Clinical trial NCT05030129: ERG/5-HTP in Fragile X Syndrome (FXS)
Official title: An Exploratory Single Blind Study of Ergoloid Mesylates, 5-Hydroxytryptophan, and the Combination in Adult Males With Fragile X Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fragile X Syndrome
Lead sponsor: Rush University Medical Center
Sponsor class: OTHER
Collaborators: name: FRAXA Research Foundation
name: Purposeful IKE
First posted: 2021-09-01
Enrollment: 15
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This study will use a single-blind, 4-period sequential design. Fifteen participants with Fragile X Syndrome ages 18-45 years will enter a Screening period of up to 28 days followed by four 4 week single-blind treatment periods (summarized below).

* Period 1: Ergoloid mesylates 1 mg and matching placebo for 5-Hydroxytryptophan 100 mg, taken three times per day
* Period 2: Ergoloid mesylates 1 mg and 5-Hydroxytryptophan 100 mg, taken three times per day
* Period 3: 5-Hydroxytryptophan 100 mg and matching placebo for Ergoloid mesylates 1mg, taken three times per day
* Period 4: Matching placebo for Ergoloid mesylates 1mg and matching placebo for 5- Hydroxytryptophan 100mg, taken three times per day
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess 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 enroll 15 males Fragile X Syndrome, ages 18-45 years old.

The study will begin with a Screening period of up to 28 days. During screening, participants and their parent/legal authorized guardian, if indicated, will review and sign an Informed Consent/Assent form prior to any study procedures being performed. Following confirmation of a prior diagnosis for Fragile X, information will be collected to further assess their eligibility.

Participants who meet entry criteria and agree to participate will proceed to a Baseline visit. At the Baseline visit (Period 1/Day 1), cognitive, behavioral, ERP and eye tracking assessments will be performed to assess current functioning.

The Baseline visit will be followed by four 4-week single-blind treatment periods. During treatment periods, participants will be placed on a different treatment regimen every 4 weeks (listed below). Throughout all 4 periods, participants will take two identical capsules three times a day. If only taking one study drug, they will take one placebo pill with the drug at each dose, and in period 4, they will take two placebo pills at each dose.

* Period 1: Ergoloid mesylates (EM) 1 mg three times per day for 4 weeks
* Period 2: Ergoloid mesylates (EM) 1 mg TID and 5-hydroxytryptophan (5-HTP) 100 mg three times per day for 4 weeks
* Period 3: 5-hydroxytryptophan (5-HTP) 100 mg three times per day for 4 weeks
* Period 4: Placebo three times per day for 4 weeks

Participants will return to the clinic at the end of each treatment period at weeks 4, 8, 12, and 16 and cognitive and behavioral evaluations will be repeated at these clinic visits. Safety and tolerability assessments will include adverse event monitoring, vital signs, blood chemistry and hematology, and urinalysis. Additionally, participants will be monitored for adverse events via a telephone call at the end of Week 1 of each Period, and one week following completion of Period 4 or following early discontinuation. Total study participation will last up to 21 weeks.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and Tolerability - Number of Treatment-Emergent Adverse Events
timeFrame: Baseline through Week 17
measure: Safety and Tolerability - Severity of Treatment Emergent Adverse Events
timeFrame: Baseline through Week 17
Secondary outcomes:
measure: Change From Baseline in KiTAP Executive Battery - Alertness Subscore (Reaction Time)
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Total Number of Correct Responses on KiTAP Executive Battery Distractibility Subtest
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Total Number of Errors on KiTAP Executive Battery Distractibility Subtest
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Total Number of Correct Responses on KiTAP Executive Battery Flexibility Subtest
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Total Number of Errors on KiTAP Executive Battery Flexibility Subtest
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Total Number of Correct Responses on KiTAP Test of Attentional Performance Go-NoGo Subtest
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Total Number of Errors on KiTAP Test of Attentional Performance Go-NoGo Subtest
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Clinical Global Impression Severity Scale Overall Score
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Aberrant Behavior Checklist (ABC) Subscores
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Anxiety, Depression, and Mood Scale (ADAMS) Subscores
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline on Vineland-3 Adaptive Behavior Scale - Subdomain Growth Scale Values
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in NIH Toolbox Cognitive Battery for Intellectual Disabilities (NIH-TCB) Total Cognition Score
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Change From Baseline in Visual Analog Scale (VAS) Assessment Domain Scores
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Event-Related Potentials (ERP) - Gamma Band Absolute Power at Resting State (Frontal)
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Event-Related Potentials (ERP) Components in Response to Standard Tones
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
measure: Event-Related Potentials - Frontal Alpha Asymmetry at Resting State
timeFrame: Baseline, Week 4 (EM Treatment), Week 8 (EM+5-HTP Treatment), Week 12 (5-HTP Treatment), Week 16 (Placebo Treatment)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
Study officials:
affiliation: Rush University Medical Center
name: Elizabeth Berry-Kravis, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: