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

10 Participants Needed

Trial Summary

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.

What evidence supports the effectiveness of the drug N-acetylcysteine for Cornelia de Lange Syndrome?

Research shows that N-acetylcysteine (NAC) can improve lung function in cystic fibrosis patients and increase cell survival under stress conditions in a mouse model of corneal dystrophy. Additionally, NAC is known to replenish glutathione, a vital antioxidant, which may help in various conditions by reducing oxidative stress. ^{1 2 3 4 5}

Is N-acetylcysteine generally safe for humans?

N-acetylcysteine is generally considered safe for humans, but it can cause side effects like nausea, vomiting, and diarrhea. It has been used safely for conditions like chronic bronchitis and as an antidote for acetaminophen poisoning. ^{1 6 7 8 9}

How does the drug N-acetylcysteine differ from other treatments for Cornelia de Lange Syndrome?

N-acetylcysteine is unique because it is primarily known as a mucolytic agent, which means it helps break down mucus, and is also used as an antidote for acetaminophen poisoning. While it is not specifically designed for Cornelia de Lange Syndrome, its ability to improve lung function and reduce mucus could offer benefits not typically addressed by other treatments for this condition. ^{1 6 10 11 12}

What is the purpose of this trial?

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 (RB) and self-injurious behavior (SIB) in patients with Cornelia de Lange Syndrome (CdLs). NAC is a known anti-oxidative stress and neuroprotective agent, which has been shown to decrease the occurrence of SIB such as skin picking. NAC has also shown partial response in trials for compulsive behaviors in Obsessive Compulsive Disorder (OCD) and related disorders in autism. Cornelia de Lange syndrome (CdLS) is a genetic disorder with autistic features, including RBs and SIB. In this randomized clinical trial, participants with CdLS will be blindly assigned one of two possible treatment arms: 1) placebo (8 weeks) and NAC (8 weeks); or 2) NAC (8 weeks) and placebo (8 weeks), with an intermediate 2-week washout period.

Research Team

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

Principal Investigator

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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 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]

References

1. England 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

UV radiation protecting efficacy of cysteine derivatives, studies with UVA-induced binding of 8-MOP and CPZ to rat epidermal biomacromolecules in vivo. [2019]

4. Netherlands 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. [2015]

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

N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical pharmacokinetics of N-acetylcysteine. [2022]

7. Denmark pubmed.ncbi.nlm.nih.gov

Acetylcysteine and its derivatives: functional and morphological effects on tracheal mucosa in vitro. [2013]

8. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients. [2018]

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

Cystic fibrosis: comparison of two mucolytic drugs for inhalation treatment (acetylcysteine and arginine hydrochloride). [2018]

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

Topical N-acetylcysteine for the treatment of lamellar ichthyosis: an improved formula. [2014]

11. Germany pubmed.ncbi.nlm.nih.gov

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

12. England pubmed.ncbi.nlm.nih.gov

Effect of N-acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial. [2020]