Clemastine plus engineered sound to improve hearing in noisy environments for age-related central auditory processing disorder

A Double-Blinded, Placebo-Controlled, Randomized, Phase 1/2a Clinical Study to Test the Safety and Efficacy of a Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound

This trial will test whether taking clemastine while listening to engineered sounds helps people aged 45–65 with age-related central auditory processing disorder hear better in noisy places.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 344 (estimated)
• Ages: 45 Years to 65 Years
• Sex: All
• Sponsor: University of Colorado, Denver (other)
• Locations: 1 site (Aurora, Colorado)
• Trial ID: NCT07304024 on ClinicalTrials.gov

What this trial studies

This adaptive Phase 1/2 interventional trial compares clemastine fumarate with and without engineered sound against placebo arms to measure changes in hearing-in-noise performance. The trial tests the Localized Oligodendrocyte Optimization Therapy (LOOT) hypothesis that sound-driven circuit activation will allow clemastine to mature oligodendrocytes and remyelinate targeted auditory pathways. Participants undergo audiometric and cognitive screening and repeated behavioral hearing-in-noise testing to track functional outcomes. The design follows promising preclinical animal results to determine if the combined drug-plus-sound approach translates to humans.

Who should consider this trial

Good fit: Ideal candidates are adults aged 45–65 with age-related CAPD who have no more than mild high-frequency hearing loss, normal middle-ear function, and no cognitive impairment.

Not a fit: People with moderate or greater hearing loss, abnormal middle-ear function, significant cognitive impairment, or hearing problems from non–age-related causes are unlikely to benefit.

Why it matters

Potential benefit: If successful, the therapy could improve speech-in-noise hearing by promoting remyelination of affected auditory circuits.

How similar studies have performed: Clemastine has shown remyelination effects in preclinical studies and small multiple sclerosis trials, and the LOOT combination was highly effective in animals, but the specific drug-plus-engineered-sound approach is novel in humans.

Eligibility criteria

Inclusion Criteria:

* Male or female between 45 and 65 years old (middle aged) at the screening/enrollment visit (Visit 1).
* Written informed consent obtained from the subject and ability for the subject to comply with the requirements of the study.
* Documentation of no more than a mild high-frequency hearing sensitivity loss and normal middle-ear function will be obtained using standard audiometric equipment with measurements done by an audiologist; Specifically, testing will show:

  * bilateral hearing thresholds \< 20 dB HL at audiometric frequencies from 250 Hz to 4000 Hz inclusively, with no air-bone gaps \> 10 dB.
  * symmetrical hearing thresholds between the ears through 8000 Hz, defined as \<20 dB difference at any single audiometric frequency or \< 15 dB difference at 2 or more contiguous frequencies.
  * normal (Type A) tympanograms bilaterally.
* No cognitive deficit shown upon screening with the Montreal Cognitive Assessment (MOCA) test (Nasreddine et al. 2005).
* Distortion product otoacoustic emission (DPOAE) showing no more than 20 dB hearing loss at audiometric frequencies from 250 Hz to 4000 Hz.
* Subjects failing the hearing in noise test at 15 degrees. Failing is defined as SNR being 12 dB below from what is found in normal hearing subjects without central hearing loss.

Exclusion Criteria:

* Any subjects who do not fall under the criteria defined above.
* Any of the following conditions which are listed as contraindications or warnings for use of the clinical trial drug (from labeling):

  * Known sensitivity to clemastine fumarate or other antihistamines of similar composition
  * Pregnancy or nursing mother as determined objectively with a urine pregnancy test
  * Lower respiratory tract disease including asthma, or breathing difficulties such as emphysema or chronic bronchitis
  * Glaucoma or increased intraocular pressure
  * Stenosing peptic ulcers or pyloroduodenal obstruction
  * Trouble urinating due to an enlarged prostate gland. Mild urinary issues (Stage 1 Benign Prostatic Hyperplasia) will not be considered an automatic exclusion but it must be emphasized to patients with this diagnosis that difficulty urinating is a possible side effect that may compound their BPH symptoms.
  * Significant cardiovascular disease, chronic hypertension or hypotension
  * Hyperthyroidism
  * Alcoholism- as defined by consuming on average 3+ drinks per day for women or 4+ drinks per day for men or previous diagnosis of alcohol use disorder by a clinician as defined by DSM V criteria.
  * Patients with a history of seizures will be excluded.
  * Patients with evidence of suicidal ideation/behavior as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS).
* We will generally exclude subjects with significant or uncontrolled medical disorders (e.g., hepatic, hematologic, renal, gastrointestinal, neurological, psychiatric disorders). We will define these patients as those who fall outside of normal ranges for a physical examination of vital signs, a 12-lead EKG, and a safety clinical laboratory assessment including complete blood count (CBC) and comprehensive metabolic panel (CMP). Exclusion with these tests will specifically focus on identifying the following disorders based on the listed criteria:
* Leukopenia as defined as a CBC white blood cell count \< 4000/ul
* Anemia as defined by a CBC Hemoglobin \<9.0 g/dL or \<10.0 g/dL (Grade 2+ CTCAE)
* Lymphopenia as defined by CBC Absolute lymphocyte count \<1000/µL.
* Neutropenia as defined by CBC ANC \<1500/µL (solid tumors), ANC \<1000/µL (hematologic malignancies). In the case of participants with African, Middle Eastern or West Indian descent a clinician's judgement will be considered to assess the possibility of benign ethnic neutropenia which is not an exclusion criteria.
* Thrombocytopenia as defined by CBC Platelet count \<75000/µL
* Hepatic Impairment based on CMP: Total bilirubin \>1.5× ULN, AST/ALT \>3× ULN (or \>5× ULN if liver metastases), Alkaline phosphatase \>3× ULN.
* Hepatic Impairment based on CMP: Serum creatinine \>2.0 mg/dL (alternative threshold).
* Metabolic abnormalities based on CMP: Albumin \<3.0 g/dL
* Taking medications that would contraindicate taking the clinical trial drug; Specifically, (from labeling):

  * Monoamine oxidase inhibitor therapy
  * CNS depressants (sedatives, tranquilizers, hypnotics)
* A history of significant otologic disorder such as repetitive ear infections or Meniere's disease
* A history of significant neurologic disorder, or current neurodegenerative diseases such as multiple sclerosis, which could present a confound and impact the electrophysiological outcome measures.
* A history of traumatic brain or closed head injury because this can cause symptoms of central auditory processing problems unrelated to aging and demyelination.
* English as a second language (non-native English speakers), which is known to negatively impact scores on speech recognition testing.
* Presence of any other condition or abnormality that in the opinion of the Investigator or his co-PIs would compromise the safety of the patient or the quality of the data.

Where this trial is running

Aurora, Colorado

• University of Colorado Anschutz Medical Center — Aurora, Colorado, United States (RECRUITING)

Study contacts

• Principal investigator: Achim Klug, PhD — Colorado University Anschutz Medical Center
• Study coordinator: Ajay Keerthy, BS

Conditions: Central Auditory Processing Disorder, Hearing Impaired, Hearing, Hearing Abnormality, Hearing Disability, Hearing Disorder, Hearing Disorders, Hearing Impairment, Sensorineural