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

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Exploratory Single Blind Study of Ergoloid Mesylates, 5-Hydroxytryptophan, and the Combination in Adult Males With Fragile X Syndrome

Conditions
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Fragile X Syndrome

Intervention / Treatment
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* Dietary Supplement: 5-Hydroxytryptophan / Vitamin B6
* Drug: Ergoloid Mesylate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male aged 18 to 45 years, inclusive. Participant has Fragile X Syndrome with a molecular genetic confirmation of the full Fragile X Mental Retardation (FMR1) mutation (≥200 CGG repeats). 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. 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. 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. 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. 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. 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. Participant has a parent, legal authorized guardian or consistent caregiver. Participant and caregiver are able to attend the clinic regularly and reliably. Participant is able to swallow capsules. 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. If participant is his own legal guardian, he can understand and sign informed consent to participate in the study. 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: 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. Clinically significant abnormalities, in the investigator's judgment, in safety laboratory tests, vital signs, as measured during Screening. History of substance abuse within the past year, according to investigator assessment. Use of CYP3A4 inhibitors, beta-blockers, MAO inhibitors or triptans at any time during participation in the study. Significant hearing or visual impairment that may affect the participant's ability to complete the test procedures. 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. Participant has active diseases that would interfere with participation, such as acquired immunodeficiency disorder, hepatitis C, hepatitis B, or tuberculosis. 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. Participant has participated in another clinical trial within the 30 days preceding Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ergoloid mesylates (EM) and 5-hydroxytryptophan (5-HTP)<br>Ergoloid mesylates (EM) 1 mg three times daily and 5-hydroxytryptophan (5-HTP) 100 mg three times daily for 4 weeks | Dietary Supplement: 5-Hydroxytryptophan / Vitamin B6<br>* 5-hydroxytryptophan, also known as 5-HTP has a nutraceutical status and has never been approved as a drug for any indication, but as a dietary supplement has been used extensively for several disorders for many years such as in the therapy of depression, fibromyalgia, obesity, insomnia and chronic headache<br>Drug: Ergoloid Mesylate<br>* Ergoloid Mesylates, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids, dihydroergocristine, dihydroergocornine, and alpha- and beta-dihydroergocryptine. Ergot alkaloids are dopamine agonists which activate dopamine receptors (in the basal ganglia and other parts of the brain involved in motor function) and a prolactin inhibitor. Ergot is a strong vasoconstrictor and thus helps to reduce bleeding by narrowing of the blood vessels.<br>|
| Placebo Comparator: Placebo<br>2 placebo capsules three times daily for 4 weeks | Other: Placebo<br>* Placebo capsules<br>|
| Experimental: Ergoloid mesylates (EM) and placebo<br>Ergoloid mesylates (EM) 1 mg three times daily and 1 placebo capsule three times daily for 4 weeks. | Drug: Ergoloid Mesylate<br>* Ergoloid Mesylates, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids, dihydroergocristine, dihydroergocornine, and alpha- and beta-dihydroergocryptine. Ergot alkaloids are dopamine agonists which activate dopamine receptors (in the basal ganglia and other parts of the brain involved in motor function) and a prolactin inhibitor. Ergot is a strong vasoconstrictor and thus helps to reduce bleeding by narrowing of the blood vessels.<br>Other: Placebo<br>* Placebo capsules<br>|
| Experimental: 5-hydroxytryptophan (5-HTP) and placebo<br>5-hydroxytryptophan (5-HTP) 100 mg three times daily and 1 placebo capsule three times daily for 4 weeks. | Dietary Supplement: 5-Hydroxytryptophan / Vitamin B6<br>* 5-hydroxytryptophan, also known as 5-HTP has a nutraceutical status and has never been approved as a drug for any indication, but as a dietary supplement has been used extensively for several disorders for many years such as in the therapy of depression, fibromyalgia, obesity, insomnia and chronic headache<br>Other: Placebo<br>* Placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | To evaluate the safety and tolerability of EM, 5-HTP, and EM + 5-HTP in fragile X syndrome. Safety and Tolerability Endpoints: ● Adverse events as assessed at each visit by Clinical Trials Common Toxicity Criteria (CTCAE) | Up to 21 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| KiTAP Executive Battery | Computerized executive battery with assessments of alertness (reaction time), distractibility, go/nogo (impulsiveness), and flexibility | Up to 21 weeks | 
| Clinical Global Impression Severity | Investigator rated (CGI-S) Standardized ranking scale with 7 rankings | Up to 21 weeks | 
| Clinical Global Impression Improvement | Investigator rated (CGI-I): Standardized ranking scale with 7 rankings | Up to 21 weeks | 
| Visual Analog Scale (VAS) | Parent/caregiver-rated assessment of participant-specific behavioral anchors: Domains of daily functioning, anxiety/irritability and language. | Up to 21 weeks | 
| Aberrant Behavior Checklist (ABC) | Parent/caregiver-rated scale with six subscales to assess irritability, social avoidance, lethargy, hyperactivity, inappropriate speech and social avoidance, using ABC-FX factoring system. | Up to 21 weeks | 
| Anxiety, Depression, and Mood Scale (ADAMS) | Parent/caregiver rated scale with a total score and five sub-scores to assess manic/hyperactive behavior, depressed mood, social avoidance, general anxiety, and obsessive/compulsive behavior. | Up to 21 weeks | 
| Vineland-3 Adaptive Behavior Scale | Clinician-administered standardized interview yielding adaptive behavior composite score and domain standard scores in domains of: communication (receptive, expressive, and written adaptive language functions), daily living skills (personal, domestic, and community skills), socialization (interpersonal relationships, play and leisure time, and coping abilities), and motor skills (gross and fine motor skills). | Up to 21 weeks | 
| NIH Toolbox Cognitive Battery Modified for Intellectual Disabilities (NIH-TCB) | Cognitive battery assessing different domains of cognition, administered using an iPad | Up to 21 weeks | 
| Event Related Potentials (ERP) | Event Related Potentials (ERP) Resting state delta power (electrical activity in the brain) will be measured from an EEG (electroencephalogram) | Up to 21 weeks | 
| Eye Tracking | Eye Tracking = Measure of gaze aversion (social anxiety) and pupilometry (autonomic function) on computer based system | Up to 21 weeks | 
| Eye Tracking - Gaze Aversion | The amount of time (in seconds) spent looking at, and away from, a visual image on a computer screen will be measured. | Up to 21 weeks | 
| Eye Tracking - Pupilometry | Measure of pupilometry (pupil size) on a computer based system. The pupil size, in millimeters, will be measured in response to a visual image on a computer screen. | Up to 21 weeks |