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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how certain medications might alleviate symptoms of Fragile X Syndrome, a genetic condition that can cause learning and behavioral challenges. Participants will receive doses of baclofen (a muscle relaxant), memantine (commonly used for Alzheimer's disease), roflumilast (used for inflammatory conditions), or a placebo to assess their effects. It is ideal for individuals with Fragile X Syndrome who have participated in a specific prior study and feel stable on their current medications. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that baclofen is generally well-tolerated, with most people experiencing no serious problems. Some individuals reported mild side effects such as headaches, nausea, and irritability.

Research on memantine indicates it is safe for use, with no major side effects observed in people with Fragile X-related conditions. It has been used to assist with thinking and memory issues.

Roflumilast has undergone testing in many individuals and has FDA approval for other uses. Common side effects include diarrhea, weight loss, nausea, and headaches, but these were mostly mild.

Overall, these treatments have been studied and are considered safe, though they may cause some mild side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments being studied for Fragile X Syndrome because they each offer unique approaches that could be more effective than current options. Baclofen works by enhancing the function of GABA, a neurotransmitter involved in reducing brain activity, which might help with symptoms like hyperactivity and anxiety. Memantine, typically used for Alzheimer's, blocks NMDA receptors, potentially addressing cognitive symptoms by normalizing brain signals. Roflumilast, a phosphodiesterase-4 inhibitor, reduces inflammation and might improve cognitive function and behavior by enhancing neural communication. These diverse mechanisms offer hope for tackling different aspects of Fragile X Syndrome more effectively than existing treatments.

What evidence suggests that this trial's treatments could be effective for Fragile X Syndrome?

Research has shown promising results for the treatments tested for Fragile X Syndrome in this trial. Participants will receive, in random order, a single dose of placebo, baclofen, roflumilast, or memantine, with a two-week washout period between doses. Baclofen has shown potential in early studies, proving effective in both animal tests and humans with Fragile X Syndrome. Although some studies did not find improvements in social behaviors, the effects on brain function are considered important. Memantine has been reported to improve attention in people with Fragile X, which is crucial for thinking and planning. Roflumilast has shown positive effects on thinking skills in other contexts, suggesting it might also help with cognitive symptoms in Fragile X Syndrome. Each treatment might work differently, but all are being studied for their potential to alleviate Fragile X symptoms. ^{1 2 3 6 7}

Who Is on the Research Team?

Craig A. Erickson, M.D.

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

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

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

My genetic test shows I have Fragile X syndrome.

General good health as determined by physical exam, medical history and laboratory work up

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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 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 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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5467054/

Arbaclofen in fragile X syndrome: results of phase 3 trials - PMC Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study.

2. jneurodevdisorders.biomedcentral.com jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-022-09455-9

Baclofen-associated neurophysiologic target engagement ... In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS.

3. fragilex.org fragilex.org/research-fx/results/single-dose-medication-study-results/

Baclofen-Associated Neurophysiologic Target ... The results found from the EEGs in both the FMR1 KO mice and humans with FXS are extremely important for the future of FXS research.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01325220

NCT01325220 | Efficacy and Safety Study of STX209 ... Efficacy and Safety Study of STX209 (Arbaclofen) for the Treatment of Social Withdrawal in Children With Fragile X Syndrome (Harbor-C). ClinicalTrials.gov ID ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5991574/

Paradoxical effect of baclofen on social behavior in ... Our results show no improvement in the FXS phenotype after chronic baclofen treatment in both social behavioral tests. As a matter of fact, baclofen seems to ...

6. fraxa.org fraxa.org/baclofen-gabab-receptor-supersensitivity-and-normalization-of-behavioral-abnormalities-by-various-gabab-agonists-including-baclofen-in-fmrp-deficient-mice/

Baclofen: GABA(B) Receptor Supersensitivity and ... The absence of FMRP in Fragile X syndrome, besides cognitive abnormalities, is associated with hyperactivity and heightened sensory sensitivity.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4025936/

Clinical potential, safety, and tolerability of arbaclofen in the ... Preliminary clinical studies support the notion that arbaclofen in the form of STX209 has promise for improving social function in the ASD population.