Single Blind Study of Ergoloid Mesylates, 5-HTP and the Combination in Adult Males With Fragile X Syndrome

Phase 2

Completed

• Conditions: Fragile X Syndrome
• Interventions: Drug: Ergoloid Mesylates; Drug: 5-Hydroxytryptophan; Drug: Matching placebo for 5-Hydroxytryptophan; Drug: Matching placebo for Ergoloid mesylates

• Registration Number: NCT05030129
• Lead Sponsor: Elizabeth Berry-Kravis

Brief Summary

A preliminary assessment of the safety, tolerability and efficacy of Ergoloid mesylates (EM) and 5-hydroxytryptophan (5-HTP) and the combination (EM + 5-HTP) compared to placebo in males aged 18-45 years old with Fragile X Syndrome.

Detailed Description

This single-center, Phase 2, single-blind, 4-period sequential study will obtain a preliminary assessment of the effects of Ergoloid mesylates (EM) 1 mg TID and 5-hydroxytryptophan (5-HTP) 100 mg TID and the combination compared to a placebo period in males aged 18-45 years old with Fragile X Syndrome. The study will consist of a Screening period of up to 28 days prior to initial study drug administration, followed by four 4 week single-blind treatment periods (up to 21 weeks total). The screening and baseline visits may occur at the same time, provided the results of safety labs can be obtained. A final follow-up visit or phone contact for safety is planned one week after the conclusion of Period 4. Safety and tolerability assessments will include adverse event monitoring, vital signs, blood chemistry and hematology, and urinalysis. Brief cognitive and behavioral assessments will be performed during each clinic visit.

Eligible participants will progress through each of 4 periods (arms) on study. The periods are not listed sequentially here in order to preserve the single blind for participants. Throughout all 4 periods, participants will take two identical capsules three times a day. If only taking one over-encapsulated drug, they will take one over-encapsulated placebo pill with the drug at each dose, and when in period 4 they will take two over-encapsulated placebo pills at each dose.

Study Timeline

• Study First Submitted: 2021-08-05
• Study First Submitted QC: 2021-08-27
• Study First Posted: 2021-09-01
• Study Start: 2021-10-07
• Primary Completion: 2023-01-19
• Study Completion: 2023-01-19
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-19
• Last Update Posted: 2023-06-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 15

Inclusion Criteria

1. Male aged 18 to 45 years, inclusive.
2. Participant has Fragile X Syndrome with a molecular genetic confirmation of the full Fragile X Mental Retardation (FMR1) mutation (≥200 CGG repeats).
3. Current treatment with no more than 3 prescribed psychotropic medications. Anti-epileptic medications are permitted and are not counted as psychotropic medications if they are used for treatment of seizures. Anti-epileptics for other indications, such as the treatment of mood disorders, count towards the limit of permitted medications.
4. Permitted concomitant psychotropic medications must be at a stable dose and dosing regimen for at least 2 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication.
5. Anti-epileptic medications must be at a stable dose and dosing regimen for 12 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication.
6. Participants with a history of seizure disorder who are currently receiving treatment with anti-epileptics must have been seizure-free for 3 months preceding screening, or must be seizure-free for 3 years if not currently receiving anti-epileptics.
7. Behavioral and therapy treatments/interventions must be stable for 4 weeks prior to Screening and must remain stable during the period between Screening and the commencement of study medication, and throughout the study. Minor changes in hours or times of therapy that are not considered clinically significant will not be exclusionary. Changes in therapies provided through a school program, due to school vacations, are allowed.
8. Participant must be willing to practice barrier methods of contraception while on study, if sexually active. Abstinence is also considered a reasonable form of birth control in this study population.
9. Participant has a parent, legal authorized guardian or consistent caregiver.
10. Participant and caregiver are able to attend the clinic regularly and reliably.
11. Participant is able to swallow capsules.
12. For participants who are not their own legal guardian, participant's parent/legal authorized guardian is able to understand and sign an informed consent form to participate in the study.
13. If participant is his own legal guardian, he can understand and sign informed consent to participate in the study.
14. If participant is not their own legal guardian, the participant provides assent for participation in the study, if the participant has the cognitive ability to provide assent.

Exclusion Criteria

1. History of, or current cardiovascular, renal, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cerebrovascular, or other systemic disease that would place the participant at risk or potentially interfere with the interpretation of the safety, tolerability, or efficacy of the study medication.

   Common diseases such as mild hypertension, well-controlled type 2 diabetes mellitus (hemoglobin A1C [Hgb A1C] <6.5%), etc. are allowed per the investigator's judgment as long as they are stable and controlled by medical therapy that is constant for at least 4 weeks before randomization.

2. Clinically significant abnormalities, in the investigator's judgment, in safety laboratory tests, vital signs, as measured during Screening.

3. History of substance abuse within the past year, according to investigator assessment.

4. Use of CYP3A4 inhibitors, beta-blockers, MAO inhibitors or triptans at any time during participation in the study.

5. Significant hearing or visual impairment that may affect the participant's ability to complete the test procedures.

6. Concurrent major psychiatric condition (e.g., Major Depressive Disorder, Schizophrenia or Bipolar Disorder) as diagnosed by the investigator. Participants with additional diagnosis of Autism Spectrum Disorder or Anxiety Disorder will be allowed as these are characteristics of FXS.

7. Participant has active diseases that would interfere with participation, such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis.

8. Participant is planning to commence psychotherapy or cognitive behavior therapy (CBT) during the period of the study or had begun psychotherapy or CBT within 4 weeks prior to Screening.

9. Participant has participated in another clinical trial within the 30 days preceding Screening.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Ergoloid mesylates (EM)	Ergoloid Mesylates	During treatment period 1, subjects will receive EM 1 mg (Medisca) and matching placebo for 5-HTP 100mg (ascorbic acid powder). One of each capsule (both size 00) will be taken three times per day for four weeks.
Ergoloid mesylates (EM)	Matching placebo for 5-Hydroxytryptophan	During treatment period 1, subjects will receive EM 1 mg (Medisca) and matching placebo for 5-HTP 100mg (ascorbic acid powder). One of each capsule (both size 00) will be taken three times per day for four weeks.
Ergoloid mesylates (EM) and 5-hydroxytryptophan (5-HTP)	5-Hydroxytryptophan	During treatment period 2, subjects will receive EM 1 mg (Medisca) and 5-HTP 100 mg (5-HTP, Basic Vitamins). One of each capsule (both size 00) will be taken three times per day for four weeks.
Ergoloid mesylates (EM) and 5-hydroxytryptophan (5-HTP)	Ergoloid Mesylates	During treatment period 2, subjects will receive EM 1 mg (Medisca) and 5-HTP 100 mg (5-HTP, Basic Vitamins). One of each capsule (both size 00) will be taken three times per day for four weeks.
5-hydroxytryptophan (5-HTP)	5-Hydroxytryptophan	During treatment period 3, subjects will receive 5-HTP 100 mg (5-HTP, Basic Vitamins) and matching placebo for EM 1 mg (ascorbic acid powder). One of each capsule (both size 00) will be taken three times per day for four weeks.
5-hydroxytryptophan (5-HTP)	Matching placebo for Ergoloid mesylates	During treatment period 3, subjects will receive 5-HTP 100 mg (5-HTP, Basic Vitamins) and matching placebo for EM 1 mg (ascorbic acid powder). One of each capsule (both size 00) will be taken three times per day for four weeks.
Placebo	Matching placebo for Ergoloid mesylates	During treatment period 4, subjects will receive matching placebo for EM 1mg (ascorbic acid powder) and matching placebo for 5-Hydroxytryptophan 100mg (ascorbic acid powder). One of each capsule (both size 00) will be taken three times per day for four weeks.
Placebo	Matching placebo for 5-Hydroxytryptophan	During treatment period 4, subjects will receive matching placebo for EM 1mg (ascorbic acid powder) and matching placebo for 5-Hydroxytryptophan 100mg (ascorbic acid powder). One of each capsule (both size 00) will be taken three times per day for four weeks.

Primary Outcome Measures

Name	Time	Method
Safety and Tolerability - Number of Treatment-Emergent Adverse Events	Baseline through Week 17	Adverse Events (AEs), including clinically meaningful laboratory abnormalities and significant behavioral changes will be recorded from the time of the subject's first dose of study drug to the end of the study (Week 17) or longer if needed. Adverse events will be assessed at each visit as well as during each phone call and will be tabulated for each treatment period.
Safety and Tolerability - Severity of Treatment Emergent Adverse Events	Baseline through Week 17	Adverse Events (AEs), including clinically meaningful laboratory abnormalities and significant behavioral changes will be tabulated for each treatment period.; The Investigator is responsible for assessing the severity (intensity) of each adverse event as mild, moderate, or severe according to the following definitions: Mild - An event that is easily tolerated and generally not interfering with normal daily activities. Moderate - An event that is sufficiently discomforting to interfere with normal daily activities. Severe - An event that is incapacitating with inability to work or perform normal daily activities.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in KiTAP Executive Battery - Alertness Subscore (Reaction Time)	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The alertness subtest requires subjects to tap a button every time a stimulus appears on the screen. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean reaction time was measured over 90 seconds and change from baseline was calculated. A lower reaction time (net decrease in reaction time) indicates better performance.
Change From Baseline in Total Number of Correct Responses on KiTAP Executive Battery Distractibility Subtest	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The distractibility subtest measures how easily the subject is distracted by extraneous stimuli. This subtest requires subjects to tap a button when a target stimulus appears on the screen while ignoring distracters that appear shortly before the stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the distractability subtest, a higher mean number of correct responses and lower mean number of errors over the 3 minutes indicates better performance.
Change From Baseline in Total Number of Errors on KiTAP Executive Battery Distractibility Subtest	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The distractibility subtest measures how easily the subject is distracted by extraneous stimuli. This subtest requires subjects to tap a button when a target stimulus appears on the screen while ignoring distracters that appear shortly before the stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the distractability subtest, a higher mean number of correct responses and lower mean number of errors over the 3 minutes indicates better performance.
Change From Baseline in Total Number of Correct Responses on KiTAP Executive Battery Flexibility Subtest	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The flexibility subtest measures the subject's ability to be flexible about shifting from one response type to another. This subtest is 2 minutes long and requires subjects to alternate between identifying blue and green dragons which seem on random sides of the screen by tapping one of two buttons. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded and change from baseline was calculated. For the flexibility subtest, a higher mean number of correct responses and lower mean number of errors indicates better performance.
Change From Baseline in Total Number of Errors on KiTAP Executive Battery Flexibility Subtest	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The flexibility subtest measures the subject's ability to be flexible about shifting from one response type to another. This subtest is 2 minutes long and requires subjects to alternate between identifying blue and green dragons which seem on random sides of the screen by tapping one of two buttons. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean number of correct responses and errors were recorded and change from baseline was calculated. For the flexibility subtest, a higher mean number of correct responses and lower mean number of errors indicates better performance.
Change From Baseline in Total Number of Correct Responses on KiTAP Test of Attentional Performance Go-NoGo Subtest	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The Go-NoGo subtest measures a subject's impulsivity by requiring subjects to tap a button when the target stimulus is presented, while refraining from hitting the button for the non-target stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). This subtest takes place over 2 minutes 30 seconds. Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the Go-NoGo subtest, a higher mean number of correct responses and a lower mean number of errors indicates better performance.
Change From Baseline in Total Number of Errors on KiTAP Test of Attentional Performance Go-NoGo Subtest	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The KiTAP is a computerized executive function battery that consists of eight nonverbal subtests measuring different basal as well as higher-order components of attention and executive functioning. The Go-NoGo subtest measures a subject's impulsivity by requiring subjects to tap a button when the target stimulus is presented, while refraining from hitting the button for the non-target stimulus. KiTAP was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). This subtest takes place over 2 minutes 30 seconds. Mean number of correct responses and errors were recorded, and change from baseline was calculated. For the Go-NoGo subtest, a higher mean number of correct responses and a lower mean number of errors indicates better performance.
Change From Baseline in Clinical Global Impression Severity Scale Overall Score	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The Clinical Global Impression-Severity (CGI-S) is a global measure to provide a clinical judgment of a participant's overall condition based on a trained clinician's assessment of cognition, behavior and activities of daily living. The clinician compares the subject with individuals of the same age and sex. The assessment of severity is with a 7-point scale: 1, not ill; 2, very mild; 3, mild; 4, moderate; 5, marked; 6, severe; 7, extremely severe. A net decrease in severity score over time indicates a positive outcome.
Change From Baseline in Aberrant Behavior Checklist (ABC) Subscores	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	This assessment is a parent/caregiver-rated scale with six subscales to assess irritability, stereotypes, lethargy, hyperactivity, inappropriate speech, and social avoidance, using ABC-FX factoring system. The ABC was was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean score for each subscale was measured and change from baseline was calculated. Lower mean scores on each subscale indicate fewer aberrant behaviors (better functioning).The range of possible scores on each subscale are irritability (0-54), lethargy (0-39), stereotypes (0-18), hyperactivity (0-30), inappropriate speech (0-12), and social avoidance (0-12).
Change From Baseline in Anxiety, Depression, and Mood Scale (ADAMS) Subscores	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The ADAMS is a parent/caregiver rated scale with five subscores to assess manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, and obsessive/compulsive behavior. The ADAMs was completed at Baseline as well as Week 4, Week 8, Week 12, and Week 16 (the end of each treatment period). Mean score for each subscale was recorded, and change from baseline was calculated for each subscore. The range of possible scores for each subscale is 0-21. Lower mean scores on each subscale indicate better functioning.
Change From Baseline on Vineland-3 Adaptive Behavior Scale - Subdomain Growth Scale Values	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	VABS-3 is a clinician-administered standardized interview. For this study, we collected data in domains of communication (receptive \& written language), daily living skills (domestic \& community skills), \& socialization (interpersonal relationships, play \& leisure time, \& coping abilities). This assessment was administered at Baseline as well as at Week 4, Week 8, Week 12, and Week 16 (end of each treatment period). Mean growth scale value (GSV) for each subdomain was recorded at each time point and change from baseline was calculated. The possible GSVs for each subdomain are receptive (10-162), written (10-163), domestic (10-110), community (10-136), interpersonal (10-152), play and leisure (10-164), \& coping skills (10-120). Higher GSVs for each subdomain indicate better functioning.
Change From Baseline in NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB) Total Cognition Score	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	The NIH-TCB is a battery of extensively validated computer-administered cognitive tests. The NIH-TCB includes 7 evaluations measuring cognitive flexibility, inhibition \& visual attention, episodic memory, immediate recall \& sequencing of different visually \& orally presented stimuli, processing speed, recognition of letters and words, \& receptive vocabulary. This assessment was administered at Baseline as well as at Week 4, Week 8, Week 12, and Week 16 (end of each treatment period). This battery produces fluid and crystallized cognition composite scores. The Total Cognition Composite Score is found by converting raw fluid and crystallized scores to standard scores, averaging these two scores, then deriving standard scores based on this new distribution. Scores range from 0-140. The normative mean of the uncorrected standard score is 100 and the standard deviation is 15. A higher mean total cognition composite score indicates better performance.
Change From Baseline in Visual Analog Scale (VAS) Assessment Domain Scores	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	IIn an attempt to measure the level of behavioral difficulty experienced by the parent/caregiver with respect to the child with FXS, the VAS allows parents to mark on a visual line measuring 10 cm with one side marked "worst behavior" and the other side marked "best behavior." The caregiver rated the participant's behavior with respect to three domains: daily functioning, anxiety/irritability and language. Distances closer to 10 cm are considered worse behavior and distances closer to 0 cm are considered better behavior. Average distance of the mark was recorded for each domain at Baseline then again at Week 4, Week 8, Week 12, and Week 16 (end of each treatment period). Change from baseline was calculated for each domain. Lower scores indicate a better outcome (closer distance to best behavior side).
Event-Related Potentials (ERP) - Gamma Band Absolute Power at Resting State (Frontal)	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific sensory, cognitive, or motor events from an overall EEG. Gamma 1 and gamma 2 waves were measured for various parts of the brain at a resting state. ERP was performed at Baseline as well as at Week 4, Week 8, Week 12, Week 16 (at the end of each treatment period). Mean power of gamma 1 and gamma 2 bands, measured by frontal EEG leads, was recorded for each time point and change from baseline was calculated. FXS patients have typically been found to exhibit greater gamma frequency band power than typically developing controls, which may be related to social and sensory processing difficulties. Therefore, lower gamma band power would indicate better functioning.
Event-Related Potentials (ERP) Components in Response to Standard Tones	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific sensory, cognitive, or motor events from an overall EEG. Auditory stimuli are presented and EEG events are assessed in relation to timing of the stimuli. ERP was performed at Baseline as well as at week Week 4, Week 8, Week 12, Week 16 (end of each treatment period). The area under the curve was measured for different components of the ERP including P1 and P2 (positive components) and N1 and N2 (negative components). The average area under the curve was recorded for each component at each time point and change from baseline was calculated. Individuals with FXS are thought to have excessive ERP response, so a decrease in area under each curve compared to baseline would indicate a favorable outcome.
Event-Related Potentials - Frontal Alpha Asymmetry at Resting State	Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)	Event-Related Potentials (ERPs) enable extraction of neural responses associated with specific sensory, cognitive, or motor events from an overall EEG. EEG data was collected when the subject was in a resting state. Frontal alpha asymmetry measures differences in alpha activity level of the right and left hemisphere of the frontal lobe of the brain. ERP was performed at Baseline as well as at Week 4, Week 8, Week 12, Week 16 (end of each treatment period). Mean alpha asymmetry at resting state was recorded and change from baseline was calculated for each time point. Higher alpha asymmetry scores indicate greater alpha power in the right hemisphere, which corresponds to increased neural activity of the left hemisphere. High activity of the left frontal lobe is hypothesized to correspond with approach behaviors, and high activity of the right frontal lobe is thought to correspond to withdrawal behaviors. In this study, higher alpha asymmetry scores indicate a better outcome.

Trial Locations

Locations (1)

Rush University Medical Center; 🇺🇸 Chicago, Illinois, United States