Safety, Tolerability, and Preliminary Effectiveness of CTH120 in Fragile X Syndrome (FXS-CTH120-01)

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

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

Study Overview

• Status: Recruiting
• Conditions: Fragile X Syndrome; Fragile X Syndrome (FXS)
• Intervention / Treatment: Drug: CTH120; Other: CTH120 placebo hard capsules

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Josep Prous, PhD; Phone Number: (+34) 934034509; Email: clinicaltrials@connectatherapeutics.com

Study Locations

• Spain
  • Barcelona
    • Barcelona, Barcelona, Spain, 08003
      • Recruiting
      • Hospital del Mar Medical Research Institute
      • Contact: Rafael De la Torre, Pharm, PhD; Phone Number: (+34) 93 3160484; Email: rtorre2@researchmar.net
      • Contact: Ana María Aldea, MD, PhD; Phone Number: (+34) 93 3160439; Email: aaldea@researchmar.net
    • Sabadell, Barcelona, Spain, 08208
      • Recruiting
      • Consorci Corporació Sanitaria Parc Taulí. Institut Investigació i Innovació Parc Taulí (I3PT)
      • Contact: Ana Roche Martínez, MD, PhD; Phone Number: (+34) 93 723 10 10; Email: aroche@tauli.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CTH120; CTH120 75 mg hard capsules will be provided by CONNECTA Therapeutics, S.L. as hard capsules for oral administration. CTH120 75 mg hard capsules contain 75 mg CTH120 drug substance (dose expressed as active moiety) and compendial excipients to be orally administered after breakfast and after dinner with a glass of water. The recommended dosage of CTH120 is 75 mg orally twice daily (BID) in fed conditions after breakfast and after dinner.	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 least 8 hours from the morning dose.
Placebo Comparator: CTH120 placebo hard capsules; CTH120 placebo hard capsules will be provided by CONNECTA Therapeutics, S.L. as hard capsules for oral administration. CTH120 matching placebo hard capsules (that contain the same compendial excipients than and are identical in appearance to CTH120 75 mg hard capsules) will be orally administered twice daily (BID) in fed conditions after breakfast and after dinner with a glass of water.	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 be taken before at least 8 hours from the morning dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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).	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.	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: rhythm.	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).	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. ECGs will be recorded using a machine that automatically calculates the following parameter: PQ/PR interval (ms).	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).	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. ECGs will be recorded using a machine that automatically calculates the following parameter: QRS duration (ms).	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).	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. ECGs will be recorded using a machine that automatically calculates the following parameter: QT (ms).	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).	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. ECGs will be recorded using a machine that automatically calculates the following parameter: QTcF (ms).	From Day 1 to End-of-study (EOS): on Day 56 (±2 days).
Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: haematology.	Primary Safety and Tolerability endpoint for FXS-CTH120-01. The following tests will be performed: • Haematology: haemoglobin, haematocrit, red blood cell count, mean corpuscular volume, mean corpuscular haemoglobin, white blood cell count (absolute and %), platelets.	Screening visit (From Day -28 to Day -1), on Day 15, on Day 28, on Day 42 and Day 56 (± 2 days) (End-of-study (EOS)).
Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: serum chemistry.	Primary Safety and Tolerability endpoint for FXS-CTH120-01. The following tests will be performed: • Serum chemistry: sodium, potassium, urea, creatinine, albumin, calcium, phosphate, glucose, total cholesterol, LDL, HDL, TG, ALT, AST, GGT, total bilirubin, CPK, LDH.	Screening visit (From Day -28 to Day -1), on Day 15, on Day 28, on Day 42 and Day 56 (± 2 days) (End-of-study (EOS)).
Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: coagulation.	Primary Safety and Tolerability endpoint for FXS-CTH120-01. The following tests will be performed: • Coagulation parameters: INR, aPTT, PT.	Screening visit (From Day -28 to Day -1), on Day 15, on Day 28, on Day 42 and Day 56 (± 2 days) (End-of-study (EOS)).
Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: urinalysis.	Primary Safety and Tolerability endpoint for FXS-CTH120-01. The following tests will be performed: • Urinalysis parameters: leucocytes, protein, bilirubin, urobilinogen, ketones, red blood cells, pH, nitrite, glucose (only at Screening visit).	Screening visit (from Day -28 to Day -1).
Treatment-emergent potentially clinically significant abnormalities (PSCAs) in safety laboratory parameters: viral serology and detection.	Primary Safety and Tolerability endpoint for FXS-CTH120-01. The following tests will be performed: • Viral serology and detection: Hepatitis B (HBsAg), Hepatitis C (Ac IgG VHC) and HIV antibody.	Screening visit (from day -28 to Day -1).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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).	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).	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).	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).	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).	On Day 15 and Day 42.
Area under the plasma concentraction-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).	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).	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).	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).	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).	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.	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.	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).	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).	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).	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. 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.	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".	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.	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.	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 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.	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.	On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.
Adaptive functioning using the Vineland Adaptive Behaviour Scale (VABS-3)	Exploratory Efficacy endpoints for FXS-CTH120-01: VABS-3 is a psychometric instrument that assesses the adaptive level of functioning by standardized interview of the person or their caregiver through their activities of daily living such as walking, talking, getting dressed, going to school, preparing a meal, etc.	On Baseline visit (From Day -14 to Day -1), on Day 14, and on Day 42.
Paediatric Quality of Life Inventory PedsQL	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); Quality of life using the PedsQL 4.0 Generic Core Scales (PARENT Reports for Young Adults (ages 18-25) and Adults (ages over 26); Quality of life using the PedsQL 2.0 Family Impact Module (parent impact for all ages)	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.	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).	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 participanta are exposed to stimuli consisting on coloured photographs of adult human faces.	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.	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.	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.	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.	On Baseline visit (From Day -14 to Day -1) and on Day 42.

Collaborators and Investigators

• Sponsor: Connecta Therapeutics, S.L.
• Collaborators: Corporacion Parc Tauli; Hospital del Mar Research Institute (IMIM); Ministry of Science and Innovation, Spain; Astrum CRO, S.L.
• Investigators: Principal Investigator: Ana Roche Martínez, MD, PhD, Consorci Corporació Sanitària Parc Taulí. Institut d'Investigació i Innovació Parc Taulí (I3PT); Principal Investigator: Rafael De la Torre, Pharm, PhD, Hospital del Mar Medical Research Institute; Principal Investigator: Ana María Aldea, MD, PhD, Hospital del Mar Medical Research Institute

Publications and helpful links

General Publications

• Tottenham N, Tanaka JW, Leon AC, McCarry T, Nurse M, Hare TA, Marcus DJ, Westerlund A, Casey BJ, Nelson C. The NimStim set of facial expressions: judgments from untrained research participants. Psychiatry Res. 2009 Aug 15;168(3):242-9. doi: 10.1016/j.psychres.2008.05.006. Epub 2009 Jun 28.
• Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213. doi: 10.1016/0165-1781(89)90047-4.
• Berry-Kravis EM, Harnett MD, Reines SA, Reese MA, Ethridge LE, Outterson AH, Michalak C, Furman J, Gurney ME. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nat Med. 2021 May;27(5):862-870. doi: 10.1038/s41591-021-01321-w. Epub 2021 Apr 29.
• Bailey DB Jr, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A. 2008 Aug 15;146A(16):2060-9. doi: 10.1002/ajmg.a.32439.
• Esbensen AJ, Rojahn J, Aman MG, Ruedrich S. Reliability and validity of an assessment instrument for anxiety, depression, and mood among individuals with mental retardation. J Autism Dev Disord. 2003 Dec;33(6):617-29. doi: 10.1023/b:jadd.0000005999.27178.55.
• Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, Berry-Kravis E, Lachiewicz A, Brown EC, Hessl D. Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment. J Autism Dev Disord. 2012 Jul;42(7):1377-92. doi: 10.1007/s10803-011-1370-2.
• Kenny A, Wright D, Stanfield AC. EEG as a translational biomarker and outcome measure in fragile X syndrome. Transl Psychiatry. 2022 Jan 24;12(1):34. doi: 10.1038/s41398-022-01796-2.
• 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.
• 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 significant mutational mechanism leading to Fragile-X syndrome. Eur J Hum Genet. 2017 Apr;25(4):423-431. doi: 10.1038/ejhg.2016.204. Epub 2017 Feb 8.
• 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.
• 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.
• 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.
• 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.
• 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.
• Darnell JC, Klann E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci. 2013 Nov;16(11):1530-6. doi: 10.1038/nn.3379. Epub 2013 Apr 14.
• Richter JD, Bassell GJ, Klann E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci. 2015 Oct;16(10):595-605. doi: 10.1038/nrn4001. Epub 2015 Sep 9.
• Gholizadeh S, Halder SK, Hampson DR. Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain. Brain Res. 2015 Jan 30;1596:22-30. doi: 10.1016/j.brainres.2014.11.023. Epub 2014 Nov 20.
• Feng Y, Gutekunst CA, Eberhart DE, Yi H, Warren ST, Hersch SM. Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J Neurosci. 1997 Mar 1;17(5):1539-47. doi: 10.1523/JNEUROSCI.17-05-01539.1997.
• Hanson AC, Hagerman RJ. Serotonin dysregulation in Fragile X Syndrome: implications for treatment. Intractable Rare Dis Res. 2014 Nov;3(4):110-7. doi: 10.5582/irdr.2014.01027.
• Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, Bochner BR, Stevenson RE, Schwartz CE. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013 Jun 3;4(1):16. doi: 10.1186/2040-2392-4-16.
• Chandana SR, Behen ME, Juhasz C, Muzik O, Rothermel RD, Mangner TJ, Chakraborty PK, Chugani HT, Chugani DC. Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism. Int J Dev Neurosci. 2005 Apr-May;23(2-3):171-82. doi: 10.1016/j.ijdevneu.2004.08.002.
• Wang H, Wu LJ, Kim SS, Lee FJ, Gong B, Toyoda H, Ren M, Shang YZ, Xu H, Liu F, Zhao MG, Zhuo M. FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron. 2008 Aug 28;59(4):634-47. doi: 10.1016/j.neuron.2008.06.027.
• Gkogkas CG, Khoutorsky A, Cao R, Jafarnejad SM, Prager-Khoutorsky M, Giannakas N, Kaminari A, Fragkouli A, Nader K, Price TJ, Konicek BW, Graff JR, Tzinia AK, Lacaille JC, Sonenberg N. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep. 2014 Dec 11;9(5):1742-1755. doi: 10.1016/j.celrep.2014.10.064. Epub 2014 Nov 26.
• Wahlstrom-Helgren S, Klyachko VA. GABAB receptor-mediated feed-forward circuit dysfunction in the mouse model of fragile X syndrome. J Physiol. 2015 Nov 15;593(22):5009-24. doi: 10.1113/JP271190. Epub 2015 Oct 2.
• Kashima R, Roy S, Ascano M, Martinez-Cerdeno V, Ariza-Torres J, Kim S, Louie J, Lu Y, Leyton P, Bloch KD, Kornberg TB, Hagerman PJ, Hagerman R, Lagna G, Hata A. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci Signal. 2016 Jun 7;9(431):ra58. doi: 10.1126/scisignal.aaf6060.
• Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model. J Neurosci. 2014 Jul 23;34(30):9867-79. doi: 10.1523/JNEUROSCI.1162-14.2014.
• Danesi C, Achuta VS, Corcoran P, Peteri UK, Turconi G, Matsui N, Albayrak I, Rezov V, Isaksson A, Castren ML. Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein. Stem Cell Reports. 2018 Dec 11;11(6):1449-1461. doi: 10.1016/j.stemcr.2018.11.003. Epub 2018 Nov 29.
• Pilaz LJ, Lennox AL, Rouanet JP, Silver DL. Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain. Curr Biol. 2016 Dec 19;26(24):3383-3392. doi: 10.1016/j.cub.2016.10.040. Epub 2016 Dec 1.
• Berry-Kravis E, Raspa M, Loggin-Hester L, Bishop E, Holiday D, Bailey DB. Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Am J Intellect Dev Disabil. 2010 Nov;115(6):461-72. doi: 10.1352/1944-7558-115.6.461.
• McLennan Y, Polussa J, Tassone F, Hagerman R. Fragile x syndrome. Curr Genomics. 2011 May;12(3):216-24. doi: 10.2174/138920211795677886.
• Sauna-Aho O, Bjelogrlic-Laakso N, Siren A, Arvio M. Signs indicating dementia in Down, Williams and Fragile X syndromes. Mol Genet Genomic Med. 2018 Sep;6(5):855-860. doi: 10.1002/mgg3.430. Epub 2018 Jul 3.
• Bartholomay KL, Lee CH, Bruno JL, Lightbody AA, Reiss AL. Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings. Brain Sci. 2019 Jan 12;9(1):11. doi: 10.3390/brainsci9010011.
• Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodev Disord. 2011 Mar;3(1):57-67. doi: 10.1007/s11689-010-9067-y. Epub 2010 Dec 3.
• Utari A, Adams E, Berry-Kravis E, Chavez A, Scaggs F, Ngotran L, Boyd A, Hessl D, Gane LW, Tassone F, Tartaglia N, Leehey MA, Hagerman RJ. Aging in fragile X syndrome. J Neurodev Disord. 2010 Jun;2(2):70-76. doi: 10.1007/s11689-010-9047-2. Epub 2010 May 12.
• Tassone F. Advanced technologies for the molecular diagnosis of fragile X syndrome. Expert Rev Mol Diagn. 2015;15(11):1465-73. doi: 10.1586/14737159.2015.1101348. Epub 2015 Oct 21.
• Rajan-Babu IS, Chong SS. Molecular Correlates and Recent Advancements in the Diagnosis and Screening of FMR1-Related Disorders. Genes (Basel). 2016 Oct 14;7(10):87. doi: 10.3390/genes7100087.
• Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E. Fragile X syndrome: a review of associated medical problems. Pediatrics. 2014 Nov;134(5):995-1005. doi: 10.1542/peds.2013-4301. Epub 2014 Oct 6.
• Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genet Med. 2001 Sep-Oct;3(5):359-71. doi: 10.1097/00125817-200109000-00006.
• Tassone F, Iong KP, Tong TH, Lo J, Gane LW, Berry-Kravis E, Nguyen D, Mu LY, Laffin J, Bailey DB, Hagerman RJ. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012 Dec 21;4(12):100. doi: 10.1186/gm401. eCollection 2012.
• Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A. 2014 Jul;164A(7):1648-58. doi: 10.1002/ajmg.a.36511. Epub 2014 Apr 3.
• Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, Warren ST. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009 Oct;85(4):503-14. doi: 10.1016/j.ajhg.2009.09.007.
• Varni JW, Limbers CA. The PedsQL 4.0 Generic Core Scales Young Adult Version: feasibility, reliability and validity in a university student population. J Health Psychol. 2009 May;14(4):611-22. doi: 10.1177/1359105309103580.
• Prosser H, Moss S, Costello H, Simpson N, Patel P, Rowe S. Reliability and validity of the Mini PAS-ADD for assessing psychiatric disorders in adults with intellectual disability. J Intellect Disabil Res. 1998 Aug;42 ( Pt 4):264-72. doi: 10.1046/j.1365-2788.1998.00146.x.
• Shields RH, Kaat AJ, McKenzie FJ, Drayton A, Sansone SM, Coleman J, Michalak C, Riley K, Berry-Kravis E, Gershon RC, Widaman KF, Hessl D. Validation of the NIH Toolbox Cognitive Battery in intellectual disability. Neurology. 2020 Mar 24;94(12):e1229-e1240. doi: 10.1212/WNL.0000000000009131. Epub 2020 Feb 24.
• Dueck A, Reis O, Bastian M, van Treeck L, Weirich S, Haessler F, Fiedler A, Koelch M, Berger C. Feasibility of a Complex Setting for Assessing Sleep and Circadian Rhythmicity in a Fragile X Cohort. Front Psychiatry. 2020 May 14;11:361. doi: 10.3389/fpsyt.2020.00361. eCollection 2020.
• Farzin F, Scaggs F, Hervey C, Berry-Kravis E, Hessl D. Reliability of eye tracking and pupillometry measures in individuals with fragile X syndrome. J Autism Dev Disord. 2011 Nov;41(11):1515-22. doi: 10.1007/s10803-011-1176-2.
• Klusek J, Moser C, Schmidt J, Abbeduto L, Roberts JE. A novel eye-tracking paradigm for indexing social avoidance-related behavior in fragile X syndrome. Am J Med Genet B Neuropsychiatr Genet. 2020 Jan;183(1):5-16. doi: 10.1002/ajmg.b.32757. Epub 2019 Aug 16.
• Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med. 2009 Dec;57(8):830-6. doi: 10.2310/JIM.0b013e3181af59c4.
• 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
• Mientjes EJ, Nieuwenhuizen I, Kirkpatrick L, Zu T, Hoogeveen-Westerveld M, Severijnen L, Rife M, Willemsen R, Nelson DL, Oostra BA. The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Neurobiol Dis. 2006 Mar;21(3):549-55. doi: 10.1016/j.nbd.2005.08.019. Epub 2005 Oct 26.
• Gaudissard J, Ginger M, Premoli M, Memo M, Frick A, Pietropaolo S. Behavioral abnormalities in the Fmr1-KO2 mouse model of fragile X syndrome: The relevance of early life phases. Autism Res. 2017 Oct;10(10):1584-1596. doi: 10.1002/aur.1814. Epub 2017 Jun 7.
• Pasciuto E, Ahmed T, Wahle T, Gardoni F, D'Andrea L, Pacini L, Jacquemont S, Tassone F, Balschun D, Dotti CG, Callaerts-Vegh Z, D'Hooge R, Muller UC, Di Luca M, De Strooper B, Bagni C. Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome. Neuron. 2015 Jul 15;87(2):382-98. doi: 10.1016/j.neuron.2015.06.032.
• Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP, Kooy F, Willems PJ, Cras P, Kozlowski PB, Swain RA, Weiler IJ, Greenough WT. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet. 2001 Jan 15;98(2):161-7. doi: 10.1002/1096-8628(20010115)98:23.0.co;2-b.
• Ethridge LE, Pedapati EV, Schmitt LM, Norris JE, Auger E, De Stefano LA, Sweeney JA, Erickson CA. Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership Fragile X Syndrome. Sci Rep. 2024 Oct 3;14(1):22982. doi: 10.1038/s41598-024-72935-6.
• Enkavi G, Girych M, Moliner R, Vattulainen I, Castren E. TrkB transmembrane domain: bridging structural understanding with therapeutic strategy. Trends Biochem Sci. 2024 May;49(5):445-456. doi: 10.1016/j.tibs.2024.02.001. Epub 2024 Mar 2.
• Dahlstrom M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. Cells. 2021 Jul 23;10(8):1871. doi: 10.3390/cells10081871.
• C. Yates, J. L. Kruse, J. B. Price, A. A. B. Robertson, and S. J. Tye, "Modulating Neuroplasticity: Lessons Learned from Antidepressants and Emerging Novel Therapeutics," Curr Treat Options Psychiatry, vol. 8, no. 4, pp. 229-257, Dec. 2021, doi: 10.1007/S40501-021-00249-9.
• Wang Y, Liang J, Xu B, Yang J, Wu Z, Cheng L. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sci. 2024 Jan 1;336:122282. doi: 10.1016/j.lfs.2023.122282. Epub 2023 Nov 24.
• Gupta AK, Gupta S, Mehan S, Khan Z, Das Gupta G, Narula AS. Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders. Mol Neurobiol. 2025 Nov;62(11):14627-14659. doi: 10.1007/s12035-025-05001-5. Epub 2025 May 9.
• Didden R, VanDerNagel J, Delforterie M, van Duijvenbode N. Substance use disorders in people with intellectual disability. Curr Opin Psychiatry. 2020 Mar;33(2):124-129. doi: 10.1097/YCO.0000000000000569.
• Nelson MA, Schmitt LM, Horn PS, Berry-Kravis E, Hessl D, Shaffer RC, Carpenter R, Budimirovic DB, Wang P, Reisinger DL, Walton-Bowen K, Erickson CA. Parent-Reported Outcome Measures for Individuals with Fragile X Syndrome: Clinically Meaningful Change Thresholds. J Autism Dev Disord. 2026 Apr;56(4):1658-1670. doi: 10.1007/s10803-024-06634-6. Epub 2024 Nov 23.
• Crawford H, Moss J, Groves L, Dowlen R, Nelson L, Reid D, Oliver C. A Behavioural Assessment of Social Anxiety and Social Motivation in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes. J Autism Dev Disord. 2020 Jan;50(1):127-144. doi: 10.1007/s10803-019-04232-5.
• Cregenzan-Royo O, Brun-Gasca C, Fornieles-Deu A. Behavior Problems and Social Competence in Fragile X Syndrome: A Systematic Review. Genes (Basel). 2022 Jan 30;13(2):280. doi: 10.3390/genes13020280.
• Budimirovic DB, Dominick KC, Gabis LV, Adams M, Adera M, Huang L, Ventola P, Tartaglia NR, Berry-Kravis E. Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study. Front Pharmacol. 2021 Oct 8;12:757825. doi: 10.3389/fphar.2021.757825. eCollection 2021.
• Guy W., "CGI clinical global impressions. In: ECDEU Assessment Manual for Psychopharmacology Revised (DHEWPubl No ADM 76-338).," Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs. Accessed: Apr. 09, 2024. [Online]. Available: https://openlibrary.org/books/OL24341821M/ECDEU_assessment_manual_for_psychopharmacology
• E. Merikle, V. Patel, T. Sebree, ; Carolyn Kreusser, and H. H. Heussler, "Content Validity in Support of the ABC-C FXS and Subscales in Fragile X Syndrome," J Autism Dev Disord, vol. 113, no. 6, pp. 1377-92, 2008.
• "Enobio® EEG systems | Neuroelectrics." Accessed: Mar. 27, 2024. [Online]. Available: https://www.neuroelectrics.com/solutions/enobio
• "Tobii Pro Fusion Product Description." Accessed: Mar. 27, 2024. [Online]. Available: https://pstnet.com/wp-content/uploads/2020/02/Tobii-fusion-descrip.pdf
• "wGT3X-BT | ActiGraph Wearable Devices." Accessed: Mar. 27, 2024. [Online]. Available: https://theactigraph.com/actigraph-wgt3x-bt
• Loesch DZ, Huggins RM, Hagerman RJ. Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev. 2004;10(1):31-41. doi: 10.1002/mrdd.20006.
• Tassone F, Hagerman RJ, Ikle DN, Dyer PN, Lampe M, Willemsen R, Oostra BA, Taylor AK. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet. 1999 May 28;84(3):250-61.
• Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M. Advances in the treatment of fragile X syndrome. Pediatrics. 2009 Jan;123(1):378-90. doi: 10.1542/peds.2008-0317.
• de Vries BB, Wiegers AM, Smits AP, Mohkamsing S, Duivenvoorden HJ, Fryns JP, Curfs LM, Halley DJ, Oostra BA, van den Ouweland AM, Niermeijer MF. Mental status of females with an FMR1 gene full mutation. Am J Hum Genet. 1996 May;58(5):1025-32.
• Kaufmann WE, Abrams MT, Chen W, Reiss AL. Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. Am J Med Genet. 1999 Apr 2;83(4):286-95.
• Reiss AL, Dant CC. The behavioral neurogenetics of fragile X syndrome: analyzing gene-brain-behavior relationships in child developmental psychopathologies. Dev Psychopathol. 2003 Fall;15(4):927-68. doi: 10.1017/s0954579403000464.
• Erickson CA, Kaufmann WE, Budimirovic DB, Lachiewicz A, Haas-Givler B, Miller RM, Weber JD, Abbeduto L, Hessl D, Hagerman RJ, Berry-Kravis E. Best Practices in Fragile X Syndrome Treatment Development. Brain Sci. 2018 Dec 15;8(12):224. doi: 10.3390/brainsci8120224.
• Jacquemont S, Berry-Kravis E, Hagerman R, von Raison F, Gasparini F, Apostol G, Ufer M, Des Portes V, Gomez-Mancilla B. The challenges of clinical trials in fragile X syndrome. Psychopharmacology (Berl). 2014 Mar;231(6):1237-50. doi: 10.1007/s00213-013-3289-0. Epub 2013 Oct 31.
• Erickson CA, Davenport MH, Schaefer TL, Wink LK, Pedapati EV, Sweeney JA, Fitzpatrick SE, Brown WT, Budimirovic D, Hagerman RJ, Hessl D, Kaufmann WE, Berry-Kravis E. Fragile X targeted pharmacotherapy: lessons learned and future directions. J Neurodev Disord. 2017 Jun 12;9:7. doi: 10.1186/s11689-017-9186-9. eCollection 2017.
• van der Lei MB, Kooy RF. From Discovery to Innovative Translational Approaches in 80 Years of Fragile X Syndrome Research. Biomedicines. 2025 Mar 27;13(4):805. doi: 10.3390/biomedicines13040805.
• C. E. Erickson et al., "NFXF Clinical Trials Committee (CTC) Consultation - Connecta Therapeutics," Aug. 2022.

Helpful Links

• Clinical Trials - CONNECTA Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: June 12, 2026
• First Submitted That Met QC Criteria: June 12, 2026
• First Posted (Actual): June 17, 2026

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Congenital Abnormalities; Fragile X; Central Nervous System Diseases; Rare Diseases; Intellectual Disability; Fragile X Syndrome; Neurobehavioral Manifestations; FXS; Orphan Diseases; Neureodevelopmental Disorders; Genetic Diseases, X linked
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Genetic Diseases, Inborn; Neurodevelopmental Disorders; Heredodegenerative Disorders, Nervous System; Sex Chromosome Disorders; Chromosome Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; X-Linked Intellectual Disability; Congenital Abnormalities; Rare Diseases; Intellectual Disability; Central Nervous System Diseases; Neurobehavioral Manifestations; Fragile X Syndrome; Genetic Diseases, X-Linked
• Other Study ID Numbers: CTH-CTH120-FXS-01; 2025-522972-97-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No