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

NCT06480968 | Completed Phase 1 DMC

• 2 other identifiers: CTH-CTH120-FIH-012022-502209-13-01
• Study Type: interventional
• Target: 76
• Locations: 1 country
• Sites: 1

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.

Conditions

Fragile X Syndrome

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

Outcome Measures

Primary Outcomes (19)

• 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.

  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.

  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.

  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.

  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)

  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).

  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)

  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).

  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)

  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).

  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).

  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).

  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).

  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).

  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.

  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.

  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.

  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).

  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.

  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).

  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).

  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).

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

Secondary Outcomes (28)

• Observed maximum concentration (Cmax).

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

• 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

• Time to observed maximum concentration (tmax).

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

• 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

• 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

Other Outcomes (15)

• 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

• Observed maximum concentration (Cmax).

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

• Time to observed maximum concentration (tmax).

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

Study Arms (2)

CTH120

EXPERIMENTAL

Hard capsules of two strengths, 10 mg and 75 mg of CTH120 to be administered with 200 mL of water. CTH120 will be supplied by CONNECTA Therapeutics. Within each dose cohort group subjects (n=8) will be randomly assigned to the CTH120 dose or to the matching placebo in a 6 to 2 randomization ratio (placebo=2 and CTH120=6 per dose).

Drug: CTH120

Placebo

PLACEBO COMPARATOR

Hard capsules of placebo to be administered with 200 mL of water. Placebo will be supplied by CONNECTA Therapeutics. Within each dose cohort group subjects (n=8) will be randomly assigned to the CTH120 dose or to the matching placebo in a 6 to 2 randomization ratio (placebo=2 and CTH120=6 per dose).

Other: Placebo

Interventions

CTH120 DRUG

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").

CTH120

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Connecta Therapeutics, S.L.: lead
• Hospital del Mar Research Institute (IMIM): collaborator
• Adknoma Health Research: collaborator
• Ministry of Science and Innovation, Spain: collaborator

Study Sites (1)

Hospital del Mar Medical Research Institute (IMIM)

Barcelona, Barcelona, 08003, Spain

Location

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Related Links

• EMEA, "Committee for Medicinal Products for Human Use (CHMP) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products," EMEA/CHMP/SWP/28367/07, 2017
• FDA, Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers Pharmacology and Toxicology Guidance for Industry.....
• FDA, "Assessment of Abuse Potential of Drugs Guidance for Industry," 2017, Accessed: Jul. 07, 2022.
• FDA, "FDA Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials - ECA Academy."
• "FDA Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies (Issued 12/2002, Posted 1/30/2003) - ECA Academy."
• U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, "Common Terminology Criteria for Adverse Events (CTCAE) v5.0," 2017
• N. Cancer Institute, "Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events (CTCAE) v5.0," 2017

MeSH Terms

Conditions

Fragile X Syndrome; Neurodevelopmental Disorders; Central Nervous System Diseases; Intellectual Disability; Neurobehavioral Manifestations; Genetic Diseases, X-Linked; Congenital Abnormalities; Rare Diseases

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Mental Disorders; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Disease Attributes; Pathologic Processes

Study Officials

• Rafael De la Torre, Pharm, PhD

  Hospital del Mar Medical Research Institute (IMIM)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: July 27, 2023
• First Posted: July 1, 2024
• Study Start: June 23, 2023
• Primary Completion: November 11, 2024
• Study Completion: November 11, 2024
• Last Updated: January 23, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1)