Use of N-Acetylcysteine in the Treatment of Repetitive and Self-Injurious Behaviors in Cornelia de Lange Syndrome

NCT ID: NCT04381897

Last Updated: 2025-11-10

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-03-01
• Study Completion Date: 2027-05-01

Brief Summary

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.

Detailed Description

Cornelia de Lange syndrome (CdLS) is a genetic condition caused by mutations in cohesin-related genes, mostly notably NIPBL. The CdLS phenotype includes physical features such as typical facies, limb abnormalities, short stature, and hirsutism as well developmental and behavioral manifestations such as intellectual disability, communication deficits, autistic traits and repetitive/self-injurious behaviors (RBs/SIB).

Behavioral challenges such as RBs/SIB pose a significant obstacle to quality of life to individuals with CdLS and families. In CdLS, disruption of developmental systems can impact neuronal and brain development, and impact GABAergic inhibitory interneuron formation, leading to RBs/SIB. Given the potential for dysregulated excitatory glutamatergic output in CdLS, neuronal oxidative stress may play a role in these maladaptive behaviors. NAC replenishes Central Nervous System (CNS) glutathione, a potent antioxidant and may ameliorate RBs/SIB. 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 is proposed to decrease RBs/SIB comprising two 8-week double-blinded active or placebo treatment with a 2-week wash out period in between. A cross-over design will afford for higher efficiency in sample size for similar power. 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. Participants will be recruited through CdLS Foundation.

Based on a mechanism for regulation glutamate transmission homeostasis in the central nervous system, the use of NAC may be particularly pertinent to individuals with CdLS. It is known that in CdLS genetic networks that impact on limb formation overlap significantly with developmental systems that impact neuronal and brain development, in particular GABAergic inhibitory interneuron formation. Given a dysregulated excitatory glutamatergic mechanism due to interneuron deficits, which can then lead to neuronal oxidative stress and programmed cell death, NAC may act as a key homeostatic regulator to prevent glutamate overactivity and neuronal damage in CdLS.

Conditions

Cornelia de Lange Syndrome

Keywords

Repetitive behaviors; Self-injurious behavior; N-acetylcysteine; Genetic disorder; Children; Psychiatric disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Group A: NAC 1800mg then Placebo

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.

Group Type: EXPERIMENTAL

N-acetyl cysteine

Intervention Type: DRUG

Oral solution for N-acetyl cysteine is prepared in syringes and provided to the participants along with instructions on how to administer them.

Placebo

Intervention Type: OTHER

NAC Placebo-matching solution is prepared in syringes and provided to the participants along with instructions on how to administer them.

Group B: Placebo then NAC 1800mg

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 Type: EXPERIMENTAL

N-acetyl cysteine

Intervention Type: DRUG

Oral solution for N-acetyl cysteine is prepared in syringes and provided to the participants along with instructions on how to administer them.

Placebo

Intervention Type: OTHER

NAC Placebo-matching solution is prepared in syringes and provided to the participants along with instructions on how to administer them.

Interventions

N-acetyl cysteine

Oral solution for N-acetyl cysteine is prepared in syringes and provided to the participants along with instructions on how to administer them.

Intervention Type: DRUG

Placebo

NAC Placebo-matching solution is prepared in syringes and provided to the participants along with instructions on how to administer them.

Intervention Type: OTHER

Other Intervention Names

Acetylcysteine; National Drug Code (NDC): 63323-690

Eligibility Criteria

Inclusion Criteria

• Ages 13 to 35 years
• A diagnosis of CdLS as determined by a physician during routine care meeting the major and minor criteria from CdLS guidelines
• Threshold criteria for the presence of RB/SIB as reported on initial screening Children's Yale-Brown Obsessive Compulsive Scale Modified for Pervasive Developmental Disorders (CYBOCS-PDD) > 6 OR Aberrant Behavior Checklist (ABC) stereotypy subscale > 7)
• Being able to attend 4 visits over the course of 18 weeks at the Johns Hopkins Hospital
• No acute safety concerns or need for hospitalization due to psychotic, manic or depressive episode
• Not currently pregnant or lactating/breastfeeding. Whether a participant is pregnant or not will be determined by the participant/caregiver report based on date last menses. If there is any suspicion of pregnancy, the PI will confer with the family to obtain testing through the primary care provider.

Exclusion Criteria

• Allergy to NAC
• Allergy to Quinine
• Contraindication to NAC (organ transplant; untreated or symptomatic gastric condition)
• Need for another medication with which NAC is contraindicated (antibiotics)

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cornelia de Lange Syndrome Foundation

UNKNOWN

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

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

Role: PRINCIPAL_INVESTIGATOR

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

Locations

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Countries

United States

Central Contacts

Masoud Salehi, M.D.

Role: CONTACT

Phone: 443-857-9365

Email: msalehi3@jhmi.edu

Facility Contacts

Masoud Salehi, MD

Role: primary

References

Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, Frazier TW, Tirouvanziam R. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012 Jun 1;71(11):956-61. doi: 10.1016/j.biopsych.2012.01.014. Epub 2012 Feb 18.

Reference Type: BACKGROUND

PMID: 22342106 (View on PubMed)

Other Identifiers

IRB00153778

Identifier Type: -

Identifier Source: org_study_id