oral administration of capsules, drug substance or placebo without any exipients.<br>* Other names: PRI-002;|
| Active Comparator: Active Comparator: Contralod 320mg<br>320 mg Contraloid/participant administered orally (for 14 days in the first cohort and for 28 days in the second cohort) as a single daily dose. | Drug: Contraloid<br>* Oral administration of capsules, drug substance or placebo without any exipients.<br>* Other names: PRI-002;|
| Placebo Comparator: Placebo Comparator (for Contraloid) 160 mg<br>160 mg placebo/participant administered orally (for 14 days in the first cohort and for 28 days in the second cohort) as a single daily dose. | Drug: Contraloid<br>* Oral administration of capsules, drug substance or placebo without any exipients.<br>* Other names: PRI-002;|
| Placebo Comparator: Placebo Comparator (for Contraloid) 320 mg<br>320 mg placebo/participant administered orally (for 14 days in the first cohort and for 28 days in the second cohort) as a single daily dose. | Drug: Contraloid<br>* Oral administration of capsules, drug substance or placebo without any exipients.<br>* Other names: PRI-002;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of safety and tolerability of Contraloid by monitoring vital signs, ECG and lab values | 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. | 21 days for cohort 1 and 35 days for cohort 2 | 
| Assessment of pharmacokinetics of Contraloid: Area under curve (AUC) in plasma | Area under curve (AUC) in plasma | 168 hours | 
| Assessment of pharmacokinetics of Contraloid: Cmax in plasma | Cmax in plasma | 21/35 days | 
| Assessment of pharmacokinetics of Contraloid: Tmax in plasma | Tmax in plasma | 21/35 days | 
| Assessment of pharmacokinetics of Contraloid: Terminal elimination half-life (t1/2) in plasma | Terminal elimination half-life (t1/2) in plasma | 21/35 days | 
| Assessment of pharmacokinetics of Contraloid: distributive half-life (t1/2alpha) in plasma | distributive half-life (t1/2alpha) in plasma | 21/35 days | 
| Assessment of pharmacokinetics of Contraloid: terminal elimination half-life (t1/2beta) in plasma | Terminal elimination half-life (t1/2beta) in plasma | 21/35 days | 
| Assessment of pharmacokinetics of Contraloid: Elimination Constant (Kel alpha) in plasma | Elimination Constant (Kel alpha) in plasma | 21/35 days | 
| Assessment of pharmacokinetics of Contraloid: Elimination Constant (Kel beta) in plasma | Elimination Constant (Kel beta) in plasma | 21/35 days | 
| AUC0-24 of Contraloid does not exceed of 2.3 µg·h/mL | 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. | 21/35 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-prionic, anti-Abeta-pionic, treatment of cognition and memory deficits, AD patients, AD stage-independent, NOT anti-amyloid, neuron specific Ca-ion reduction