Lexiva for the Treatment of LPR

Study Overview
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Brief Summary
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Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and if left untreated can promote the development of laryngeal cancer. More than 20% of the United Stated population suffer from LPR, yet there is no effective medical therapy. Proton pump inhibitors (PPIs), which inhibit gastric acid production but do not prevent reflux events, continue to be prescribed for LPR despite their poor efficacy for this patient population, high cost ($26 billion/year), and associated risks. Pepsin, detected in the airway of these patients and now known to cause laryngeal inflammation and promote disease independent of gastric acid, is a key therapeutic target. We report preclinical studies of select HIV inhibitors that bind to and inhibit pepsin and thus hold promise for the treatment of LPR. In support, a very low incidence of LPR was found in patients taking these drugs compared to the general population. HIV inhibitors are ideal drugs to repurpose because they target a foreign virus. Thus, a repurposing approach can be used to safely perform proof of concept testing of the efficacy of a pepsin inhibitor for LPR. The Specific Aim of this project is to perform a 12-week randomized, double-blind, placebo-controlled clinical trial to assess the efficacy of fosamprenavir/Lexiva for LPR. Lexiva will be used at the FDA approved, manufacturers recommended dose for HIV for 12 weeks in medically refractory patients with clinically diagnosed moderate/severe LPR and combined multi-channel intraluminal impedance - pH (MII-pH) confirmed laryngeal reflux events. Routine clinical outcome measures for LPR (Reflux Symptom Index and Reflux Finding Score) will be documented pre- and post-treatment with Lexiva (n = 52) and placebo (n = 52). Saliva will be collected pre- and post-treatment for both pepsin protein analysis and kinetic activity assay to compare with clinical measures. There is currently no effective medical therapy for LPR and pepsin is the key therapeutic target. Identification of an FDA approved drug which inhibits pepsin allows for a clinical trial to determine efficacy using a faster and safer repurposing approach to address a significant gap.

Official Title
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A 12-Week Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Efficacy of Fosamprenavir/Lexiva for Laryngopharyngeal Reflux (LPR)

Conditions
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Laryngopharyngeal Reflux

Intervention / Treatment
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* Drug: Lexiva


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of LPR Age ≥ 18 years RSI ≥ 20 RFS ≥ 11 Documented LPR by MII-pH testing (>1 proximal event) Failed 3 month bid PPI therapy Attending laryngology clinic and having flexible laryngoscopy and MII-pH testing per routine clinical care with a minimum of three months between clinic visits (standard practice) Patients must be deemed able to comply with the saliva sample collection, treatment plan, and follow-up schedule Patients must provide study-specific informed consent prior to study entry Exclusion Criteria: Elderly (age >65 years), pregnant (or plan to be) and nursing mothers as Lexiva not recommended for those populations Currently being treated with another investigational medical device and/or drug A history of gastric or esophageal surgery GI disease that might interfere symptom questionnaire, e.g. IBD A history of laryngeal or neck surgery including thyroidectomy and laryngomicroscopic surgery Suspected esophageal cancer Nasopharyngeal cancer Previously undergone anti-reflux surgery Polypharmacy (five or more concurrent medications due to comorbidities) Potential contradictions or known interactions with Lexiva Anticipated poor understanding or compliance of the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lexiva<br>Lexiva/fosamprenavir at the FDA approved and manufacturers recommended dose (1,400mg twice daily) for 12 weeks | Drug: Lexiva<br>* A repurposing approach, prospective, placebo-controlled clinical trial of Lexiva (used at the FDA approved, manufacturers recommended dose for HIV (1,400mg twice daily) for 12 weeks in medically refractory patients with clinically diagnosed moderate/severe LPR (RSI ≥ 20, RFS ≥ 11 and MII-pH confirmed laryngeal reflux events).<br>|
| Placebo Comparator: Placebo<br>standard of care | Drug: Lexiva<br>* A repurposing approach, prospective, placebo-controlled clinical trial of Lexiva (used at the FDA approved, manufacturers recommended dose for HIV (1,400mg twice daily) for 12 weeks in medically refractory patients with clinically diagnosed moderate/severe LPR (RSI ≥ 20, RFS ≥ 11 and MII-pH confirmed laryngeal reflux events).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Reflux finding score (RFS) | Clinical scoring system to rate the physical findings of reflux observed upon fiberoptic laryngeal exam. The scale ranges from 0 (no abnormal findings) to a maximum of 26 (worst score possible). An RFS greater than 7 indicates that the patient has LPR with 95% certainty. | Baseline and 12 weeks of treatment with Lexiva. | 
| Change in Reflux Symptom Index (RSI) | Patient administered questionnaires to assess symptom severity. The scale ranges from 0 (no abnormal findings) to 45 (worst score possible). An RSI score greater than 13 is defined as abnormal and indicates LPR. | Baseline and 12 weeks of treatment with Lexiva. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in salivary pepsin enzyme activity | Subjects saliva will be analyzed for pepsin activity by kinetic activity assay. Salivary pepsin is a biomarker for LPR. If Lexiva treatment is effective, peptic activity detected prior to treatment (active, yes) will not be detected after treatment (active no). | Baseline and 12 weeks of treatment with Lexiva. |