A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound (CAPD-LOOT)

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

The goal of this clinical trial is to determine the efficacy of Clemastine Fumarate in the presence of engineered sound to treat age-related central auditory processing disorder (CAPD). This disorder impacts 800M patients worldwide, including ~1/3 people over 40 years of age and ~1/2 people over 65, resulting in an inability to hear in noisy environments.

The primary hypothesis this study aims to test is: engineered sound, driving localized neural circuit activity, will enable Clemastine Fumarate to mature Oligodendrocyte cells and thus remyelinate these activated neural circuits. This Localized Oligodendrocyte Optimization Therapy (LOOT) was highly effective in preclinical animal studies so this clinical trial aims to answer if this therapy will translate to humans.

The study is an adaptive design intended to compare the efficacy of the drug in the presence or absence of the engineered sound for improving hearing in noise ability. Trial participants will be tested for hearing thresholds and ability to isolate a sound signal from background noise. If they meet the inclusion criteria, they will be enrolled into one of the four arms of the study and undergo the proposed one-month treatment (drug and sound or respective placebos). After the treatment period, trial participants will be tested again for hearing thresholds and their ability to isolate s sound source of interest from background noise. The hypothesis to be tested in this clinical trial is that the one-month treatment will significantly improve the participant's ability to isolate a sound source of interest from background noise.

The design has four arms, drug+sound, placebo+sound, drug+white noise, and placebo+white noise. Based on our preclinical data, control arms are all expected to show identical results, thus our adaptive design includes interim analyses to allow for dropping of two of the three placebo arms should the preclinical results be replicated as anticipated.

We will also monitor each participant's general health during the duration of the clinical trial, which will be done by performing a number of blood tests, an EKG and a general physical before and after the one-month treatment period. We expect no significant changes since participants will take the drug for the one-month period at dosages already demonstrated safe in several Phase II studies of multiple sclerosis. Similarly, the engineered sound will be listened to for one hour per day during this month at sound intensities well below threshold that might cause noise-induced hearing damage.

Study Overview

• Status: Recruiting
• Conditions: Hearing Loss; Hearing Disorders; Age Problem; Noise Exposure; Hearing Impairment; Noise Induced Hearing Loss; Hearing Disability; Hearing Impairment, Sensorineural; Hearing Disorder; CAPD; Central Auditory Processing Disorder; Hearing Impaired; Sound Perception; Hearing Abnormality; Noise-Induced Hearing Loss; Hearing; Hearing Impaired (Partially); Myelin Integrity; Myelin Degeneration; Central Auditory Disease; Hidden Hearing Loss; Myelinopathy; Hearing Handicap; Remyelination; Cocktail Party Skill; Cocktail Party Syndrome
• Intervention / Treatment: Combination product: Clemastine Fumarate Combined With Engineered Sound; Drug: Clemastine Fumarate Combined With Pink Noise; Combination product: Placebo Drug With Engineered Sound; Combination product: Placebo - Placebo

• Study Type: Interventional
• Enrollment (Estimated): 344
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ajay Keerthy, BS; Phone Number: 248-421-5796; Email: ajay.keerthy@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz Medical Center
      • Contact: Achim Klug, PhD; Phone Number: 303-724-4621; Email: achim.klug@cuanschutz.edu
      • Contact: Samuel Budoff, PhD, MS; Email: samuel.budoff@CUANSCHUTZ.EDU
      • Principal Investigator: Achim Klug, PhD
      • Sub-Investigator: Samuel A Budoff, PhD, MS
      • Sub-Investigator: Enrique Alvarez, MD, PhD
      • Sub-Investigator: Yuri Agrawal, MD, MPH
      • Sub-Investigator: Vinaya Manchaiah, AuD, PhD

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Group; Active clemastine fumarate + engineered sound stimulation	Combination product: Clemastine Fumarate Combined With Engineered Sound; Treatment Group: Drug: 16.08 mg clemastine fumarate (8.04 mg in the morning and 8.04 mg in the evening) during the first week of the 30 day treatment period, followed by 10.72 mg clemastine fumarate once daily in the evening for the remainder of the 30 day period. Tablets taken with water in morning and evening with or without food. This dosage corresponds to 12 mg clemastine base daily during the first week followed by 8 mg clemastine base daily for the remainder of the 30 day period. This matches dosing proven safe in previous Phase II multiple sclerosis trials. Sound: This medication will be combined with a proprietary engineered acoustic stimulus designed to activate central auditory processing pathways, delivered via provided headphones for 60 minutes daily during the 30-day treatment period. Sound consists of spatially modulated frequency sweeps targeting neural circuits involved in speech-in-noise processing. Participants instructed to listen during quiet, awake periods.; Other Names: Localized Oligodendrocyte Optimization Therapy; LOOT
Active Comparator: Placebo Sound; Active clemastine fumarate + placebo sound (white/pink noise)	Drug: Clemastine Fumarate Combined With Pink Noise; Drug and Placebo Sound Group: Drug: 16.08 mg clemastine fumarate (8.04 mg in the morning and 8.04 mg in the evening) during the first week of the 30 day treatment period, followed by 10.72 mg clemastine fumarate once daily in the evening for the remainder of the 30 day period. Tablets taken with water in morning and evening with or without food. This dosage corresponds to 12 mg clemastine base daily during the first week followed by 8 mg clemastine base daily for the remainder of the 30 day period. This matches dosing proven safe in previous Phase II multiple sclerosis trials. Sound: Broadband white noise matched for average intensity to engineered sound. Delivered via provided headphones for 60 minutes daily during the 30-day treatment period. Serves as acoustic control to maintain participant and investigator blinding. Participants instructed to listen during quiet, awake periods.; Other Names: Tavist; Dayhist
Placebo Comparator: Placebo Drug; Placebo drug + engineered sound stimulation	Combination product: Placebo Drug With Engineered Sound; Placebo Drug and Engineered Sound Group: Drug: Matching placebo tablets administered orally twice daily during the first week and once daily for the remainder of the 30 consecutive days. Tablets identical in appearance, taste, and smell to active drug. Taken with water in morning and evening with or without food. Sound: This placebo will be combined with a proprietary engineered acoustic stimulus designed to activate central auditory processing pathways, delivered via provided headphones for 60 minutes daily during the 30-day treatment period. Sound consists of spatially modulated frequency sweeps targeting neural circuits involved in speech-in-noise processing. Participants instructed to listen during quiet, awake periods.
Placebo Comparator: Control Group - Double Placebo; Placebo drug + placebo sound (white/pink noise)	Combination product: Placebo - Placebo; Placebo Drug and Placebo Sound Group: Drug: Matching placebo tablets administered orally twice daily during the first week and once daily for the remainder of the 30 consecutive days. Tablets identical in appearance, taste, and smell to active drug. Taken with water in morning and evening with or without food. Sound: Broadband white noise matched for average intensity to engineered sound. Delivered via provided headphones for 60 minutes daily during the 30-day treatment period. Serves as acoustic control to maintain participant and investigator blinding. Participants instructed to listen during quiet, awake periods.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in hearing-in-noise at 15 degree separation	Measures ability to understand speech in background noise, tested in a sound chamber with speakers arranged in a circle. Participants listen to sentences spoken by a female speaker while 6-person babble noise plays from a speaker 15 degrees away. Test uses Harvard IEEE sentences (5 keywords each) at 60 dB with varying signal-to-noise ratios (SNR). Participants repeat words they hear. An adaptive procedure determines the SNR needed for 40% accuracy (>2/5 words correct) and 80% accuracy (>4/5 words correct). Lower SNR values indicate better performance. Primary outcome is change in SNR from baseline to post-treatment (Day 30). This tests central auditory processing, not peripheral hearing, as it requires the brain to separate speech from noise when sounds come from different directions. Analysis uses linear regression comparing treatment groups to placebo for change in SNR, with p<0.017 considered significant due to multiple endpoints. Success is group-wise improvement of >3dB.	At enrollment and again after intervention (Week 5 or 6)
Improvement in hearing-in-noise at 30 degree separation	Measures ability to understand speech in background noise, tested in a sound chamber with speakers arranged in a circle. Participants listen to sentences spoken by a female speaker while 6-person babble noise plays from a speaker 30 degrees away. Test uses Harvard IEEE sentences (5 keywords each) at 60 dB with varying signal-to-noise ratios (SNR). Participants repeat words they hear. An adaptive procedure determines the SNR needed for 40% accuracy (>2/5 words correct) and 80% accuracy (>4/5 words correct). Lower SNR values indicate better performance. Primary outcome is change in SNR from baseline to post-treatment (Day 30). This tests central auditory processing, not peripheral hearing, as it requires the brain to separate speech from noise when sounds come from different directions. Analysis uses linear regression comparing treatment groups to placebo for change in SNR, with p<0.017 considered significant due to multiple endpoints. Success is group-wise improvement of >3dB.	At enrollment and again after intervention (Week 5 or 6)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Speech, Spatial, and Qualities questionnaire (SSQ)	Speech, Spatial, and Qualities questionnaire (SSQ) by Gatehouse & Noble, 2004. Self-report questionnaire assessing speech understanding, spatial hearing, and sound quality in daily life. The evaluation ranges from 0-10 for each item. With higher scores indicating better function.	At enrollment and again after intervention (Week 5 or 6)
Tinnitus Handicap Inventory [THI]	Newman et al., 1996. 25-item questionnaire measuring tinnitus severity and impact on daily life. Scores range from 0-100 with higher scores indicating greater handicap.	At enrollment and again after intervention (Week 5 or 6)
Wave III amplitude of the ABR	This physiological measurement is not relevant in the participant's daily life, however, changes in ABR waves will give us valuable insights into the mechanisms of the treatment. ABR will be measured via existing predicate devices and/or with FDA cleared EEG devices and standard auditory stimuli appropriate for measuring auditory brainstem response (ABR) waves. This assessment is non-invasive and involves an electrode placed on appropriate locations of a participants head to record electrophysiologic activity while the patient listens to auditory stimuli such as clicking that stimulates the relevant neural circuits.	At enrollment and again after intervention (Week 5 or 6)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Audiological Safety & Eligibility	Auditory function assessments will include: Audiogram, and Distortion product otoacoustic emission (DPOAE) tests. For the audiogram and DPOAE, right, left, and bilateral thresholds will be recorded in the range of 250-8000 Hz. To include subjects or determine if an adverse event (AE) has occured, these measures will verify normal thresholds and symmetrical hearing between the ears. On the bilateral audiogram the normal threshold is < 21 dB hearing loss in the range of (250-4000 Hz) and no air-bone gaps >10 dB. Symmetrical hearing will be defined by <21 dB differences OR any single frequency and <16 dB difference at 2+ contiguous frequencies. For the DPOAE <20 dB hearing loss will be defined as normal. Clinician judgement will be used to over-rule exclusion or determination of AE.	At enrollment and again after intervention (Week 5 or 6)
Participant Journal	A participant journal will be completed during the trial to assess deviations from compliance or other self-reported observations.	Journal entries will be recorded daily during intervention and returned upon final evaluation (Week 5 or 6)

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Achim Klug, PhD, Colorado University Anschutz Medical Center; Study Director: Samuel A Budoff, PhD, MS, Colorado University Anschutz Medical Center

Publications and helpful links

General Publications

• Gatehouse S, Noble W. The Speech, Spatial and Qualities of Hearing Scale (SSQ). Int J Audiol. 2004 Feb;43(2):85-99. doi: 10.1080/14992020400050014.
• Newman CW, Jacobson GP, Spitzer JB. Development of the Tinnitus Handicap Inventory. Arch Otolaryngol Head Neck Surg. 1996 Feb;122(2):143-8. doi: 10.1001/archotol.1996.01890140029007.
• Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, Miao E, Lee S, Mayoral SR, Redmond SA, Etxeberria A, Xiao L, Franklin RJM, Green A, Hauser SL, Chan JR. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014 Aug;20(8):954-960. doi: 10.1038/nm.3618. Epub 2014 Jul 6.
• Cox RM, Alexander GC, Gilmore C. Development of the Connected Speech Test (CST). Ear Hear. 1987 Oct;8(5 Suppl):119S-126S. doi: 10.1097/00003446-198710001-00010.
• Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Budingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. Epub 2017 Oct 10.
• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.
• Manousi A, Kury P. Small molecule screening as an approach to encounter inefficient myelin repair. Curr Opin Pharmacol. 2021 Dec;61:127-135. doi: 10.1016/j.coph.2021.09.008. Epub 2021 Nov 6.
• Schran HF, Petryk L, Chang CT, O'Connor R, Gelbert MB. The pharmacokinetics and bioavailability of clemastine and phenylpropanolamine in single-component and combination formulations. J Clin Pharmacol. 1996 Oct;36(10):911-22. doi: 10.1002/j.1552-4604.1996.tb04758.x.
• Killion MC, Niquette PA, Gudmundsen GI, Revit LJ, Banerjee S. Development of a quick speech-in-noise test for measuring signal-to-noise ratio loss in normal-hearing and hearing-impaired listeners. J Acoust Soc Am. 2004 Oct;116(4 Pt 1):2395-405. doi: 10.1121/1.1784440.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: December 19, 2025
• First Submitted That Met QC Criteria: December 23, 2025
• First Posted (Actual): December 26, 2025

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: CAPD; Sound Therapy; Cocktail Party; central auditory processing disorder; clemastine fumarate; Hidden Hearing Loss; Engineered Sound; Hearing in noise; oligodendrocyte; Localized Oligodendrocyte Optimization Therapy; LOOT; Age-Related Hearing Loss
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurobehavioral Manifestations; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Communication Disorders; Retrocochlear Diseases; Language Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hearing Loss, Hidden; Hearing Loss; Hearing Loss, Sensorineural; Hearing Loss, Noise-Induced; Language Development Disorders; Hearing Disorders; Presbycusis; Auditory Diseases, Central; Health Care Quality, Access, and Evaluation; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quality of Health Care; Public Health; Environment and Public Health; Pyrrolidines; Epidemiologic Factors; Effect Modifier, Epidemiologic; Clemastine; Placebo Effect
• Other Study ID Numbers: 25-1184

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared due to: (1) proprietary nature of the engineered acoustic intervention which is core intellectual property, (2) potentially small sample size due to potential early stopping creates re-identification risks despite de-identification efforts, and (3) lack of dedicated data sharing infrastructure as an academic investigator led trial. Aggregate results will be published in peer-reviewed journals.

Drug and device information, study documents

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