Fragile X Syndrome
Conditions
Keywords
Fragile X Syndrome, FXS, Fragile X, Neurodevelopmental Disorders, Central Nervous System Diseases, Intellectual Disability, Neurobehavioral Manifestations, Genetic Diseases, X-Linked, Congenital Abnormalities, Orphan Diseases, Rare Diseases
Brief summary
The purpose of this First-in-Human Phase I study is to investigate the safety, tolerability and pharmacokinetics of CTH120 in adult healthy volunteers.
Detailed description
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.
Interventions
DRUGCTH120
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).
OTHERPlacebo
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.
Sponsors
Hospital del Mar Research Institute (IMIM)
Adknoma Health Research
Ministry of Science and Innovation, Spain
Connecta Therapeutics, S.L.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
FIH-CTH120-SAD and FIH-CTH120-MAD: double-blind, placebo-controlled trial preventing the knowledge of the study drug allocation. Thus, all trial stakeholders but the Pharmacy personnel will be blinded throughout the trial including the Sponsor personnel, the participating subjects, the study team at the investigational site, including the person administering the study drugs to the subject as well as the CRO personnel involved in the data management and statistical analysis. FIH-CTH120-FI: open-label study.
Intervention model description
FIH-CTH120-SAD: Prospective, monocentre, double-blind, randomized, placebo-controlled, subsequent-group, Phase I investigation to assess the safety, tolerability and pharmacokinetics of CTH120 administered orally in single ascending doses. FIH-CTH120-MAD: Prospective, monocentre, double-blind, randomized, placebo-controlled, subsequent-groups, Phase I investigation to assess the safety, tolerability and pharmacokinetics of CTH120 administered orally in multiple ascending doses. FIH-CTH120-FI: Prospective, open-label single dose, two-condition (fed versus fasting), two sequences, crossover Phase I investigation to assess the effects of food on the bioavailability of CTH120.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: QRS duration (ms) | 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 | 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). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: PR interval (ms) | 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 | 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: PR interval (ms). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: heart rate (bpm) | 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 | 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: heart rate (bpm). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: normal sinus rhythm (NSR) | 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 | 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 to observed maximum concentration (tmax) after fed and fasting conditions. | FIH-CTH120-FI: On Day 1 of Period 1, and on Day 14/21/25 of Period 2 | 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). |
| Observed maximum concentration (Cmax) after fed and fasting conditions. | FIH-CTH120-FI: On Day 1 of Period 1, and on Day 14/21/25 of Period 2 | 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). |
| Psychometric tests:Immediate Mood Scaler (IMS). | FIH-CTH120-SAD: on Day -1 and Day 2; FIH-CTH120-MAD: on Day -1, Day 1, and Day 7 | 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. |
| Psychometric tests: Hospital Anxiety/Depression rating Scale (HADS) | FIH-CTH120-SAD: on Day -1 and Day 2; FIH-CTH120-MAD: on Day -1, Day 1, and Day 7 | 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). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: urinalysis | 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 | 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. |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: coagulation | 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 | 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. |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: serum chemistry | 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 | 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. |
| Area under the concentration-time curve (AUC0-24h, AUC0-t, AUC0-∞) after fed and fasting conditions. | FIH-CTH120-FI: AUC0-24h on Day 1; AUC0-t, AUC0-∞ where t is the last or the latest timepoint observed | 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). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: haematology | 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 | 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). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: QTcF (ms) | 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 | 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). |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in electrocardiogram (ECG) values: QT (ms) | 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 | 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). |
| Treatment-emergent adverse events (TEAEs). | 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 | 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. |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in blood pressure (mmHg) | 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 | 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. |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in pulse rate (bpm) | 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 | 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. |
| Treatment-emergent potentially clinically significant abnormalities (PSCAs) in oral body temperature (ºC) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to observed maximum concentration (tmax). | FIH-CTH120-SAD: On Day 1; FIH-CTH120-MAD: on Day 1, and Day 7 | 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 to first measurable plasma concentration (tlag). | 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 | 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 to last measurable plasma concentration (tlast). | 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 | 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). |
| Area under the concentration-time curve (AUC0-24h, AUC0-t, AUC0-∞). | 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 | 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). |
| Terminal elimination half-life (t1/2). | 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 | 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). |
| Apparent clearance (CL/F). | 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 | 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). |
| Apparent volume of distribution: Vd/F. | 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 | 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). |
| Elimination rate constant (λz). | 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 | 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). |
| Serotonin (5-HT) metabolite profile. | FIH-CTH120-SAD: on Day 1 and Day 2; FIH-CTH120-MAD: on Day 1, Day 2, Day 7, and Day 8 | 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). |
| Treatment-emergent PSCAs in safety laboratory parameters: urinalysis | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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. |
| Treatment-emergent AEs (TAES). | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | 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. |
| Treatment-emergent PSCAs in vital signs: blood pressure (mmHg) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (FIH-CTH120-FI). • Blood pressure (mmHg) will be measured in the supine position following a 5 min rest. |
| Treatment-emergent PSCAs in vital signs: pulse rate (bpm) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (FIH-CTH120-FI). • Pulse rate (bpm) will be measured in the supine position following a 5 min rest. |
| Treatment-emergent PSCAs in vital signs: Oral body temperature (ºC) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (FIH-CTH120-FI). • Oral body temperature (ºC) will be measured using an automated vital sign monitor device. |
| Treatment-emergent PSCAs in ECG values: heart rate (bpm) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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 parameters will be recorded: heart rate (bpm). |
| Treatment-emergent PSCAs in ECG values: normal sinus rhythm (NSR) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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). |
| Treatment-emergent PSCAs in ECG values: PR interval (ms) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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: PR interval (ms) |
| Treatment-emergent PSCAs in ECG values: QRS duration (ms) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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). |
| Treatment-emergent PSCAs in ECG values: QT (ms) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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). |
| Treatment-emergent PSCAs in ECG values: QTcF (ms) | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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). |
| Treatment-emergent PSCAs in safety laboratory parameters: haematology | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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). |
| Treatment-emergent PSCAs in safety laboratory parameters: serum chemistry | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (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. |
| Treatment-emergent PSCAs in safety laboratory parameters: coagulation | FIH-CTH120-FI: from Day 1 to End-of-study. EOS will be on Day 28, or 35 or 42 (±1 day) depending on the length of the washout period determined | Secondary Safety and tolerability endpoints (FIH-CTH120-FI). The following tests will be performed: • Coagulation parameters: activated partial thromboplastin time (aPTT), PT and INR. |
| Noradrenaline (NA) metabolite profile. | FIH-CTH120-SAD: on Day 1 and Day 2; FIH-CTH120-MAD: on Day 1, Day 2, Day 7, and Day 8 | 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). |
| Psychometric tests: HADS | FIH-CTH120-FI: On Day -1, Day 2, Day 13/20/27 and Day 15/22/29 | Secondary Safety and tolerability endpoints (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 ranging 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). |
| Psychometric tests: IMS | FIH-CTH120-FI: On Day -1, Day 2, Day 13/20/27 and Day 15/22/29 | Secondary Safety and tolerability endpoints (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. |
| Observed maximum concentration (Cmax). | FIH-CTH120-SAD: On Day 1; FIH-CTH120-MAD: on Day 1, and Day 7 | 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). |
| Observed minimum concentration (Cmin). | 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 | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Urine elimination rate constant (h-1) | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Urine pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Urine elimination rate constant (h-1): calculated as the slope (semilog plot) of the cumulative amount of drug excreted after each collection interval against the median of the collection interval. Nominal or actual times can be used as appropriate. |
| Urinary excretion rate (UER) | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Urine pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. The urinary excretion rate (μg/h) is the product of the urine flow rate (mL/h) and the urine analyte concentration (ng/mL), where: * Urine flow rate (UFR) is the quotient between the Urine volume (mL) and the time interval (h), where urine volume is the total urine volume collected in the time interval (mL). * Urine analyte concentration: concentration of the analyte in urine (ng/mL). |
| Amount excreted: relative to dose as fe/F | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Urine pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • The excreted amount will be calculated as relative to dose as fe/F: fraction of the oral administered drug excreted into the urine (%). |
| Amount excreted: absolute value as Ae | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Urine pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • The excreted amount will be calculated as absolute value as Ae: cumulative amount of unchanged drug excreted into the urine (interval) (µg). |
| Renal clearance (CLr) | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Urine pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. Renal clearance (L/h), as a Volume/time, calculated as CLr = Ae/PlasmaAUC0-∞, where Ae (µg) is the cumulative amount of unchanged drug excreted into the urine (0-48 h interval) and Plasma AUC0-∞ (ng.h/mL) is the area under the plasma concentration-time curve from time zero to infinity. |
| Elimination rate constant (λz) | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: λz (1/h). |
| Metabolic ratio AUC0-24 (MR AUC0-24) | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: MR AUC0-24 (n-fold) |
| Metabolic ratio Cmax (MR Cmax) | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: MR Cmax (n-fold). |
| Terminal elimination half-life (t1/2). | FIH-CTH120-FI: from Day 1 to Day28/35/42 | Exploratory objective (FIH-CTH120-FI). • Plasma PK parameter calculated using a non-compartmental model: t1/2 (h). |
| Time to last measurable plasma concentration (tlast). | FIH-CTH120-FI: on Day 2 of Period 1 and Day 15/22/29 of Period 2 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: tlast (h). |
| Time to first measurable plasma concentration (tlag). | FIH-CTH120-FI: on Day 1 of Period 1 and on Day 14/21/25 of Period 2 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: tlag (h). |
| Observed minimum concentration (Cmin). | FIH-CTH120-FI: on Day 2 of Period 1 and Day 15/22/29 of Period 2 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: Cmin (ng/mL). |
| Time to observed maximum concentration (tmax). | FIH-CTH120-FI: on Day 1 of Period 1 and on Day 14/21/25 of Period 2 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: tmax (h). |
| Observed maximum concentration (Cmax). | FIH-CTH120-FI: on Day 1 of Period 1 and on Day 14/21/25 of Period 2 | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: Cmax (ng/mL). |
| Area under the concentration-time curve (AUC0-24h, AUC0-t, AUC0-∞). | FIH-CTH120-FI: AUC0-24h on Day 1; AUC0-t, AUC0-∞ where t is the last or the latest timepoint observed | Exploratory objective (FIH-CTH120-FI). Plasma pharmacokinetics of the major metabolite of CTH120 after CTH120 single dose administration. • Plasma PK parameter calculated using a non-compartmental model: AUC0-24h (h \* ng/mL), AUC0-t (h \* ng/mL) AUC0-∞ (h \* ng/mL). |
Countries
Spain
Outcome results
None listed