Cannabidiol Gel for Fragile X Syndrome

(RECONNECT Trial)

Recruiting at 40 trial locations

Overseen By Kristen Kaplan

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Zynerba Pharmaceuticals, Inc.

Must be taking: Antiseizure, Psychoactive

Must not be taking: Cannabis, Benzodiazepines, CYP3A4 drugs

Disqualifiers: Pregnancy, Drug abuse, Cardiovascular disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 9

Duration: 18 weeks

250 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a randomized, double-blind, placebo-controlled, multiple-center study, to assess the efficacy and safety of Cannabidiol administered as ZYN002 for the treatment of children, adolescent, and young adult patients with Fragile X Syndrome (FXS). Eligible participants will participate in up to an 18-week treatment period, where all participants will receive placebo or active study drug. Patients ages 3 to \< 30 years will be eligible to participate.

Will I have to stop taking my current medications?

The trial requires that participants maintain a stable regimen of psychoactive medications and anti-seizure medications if they are already on them. However, certain medications like cannabis products, specific anti-seizure drugs, and strong CYP3A4 inhibitors or inducers must be stopped before joining the study.

What evidence supports the effectiveness of the drug ZYN002 (cannabidiol transdermal gel) for treating Fragile X Syndrome?

Research suggests that cannabidiol (CBD) can help reduce symptoms like anxiety, social avoidance, and sleep problems in Fragile X Syndrome (FXS). Studies have shown that CBD, including the ZYN002 gel, may improve social interaction and reduce irritability, especially in patients with high levels of FMR1 gene methylation, which is linked to FXS. ^{1 2 3 4 5}

Is the cannabidiol gel safe for humans?

Research suggests that cannabidiol (CBD) gel, like ZYN002, is generally safe for humans. Studies have shown it to be well-tolerated in both children and adults, with no major safety concerns reported in trials for conditions like Fragile X Syndrome. ^{1 2 3 6 7}

How is the drug ZYN002 different from other treatments for Fragile X Syndrome?

ZYN002 is unique because it is a transdermal gel, meaning it is applied to the skin, which can offer a more consistent delivery of cannabidiol (CBD) compared to oral solutions. This method may reduce the risk of side effects and improve the management of symptoms like anxiety and social avoidance in Fragile X Syndrome. ^{1 2 4 6 8}

Eligibility Criteria

This trial is for children, adolescents, and young adults aged 3 to less than 23 with Fragile X Syndrome. Participants must be in good health, have a stable regimen of medications if taking any, and not use cannabis products. Girls who can have babies must test negative for pregnancy.

Inclusion Criteria

Judged by the Investigator to be in generally good health at Screening based upon the results of medical history, physical exam, 12-lead ECG and clinical laboratory test results. -Laboratory results outside the reference range must be documented as not clinically significant by both the Investigator and Sponsor.

I am between 3 and 17 years old.

I've been on a stable dose of up to 3 psychoactive medications for at least 4 weeks.

Exclusion Criteria

You answered "yes" to Question 4 or 5 on the Children's Columbia-Suicide Severity Rating Scale during screening or at any time during the study.

I am taking medication for seizures or epilepsy.

I am not pregnant, nursing, or planning to become pregnant and agree to use effective birth control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ZYN002 or placebo transdermal gel for 18 weeks

18 weeks

7 visits (combination of in-person and virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (telephone follow-up)

Treatment Details

Interventions

• Placebo
• ZYN002 - CBD transdermal gel
• ZYN002 - transdermal gel

Trial Overview The study tests the safety and effectiveness of a Cannabidiol gel (ZYN002) compared to a placebo over an 18-week period. It's randomized and double-blind, meaning neither the researchers nor participants know who gets the real treatment or placebo.

Participant Groups

Group I: ZYN002 - transdermal gel Experimental Treatment 1 Intervention

Pharmaceutically manufactured. Cannabidiol is formulated as a clear gel for transdermal delivery.

Group II: Placebo transdermal gel Placebo Group 1 Intervention

Placebo is formulated as a clear gel for transdermal delivery.

Who Is Running the Clinical Trial?

Zynerba Pharmaceuticals, Inc.

Lead Sponsor

Trials

4

Recruited

1,000+

Findings from Research

In a study involving 20 children and adolescents with Fragile X syndrome, the transdermal CBD gel (ZYN002) was found to be well tolerated, with 85% of participants reporting only mild side effects and no serious adverse events.

The treatment led to significant reductions in anxiety and behavioral symptoms, as measured by various scales, indicating its potential efficacy for managing symptoms associated with Fragile X syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome. Heussler, H., Cohen, J., Silove, N., et al.[2020]

A narrative review and case series involving three patients with Fragile X syndrome (FXS) treated with oral CBD-enriched solutions showed functional benefits, including reduced anxiety and improved sleep and language skills.

The case series suggests that CBD may help manage symptoms of FXS, as two patients experienced a return of symptoms after stopping treatment, which improved again upon reintroduction of CBD, indicating its potential therapeutic role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Fragile X Syndrome with Cannabidiol: A Case Series Study and Brief Review of the Literature. Tartaglia, N., Bonn-Miller, M., Hagerman, R.[2023]

In a study using Fmr1-knockout mice, CBDV showed limited effectiveness when administered during adulthood, only improving some acoustic responses and neurotrophin levels.

However, when given during adolescence, CBDV significantly prevented cognitive, social, and sensory issues in adult Fmr1-KO mice, suggesting that early treatment may be crucial for its therapeutic benefits in Fragile X syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome. Premoli, M., Fyke, W., Bellocchio, L., et al.[2023]

A qualitative survey of parents and caregivers revealed that many are using various forms and doses of cannabidiol (CBD) to treat symptoms of Fragile X Syndrome (FXS), citing its perceived benefits and fewer side effects compared to traditional medications.

Most respondents reported that CBD improved symptoms such as anxiety and hyperactivity in individuals with FXS, indicating its potential therapeutic value, although further research is needed to fully understand its effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Parent and Caregiver Perspectives towards Cannabidiol as a Treatment for Fragile X Syndrome. Maertens, M., Silver, H., Dixon Weber, J., et al.[2022]

The endocannabinoid system (ECS) plays a crucial role in neuronal development and cognitive function, and its dysregulation is linked to fragile X syndrome (FXS), which is caused by the absence of the FMR1 protein due to gene silencing.

Cannabidiol (CBD) shows promise as a treatment for FXS by potentially restoring synaptic balance and reducing receptor overstimulation, with clinical evidence from the CONNECT-FX trial indicating improvements in social behaviors in patients with high FMR1 gene methylation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment. Palumbo, JM., Thomas, BF., Budimirovic, D., et al.[2023]

PTL101, an oral formulation of highly purified CBD, was found to be safe and well-tolerated in healthy volunteers, showing a significant increase in CBD absorption compared to the Sativex oromucosal spray.

The 10 mg dose of PTL101 demonstrated 134% bioavailability relative to the reference spray, indicating that it delivers CBD more effectively, which could make it a promising option for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology. Atsmon, J., Heffetz, D., Deutsch, L., et al.[2022]

In a study involving 17 healthy adults, different doses of oral cannabidiol (CBD) did not impair driving performance, as measured by standard deviation of lateral position (SDLP), suggesting that CBD is safe for driving tasks.

CBD did not induce feelings of intoxication or impair cognitive function, indicating its potential for safe use in everyday activities, including driving, even at higher doses like 1500 mg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cannabidiol on simulated driving and cognitive performance: A dose-ranging randomised controlled trial. McCartney, D., Suraev, AS., Doohan, PT., et al.[2023]

In a study involving 34 children aged 4-10 with Dravet syndrome, purified cannabidiol (CBD) was found to be generally well-tolerated, with a dose-proportional increase in exposure to CBD and its metabolites, indicating effective pharmacokinetics.

While CBD treatment resulted in more adverse events (AEs) compared to placebo, such as pyrexia and sedation, no significant safety concerns were identified, and all patients recovered from any elevated liver enzymes without meeting criteria for drug-induced liver injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Devinsky, O., Patel, AD., Thiele, EA., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome. [2020]

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

Treatment of Fragile X Syndrome with Cannabidiol: A Case Series Study and Brief Review of the Literature. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Parent and Caregiver Perspectives towards Cannabidiol as a Treatment for Fragile X Syndrome. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment. [2023]

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

Single-Dose Pharmacokinetics of Oral Cannabidiol Following Administration of PTL101: A New Formulation Based on Gelatin Matrix Pellets Technology. [2022]

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

Effects of cannabidiol on simulated driving and cognitive performance: A dose-ranging randomised controlled trial. [2023]

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

Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. [2022]