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

58 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a medication called NAC in children aged 8-16 with a condition called NF1. These children often have problems with movement and behavior, and there is no current treatment for these issues. NAC works by reducing harmful molecules in the brain, which may help improve these symptoms.

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 N-Acetyl cysteine (NAC) safe for use in humans?

N-Acetyl cysteine (NAC) has been studied for its ability to reduce oxidative damage and side effects of chemotherapy in pediatric cancer models, suggesting it is generally safe for use in humans. ^{1 2 3 4 5}

How does the drug N-Acetyl cysteine (NAC) differ from other treatments for Neurofibromatosis Type 1?

N-Acetyl cysteine (NAC) is unique because it is an antioxidant that aims to reduce oxidative stress, which is a different approach compared to other treatments that may not target oxidative stress directly. This drug is also used in other conditions to protect cells from damage, which highlights its potential to address underlying cellular issues in Neurofibromatosis Type 1. ^{3 6 7 8 9}

What evidence supports the effectiveness of the drug N-Acetyl cysteine (NAC) for treating Neurofibromatosis Type 1?

Research suggests that oxidative stress plays a role in the development of tumors in Neurofibromatosis Type 1 (NF1), and NAC is known to help reduce oxidative stress. Although not directly tested for NF1, NAC's ability to balance oxidative stress may offer potential benefits for managing NF1-related conditions. ^{1 2 4 10 11}

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. Italy pubmed.ncbi.nlm.nih.gov

Dynamic thiol/disulphide homeostasis in children with neurofibromatosis type 1 and tuberous sclerosis. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

The Contribution of Oxidative Stress to NF1-Altered Tumors. [2023]

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

Peroxynitrite supports a metabolic reprogramming in merlin-deficient Schwann cells and promotes cell survival. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Tumor growth of neurofibromin-deficient cells is driven by decreased respiration and hampered by NAD+ and SIRT3. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma. [2021]

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

N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models. [2018]

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

Metabolic activation and genotoxicity of N-hydroxy-2-acetylaminofluorene and N-hydroxyphenacetin derivatives in Reuber (H4-II-E) hepatoma cells. [2013]

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

A Phase II Randomized Placebo-Controlled Trial of Oral N-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress In Vivo. [2021]

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

Use of oral N-acetylcysteine for protection of melanocytic nevi against UV-induced oxidative stress: towards a novel paradigm for melanoma chemoprevention. [2021]

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

Antioxidants accelerate lung cancer progression in mice. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Antioxidants Promote Intestinal Tumor Progression in Mice. [2021]