N-Acetylcysteine for Cornelia de Lange Syndrome

Overseen By Masoud Salehi, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Johns Hopkins University

Must not be taking: Antibiotics

Disqualifiers: Allergy to NAC, Quinine, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates the effectiveness of N-acetylcysteine (NAC) in reducing repetitive and self-injurious behaviors in individuals with Cornelia de Lange Syndrome (CdLS), a genetic disorder often associated with these behaviors. NAC is under examination because it has shown promise in reducing similar behaviors in other disorders. Participants will receive both NAC and a placebo (a substance with no active treatment) at different times during the study. This trial may suit individuals with CdLS who experience repetitive behaviors or self-harm and can attend appointments at Johns Hopkins Hospital. As a Phase 2 trial, this research measures how well NAC works in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are taking antibiotics, you may need to stop, as NAC is contraindicated (not recommended) with them.

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

Research shows that N-acetylcysteine (NAC) is generally safe for people and is usually well-tolerated, meaning most people don't experience problems with it. Some mild side effects can occur, such as nausea, vomiting, or diarrhea, but these issues are rare and often depend on the method of administration and dosage.

NAC is already used in other treatments, which supports its safety. It has been safely used for conditions like asthma, and its safety has been well-studied, confirming it is mostly safe.

Past studies have shown that NAC can reduce self-harming behaviors, such as skin picking. It has also helped with compulsive behaviors in people with Obsessive Compulsive Disorder (OCD) and autism-related disorders. This suggests it might be safe and helpful for people with Cornelia de Lange Syndrome as well. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Cornelia de Lange Syndrome?

N-acetyl cysteine (NAC) is unique because it offers a new approach to managing Cornelia de Lange Syndrome by potentially reducing oxidative stress, which is thought to play a role in the condition's symptoms. Unlike current standard treatments that primarily address specific symptoms like behavioral issues or growth delays, NAC works at a cellular level to protect against damage. Researchers are excited about NAC because it could provide a more holistic improvement by addressing an underlying cause rather than just mitigating surface-level symptoms.

What evidence suggests that N-acetylcysteine might be an effective treatment for Cornelia de Lange Syndrome?

Research has shown that N-acetylcysteine (NAC) can help reduce behaviors like skin picking, especially in people with autism. In studies on obsessive-compulsive disorder (OCD) and similar behaviors, NAC has demonstrated some benefits. This is encouraging because Cornelia de Lange Syndrome (CdLS) shares similarities with autism, including repetitive and self-harming behaviors. In this trial, participants will receive NAC in one of the treatment arms. NAC acts as an antioxidant and protects nerve cells, reducing stress in the brain. These effects suggest it could be useful for managing symptoms in CdLS, particularly for those dealing with repetitive and self-harming behaviors. ^{1 2 5 6 7}

Who Is on the Research Team?

Marco A Grados, M.D., M.P.H.

Principal Investigator

Department of Psychiatry & Behavioral Sciences, Johns Hopkins School of Medicine

Are You a Good Fit for This Trial?

This trial is for individuals aged 13 to 35 with Cornelia de Lange Syndrome, exhibiting repetitive behaviors or self-injury. They must meet specific diagnostic criteria and be able to attend four visits over 18 weeks at Johns Hopkins Hospital. Pregnant or breastfeeding individuals, those with certain allergies, untreated gastric conditions, organ transplants, or on conflicting medications cannot participate.

Inclusion Criteria

I can go to Johns Hopkins Hospital 4 times over 18 weeks.

I am not pregnant or breastfeeding.

I have been diagnosed with Cornelia de Lange Syndrome (CdLS) by a doctor.

Exclusion Criteria

I cannot have chemotherapy due to an organ transplant or stomach issues.

I need a medication that cannot be taken with NAC.

You are allergic to NAC.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either NAC or placebo for 8 weeks, followed by a 2-week washout period, then switch to the alternate treatment for another 8 weeks

18 weeks

Weekly visits for dosage titration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• N-acetyl cysteine
• Placebo

Trial Overview The study tests N-Acetylcysteine (NAC), a neuroprotective agent that may reduce self-harm in patients with CdLS. Participants will randomly receive either NAC or a placebo for eight weeks each, separated by a two-week break to see if there's any change in their behavior.

How Is the Trial Designed?

Group I: Group B: Placebo then NAC 1800mg Experimental Treatment 2 Interventions

NAC Placebo-matching solution, orally every 8 hours, for 8 weeks, followed by a 2-week wash-out period, followed by NAC 1800 milligrams (mg), oral solution, every 8 hours for 8 weeks. Dosage will be titrated weekly starting at 600 mg daily and then increased by 600 mg every week to a target dose of 1800 mg per day.

Group II: Group A: NAC 1800mg then Placebo Experimental Treatment 2 Interventions

NAC 1800 milligrams (mg), oral solution, every 8 hours for 8 weeks, followed by a 2-week wash-out period, followed by NAC Placebo-matching solution, orally every 8 hours, for 8 weeks. Dosage will be titrated weekly starting at 600 mg daily and then increased by 600 mg every week to a target dose of 1800 mg per day.

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

Approved in United States as Acetylcysteine for:

• Acetaminophen overdose
• Chronic bronchitis
• Chronic obstructive pulmonary disease (COPD)
• Cystic fibrosis

Approved in European Union as Acetylcysteine for:

• Acetaminophen overdose
• Chronic bronchitis
• Chronic obstructive pulmonary disease (COPD)
• Cystic fibrosis

Approved in Canada as Acetylcysteine for:

• Acetaminophen overdose
• Chronic bronchitis
• Chronic obstructive pulmonary disease (COPD)
• Cystic fibrosis

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Cornelia de Lange Syndrome Foundation

Collaborator

Trials

2

Recruited

20,000+

Published Research Related to This Trial

N-acetylcysteine (NAC) significantly improves the survival of corneal endothelial cells under oxidative and endoplasmic reticulum stress, as shown by increased cell viability in cultured cells pre-treated with NAC.

In a mouse model of early-onset Fuchs endothelial corneal dystrophy, systemic NAC treatment led to higher corneal endothelial cell density and lower cell stress markers, suggesting it could be a promising treatment for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy. Kim, EC., Meng, H., Jun, AS.[2022]

A study involving 46 healthy participants demonstrated that a new 2% oral N-acetylcysteine formulation is bioequivalent to an existing reference product, meaning they have similar pharmacokinetic profiles.

The new formulation was found to be safe and well tolerated, with most side effects being mild or moderate and not linked to the study drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, open-label, crossover study evaluating bioequivalence of two N-acetylcysteine 2% oral solution formulations in healthy subjects . Donath, F., Armogida, M., Shneyer, L.[2019]

In a study involving 12 hemodialysis patients, intravenous administration of 2 g of N-acetylcysteine (NAC) over 3 hours was found to be safe, with no observed side effects during the six dialysis sessions.

NAC reached a steady state concentration after the fourth infusion, indicating effective pharmacokinetics in dialysis patients, with a significant dialytic clearance of 5.52 l/h.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. Soldini, D., Zwahlen, H., Gabutti, L., et al.[2018]

N-Acetylcysteine is effective as a mucolytic agent for chronic bronchitis and as an antidote for paracetamol poisoning, with peak plasma concentrations achieved within 1 to 2 hours after oral doses of 200 to 400 mg.

While it has significant therapeutic benefits, common side effects include nausea, vomiting, and diarrhea, and it may interact with other drugs, particularly paracetamol and certain anticancer agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of N-acetylcysteine. Holdiness, MR.[2022]

In a double-blind, placebo-controlled trial involving 41 cystic fibrosis (CF) patients and 13 primary ciliary dyskinesia (PCD) patients, N-acetylcysteine (NAC) showed improved lung function in CF patients during periods of lower airway infections.

No beneficial effects of NAC were observed in PCD patients, indicating that the treatment may be more effective for those with cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical effect and the effect on the ciliary motility of oral N-acetylcysteine in patients with cystic fibrosis and primary ciliary dyskinesia. Stafanger, G., Garne, S., Howitz, P., et al.[2022]

In a 12-month study involving 161 bronchiectasis patients, those treated with N-acetylcysteine experienced significantly fewer exacerbations (1.31 vs. 1.98 per patient-year) compared to the control group, indicating its efficacy in reducing flare-ups.

The N-acetylcysteine group also showed a notable improvement in quality of life and a significant reduction in sputum volume, with no severe adverse events reported, suggesting it is a safe long-term treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. Qi, Q., Ailiyaer, Y., Liu, R., et al.[2020]

In a study involving 70 cystic fibrosis (CF) patients over 24 weeks, those taking oral N-acetylcysteine (NAC) maintained or slightly improved their lung function, while those on placebo experienced a decline, indicating NAC's potential to stabilize lung health in CF.

Despite the positive effects on lung function, NAC did not significantly reduce levels of human neutrophil elastase (HNE), a marker of inflammation, suggesting that while NAC may help with lung function, its mechanism of action regarding inflammation needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. Conrad, C., Lymp, J., Thompson, V., et al.[2015]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04381897?cond=(CORNELIA%20DE%20LANGE%20SYNDROME)%20OR%20(NIPBL)&rank=4

Use of N-Acetylcysteine in the Treatment of Repetitive and ... NAC has been shown to decrease maladaptive behaviors in autism and grooming disorders such as excoriation disorder (skin picking). An 18-week cross-over trial ...

2. withpower.com withpower.com/trial/phase-3-de-lange-syndrome-11-2021-13d4b

N-Acetylcysteine for Cornelia de Lange Syndrome This research project is a randomized cross-over pilot trial which aims to test the efficacy of N-acetylcysteine (NAC) for the treatment of Repetitive ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9987326/

Cornelia de Lange syndrome, related disorders, and the ... All outcomes are measured at baseline 1, week 8, baseline 2 and week 8 (crossover). Conclusion: Pilot efficacy data on use of NAC to decrease RB-SIB in CdLS can ...

4. smartpatients.com smartpatients.com/trials/NCT04381897

Use of N-Acetylcysteine in the Treatment of Repetitive and ... This research project is a randomized cross-over pilot trial which aims to test the efficacy of N-acetylcysteine (NAC) for the treatment of Repetitive Behaviors ...

5. mdpi.com mdpi.com/2077-0383/13/8/2423

Advancing the Clinical and Molecular Understanding of ... This article provides a case series review of pediatric CdLS patients alongside a comprehensive literature review, exploring clinical variability.

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 ...

7. trial.medpath.com trial.medpath.com/clinical-trial/c9959c763f025d47/nct02605824-clinical-trial-nac-asthma

Clinical Trial of NAC in Asthma - MedPath This study evaluates 20% n-acetylcystine (NAC) in the treatment of moderate-to-severe asthma that is complicated by mucus in the airway, as determined by CT ...