CTH120 First-in-Human Study: Single and Multiple Ascending Doses and Potential Food Interaction

Connecta Therapeutics, S.L.76 enrolled

Overview

The purpose of this First-in-Human Phase I study is to investigate the safety, tolerability and pharmacokinetics of CTH120 in adult healthy volunteers.

This trial is divided in three parts: FIH-CTH120-SAD (Single Ascending Doses), FIH-CTH120-MAD (Multiple Ascending Doses) and FIH-CTH120-FI (Food Interaction). FIH-CTH120-SAD will start first. The start of FIH-CTH120-MAD will await the results of at least three cohorts from the FIH-CTH120-SAD study before initiated. The starting dose of the FIH-CTH120-MAD will have been shown to be well tolerated in FIH-CTH120-SAD. FIH-CTH120-FI will be the last to start.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Fragile X Syndrome

Interventions

CTH120DRUG

FIH-CTH120-SAD: Each independent cohort of 8 subjects (placebo=2 and CTH120=6 per dose) will receive a single administration of CTH120 or placebo. Four consecutive dose levels (20 mg/day, 40 mg/day, 85 mg/day and 160 mg/day) are planned. If no significant clinical adverse events are observed in the FIH-CTH120-SAD phase, an additional 5th cohort will be recruited to conduct the 5th dose level. FIH-CTH120-MAD: Each independent cohort of 8 subjects (placebo=2 and CTH120=6 per dose) will receive a daily administration of CTH120 or placebo for 7 days. Three consecutive dose levels are planned. The starting dose will be confirmed following the observed results of FIH-CTH120-SAD. FIH-CTH120-FI: One dosage of CTH120 will be assessed in 12 healthy male and female subjects in two conditions (Fed and Fasting). Subjects will be randomly assigned to 2 sequences: 6 subjects in a sequence "fed then fasting condition", 6 subjects in the reverse sequence ("fasting, then fed condition").

PlaceboOTHER

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy male subjects: As the effect of the study drug on sperm is still unknown, male subjects should refrain from donating sperm or plan a pregnancy with their partner throughout the study and after 90 days after the trial and must report immediately to the study doctor if its partner becomes pregnant during the study and during 90 days after the study. The male subject will have to use double- barrier contraceptive methods: male condoms and spermicide. * Healthy female subjects of non-child-bearing potential: females may be accepted if they are documented to be surgically sterile i.e., hysterectomy, tubal ligation or post-menopausal with a negative pregnancy test. * Age ≥ 18 and ≤ 55 years. * Weight ≥ 50 kg and ≤ 100 kg. * Body mass index (BMI) ≥ 18 and ≤ 30. * Negative serum pregnancy test (women only). * Non-smoking. * No history of or ongoing clinically relevant diseases or conditions. * No clinically relevant findings in physical examination, vital signs (blood pressure, heart rate and body temperature), ECG and safety laboratory parameters that should be within normal ranges or considered as non-clinically relevant by the investigator. * Able/willing to accept restrictions regarding diet, physical exercise, and consumption of alcohol and/or xanthine containing items during the duration of the trial including when out of CRU. * Able to read Spanish or Catalan and adhere to study requirements. * Not under any administrative or legal supervision. * Signed informed consent prior to any study-mandated procedure. Exclusion Criteria: * Women of child-bearing potential. * Life-time substance use disorders (SUD) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). * Recreational use of drugs of abuse within the last month prior to study drug administration (verified by hair testing). * Positive blood or urine test for drugs of abuse or alcohol breath test prior to study drug administration. * Life-time history of mental diseases. * History of anxiety or depression not completely recovered within 12 months prior to study drug administration, as assessed by the Dual Diagnosis Screening Interview (DDSI). * Clinically relevant cognitive impairment preventing the administration of the psychometric tests. * Any other clinically relevant disease or condition that in the judgment of the investigator might interfere with the subject's ability to comply with study procedures or requirements and/or bias the interpretation of the study results and/or jeopardize the subject's safety. * Ongoing gastrointestinal diseases or history of gastrointestinal surgery affecting absorption. * Subjects with a clinically significant disease within one month prior to study drug administration. * Any clinically relevant findings in physical examination, vital signs, ECG and safety laboratory parameters. * A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>450 ms). * A history of additional risk factors for TdP (e.g., heart failure, hypokalaemia, family history of Long QT Syndrome). * The use of concomitant medications that prolong the QT/QTc interval. * Positive hepatitis or HIV test. * Known hypersensitivity to drug or drug excipients. * Use of drugs known to induce or inhibit hepatic drug metabolism within one month prior to study administration or during the study and use of citrus juice during the study. * Any prescription or over-the-counter (OTC) product including herbal, homeopathic, vitamins, minerals and nutritional supplements within 2 weeks (or more, considering the elimination half-life of the product) prior to study drug administration. * Donation of blood or plasma within one month prior to study drug administration or transfusion of blood or plasma for medical/surgical reasons or intention to donate blood or plasma within one month after study drug administration. * History of inadequate venous access and/or experience of difficulty donating blood. * Not able/not willing to accept restrictions regarding diet, physical exercise, and consumption of alcohol and/or xanthine containing items when out of CRU. * Subject included in a clinical study within 3 months prior to study drug administration. * Subject already included in other parts of this study.

Locations (1)

Hospital del Mar Medical Research Institute (IMIM)

Barcelona, Barcelona, Spain

Outcomes

Primary Outcomes

Treatment-emergent adverse events (TEAEs).

Primary Safety and Tolerability endpoint for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • AEs will be described in terms of result, frequency, intensity, medical decision, relation with study drug, as well as treatment received and subject retirement, duration, and time elapsed. AEs will also be listed and coded using the MedDRA Dictionary (version 26.0) for the term's codification.

Time frame: From Day 1 to End-of-study: EOS will be on Day 8 (± 1 day) for FIH-CTH120-SAD and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in blood pressure (mmHg)

Primary Safety and Tolerability endpoint for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • Blood pressure (mmHg) will be measured in the supine position following a 5 min rest.

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in pulse rate (bpm)

Primary Safety and Tolerability endpoint for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • Pulse rate (bpm) will be measured in the supine position following a 5 min rest.

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in oral body temperature (ºC)

Primary Safety and Tolerability endpoint for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • Oral body temperature (ºC) will be measured using an automated vital sign monitor device.

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: normal sinus rhythm (NSR)

Data from ClinicalTrials.gov

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Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI) • Computerized 12-lead electrocardiogram (ECG) recordings will be obtained. Each lead shall be recorded for at least 3 beats at a speed of 25 mm/s. Triplicate recordings will be made at the time points evaluated. The following parameter will be recorded: normal sinus rhythm (NSR).

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: heart rate (bpm)

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: PR interval (ms)

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: QRS duration (ms)

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI) • Computerized 12-lead electrocardiogram (ECG) recordings will be obtained. Each lead shall be recorded for at least 3 beats at a speed of 25 mm/s.Triplicate recordings will be made at the time points evaluated. The following parameter will be recorded: QRS duration (ms).

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: QT (ms)

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI) • Computerized 12-lead electrocardiogram (ECG) recordings will be obtained. Each lead shall be recorded for at least 3 beats at a speed of 25 mm/s.Triplicate recordings will be made at the time points evaluated. The following parameter will be recorded: QT (ms).

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: QTcF (ms)

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI) • Computerized 12-lead electrocardiogram (ECG) recordings will be obtained. Each lead shall be recorded for at least 3 beats at a speed of 25 mm/s.Triplicate recordings will be made at the time points evaluated. The following parameter will be recorded: QTcF (ms).

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: haematology

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). The following tests will be performed: • Haematology: complete blood count (complete blood count \[CBC\]; including haemoglobin, haematocrit, red blood cell \[RBC\], white blood cell (WBC), platelet count, and percent and absolute differential count (neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells).

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: serum chemistry

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). The following tests will be performed: • Serum chemistry: sodium, potassium, chloride, non-fasting glucose, urea, creatinine, calcium, phosphate, magnesium, total and direct bilirubin, total protein, albumin, ALT, AST, ALP, lactate dehydrogenase.

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: coagulation

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). The following tests will be performed: • Coagulation parameters: activated partial thromboplastin time (aPTT), PT and INR.

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: urinalysis

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). The following tests will be performed: • Urinalysis parameters: * Macroscopic examination: specific gravity, pH, protein, glucose, ketones, blood, bilirubin, leukocyte, urobilinogen, and nitrite. * Microscopic examination: RBCs, WBCs, epithelial cells, casts, crystals, bacteria, and yeast.

Time frame: From Day 1 to End-of-study (EOS): on Day 8 (± 1 day) for FIH-CTH120-SAD, and on Day 15 (+ 2 days) for FIH-CTH120-MAD

Psychometric tests: Hospital Anxiety/Depression rating Scale (HADS)

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • HADS: Self-reported questionnaire used to detect depression and anxiety. It consists of 14 items (7 related to depression and 7 to anxiety) scored using a 4-point Likert scale (each item ranging from 0 to 3). Two scores are generated one for depression and one for anxiety each score ranging from 0 to 21. Higher scores indicate greater levels of anxiety or depression. Both scores can be categorized into: Normality (0-7); Probable case of anxiety or depression (8-10); Case of anxiety or depression (11-21).

Time frame: FIH-CTH120-SAD: on Day -1 and Day 2; FIH-CTH120-MAD: on Day -1, Day 1, and Day 7

Psychometric tests:Immediate Mood Scaler (IMS).

Primary Safety and Tolerability endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • IMS: The IMS is a tool to remotely and quickly track mood changes related to depression and anxiety in the moment. It consists of 22 items, scored between 1 and 7. The total score for this scale is the sum of the scores on all 22 items: ranging from 22 to 154. Lower scores reflect more negative mood states.

Time frame: FIH-CTH120-SAD: on Day -1 and Day 2; FIH-CTH120-MAD: on Day -1, Day 1, and Day 7

Area under the concentration-time curve (AUC0-24h, AUC0-t, AUC0-∞) after fed and fasting conditions.

Primary Pharmacokinetic endpoint for FIH-CTH120-FI (Not applicable for FIH-CTH120-SAD and FIH-CTH120-MAD). • Plasma PK parameter calculated using a non-compartmental model: AUC0-24h (h \* ng/mL), AUC0-t (h \* ng/mL) AUC0-∞ (h \* ng/mL).

Time frame: FIH-CTH120-FI: AUC0-24h on Day 1; AUC0-t, AUC0-∞ where t is the last or the latest timepoint observed

Observed maximum concentration (Cmax) after fed and fasting conditions.

Primary Pharmacokinetic endpoint for FIH-CTH120-FI (Not applicable for FIH-CTH120-SAD and FIH-CTH120-MAD) • Plasma PK parameter calculated using a non-compartmental model: Cmax (ng/mL).

Time frame: FIH-CTH120-FI: On Day 1 of Period 1, and on Day 14/21/25 of Period 2

Time to observed maximum concentration (tmax) after fed and fasting conditions.

Primary Pharmacokinetic endpoint for FIH-CTH120-FI (Not applicable for FIH-CTH120-SAD and FIH-CTH120-MAD) • Plasma PK parameter calculated using a non-compartmental model: tmax (h).

Time frame: FIH-CTH120-FI: On Day 1 of Period 1, and on Day 14/21/25 of Period 2

Secondary Outcomes

Observed maximum concentration (Cmax).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • Plasma PK parameter calculated using a non-compartmental model: Cmax (ng/mL).

Time frame: FIH-CTH120-SAD: On Day 1; FIH-CTH120-MAD: on Day 1, and Day 7

Observed minimum concentration (Cmin).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: Cmin (ng/mL).

Time frame: FIH-CTH120-SAD: On Day 2; FIH-CTH120-MAD: from Day 2 to Day 7 pre-dose and regularly after the last dose; FIH-CTH120-FI: on Day 2 of Period 1 and Day 15/22/29 of Period 2

Time to observed maximum concentration (tmax).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • Plasma PK parameter calculated using a non-compartmental model: tmax (h).

Time frame: FIH-CTH120-SAD: On Day 1; FIH-CTH120-MAD: on Day 1, and Day 7

Time to first measurable plasma concentration (tlag).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: tlag (h).

Time frame: FIH-CTH120-SAD: On Day 1; FIH-CTH120-MAD: on Day 1, and Day 7; FIH-CTH120-FI: on Day 1 of Period 1 and on Day 14/21/25 of Period 2

Time to last measurable plasma concentration (tlast).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD, and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: tlast (h).

Time frame: FIH-CTH120-SAD: On Day 2; FIH-CTH120-MAD: on Day 1, and Day 7; FIH-CTH120-FI: on Day 2 of Period 1 and Day 15/22/29 of Period 2

Area under the concentration-time curve (AUC0-24h, AUC0-t, AUC0-∞).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). • Plasma PK parameter calculated using a non-compartmental model: AUC0-24h (h \* ng/mL), AUC0-t (h \* ng/mL) AUC0-∞ (h \* ng/mL).

Time frame: FIH-CTH120-SAD: AUC0-24h on Day 1; AUC0-t, AUC0-∞ where t is Day 8 (+/- 1 days) or the latest timepoint observed; FIH-CTH120-MAD: "AUC0-24h on Day 1 and Day 7; AUC0-t, AUC0-∞ after last dose, where t is Day 15 (+ 2 days) or the last timepoint observed

Terminal elimination half-life (t1/2).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD, and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: t1/2 (h).

Time frame: FIH-CTH120-SAD: from Day 1 to Day 8; FIH-CTH120-MAD: from Day 1 to Day 15; FIH-CTH120-FI: from Day 1 to Day28/35/42

Apparent clearance (CL/F).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD, and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: CL/F (mL/h \* kg).

Time frame: FIH-CTH120-SAD: from Day 1 to Day 8; FIH-CTH120-MAD: from Day 1 to Day 15; FIH-CTH120-FI: from Day 1 to Day28/35/42

Apparent volume of distribution: Vd/F.

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD, and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: Vd/F (mL/kg).

Time frame: FIH-CTH120-SAD: from Day 1 to Day 8; FIH-CTH120-MAD: from Day 1 to Day 15; FIH-CTH120-FI: from Day 1 to Day28/35/42

Elimination rate constant (λz).

Secondary Pharmacokinetics endpoints for FIH-CTH120-SAD, FIH-CTH120-MAD, and FIH-CTH120-FI. • Plasma PK parameter calculated using a non-compartmental model: λz (1/h).

Time frame: FIH-CTH120-SAD: from Day 1 to Day 8; FIH-CTH120-MAD: from Day 1 to Day 15; FIH-CTH120-FI: from Day 1 to Day28/35/42

Serotonin (5-HT) metabolite profile.

Secondary Pharmacodynamic endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). Concentrations of 5-Hydroxy indoleacetic acid (5-HIAA) (ng/mL).

Time frame: FIH-CTH120-SAD: on Day 1 and Day 2; FIH-CTH120-MAD: on Day 1, Day 2, Day 7, and Day 8

Noradrenaline (NA) metabolite profile.

Secondary Pharmacodynamic endpoints for FIH-CTH120-SAD and FIH-CTH120-MAD (Not applicable for FIH-CTH120-FI). Concentrations of 3-Methoxy-4-hydroxyphenylglycol (MHPG) (ng/mL).

Time frame: FIH-CTH120-SAD: on Day 1 and Day 2; FIH-CTH120-MAD: on Day 1, Day 2, Day 7, and Day 8

Treatment-emergent AEs (TAES).

Secondary Safety and tolerability endpoints (FIH-CTH120-FI). • AEs will be described in terms of result, frequency, intensity, medical decision, relation with study drug, as well as treatment received and subject retirement, duration, and time elapsed. AEs will also be listed and coded using the MedDRA Dictionary (version 26.0) for the term's codification.