A Phase 1, Randomized, Double-Blinded, Placebo-Controlled study to Evaluate the Safety, Tolerability,and Pharmacokinetics of Single and Multiple Ascending Doses of CBT101 given intranasally in Healthy Male Subjects.

The product developed by Ceres-Brain Therapeutics is a creatine-based drug called CBT101.

CBT101 is a product designed to deliver creatine to brain cells. CBT101 will be administered into the nasal cavity via a nasal spray, enabling the product to reach the brain, and neurons in particular, rapidly. In the neurons, CBT101 will be converted into creatine.

This product is indicated for adults and children suffering from creatine deficiency syndrome, or for neurological diseases where a supply of energy, in the form of creatine, would be useful. These include Creatine Transporter Deficiency (a rare genetic disease that affects children and manifests itself in autistic disorders, intellectual deficits, major communication and developmental disorders, particularly psychomotor disorders, and epileptic seizures) and Charcot's disease (a degenerative disease of neurons that unfortunately currently has no curative treatment).This study is divided into 2 parts and will include a total of 48 healthy male volunteers aged between 18 and 55.

The primary objective is to evaluate the safety and tolerability of CBT101 after 14 days of repeated intranasal dosing at 3 ascending doses.

The secondary objective is to determine the pharmacokinetic parameters (study of the fate of the drug in the body) of CBT101 or its metabolites. The first part is a Single Ascending Doses (SAD) composed of 3 cohorts at the following doses: 4.2 mg, 8.4 mg and 12.6 mg. The second part is a Multiple Ascending Doses (MAD), comprising 3 cohorts at the following doses: 4.2 mg, 8.4 mg and 12.6 mg. There will be 8 participants per cohort, of whom 6 will receive CBT101 and 2 will receive placebo.

Inclusion Criteria:

• Healthy male aged to 18-55 years inclusive;

• Must agree to adhere to the contraception requirements: use of condom by the male subject plus an effective method of contraception for the subject partner of childbearing potential from the time of informed consent signature up to 3 months after last administration. Highly effective method of birth control such as combined hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intra uterine devices (IUDs), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion) In accordance with CTFG guidelines;

• Non-smoker subject or smoker of not more than 5 cigarettes a day who stops smoking at least 1 week before the Screening;

• Body Mass Index (BMI) between 18,0 and 30,0 (kg/m2) inclusive, with body weight between 50 and 95 kg inclusive, at Screening and Day -1;

• Considered as healthy after a comprehensive clinical assessment (detailed medical history and complete physical examination);

• Normal Blood Pressure (BP), and Heart Rate (HR) at the screening visit after 10 minutes in supine position:

  1. 95 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 140 mmHg,
  2. 50 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg,
  3. 45 bpm ≤ HR ≤ 90 bpm,
  4. Or considered NCS by investigators;

• Normal ECG recording on a 12-lead ECG at the screening visit:

  e. 120 ≤ PR < 210 ms, f. QRS < 120 ms, g. QTcf ≤ 450 ms, h. No sign of any trouble of sinusal automatism, i. Or considered NCS by investigators;

• Laboratory parameters within the normal range of the laboratory (hematology, hemostasis and blood biochemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged clinically non-relevant by the Investigator, however serum creatinine, alkaline phosphatase, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase), and total bilirubin (unless the subject has documented Gilbert syndrome) should not exceed the upper laboratory norm (isolated bilirubin up to 1.5 is accepted );

• Normal dietary habits;

• Normal nasal examination (including rhinoscopy) at Screening and Day-1;

• Signing a written informed consent prior to selection;

• Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.

Exclusion Criteria:

• Any relevant history or presence of cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic, hematological, neurologic, psychiatric, systemic, infectious disease, endocrine, immunologic, dermatologic or/and any relevant disease;
• Any current or recent (< 2 month) active nasal disease e.g., acute, and chronic rhinosinusitis, allergic rhinitis, Epistaxis, intra nasal polyp(s), nasal septum with strong deviation, otolaryngology inflammation;
• Any treatment or other nasal administration < 2 months;
• Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician;
• Frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month);
• Any medication (including St John's Wort) within 14 days before inclusion or within 5 times the elimination half-life of the medication; any vaccination within the last 28 days;
• Any food supplement containing creatine within the last 14 days before inclusion;
• Symptomatic hypotension whatever the decrease of the blood pressure or asymptomatic postural hypotension defined by a decrease in SBP equal to or greater than 20 mmHg or DBP equal to or greater than 10 mmHg within two minutes of changing from supine to standing position;
• Positive urine drug testing (amphetamines, methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates) or alcohol testing at Screening or Day -1;
• Positive Hepatitis B surface (HBs) antigen or anti Hepatitis C Virus (HCV) antibody, or positive results for Human Immunodeficiency Virus (HIV) 1 or 2 tests;
• Clinical symptoms suspected of acute infectious disease within 2 weeks before the first study drug administration;
• History or presence of drug in particular per inhalation, or alcohol abuse (alcohol consumption > 40 grams / day);
• Excessive consumption of beverages containing xanthine bases (more than 4 cups or glasses per day);
• Blood donation (including as part of a clinical trial) in the 2 months before the administration;
• General anesthesia in the 3 months before administration;
• Inability to abstain from intense muscular effort;
• No possibility of contact in case of emergency;
• Subject who, in the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development;
• Persons deprived of their liberty by judicial or administrative decision; persons under coercive psychiatric care; adults under legal protection (guardianship/trusteeship); persons under court protection;
• Subject in the exclusion period of a previous study and within less than 4 weeks or 5 half-lives of the last administration of an experimental drug;
• Subject who would receive more than 6000 euros as indemnities for his participation in biomedical research within the 12 last months, including the indemnities for the present study.