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)

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.