Single Dose Drug Challenge for Fragile X Syndrome

Overseen By Hannah J. Sachs, MPA

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must be taking: Psychotropic drugs

Must not be taking: Barbiturates, Benzodiazepines, Antiepileptics, others

Disqualifiers: Substance abuse, Epilepsy, Renal impairment, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

45 Participants Needed

Trial Summary

What is the purpose of this trial?

The aim of this study is to utilize neurophysiologic assessments, behavioral measures and clinical measures to assess how much deficits associated with Fragile X Syndrome from pre-dose to post-dose using pharmacology.

Will I have to stop taking my current medications?

The trial requires that you have been on stable doses of psychiatric medications for at least 4 weeks before starting. However, you cannot participate if you are currently using certain medications like barbiturates, benzodiazepines, or specific drugs listed in the exclusion criteria.

What data supports the effectiveness of the drug for Fragile X Syndrome?

Research shows that memantine was modestly effective in some patients with Fragile X Syndrome, with 67% showing overall clinical improvement, although specific symptoms did not show significant improvement. Additionally, baclofen improved sensory and cognitive disturbances in a mouse model of Fragile X Syndrome, suggesting potential benefits for these symptoms. ^{1 2 3 4 5}

Is memantine generally safe for humans?

Memantine has been shown to be safe and well-tolerated in patients with moderate to severe Alzheimer's disease, and it is approved by the FDA for this use. It is considered a safe drug with a good safety profile, making it suitable for further research in other conditions. ^{2 4 6 7 8}

How does the drug combination of Baclofen, Memantine, and Roflumilast differ from other treatments for Fragile X Syndrome?

This drug combination is unique because it includes Baclofen, which has shown potential in normalizing sensory and cognitive disturbances in Fragile X Syndrome by targeting the GABA-B receptor, and Memantine, which addresses glutamatergic dysfunction. These mechanisms are distinct from other treatments that have not broadly improved symptoms in clinical trials. ^{1 3 9 10 11}

Research Team

Craig A. Erickson, M.D.

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

This trial is for adults aged 18-45 with Fragile X Syndrome, confirmed by genetic testing, who are generally healthy and have a Stanford Binet IQ under 85. Participants must not be pregnant or breastfeeding, should have been on stable psychotropic drugs for at least four weeks, and cannot have certain medical conditions or history of drug intolerance.

Inclusion Criteria

I am aged 18-45 with fragile X syndrome and participated in a specific study or provided baseline measures.

Your IQ score is less than 85 on the Stanford Binet test.

My genetic test shows I have Fragile X syndrome.

Exclusion Criteria

You can't participate if you have taken a new or experimental drug in the past 3 months, have a history of substance abuse in the past 6 months, or have a serious mental or brain-related illness not related to FXS.

You have hearing or vision problems that can't be fixed according to specific tests.

I am currently taking medications like painkillers, sedatives, or specific antibiotics and antifungals.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of placebo, baclofen, roflumilast, or memantine with a two-week washout period between doses

8 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Baclofen
• Memantine
• Placebo
• Roflumilast

Trial Overview The study tests the effects of Baclofen, Memantine, Roflumilast versus a placebo in improving neurophysiologic functions and clinical symptoms associated with Fragile X Syndrome. It measures changes from before to after dosing using various assessments.

Participant Groups

Group I: Experimental Study Participants Experimental Treatment 3 Interventions

Participants received, in random order, a single dose of placebo, baclofen, roflumilast or memantine with a two-week washout period between doses.

Group II: Control Study Participants Placebo Group 1 Intervention

Participants received, in random order, a single dose of placebo, baclofen, roflumilast or memantine with a two-week washout period between doses.

Baclofen is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Lioresal for:

• Severe spasticity of cerebral or spinal origin
• Multiple sclerosis
• Traumatic brain injury

Approved in Canada as Lioresal for:

• Severe spasticity of cerebral or spinal origin
• Multiple sclerosis
• Traumatic brain injury

Approved in European Union as Lioresal for:

• Severe spasticity of cerebral or spinal origin
• Multiple sclerosis
• Traumatic brain injury

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

In a pilot study involving 6 patients with fragile X syndrome (FXS), memantine was found to provide global clinical benefit for 67% of participants over an average treatment duration of 34.7 weeks.

Despite some patients experiencing irritability as a side effect, the results suggest that memantine may have modest effectiveness for managing symptoms associated with FXS, indicating the need for further research to explore its potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label memantine in fragile X syndrome. Erickson, CA., Mullett, JE., McDougle, CJ.[2022]

In a study involving 19 subjects, two 10-mg formulations of memantine were found to be bioequivalent, meaning they have similar absorption and effectiveness in the body.

The pharmacokinetic analysis showed that both formulations had comparable AUC0-72h and Cmax values, allowing them to be prescribed interchangeably without concerns about differences in efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence of two memantine tablet formulations in healthy Indonesian subjects. Harahap, Y., Prasaja, B., Sandra, M., et al.[2019]

Racemic baclofen, a GABA-B agonist, was found to normalize sensory processing and cognitive deficits in Fmr1 knockout mice, a model for fragile X syndrome, indicating its potential therapeutic effects for sensory and cognitive disturbances associated with the condition.

While baclofen improved working memory and reduced anxiety-like behaviors in these mice, it did not enhance sociability, suggesting that while it may help with certain symptoms of fragile X syndrome, it may not address all behavioral challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome. Sinclair, D., Featherstone, R., Naschek, M., et al.[2023]

In a study involving 30 patients aged 55 to 84 with moderate to severe Alzheimer's disease, memantal (a generic form of memantine) demonstrated moderate positive effects on cognitive functions and daily activities over a 3-month treatment period.

The treatment was found to be safe, with no adverse effects reported, indicating that memantal is both effective and well-tolerated for managing symptoms of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical experience of the use of memantal in patients with moderate and severe Alzheimer's disease]. Gavrilova, SI., Kolykhalov, IV., Kulik, AS., et al.[2018]

In the FXLEARN trial, which involved 110 children with fragile X syndrome (FXS), the mGluR5 negative allosteric modulator AFQ056 did not show a significant improvement in language learning compared to placebo, despite both groups making progress.

The study highlights that the promising results seen in animal models for mGluR5 NAMs do not necessarily translate to benefits in human subjects with FXS, indicating a need for better strategies to connect preclinical findings to human treatments in genetic neurodevelopmental disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of AFQ056 on language learning in fragile X syndrome. Berry-Kravis, E., Abbeduto, L., Hagerman, R., et al.[2023]

In a 6-month observational study involving 2,570 patients with Alzheimer's disease, memantine significantly improved cognitive function and daily living activities, as measured by the MMSE and IADL scales.

The treatment was well tolerated, with only 7.1% of patients reporting adverse drug reactions, and a very low discontinuation rate of 0.7% due to these reactions, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label, multicenter observational study for patients with Alzheimer's disease treated with memantine in the clinical practice. Stamouli, SS., Tzanakaki, M., Giatas, S., et al.[2021]

Memantine is a unique NMDA receptor antagonist that selectively blocks harmful glutamate activity associated with Alzheimer's disease while preserving normal cognitive function, making it a promising treatment option.

Clinical studies have shown that memantine improves symptoms and slows clinical deterioration in patients with moderate-to-severe Alzheimer's disease, leading to its approval in the US in 2003.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of memantine for the treatment of Alzheimer's disease. Ferris, SH.[2019]

Memantine is an FDA-approved treatment for moderate to severe Alzheimer's disease, demonstrating both safety and efficacy as a standalone therapy or in combination with cholinesterase inhibitors.

Research suggests that memantine may also have potential therapeutic effects in other neuropsychiatric conditions, warranting further investigation into its broader applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. Thomas, SJ., Grossberg, GT.[2022]

The experimental drug BAER-101, a selective GABAA α2/α3 agonist, showed promise in reducing hyperexcitability in cortical circuits and improving certain cognitive functions in Fmr1 knockout mice, which are a model for Fragile X syndrome (FXS).

While BAER-101 improved specific symptoms like seizure susceptibility and memory, it did not affect other FXS-related traits, indicating that targeted GABAA receptor modulation may be a viable treatment strategy for some aspects of FXS, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GABAA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome. Schaefer, TL., Ashworth, AA., Tiwari, D., et al.[2021]

In two phase 3 clinical trials involving 125 adolescents and adults and 172 children with fragile X syndrome, arbaclofen did not show significant improvement in social avoidance compared to placebo, indicating limited efficacy in older patients.

However, in the child study, the highest dose of arbaclofen showed some benefits on irritability and parenting stress, suggesting that younger patients may respond better, warranting further investigation with larger cohorts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arbaclofen in fragile X syndrome: results of phase 3 trials. Berry-Kravis, E., Hagerman, R., Visootsak, J., et al.[2019]

In a pilot trial involving 20 individuals with Fragile X syndrome (ages 13-32), minocycline treatment significantly improved behavioral issues, as measured by the Aberrant Behaviour Checklist and other scales, indicating its potential efficacy in managing symptoms of FXS.

Minocycline was well-tolerated with only minor side effects reported, such as diarrhea and positive antinuclear antibody tests, suggesting it is a safe option for treating behavioral abnormalities associated with FXS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label add-on treatment trial of minocycline in fragile X syndrome. Paribello, C., Tao, L., Folino, A., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Open-label memantine in fragile X syndrome. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence of two memantine tablet formulations in healthy Indonesian subjects. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome. [2023]

4. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Clinical experience of the use of memantal in patients with moderate and severe Alzheimer's disease]. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Effects of AFQ056 on language learning in fragile X syndrome. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

An open-label, multicenter observational study for patients with Alzheimer's disease treated with memantine in the clinical practice. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Evaluation of memantine for the treatment of Alzheimer's disease. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

GABAA Alpha 2,3 Modulation Improves Select Phenotypes in a Mouse Model of Fragile X Syndrome. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Arbaclofen in fragile X syndrome: results of phase 3 trials. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Open-label add-on treatment trial of minocycline in fragile X syndrome. [2021]