Clinical trial NCT04383262: Oral Fosamprenavir-Sodium Alginate for LPR
Official title: A 12-Week Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Assess the Efficacy of Oral Fosamprenavir for Laryngopharyngeal Reflux
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Laryngopharyngeal Reflux
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
First posted: 2020-05-12
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Proof-of-Concept
Primary purpose: TREATMENT

Brief summary: 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 fosamprenavirvpills for LPR. Fosamprenavir 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, Reflux Finding Score, Voice Handicap Index) will be documented pre- and post-treatment with Oral Fosamprenavir for LPR(n = 52) and placebo (n = 52). Additional research measures will include repeat administration of a newly created Daily Symptom Reflex Diary, as well as an intermittently distributed Patient Global Impression - Static \& Change scales. 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.


Eligibility criteria: Inclusion Criteria

* Clinical diagnosis of LPR
* Age ≥ 18 years
* RSI \> 13
* RFS \> 7
* Documented LPR by MII-pH testing (\> 1 proximal event)
* Failed 3 month bid PPI therapy
* Attending laryngology clinic with study providers, 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
* Hepatic Function Panel must be within normal limits
* Results from V1 safety labs must all be within normal limits
* Additionally, subjects must have the following

  * Ownership of an electronic device meeting minimum hardware and software specifications required to conduct the DRSD, PGI-S, and PGI-C
  * Internet access
  * A valid email address for notifications
  * Agreement not to turn off notifications related to the study

Exclusion Criteria

* Age ≥ 65 years
* Pregnant (or plan to be) and nursing mothers
* Women of child-bearing potential not willing to comply with contraceptive requirements during the study treatment and for 1 week following the last dose of study drug.

Definition of women of child-bearing potential

• Non-post-menopausal female, who has not had a bilateral oophorectomy or medically documented ovarian failure. A subject may be considered to be post-menopausal when there is either:

* twelve (12) months of spontaneous amenorrhea or;
* six (6) months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL or;
* six (6) weeks postsurgical bilateral oophorectomy with or without hysterectomy. A female who has had a tubal ligation sterilization or hysterectomy would not be considered to be of reproductive potential unless participating in activities of reproductive potential other than heterosexual intercourse (e.g., egg donation, participation in in vitro fertilization).

  * Contraceptive requirements Fosamprenavir may decrease the effectiveness of combined hormonal contraception through significant CYP3A4 induction of estrogen. If subjects' preferred choice of contraception is combined hormonal contraception, subjects must also agree to use a second method of contraception (condom + spermicide) during study drug treatment.

Other acceptable highly effective forms of contraception include:

* Medroxyprogesterone acetate injectable
* Intrauterine Device
* Female Sterilization
* Male Sterilization

  * 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)
  * Any contraindications to FOS
  * Anticipated poor understanding or compliance of the study protocol
  * History of hepatic impairment
  * Sulfa Allergy
  * Hemophilia
  * Active tuberculosis (TB) or history of active TB.
  * History of latent TB (e.g., positive QuantiFERON-TB test) without history of active TB unless the subject has completed a documented course of prophylactic treatment.
  * History of human immunodeficiency virus (HIV) infection or positive for HIV
  * Seropositive for hepatitis B surface antigen (HBsAg).
  * Hepatitis C virus (HCV) RNA positive.

Primary outcomes:
measure: Change in Daily Symptom Reflux Diary (DRSD)
timeFrame: From baseline to 12-week post-treatment.
measure: Change in Reflux Symptom Index (RSI)
timeFrame: Baseline to 12-week post-treatment.
Secondary outcomes:
Other outcomes:
measure: Change in Reflux Symptom Scale (RSS).
timeFrame: Baseline to 12-week post-treatment.
measure: Change in Voice Handicap Index 10 (VHI-10)
timeFrame: Baseline to 12-week post-treatment.
measure: Change in Reflux Finding (RFS)
timeFrame: Baseline to 12-week post-treatment.
measure: Change in Reflux Sign Assessment (RSA)
timeFrame: Baseline to 12-week post-treatment.
Locations:
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
Study officials:
References: