1.0 Study OP0201-C-006 ("C-006") Protocol Summary


Date: 21 August 2019

1.1 Synopsis

Protocol Title:

A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an Adjunct Treatment for Acute Otitis Media in Infants and Children Aged 6 to 24 Months

Rationale:

Novus Therapeutics, Inc. is developing OP0201 metered dose inhaler (“OP0201”), a drug-device combination product comprised of a 20:1 fixed combination of dipalmitoylphosphatidylcholine (DPPC; a phospholipid surfactant) and cholesteryl palmitate (CP; a neutral phospholipid spreading agent) suspended in a propellant (hydrofluoroalkane-134a [HFA-134a]). There are no other ingredients (ie, no excipients, no fillers) in the formulation other than the active ingredients and the propellant. None of these ingredients contain any animal or human derivatives.

Both DPPC and CP are highly endogenous surfactants in the human respiratory tract, Eustachian tube (ET) and nasopharynx. The product is administered via an intranasal pressurized metered dose inhaler (pMDI). Together these 2 active ingredients effectively absorb the mucosal air-liquid interface and reduce the interfacial surface tension and passive opening pressure of the ET to promote “de-sticking” and restoration of the physiologic activity of the ET. In the setting of inflammation in the nasopharynx, the ET fails to open as it should and therefore the middle ear is not ventilated. It is well established that Eustachian tube dysfunction (ETD) is an important underlying cause of otitis media. To date, there is no drug product that has been approved to treat or prevent otitis media.

The study treatment will be delivered as a local treatment through each nostril using a pMDI device. This device holds the canister that contains the drug product. The device has an angled tip to deliver the drug towards the lateral wall of the nasal cavity so that the usual nasal mucociliary clearance pathway can facilitate delivery of the drug to the ET.

The purpose of this study is to develop a better understanding of the safety, tolerability, and efficacy of intranasal OP0201 as an adjunct treatment to oral antibiotics for acute otitis media (AOM) in infants and children, and to assist in the design of future clinical studies. The study will assess whether 20 mg per day intranasal OP0201 (10 mg administered twice daily [BID] for a total of 20 doses [over approximately 10 days]) as an adjunct treatment to 20 doses of oral antibiotics is at least 25 percentage points more effective than placebo in AOM resolution as evidenced by no bulging of the tympanic membrane(s) (TM[s]) at the Day 4 Visit or is at least 25 percentage points more effective than placebo in reducing the likelihood of MEE (OME) assessed at the Day 12 Visit. OP0201 has an acceptable safety and tolerability profile when given to healthy adult volunteers and adults with otitis media or ETD. To date only 1 child has been exposed via the intranasal route to the active ingredients in OP0201 (Investigator’s Brochure [IB]). This study will provide further data on the safety and tolerability of intranasal OP0201 in infants and children.

Objectives and Endpoints

Objectives

Endpoints

Primary  
  • The primary objectives of the study are to evaluate the safety, tolerability, and efficacy of intranasal OP0201 compared with placebo in accelerating AOM resolution by reducing and/or eliminating middle ear effusion (MEE) in infants and children when given as an adjunct treatment to oral antibiotics as assessed using pneumatic otoscopy.
  • Incidence, seriousness, severity, and relatedness to study treatment of adverse events (AEs) and shifts from baseline (normal, abnormal) in vital signs, physical examination (including visual examination of the nasopharynx and oropharynx), and examination of TM (via otoscopy and endoscopy).
  • No bulging of the TM assessed at the Day 4 Visit by pneumatic otoscopy.
  • No MEE (OME) assessed at the Day 12 Visit by pneumatic otoscopy.
Secondary  
  • The secondary objectives of the study are to evaluate the efficacy of intranasal OP0201 compared with placebo in accelerating and maintaining AOM resolution, and reducing the likelihood of MEE (OME) in infants and children when given as an adjunct treatment to oral antibiotics as assessed using other measures (ie, tympanometry, Acute Otitis Media Severity of Symptom [AOM-SOS] score, AOM recurrence, and AOM relapse rates).
The following secondary endpoints will be evaluated at the stated visits:
  • No MEE assessed at the Day 4 Visit and the Day 28 Visit by pneumatic otoscopy.
  • No bulging of the TM assessed at the Day 12 Visit and the Day 28 Visit by pneumatic otoscopy.
  • Normal tympanogram (Type A) assessed at the Day 4 Visit, the Day 12 Visit, and the Day 28 Visit by tympanometry.
  • Complete or near complete resolution of symptoms (AOM cure), defined as an AOM-SOS score ≤2, assessed at the Day 4 Visit, the Day 12 Visit, and the Day 28 Visit by in-clinic AOM-SOS score assessments.
  • Change from baseline in AOM-SOS score over the planned 10-day treatment period by parent/caregiver diary data.
  • At least a 50% reduction from baseline in the AOM-SOS score assessed at the Day 4 Visit, the Day 12 Visit, and the Day 28 Visit by in-clinic AOM-SOS score assessments.
  • AOM treatment failure (clinical failure)* at the Day 12 Visit.
  • AOM relapse defined as those with clinical success# at the Day 12 Visit and return for an interim/sick visit before Day 17 and have AOM.
  • AOM recurrence defined as those with clinical success# at the Day 12 Visit and return for an interim/sick visit from Day 17 through Day 28 and have AOM.


*Treatment failure (clinical failure) is defined as (1) moderate to severe bulging of the TM (Key Action Statement 1A), or (2) mild bulging of TM and recent (less than 48 hours) onset of ear pain (otalgia) (Key Action Statement 1B), or (3) mild bulging of the TM and intense erythema of the TM (Key Action Statement 1B).

#Clinical success for AOM relapse and AOM recurrence endpoints is defined as (1) no moderate to severe bulging of the TM (Key Action Statement 1A), and (2) no mild bulging of TM and no recent (less than 48 hours) onset of ear pain (otalgia) (Key Action Statement 1B), and (3) no mild bulging of the TM and no intense erythema of the TM (Key Action Statement 1B).

Other  
  • Another objective of this study is to obtain feedback from parents/caregivers on the pMDI device to optimize design of the device for pivotal studies.
  • Parent/caregiver’s input on device experience at the Day 12 Visit.
Overall Design:

This is a Phase 2a, single center, double-blind, randomized, placebo-controlled, parallel group study to assess the safety, tolerability, and efficacy of 20 mg per day intranasal OP0201 (10 mg administered BID for a total of 20 doses) as an adjunct therapy to oral antibiotic treatment of AOM in infants and children aged 6 to 24 months (inclusive). Participants will be followed for up to 20 days after study treatment is discontinued. The total duration of study participation for each Participant is up to 30 days, which includes 4 clinic visits: Visit 1: (Day 1) Screening/Enrollment and initiation of the study treatment and oral antibiotics administration; Visit 2: (Day 4 [+2]); Visit 3: (Day 12 [+2]); and Visit 4: (Day 28 [±2]) Study Exit. On Day 1 potential Participants’ parents/legal guardians in attendance at the study center will be told about the study and those Participants whose parents/legal guardian provide written informed consent will be evaluated for study eligibility. Those who meet all inclusion and no exclusion criteria will be enrolled and randomized (1:1 ratio) to receive a total of 20 intranasal doses (over approximately 10 days) with 20 mg per day OP0201 (10 mg BID) or placebo as an adjunct treatment to standard oral antibiotics (amoxicillin-clavulanate given BID for 20 doses).

Parents/caregivers of the Participants will complete an electronic daily diary on all days when study treatment is given (approximately 10 days) to record BID administration of the oral antibiotic and study treatment, and to record daily AOM-SOS scores.

At each study visit, assessments include a physical examination (including visual examination of the nasopharynx and oropharynx) and measurement of vital signs, pneumatic otoscopy to assess TM of each ear, endoscopic examination with image capture of each ear when possible, and tympanogram of each ear (to be performed when possible). Adverse events (AEs) and concomitant medication use will be recorded. At the Day 12 Visit, parents/caregivers will complete the Device Experience Questionnaire.

Parents/caregivers will be instructed to contact the Investigators if concerned about the Participant’s status. An interim evaluation will be scheduled if a parent/caregiver notifies the Investigators that the Participant shows no improvement, has significantly worsened, or has recurrence of signs and symptoms of AOM or develops symptoms that may be related to the study treatment. If a child failed treatment, based on clinical judgment, after receiving antibiotics and study treatment for at least 48 to 72 hours, and additional antimicrobial therapy is deemed advisable, the child will receive guideline-concordant therapy.

Number of Investigators and Study Centers:

One Principal Investigator at 1 study center along with up to 4 satellite sites in the US are expected to participate in this study.

Number of Participants:

Approximately 140 Participants with AOM in at least 1 ear will be randomly assigned to study treatment such that approximately 70 evaluable Participants per treatment group complete the study.

Treatment Groups and Duration:

Twice daily treatment with 10 mg intranasal OP0201 or 0 mg intranasal placebo for a total of 20 doses, as well as standard oral antibiotic treatment for a total of 20 doses, will be initiated on Day 1. The first dose of the intranasal study treatment will be administered in the study center under supervision of the study staff.

Statistical methods:
Power Calculation

The power calculation is based on a 2-sided Pearson chi square test of each of the 2 endpoints in the primary efficacy endpoint family and control for Type 1 error using the step-up Hochberg procedure. The minimally important difference in proportions for both endpoints is approximately 0.25. With 70 Participants randomized per treatment group, and assuming a 12% dropout rate with dropouts counted as failures, this Phase 2a study will have 87% power to detect a treatment effect in at least 1 of the 2 endpoints assuming 40% of placebo-treated Participants will have no bulging TM at Day 4 and 30% of placebo-treated Participants will have no MEE at Day 12.

Populations for Analyses

Four populations will be considered.

Screened population is defined as all Participants whose parent/legal guardian signs the informed consent form.

Safety population is defined as all Participants who received at least 1 intranasal spray of study treatment and will be used to assess the safety and secondary efficacy endpoints.

Intent-to-treat (ITT) population is defined as all randomized Participants and will be used to assess the primary efficacy endpoint family.

Per-Protocol (PP) population is defined as the subset of the ITT population who have no protocol violations affecting the primary efficacy endpoint family and will be used to confirm results from the primary efficacy endpoint family.

Statistical Analyses

The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will describe the Participant population sets to be included in the analyses, and procedures for accounting for missing, unused, and spurious data.

Safety Analyses

Safety will be evaluated using the safety population.

Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened in severity after administration of study treatment and no later than 2 calendar days after the last dose of study treatment.

Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For each study treatment, numbers of TEAEs and incidence rates will be tabulated by primary system organ class (SOC) and by preferred term within each primary SOC.

Treatment-emergent AEs, TEAEs related to study treatment, serious adverse events (SAE), and TEAEs leading to discontinuation of study treatment will be summarized.

Vital sign measurements and changes from baseline will be summarized.

Test results from otoscopy, AOM-SOS, physical examination, nasopharynx, and oropharynx will be summarized.

Efficacy Analyses

The primary efficacy endpoint family consists of 2 endpoints: (1) no bulging of the TM at the Day 4 Visit assessed by pneumatic otoscopy and (2) no MEE (OME) at the Day 12 Visit assessed by pneumatic otoscopy. The step-up Hochberg procedure will be used to adjust for multiplicity. Specifically, the endpoint with the highest p-value will be tested first at the 0.05 significance level and, if significant, both endpoints will be declared significant; if the endpoint with the highest p-value is not significant at the 0.05 level, the other endpoint will be tested at the 0.025 significance level. A positive treatment effect on efficacy will be concluded if at least 1 of the 2 endpoints is significant.

In general, categorical variables (including binary outcomes) will be summarized as frequencies and percentages and will be analyzed using logistic regression to control for covariates, including the randomization stratifiers. Continuous variables will be summarized by numbers of observations, means, measures of variances, percentiles, and ranges and will be analyzed using general linear models to control for covariates.

Safety Monitoring Committee: Yes

The Safety Monitoring Committee (SMC) will review blinded safety data for all Participants when approximately 25% of enrolled Participants have completed the Day 12 Visit. Safety data will be evaluated on an ongoing basis to ensure it is safe to continue study enrollment and treatment. The composition, responsibilities, and meeting schedule of the SMC will be specified in a separate charter document.

Additional information about the study can be found at clinicaltrials.gov using the identifier NCT03818815.