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).

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.