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

Official title

Evaluation of the Safety, Tolerability, and Effectiveness of CTH120 in Adult Males With Fragile X Syndrome

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.

Detailed description

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.

Interventions

• Drug CTH120
  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 l
• Other CTH120 placebo hard capsules
  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 b

Primary outcome measures

• Treatment-emergent adverse events (TEAEs). [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). [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). [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). [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). [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: rhythm. [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: PQ/PR interval (ms). [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: QRS duration (ms). [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: QT (ms). [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: QTcF (ms). [Time frame: From Day 1 to End-of-study (EOS): on Day 56 (±2 days).]

Secondary outcome measures (12)

• Observed maximum concentration (Cmax). [Time frame: On Day 15 and Day 42.]
• Measured concentration at the end of a dosing interval at steady state (Ctrough). [Time frame: On Day 15, Day 28 and Day 42.]
• Last analytically quantifiable plasma concentration above LLOQ (Clast). [Time frame: On Day 15 and Day 42.]
• Time to reach Cmax (tmax). [Time frame: On Day 15 and Day 42.]
• Lag-time (time delay between drug administration and first observed concentration above LOQ in plasma) (tlag). [Time frame: On Day 15 and Day 42.]
• Time post administration of the last analytically quantifiable concentration (above LLOQ) (tlast). [Time frame: On Day 15 and Day 42.]
• Area under the plasma concentration-time curve (AUC0-t, AUC0-∞, AUCextrap %) [Time frame: On Day 15 and Day 42.]
• Elimination rate constant (λz). [Time frame: On Day 15 and Day 42.]
• Terminal half-life (t1/2). [Time frame: On Day 15 and Day 42.]
• Apparent clearance (CL/F). [Time frame: On Day 15 and Day 42.]
• Apparent volume of distribution during terminal phase after oral administration: (Vz/F). [Time frame: On Day 15 and Day 42.]
• Accumulation ratio calculated from Cmax after repeated dosing and Cmax after 1st dosing (RAC Cmax). [Time frame: On Day 42.]

Eligibility criteria

Inclusion criteria

• Adult male participants.
• Aged ≥ 18 and ≤ 45 years.
• Weight ≥ 50 kg and ≤ 100 kg.
• Body mass index (BMI) ≥ 18.5 and ≤ 32.
• Clinical and molecular diagnosis of Fragile X syndrome (> 200 CGG repeats in the promoter region of the FMR1 gene).
• 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.
• 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.
• Participant assenting and/or willing to participate.
• Signed informed consent by legal representative prior to any study-mandated procedure.
• 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.
• Participants are expected to complete all procedures scheduled during the study visits.
• VCI scaled score >4 on the WISC-V, based on mental age.

Exclusion criteria

• Personal history of infantile spasms/convulsions/epilepsy, severe head trauma or CNS infections (e.g. meningitis), except for infantile febrile seizures.
• 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.
• Substance use disorder according to the DSM-5 criteria.
• Epileptiform abnormalities on EEG (excluding isolated sharp waves and beyond those expected for age).
• Any life-threatening medical disease.
• 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.
• Any clinically significant findings on physical examination including clinically significant vital sign abnormalities, from the perspective of the investigator.
• 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.
• Known hypersensitivity or intolerance to any component of the investigational medicinal product or its excipients.
• 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.
• More than 3 psychotropic medications simultaneously in the 8 weeks prior to Screening and also during the study.
• Any new prescription or over the counter drug (except occasional use of paracetamol) in the last 2 weeks before Day 1.
• Participation in a clinical study with investigational treatments in the last 8 weeks prior to screening.
• Auditory or visual impairments that cannot be corrected.
• Positive EtG/EtS test in urine.
• Positive drug test in urine.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Spain · 2 centers

• Hospital del Mar Medical Research Institute — Barcelona
• Consorci Corporació Sanitaria Parc Taulí. Institut Investigació i Innovació Parc Taulí (I3 — Sabadell

Publications

• 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, Accessed: Jul. 07, 2022. [Online]. Available: www.ema.europa.eu/contact
• Myrick LK, Nakamoto-Kinoshita M, Lindor NM, Kirmani S, Cheng X, Warren ST. Fragile X syndrome due to a missense mutation. Eur J Hum Genet. 2014 Oct;22(10):1185-9. doi: 10.1038/ejhg.2013.311. Epub 2014 Jan 22. PMID 24448548
• Quartier A, Poquet H, Gilbert-Dussardier B, Rossi M, Casteleyn AS, Portes VD, Feger C, Nourisson E, Kuentz P, Redin C, Thevenon J, Mosca-Boidron AL, Callier P, Muller J, Lesca G, Huet F, Geoffroy V, El Chehadeh S, Jung M, Trojak B, Le Gras S, Lehalle D, Jost B, Maury S, Masurel A, Edery P, Thauvin-Robinet C, Gerard B, Mandel JL, Faivre L, Piton A. Intragenic FMR1 disease-causing variants: a signif PMID 28176767
• Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ. Fragile X syndrome. Nat Rev Dis Primers. 2017 Sep 29;3:17065. doi: 10.1038/nrdp.2017.65. PMID 28960184
• Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010 Jul;7(3):264-74. doi: 10.1016/j.nurt.2010.05.005. PMID 20643379
• Grigsby J. The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology. Clin Neuropsychol. 2016 Aug;30(6):815-33. doi: 10.1080/13854046.2016.1184652. Epub 2016 Jun 29. PMID 27356167
• Banerjee A, Ifrim MF, Valdez AN, Raj N, Bassell GJ. Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies. Brain Res. 2018 Aug 15;1693(Pt A):24-36. doi: 10.1016/j.brainres.2018.04.008. Epub 2018 Apr 10. PMID 29653083
• Bakker CE, Oostra BA. Understanding fragile X syndrome: insights from animal models. Cytogenet Genome Res. 2003;100(1-4):111-23. doi: 10.1159/000072845. PMID 14526171

Identifiers

NCT: NCT07654114 · CTH-CTH120-FXS-01 · 2025-522972-97-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗