Safety, Tolerability, and Preliminary Effectiveness of CTH120 in Fragile X Syndrome

Phase 2RecruitingNCT07654114

Connecta Therapeutics, S.L.30 enrolled

Overview

The purpose of this Phase IIa study is to evaluate the safety, tolerability, and effectiveness of CTH120 in adult males with Fragile X syndrome.

A total of 30 randomized adult participants with Fragile X syndrome will participate in the clinical trial (randomization ratio 1:1 treated vs placebo arms). The expected distribution between sites will be 1:1. This trial will consist of a Screening period of up to 28 days prior to treatment period. A final follow-up period for safety of 14 days (± 2 days) is planned after the end of treatment. The duration of the study will be approximately 3 months for each participant.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Fragile X Syndrome (FXS)Fragile X Syndrome

Interventions

CTH120DRUG

15 participants will be randomized to receive CTH120 75 mg hard capsules. Capsules of CTH120 will be administered by the oral route to participants twice a day, one capsule in the morning and one capsule in the evening, at approximately the same times each day, after breakfast (morning dose) and after dinner (evening dose), with a glass of water. The evening dose will be taken approximately 12 h from the morning dose, and preferably before midnight. The evening dose must not be taken before at least 8 hours from the morning dose.

CTH120 placebo hard capsulesOTHER

15 participants will be randomized to receive CTH120 placebo hard capsules. Capsules of CTH120 matching placebo will be administered by the oral route to participants twice a day, one capsule in the morning and one capsule in the evening, at approximately the same times each day, after breakfast (morning dose) and after dinner (evening dose), with a glass of water. The evening dose will be taken approximately 12 h from the morning dose, and preferably before midnight. The evening dose must not be taken before at least 8 hours from the morning dose.

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult male participants. 2. Aged ≥ 18 and ≤ 45 years. 3. Weight ≥ 50 kg and ≤ 100 kg. 4. Body mass index (BMI) ≥ 18.5 and ≤ 32. 5. Clinical and molecular diagnosis of Fragile X syndrome (\> 200 CGG repeats in the promoter region of the FMR1 gene). 6. Participants must have a parent, or other reliable caregiver, who agrees to accompany the participant to all study visits, provide information about the participant as required by the protocol, and ensure compliance with study tests. 7. Legal representative understands and accepts the study procedures. If only one parent signs, he/she should confirm that the other parent does not object to the patient's participation in the study. 8. Participant assenting and/or willing to participate. 9. Signed informed consent by legal representative prior to any study-mandated procedure. 10. Participant with a CGI-S score ≥ 3 evaluated by a clinician with experience on Fragile X syndrome, independently mobile and having sufficient vision and hearing to participate in study evaluations. They must be able to be understood most of the time and must not depend upon other forms of communication, signs, symbol boards or devices as their primary form of communication. 11. Participants are expected to complete all procedures scheduled during the study visits. 12. VCI scaled score \>4 on the WISC-V, based on mental age. Exclusion Criteria: 1. Personal history of infantile spasms/convulsions/epilepsy, severe head trauma or CNS infections (e.g. meningitis), except for infantile febrile seizures. 2. Participants with a current diagnosis of severe (Level 3) autism spectrum disorder or any primary psychiatric diagnosis according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-DSM-5). Diagnoses that are secondary, such as attention deficit hyperactivity disorder, depressive disorders, anxiety disorders and conduct disorders are allowed if they are considered to not interfere with study conduct and are stable during the 8 weeks prior to screening. Related allowed treatments must be on stable dosing for the last 3 months. 3. Substance use disorder according to the DSM-5 criteria. 4. Epileptiform abnormalities on EEG (excluding isolated sharp waves and beyond those expected for age). 5. Any life-threatening medical disease. 6. Any other clinically relevant concomitant disease or condition or finding at screening that in the judgment of the investigator could interfere with the treatment, the conduct of the study and related procedures and/or might bias the study results interpretation or could jeopardize the participant's safety. 7. Any clinically significant findings on physical examination including clinically significant vital sign abnormalities, from the perspective of the investigator. 8. Any clinically significant laboratory or ECG abnormalities, from the perspective of the investigator, at Screening and/or prior to the initiation of the study medication. 9. Known hypersensitivity or intolerance to any component of the investigational medicinal product or its excipients. 10. Neuroleptic or antidepressant (SSRI) drugs within the 8 weeks prior to screening, except for sertraline at maximum 100 mg/day, and with no changes in the 8 weeks prior the initiation of the study. 11. More than 3 psychotropic medications simultaneously in the 8 weeks prior to Screening and also during the study. 12. Any new prescription or over the counter drug (except occasional use of paracetamol) in the last 2 weeks before Day 1. 13. Participation in a clinical study with investigational treatments in the last 8 weeks prior to screening. 14. Auditory or visual impairments that cannot be corrected. 15. Positive EtG/EtS test in urine. 16. Positive drug test in urine.

Locations (2)

Hospital del Mar Medical Research Institute

Barcelona, Barcelona, Spain

RECRUITING

Consorci Corporació Sanitaria Parc Taulí. Institut Investigació i Innovació Parc Taulí (I3PT)

Sabadell, Barcelona, Spain

RECRUITING

Outcomes

Primary Outcomes

Treatment-emergent adverse events (TEAEs).

Primary Safety and Tolerability endpoint for FXS-CTH120-01. 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 for the term's codification.

Time frame: From Day 1 to End-of-study: EOS will be on Day 56 (±2 days).

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

Primary Safety and Tolerability endpoint for FXS-CTH120-01. 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 56 (±2 days).

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

Primary Safety and Tolerability endpoint for FXS-CTH120-01. 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 56 (±2 days).

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

Primary Safety and Tolerability endpoint for FXS-CTH120-01. Body temperature will be measured using an automated vital sign monitor device.

Time frame: From Day 1 to End-of-study (EOS): on Day 56 (±2 days).

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

Primary Safety and Tolerability endpoint for FXS-CTH120-01. Triplicate 12-lead ECGs will be recorded in a supine position after at least 10-minute rest. Each lead will be recorded for at least 3 beats at a speed of 25 mm/s.CGs will be recorded using a machine that automatically calculates the following parameter: heart rate (bpm).

Time frame: From Day 1 to End-of-study (EOS): on Day 56 (±2 days).

Central Contacts

Josep Prous, PhD

CONTACT

(+34) 934034509 clinicaltrials@connectatherapeutics.com

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Observed maximum concentration (Cmax).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: Cmax (ng/mL).

Time frame: On Day 15 and Day 42.

Measured concentration at the end of a dosing interval at steady state (Ctrough).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: Ctrough (ng/mL).

Time frame: On Day 15, Day 28 and Day 42.

Last analytically quantifiable plasma concentration above LLOQ (Clast).

Secondary Pharmacokinetics endpoint CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: Clast (ng/mL).

Time frame: On Day 15 and Day 42.

Time to reach Cmax (tmax).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: tmax (h).

Time frame: On Day 15 and Day 42.

Lag-time (time delay between drug administration and first observed concentration above LOQ in plasma) (tlag).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: tlag (h).

Time frame: On Day 15 and Day 42.

Time post administration of the last analytically quantifiable concentration (above LLOQ) (tlast).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: tlast (h).

Time frame: On Day 15 and Day 42.

Area under the plasma concentration-time curve (AUC0-t, AUC0-∞, AUCextrap %)

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: AUC0-t (h \* ng/mL), AUC0-∞ (h \* ng/mL), AUCextrap % (h \* ng/mL).

Time frame: On Day 15 and Day 42.

Elimination rate constant (λz).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: λz (1/h).

Time frame: On Day 15 and Day 42.

Terminal half-life (t1/2).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: t1/2 (h).

Time frame: On Day 15 and Day 42.

Apparent clearance (CL/F).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model:CL/F (mL/h \* kg).

Time frame: On Day 15 and Day 42.

Apparent volume of distribution during terminal phase after oral administration: (Vz/F).

Secondary Pharmacokinetics endpoint for CTH120 for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: Vz/F (mL/kg).

Time frame: On Day 15 and Day 42.

Accumulation ratio calculated from Cmax after repeated dosing and Cmax after 1st dosing (RAC Cmax).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: RAC Cmax.

Time frame: On Day 42.

Accumulation ratio calculated from AUC0-t after repeated dosing and AUC0-t (RAC AUC0-t).

Secondary Pharmacokinetics endpoint for CTH120 and its main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: RAC AUC0-t.

Time frame: On Day 42.

Metabolic ratio of metabolite Cmax and parent drug Cmax (MR Cmax).

Secondary Pharmacokinetics endpoint for CTH120's main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: MR Cmax (n-fold).

Time frame: On Day 15 and Day 42.

Metabolic ratio of metabolite AUC0-t and parent drug AUC0-t (MR AUC0-t).

Secondary Pharmacokinetics endpoint for CTH120's main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: MR AUC0-t (n-fold).

Time frame: On Day 15 and Day 42.

Metabolic ratio of metabolite AUC0-∞ and parent drug AUC0-∞ (MR AUC0-∞).

Secondary Pharmacokinetics endpoint for CTH120's main metabolite for FXS-CTH120-01. • Plasma PK parameter calculated using a non-compartmental model: MR AUC0-∞ (n-fold).

Time frame: On Day 15 and Day 42.

Global functioning using the Visual Analogue Scale (VAS)

Secondary exploratory Efficacy endpoints for FXS-CTH120-01: • The VAS consists of a 100 mm horizontal line anchored at each end with descriptors representing opposite extremes of a behavioural or functional domain (Left-end representing the lowest or most impaired level, and the right-end representing the highest or least impaired level). The VAS will be used to evaluate the clinician's perception of the participant's current condition across five specific domains relevant to Fragile X syndrome by placing a mark along the line at the position that best reflects their clinical judgment of the individual's status. This mark is then measured from the left end of the line (0 mm) to the mark (up to 100 mm) to produce a numeric score.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, on Day 42 and on Day 56 (± 2 days) (End-of-study (EOS)).

Global severity using the Clinical Global Impression Severity Scale (CGI-S)

Secondary exploratory Efficacy endpoints for FXS-CTH120-01. CGI-S establishes the baseline illness status and rates illness severity on a 7-point scale, with anchors ranging from "1 = Normal, not at all sick" to "7 = Among the most extremely sick patients".

Time frame: On Baseline visit (From Day -14 to Day -1) and on Day 14.

Global improvement using the Clinical Global Impression Improvement Scale (CGI- I)

Secondary exploratory Efficacy endpoints for FXS-CTH120-01. CGI-I rates how much the participant's illness has improved or worsened relative to the baseline state (CGI-S) on a similar 7-point scale: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; and 7 = very much worse.

Time frame: On Day 14, on Day 42 and on Day 56 (± 2 days) (End-of-study (EOS)).

Behaviour troubles using the Aberrant Behaviour Checklist-Community in FXS (ABC-CFXS)

Secondary exploratory Efficacy endpoints for FXS-CTH120-01: The ABC-CFXS is an adapted version of the Aberrant Behaviour Checklist - Community (ABC-C), specifically tailored for individuals with Fragile X syndrome (FXS). It includes 55 items rated on a 4-point Likert scale ranging from 0 ("not at all a problem") to 3 ("the problem is severe in degree"), assessing six behavioural domains: irritability, hyperactivity, lethargy, social avoidance, stereotypy, and inappropriate speech.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, on Day 42 and on Day 56 (± 2 days) (End-of-study (EOS)).

Cognitive functioning using the National Institutes of Health Toolbox Cognition Battery Intellectual disability NIH-TCB-ID

Secondary exploratory Efficacy endpoints for FXS-CTH120-01: The Fluid Cognition composite score of the NIH Toolbox cognitive battery combines the scores of five tests assessing the following cognitive domains: Cognitive flexibility, Inhibitory control and visual attention, Episodic memory, Processing speed and Working memory. Higher composite scores indicate better cognitive functioning, whereas lower scores indicate greater cognitive impairment.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Anxiety, Depression, and Mood Scale (ADAMS).

Exploratory Efficacy endpoints for FXS-CTH120-01: ADAMS is a scale to assess 28 items, categorized into the following five subscales: Manic/Hyperactive Behaviour, Depressed Mood, Social Avoidance, General Anxiety and Compulsive Behaviour. Each item is evaluated on a 4-point Likert scale rating from 0 (not a problem) to 3 (severe problem). The scores for the 5 subscales will be collected in the eCRF.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Adaptive functioning using the Vineland Adaptive Behaviour Scale 3 (VABS-3)

Exploratory Efficacy endpoints for FXS-CTH120-01: Vineland Adaptive Behavior Scales, Third Edition (VABS-3) is a psychometric instrument that assesses adaptive functioning through a standardized interview with the participant or their caregiver. It evaluates activities of daily living across the domains of Communication, Daily Living Skills, and Socialization. Outcomes include raw scores, V-scale scores, Growth Scale Values (GSVs), domain standard scores, and the Adaptive Behavior Composite (ABC). The Adaptive Behavior Composite (ABC) standard score ranges from 20 to 123. Higher scores indicate better adaptive functioning, whereas lower scores indicate greater adaptative functioning impairment.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Paediatric Quality of Life Inventory (PedsQL) 2.0

Exploratory Efficacy endpoints for FXS-CTH120-01: PedsQL evaluates quality of life involving physical, psychological, social, and cognitive aspects. Quality of life using the PedsQL 2.0 Family Impact Module (parent impact for all ages). Items are rated on a 5-point scale from 0 (never a problem) to 4 (almost always a problem). Items are reversed scored and linearly transformed on a scale ranging from 0 to 100. Higher scores indicate better health-related quality of life.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Paediatric Quality of Life Inventory (PedsQL) 3.0

Exploratory Efficacy endpoints for FXS-CTH120-01: PedsQL evaluates quality of life involving physical, psychological, social, and cognitive aspects. Cognitive functioning using the PedsQL 3.0 Cognitive Functioning Scale (PARENT Reports for Young Adults (ages 18-25) and Adults (ages over 26)). Items are rated on a 5-point scale from 0 (never a problem) to 4 (almost always a problem). Items are reversed scored and linearly transformed on a scale ranging from 0 to 100. Higher scores indicate better health-related quality of life.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Paediatric Quality of Life Inventory (PedsQL) 4.0

Exploratory Efficacy endpoints for FXS-CTH120-01: PedsQL evaluates quality of life involving physical, psychological, social, and cognitive aspects. Quality of life using the PedsQL 4.0 Generic Core Scales (PARENT Reports for Young Adults (ages 18-25) and Adults (ages over 26). Items are rated on a 5-point scale from 0 (never a problem) to 4 (almost always a problem). Items are reversed scored and linearly transformed on a scale ranging from 0 to 100. Higher scores indicate better health-related quality of life.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Quality of sleep using the Pittsburgh Sleep Quality Index (PSQI)

Exploratory Efficacy endpoints for FXS-CTH120-01: Pittsburgh sleep quality index (PSQI) is a self-report questionnaire that assesses sleep quality and quantity. The 19-item self-report questionnaire yields 7 component scores: subjective sleep quality, sleep latency, duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. There are five additional questions that are completed by a bed partner if there is one. The sum of the 7 individual scores (from 0 to 3), ranges from 0 to 21. A total score of less or equal than 5 is associated with good sleep quality. A total score of more than 5 is associated with poor sleep quality.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Neural functioning using Electroencephalography (EEG) (auditory oddball, resting-state and auditory steady-state response)

Exploratory Efficacy endpoints for FXS-CTH120-01: EEG will be recorded using a mobile wireless helmet for high-precision EEG monitoring (Neuroelectrics Enobio® 20 5G, Starlab technology, Spain).

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Social avoidance using eye-tracking

Exploratory Efficacy endpoints for FXS-CTH120-01: An eye tracker (Tobii Technology, Sweden) will be used to record X and Y coordinates of eye position and pupil diameter while participants are exposed to stimuli consisting on coloured photographs of adult human faces.

Time frame: On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.

Biorhythm characteristics using Actigraphy

Exploratory Efficacy endpoints for FXS-CTH120-01: Sleep-wake rhythms will be assessed using an actigraph (GT3X-BT model) placed on the wrist of a non-dominant hand. The actigraph is a non-invasive device, useful for monitoring circadian rhythms and it records consecutive periods of 60 seconds throughout the 24 hours/day. The minimum actigraphy recording will be at least 7 days.

Time frame: Between Baseline visit (From Day -14 to Day -1) and Day 14, and between Day 28 and Day 42.

Protein levels of FMRP in peripheral blood

Exploratory Efficacy endpoints for FXS-CTH120-01: Venous blood samples (9 mL each) will be obtained by extraction of peripheral blood from participants in a EDTA tube.

Time frame: On Baseline visit (From Day -14 to Day -1) and on Day 42.

BDNF concentrations in plasma

Exploratory Efficacy endpoints for FXS-CTH120-01: Venous blood samples (6 mL each) will be obtained by extraction from a cubital vein from participants. A single venipuncture will be used to obtain three aliquots.

Time frame: On Baseline visit (From Day -14 to Day -1) and on Day 42.

miRNA profile in plasma

Exploratory Efficacy endpoints for FXS-CTH120-01: Approximately, 200 µL of human plasma obtained from blood samples collected for BDNF measurement will be processed to extract RNA enriched in small RNAs. RNA quality and concentration will be assessed using the prior library preparation. Libraries will be sequenced at CRG using Nextseq500 sequencer. Processed reads will be mapped to miRBase database using STAR software, and count tables will be generated with FeatureCounts (Subread package). For differential expression (DE) analysis, read counts will be transformed to log2-counts-per-million (logCPM), and variance will be modelled using the voom approach in the limma package.

Time frame: On Baseline visit (From Day -14 to Day -1) and on Day 42.