An Open Label Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacologic Properties of High Dose Ambroxol Hydrochloride in Adult (≥ 18 Years of Age) Subjects With MPS III

A dose escalation study to evaluate the safety, tolerability, and pharmacologic properties of Ambroxol in adult participants with Sanfilippo disease(s) (MPS3).

Study Overview

• Status: Recruiting
• Conditions: Sanfilippo Syndrome; MPS3
• Intervention / Treatment: Drug: Ambroxol Hydrochloride 30 mg tablet - 9 mg/kg/day; Drug: Ambroxol Hydrochloride 30 mg tablet - 18 mg/kg/day; Drug: Ambroxol Hydrochloride 30 mg tablet - 27 mg/kg/day

Detailed Description

This is a dose escalation study in which open label Ambroxol 30mg (study drug) will be administered to adult patients with Sanfilippo Disease (MPS3). Administration route of study drug will be either crushed and mixed with soft foods or as an Ambroxol suspension through a feeding tube, if applicable.

Study Timeline - Screening: 4 weeks (28 days) Treatment Period: 52 weeks Post-Treatment (after Week 52): 4 weeks withdrawal/safety follow-up period

Patients will be screened at which point a thorough review of the Informed Consent form will be completed, sNFL levels, urinary GAGs, and serum HS results/data from the previous 12 months will be reviewed, urine and blood will be collected, complete questionnaires, Motor skills assessments, and evaluation by the Principal Investigator (PI).

Eligible patients will proceed to receive the initial Ambroxol dose of 9mg/kg/day (maximum dose of 150 mg TID) divided into three equal doses per day, on-site. Other assessments including blood and urine collection, ECG, motor skills assessments, hearing test, questionnaires, and evaluation by the PI will be completed.

Following the first day of dosing, a virtual visit will be performed via Telemedicine within 1 week of dose start to assess safety.

At Weeks 12 and 24, enrolled patients will return to site for Ambroxol dose escalation to 18mg/kg/day (max dose of 300 mg TID) and 27mg/kg/day (max dose of 1350 mg/day), respectively. Assessments including blood and urine collection, ECG, motor skills assessments, hearing test, questionnaires, and evaluation by the PI will be completed at these visits.

Telemedicine visits will take place at Weeks 13 and 25, to assess safety.

At Week 36, a safety visit will be performed in which blood and urine will be collected.

At Week 52, end of study assessments will be completed which includes blood and urine collection, motor skills assessments, hearing test questionnaires, and evaluation by the PI will be conducted and treatment will be stopped.

A safety follow-up visit will be done 4 weeks after Week 52 visit is completed in which the patient will be evaluated by the PI.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Arooj Agha; Phone Number: 571-732-4575; Email: aagha@ldrtc.org
• Study Contact Backup: Name: Lauren Noll; Phone Number: 571-732-4655; Email: lnoll@ldrtc.org

Study Locations

• United States
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Recruiting
      • Lysosomal & Rare Disorders Research & Treatment Center, Inc.
      • Contact: Arooj Agha; Phone Number: 571-732-4575; Email: aagha@ldrtc.org
      • Contact: Lauren Noll; Phone Number: 571-732-4655; Email: lnoll@ldrtc.org
      • Principal Investigator: Ozlem Goker-Alpan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. IRB - approved informed consent/assent signed by subject and/or parent(s) or legal guardian(s).
2. Genetically confirmed diagnosis of MPS III disease.
3. Genomic DNA analysis demonstrating a homozygous or compound heterozygous pathogenic variants in SGSH (type A), NAGLU (type B), HGSNAT (type C), or GNS (type D) genes. Type E will not be studied.
4. Elevated excretion of urinary GAGs and/or serum HS (if no historical data is available, screening GAGs and serum HS values will be utilized to assess inclusion criteria).
5. Male or female; eighteen years of age and older, who is able to take Ambroxol Hydrochloride orally.
6. Negative urine pregnancy test at screening for female subjects with child-bearing potential.
7. The subject is willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit containing products for 72 hours prior to administration of the first dose of Ambroxol and for the duration of the treatment period.

Exclusion Criteria:

1. Unwilling or unable to follow protocol requirements as per principal investigator.
2. Any serious or chronic medical illness, including significant cardiac or severe debilitating pulmonary disease.
3. Poorly controlled seizures, defined as more than one seizure per day for the past 6 months.
4. Medications identified as a strong inducers or inhibitors of CYP3A, and changing to another alternative drug to treat the condition would place the subject at undue risk.
5. Any medical condition that, in the opinion of the PI, would make the subject unsuitable to participate in the study.
6. Inability to cooperate for clinical and safety data collection.
7. Known hypersensitivity to Ambroxol or any of its excipients.
8. Use of genistein or Miglustat within one week of starting screening.
9. Evidence of hepatitis B or hepatitis C infection upon serological testing at screening.
10. Currently participating in another clinical trial or has completed an interventional trial less than 2 weeks prior to screening visit.
11. The subject has received strong inducers (Note: eg, herbal supplements) or inhibitors of CYP3A within 15 days or 5 half-lives from screening, whichever is longer, prior to enrollment. This also includes the consumption of grapefruit, grapefruit juice, or grapefruit containing products within 72 hours of starting Ambroxol administration.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ambroxol Hydrochloride 30mg - 9mg/kg/day; Ambroxol Hydrochloride 30mg Dose escalation: Initial dose of 9mg/kg/day (or max dose 150mg TID)	Drug: Ambroxol Hydrochloride 30 mg tablet - 9 mg/kg/day; Ambroxol Hydrochloride 30 mg oral pill/tablet - 9 mg/kg/day; Other Names: Ambroxol
Experimental: Ambroxol Hydrochloride 30mg - 18mg/kg/day; Ambroxol Hydrochloride 30mg Dose escalation: 18mg/kg/day (or max dose 300mg TID)	Drug: Ambroxol Hydrochloride 30 mg tablet - 18 mg/kg/day; Ambroxol Hydrochloride 30 mg oral pill/tablet - 18 mg/kg/day; Other Names: Ambroxol
Experimental: Ambroxol Hydrochloride 30mg - 27mg/kg/day; Ambroxol Hydrochloride 30mg Dose escalation: 27mg/kg/day (or max dose 1350mg QD)	Drug: Ambroxol Hydrochloride 30 mg tablet - 27 mg/kg/day; Ambroxol Hydrochloride 30 mg oral pill/tablet - 27 mg/kg/day; Other Names: Ambroxol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	1. Safety and tolerability as measured by number of Participants with at least one serious and at least one non-serious Treatment Emergent Adverse Events (TEAEs), assessed by CTCAE v4.0.	From baseline to 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in physical examination from baseline in motor capabilities and disease state: Physician (Clinician) Global Impression of Change	Physician (Clinician) Global Impression of Change (scale: 0-very much worse - 7-Very much improved).	From baseline to 52 weeks
Change from baseline in EQ-5D-5L™ or EQ-5D-Y™	Change from baseline in EQ-5D-5L™ or EQ-5D-Y™	From baseline to 52 weeks
Change from baseline in VABS-III age equivalent scores (AEqs)	Vineland Adaptive Behavior scale-III	From baseline to 52 weeks
Assessment of Pharmacokinetics of Ambroxol in subjects with MPS III	Plasma PK parameter estimates for oral Ambroxol include the area under the curve (AUC).	From baseline to 52 weeks
Assessment of Pharmacokinetics of Ambroxol in subjects with MPS III	Plasma PK parameter estimates for oral Ambroxol include maximum concentration (Cmax).	From baseline to 52 weeks
Assessment of Pharmacokinetics of Ambroxol in subjects with MPS III	Plasma PK parameter estimates for oral Ambroxol include time to maximum dose concentration (Tmax).	From baseline to 52 weeks
Assessment of Pharmacokinetics of Ambroxol in subjects with MPS III	Plasma PK parameter estimates for oral Ambroxol include terminal half-life (t1/2).	From baseline to 52 weeks
Assessment of Pharmacodynamics of Ambroxol in subjects with MPS III	Changes from baseline in Urinary GAG levels as measured by total quantified concentration. Changes from baseline will be analyzed using main effects, fixed for treatment (dose), categorical visit number, treatment-by-visit interaction, baseline value as covariate, and subject as the random effect.	From baseline to 52 weeks
Assessment of Pharmacodynamics of Ambroxol in subjects with MPS III	Serum Heparan sulfate (HS) level changes from baseline as measured by total quantified concentration. Changes from baseline will be analyzed using main effects, fixed for treatment (dose), categorical visit number, treatment-by-visit interaction, baseline value as covariate, and subject as the random effect.	From baseline to 52 weeks
Change from baseline in Timed up and go (TUG) test	Change from baseline in Timed up and go (TUG) test and in ABR at Week 52 may also be tested for correlations.	From baseline to 52 weeks
Change from baseline in 10-meter walk test	Change from baseline in 10-meter walk test, may also be tested for correlations.	From baseline to 52 weeks
Change from baseline in SBRS	Change from baseline in SBRS	From baseline to 52 weeks

Collaborators and Investigators

• Sponsor: Ozlem Goker-Alpan
• Collaborators: Team Sanfilippo
• Investigators: Principal Investigator: Ozlem Goker-Alpan, MD, Lysosomal & Rare Disorders Research & Treatment Center, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2024
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: August 28, 2024
• First Submitted That Met QC Criteria: September 25, 2024
• First Posted (Actual): September 26, 2024

Study Record Updates

• Last Update Posted (Actual): August 20, 2025
• Last Update Submitted That Met QC Criteria: August 18, 2025
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Mucopolysaccharidosis III; Expectorants; Respiratory System Agents; Ambroxol
• Other Study ID Numbers: 24-LDRTC-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No