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
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 344
- 试验地点
- 1
- 主要终点
- Improvement in hearing-in-noise at 15 degree separation
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Study coordinators and all study personnel interacting with participants will be masked. The study statistician performing the interim analysis for the adaptive design will remain blinded to treatment allocation, using coded group assignments. A secondary statistician will evaluate study data as it is generated but will not have any contact with assigned participants or influence on study coordinators, care providers, or outcome assessors. Pharmacy staff preparing study medications will not be blinded but will have no participant contact.
入排标准
- 年龄范围
- 45 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Treatment Group
Active clemastine fumarate + engineered sound stimulation
干预措施: Clemastine Fumarate Combined With Engineered Sound (Combination Product)
Placebo Sound
Active clemastine fumarate + placebo sound (white/pink noise)
干预措施: Clemastine Fumarate Combined With Pink Noise (Drug)
Placebo Drug
Placebo drug + engineered sound stimulation
干预措施: Placebo Drug With Engineered Sound (Combination Product)
Control Group - Double Placebo
Placebo drug + placebo sound (white/pink noise)
干预措施: Placebo - Placebo (Combination Product)
结局指标
主要结局
Improvement in hearing-in-noise at 15 degree separation
时间窗: At enrollment and again after intervention (Week 5 or 6)
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.
Improvement in hearing-in-noise at 30 degree separation
时间窗: At enrollment and again after intervention (Week 5 or 6)
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.
次要结局
- Speech, Spatial, and Qualities questionnaire (SSQ)(At enrollment and again after intervention (Week 5 or 6))
- Tinnitus Handicap Inventory [THI](At enrollment and again after intervention (Week 5 or 6))
- Wave III amplitude of the ABR(At enrollment and again after intervention (Week 5 or 6))