Antioxidant Therapy for Neurofibromatosis Type 1

(DoDNAC Trial)

Overseen By Donald L Gilbert, MD MS

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Antidepressants, Dopamine blockers, Mood stabilizers

Disqualifiers: Epilepsy, Major depression, Asthma, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the antioxidant N-acetylcysteine (NAC) can improve motor skills and learning in children with neurofibromatosis type 1 (NF1), a condition that often affects behavior and movement. Researchers aim to determine if NAC is safe and beneficial for children with this condition. Children aged 8 to 16 with NF1 who experience difficulties with movement or learning might be suitable for this study. Participants will receive either NAC or a placebo (a pill with no active ingredient) and will be monitored for any changes or side effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

If you are taking stimulant or psychotropic medications, you need to stay on a stable dose for at least 30 days before joining the study and keep that dose during the study. If you are using antidepressants, dopamine blocking agents, or mood stabilizers, you cannot participate in the trial.

Is there any evidence suggesting that N-acetylcysteine (NAC) is likely to be safe for children with neurofibromatosis type 1?

Research has shown that N-acetylcysteine (NAC) is generally safe. Studies have found that both children and adults usually tolerate NAC well. Problems are rare and typically occur only with very high doses or specific methods of administration. In this trial, researchers carefully control doses to ensure safety for children.

Previous health studies have used NAC for various conditions, supporting its safety. NAC acts as an antioxidant, reducing harmful substances in the body, which contributes to its safety.

Participants in this trial will be closely monitored for any side effects. This careful monitoring helps catch potential issues early. Overall, NAC is considered a safe option for studying its effects on neurofibromatosis type 1 (NF1) symptoms in children. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

N-Acetylcysteine (NAC) is unique for treating Neurofibromatosis Type 1 (NF1) because it harnesses the power of antioxidants to potentially improve brain function. Researchers are excited about NAC because it targets oxidative stress, a key player in the cognitive issues faced by NF1 patients, unlike most current treatments that primarily focus on managing physical symptoms. By addressing this oxidative stress, NAC may help improve executive functions like attention and self-control, offering a novel approach compared to standard therapies. Additionally, NAC is well-known for its safety profile, as it's already used for other conditions, which could expedite its path to becoming a treatment option for NF1.

What evidence suggests that N-Acetyl cysteine might be an effective treatment for neurofibromatosis type 1?

Research has shown that N-acetylcysteine (NAC), which participants in this trial may receive, might help with thinking and movement problems in children with neurofibromatosis type 1 (NF1). In animal studies, NAC improved behavior and corrected cell issues related to NF1. These findings suggest that NAC can help with brain and behavior problems in NF1. Some early observations in children also support this idea, indicating that NAC might be effective in treating NF1-related difficulties. ^{1 3 4 5 6}

Who Is on the Research Team?

Donald Gilbert, MD MS

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for children aged 8-16 with neurofibromatosis type 1 (NF1) and an IQ of 70 or above. They must have a specific abnormal score on a motor skills test and be on stable doses of any psychotropic medication. It excludes those without NF1, under chemotherapy, with epilepsy, certain medical devices, using specific drugs like MEKINIST within the last month, or with severe psychiatric disorders.

Inclusion Criteria

You have an abnormal PANESS score.

I have been diagnosed with neurofibromatosis type 1.

I have been on a stable dose of my psychiatric medication for at least 30 days.

Exclusion Criteria

I have epilepsy.

I have a stable low-grade brain tumor or epilepsy.

For females, pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive N-acetylcysteine (NAC) or placebo for 8 weeks to assess safety, tolerability, and efficacy on motor behavior and neurocognitive symptoms

8 weeks

Visits at weeks 0, 8, and 12

Washout

Participants undergo a 4-week washout period after treatment to assess the persistence of NAC effects

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Visit at week 12

What Are the Treatments Tested in This Trial?

Interventions

• N-Acetyl cysteine
• Placebo

Trial Overview The study tests N-acetylcysteine (NAC), an antioxidant therapy against a placebo in children with NF1 to see if it improves cognitive and motor functions. This Phase II trial is double-blind and controlled; participants won't know which treatment they're getting to ensure unbiased results.

How Is the Trial Designed?

Group I: N-Acetylcysteine (NAC) Experimental Treatment 1 Intervention

Each subject will be dosed with approximately 70 mg/kg/day of NAC for 8 weeks. To facilitate drug compounding, three tiers of drug dose will be administered based on body weight as described in Table 3. Table 3: NAC Dosing Participant's weight (kg) Dose (BID) \< 20 700 mg 21-39 1050 mg \> 40 1350 mg \*Max dose not to exceed 2700mg/day (1350mg BID)

Group II: Single Visit/Non-Treatment Arm Active Control 1 Intervention

Based on preliminary data, an additional "Single visit, non-treatment" cohort will include 40 individuals with NF1 for a single "biomarker" study visit. These individuals will undergo motor function (PANESS) and brain-based measures (TMS, MRI-MRS, DTI) as biomarkers of impaired executive function (ADHD-RS; BRIEF-2; TOVA) but will not be assigned to receive NAC/Placebo.

Group III: Placebo Placebo Group 1 Intervention

Each subject will be dosed with placebo for 8 weeks.

N-Acetyl cysteine is already approved in United States, European Union for the following indications:

Approved in United States as NAC for:

• Antidote for acetaminophen overdose
• Mucolytic agent

Approved in European Union as NAC for:

• Antidote for paracetamol overdose
• Mucolytic agent

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04481048

Antioxidant Therapy With N-acetylcysteine for Children ... This data from animal models of NF1 along with uncontrolled clinical observations in children with NF1 suggest that the antioxidant compound, NAC, may reduce ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04481035

Antioxidant Therapy With N-acetylcysteine for Learning ... The primary outcome of this study is motor function rated with the Physical and Neurological Examination for Subtle Signs (PANESS), a validated scale that ...

3. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04481048/antioxidant-therapy-with-n-acetylcysteine-for-children-with-neurofibromatosis-type-1

Antioxidant Therapy With N-acetylcysteine for Children ... Treating these mice with NAC corrected cellular and behavioral abnormalities. This data from animal models of NF1 along with uncontrolled ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10140479/

N-acetylcysteine overcomes NF1 loss-driven resistance to ... We show now that N-acetylcysteine (NAC), a reducing amino acid derivative, synergizes with PI3Kα inhibition and diminishes mTOR signaling, with ...

5. cdmrp.health.mil cdmrp.health.mil/nfrp/clinical_trials/nf1

Neurofibromatosis Research Program, NFRP Supported ... Summary: The goal of this Phase II study is to explore efficacy of N-acetylcysteine (NAC), an antioxidant, on motor behavior and attention ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8234027/

N-Acetylcysteine (NAC): Impacts on Human Health - PMC It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant ...