Assessment of the Effects and Tolerability of RD03/2016 for the Treatment of Bacterial Conjunctivitis in Adults (MIRAKLE)

Assessment of the Effects and Tolerability of RD03/2016 (Levofloxacin; Ketorolac Trometamol 0.5+0.5% w/v Eye Drops Solution) for the Treatment of Bacterial Conjunctivitis in Adults: a Multicentre, Randomized, Blinded-assessor, Phase II Non Inferiority Study - MIRAKLE

This is a phase II, randomized, parallel-group, blinded-assessor, multicentre study to assess the non-inferiority of RD03/2016 eye drops vs. levofloxacin eye drops alone (1:1) in microbiological eradication in patients with a clinical diagnosis of bacterial conjunctivitis with moderate/severe signs.

Study Overview

• Status: Completed
• Conditions: Conjunctivitis, Bacterial
• Intervention / Treatment: Drug: RD03/2016 eye drops; Drug: Levofloxacin 0.5% eye drops solution (Oftaquix®)

Detailed Description

This study will enroll 252 patients with clinical diagnosis of acute bacterial conjunctivitis with moderate/severe signs (score ≥ 2 for each cardinal sign, i.e., bulbar conjunctival injection, palpebral conjunctival injection and conjunctival discharge).

Enrolled patients will attend three study visits: baseline (Day 0), On-Therapy (OT; Day 3-4) and final visit (Day 7-9). The duration of the study for each patient will be 7-9 days.

Enrolled patients will undergo the following assessments: anamnesis; ophthalmological examination; swab of the lower conjunctiva for bacteriological examination, and a urine pregnancy test (for women of childbearing potential). Patients will be provided with a study smartphone to take photographs of the affected eye at home. Photographs will be taken by the person (a relative or a caregiver) assisting the patient and uploaded on the server of the study eCRF through eyePRO.net.

Test product (i.e. RD03/2016 - Levofloxacin; Ketorolac Trometamol 0.5+0.5% w/v eye drops solution) is the first fixed dose association between a quinolone antibiotic (i.e. levofloxacin) highly effective on the pathogenic bacteria that most frequently cause eye infections, and a nonsteroidal anti-inflammatory drug (NSAID) (i.e. ketorolac) highly effective in the control of signs and symptoms associated with inflammation.

The dosage proposed for RD03/2016 is one drop 4 times a day for 5 days, lower than that currently approved for levofloxacin alone. In patients with clinical diagnosis of bacterial conjunctivitis and in presence of moderate/severe signs and symptoms requiring an anti-inflammatory treatment for rapid symptomatic improvement, the use of RD03/2016 compared to treatment with levofloxacin alone could lead to a substantial simplification of the therapeutic regimen, without changing the rate of microbiological eradication.

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Karlsruhe, Germany
    • Städtisches Klinikum Karlsruhe Augenklinik
• Italy
  • Bari, Italy
    • A.O.U. Policlinico Consorziale di Bari
  • Bergamo, Italy
    • Asst Papa Giovanni XXIII
  • Camaiore, Italy
    • Ospedale della Versilia
  • Carrara, Italy
    • Centro Polispecialistico Achille Sicari
  • Catania, Italy
    • Presidio Ospedaliero G. Rodolico - A.O.U. "Policlinico - Vittorio Emanuele"
  • Chiari, Italy
    • ASST Franciacorta - Ospedale di Chiari
  • Chieti, Italy
    • Clinica Oftalmologica Ospedale SS Annunziata
  • Firenze, Italy
    • Clinica Oculistica Azienda Ospedaliero-Universitaria Careggi di Firenze
  • Messina, Italy
    • Clinica Oculistica Azienda Ospedaliero - Universitaria Policlinico "G. Martino"
  • Milano, Italy
    • ASST Fatebenefratelli Sacco
  • Milano, Italy
    • ASST Fatebenefratelli Sacco - Istituto Fatebenefratelli e Oftalmico
  • Milano, Italy
    • ASST Santi Carlo e Paolo
  • Milano, Italy
    • Clinica Oculistica Ospedale San Giuseppe
  • Milano, Italy
    • Ospedale Maggiore Policlinico - U.O. Oculistica Fondazione IRCCS Ca' Granda
  • Milazzo, Italy
    • Oculistica Ospedale G. Fogliani
  • Napoli, Italy
    • U.O.S.C. Oculistica Az. Osp. di Rilievo Nazionale A. Cardarelli
  • Palermo, Italy
    • A.O.U. Policlinico P. Giaccone
  • Palermo, Italy
    • ARNAS Civico Di Cristina Benfratelli
  • Pisa, Italy
    • Presidio Ospedaliero di Cisanello - Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy
    • Azienda Ospedaliera Sant'Andrea
  • Roma, Italy
    • Fondazione Policlinico Universitario - IRCSS Agostino Gemelli
  • Roma, Italy
    • IRCCS Fondazione G.B. Bietti
  • San Giovanni Rotondo, Italy
    • IRCCS Casa Sollievo della Sofferenza
  • Savigliano, Italy
    • S.S. Annunziata di Savigliano
  • Siena, Italy
    • Azienda Ospedaliera Universitaria Senese
  • Treviso, Italy
    • Ospedale di Treviso, AULSS2 Treviso
  • Verona, Italy
    • Azienda Ospedaliera Universitaria Integrata Verona
• Russian Federation
  • Ivanovo, Russian Federation
    • Regional Budgetary Institution of Healthcare "Ivanovo Regional Clinical Hospital"
  • Moscow, Russian Federation
    • Federal State Autonomous Institution "S.N. Fedorov National Medical Research Center "MNTK "Eye Microsurgery" of the Ministry of Health of the Russian Federation
  • Moscow, Russian Federation
    • Federal State Budgetary Educational Institution of High Professional Education "Moscow State Medical Stomatology University named after A.I.Evdokimov"
  • Moscow, Russian Federation
    • State Budgetary Institution "National Medical Research Center for Eye Diseases named after Helmholts" of the Ministry of Healthcare of the Russian Federation
  • Omsk, Russian Federation
    • State Budgetary Healthcare Institution of the Omsk Region "Clinical Ophthalmological Hospital named after V.P. Vykhodtsev"
  • Saint Petersburg, Russian Federation
    • Private Institution of Healthcare "Clinical hospital "RR-Medicine" of the city of Saint-Petersburg"
  • San Pietroburgo, Russian Federation
    • LLC Sphera-Med
  • Yaroslavl, Russian Federation
    • State Budgetary Healthcare Institution of Yaroslavl Region "Clinical Hospital #2"
• Spain
  • Madrid, Spain
    • Sección De Cornea, Hospital Universitario La Paz
  • Marbella, Spain
    • Ophthalmology Unit Empresa Pública Hospital Costa del Sol
  • Valencia, Spain
    • Hospital La Fe Avenida de Fernando Abril Martorell
  • Valladolid, Spain
    • Servicio De Oftalmología Hospital Universitario Rio Hortega
  • Vigo, Spain
    • Servicio Oftalmología (Unidad Córnea Y Superficie Ocular) - Hospital do Meixoeiro Camino De Meixoeiro

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Ability of patient to consent and provide signed written informed consent
2. Male or female aged ≥ 18 year.
3. Clinical diagnosis of acute bacterial conjunctivitis with moderate/severe signs (score ≥ 2 for each cardinal signs, i.e. bulbar conjunctival injection, palpebral conjunctival injection and conjunctival discharge, in at least one eye), not previously treated with antibiotics, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs).
4. Able and willing to follow study procedures.
5. Availability of a person (a relative or a caregiver) to be trained for the execution of the photographic documentation required by the study and for the use of eyePRO.net.
6. Willing to interrupt the use of contact lenses for the entire duration of the study.

Exclusion Criteria:

1. Any acute ocular clinical disease other than bacterial conjunctivitis.
2. Any ocular surgery (including laser treatment) in the study eye within 30 days prior to study entry.
3. Any ocular (in the study eye) or systemic antimicrobial agents administered concurrently or within 3 days prior to study entry.
4. Any ocular (in the study eye) or systemic steroids or NSAIDs administered concurrently.
5. Pathological conditions or treatments that in the opinion of the Investigator may interfere with the efficacy and/or safety evaluations of the study (e.g. chronic blepharitis, glaucoma, moderate-severe dry eye).
6. Participation in previous clinical studies if less than 5 half-lives of the Investigational Medicinal Product (IMP) used have passed.
7. Hypersensitivity to the products, other quinolones, acetylsalicylic acid and other NSAIDs (due to potential for cross-sensitivity), or their excipients.
8. Contraindications to ocular treatment with levofloxacin and/or ketorolac.
9. Pregnancy or breastfeeding. Women of childbearing potential must have a negative urine pregnancy test at baseline visit and practice effective contraceptive measures throughout the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test arm; Patients will be randomly assigned (1:1) to one of the two treatment groups	Drug: RD03/2016 eye drops; 1 drop, 4 times a day (approximately every 4 hours while awake) for 5 days starting from Day 1.; Other Names: Levofloxacin + Ketorolac Trometamol 0.5+0.5% w/v eye drops solution
Active Comparator: Standard drug arm; Patients will be randomly assigned (1:1) to one of the two treatment groups	Drug: Levofloxacin 0.5% eye drops solution (Oftaquix®); 1 drop, 8 times a day (approximately every 2 hours while awake) on Days 1 and 2, and 1 drop, 4 times a day (approximately every 4 hours while awake) on Days 3 through 5.; Other Names: Oftaquix® 5 mg/ml eye drops solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with microbiological eradication	Absence/no growth of pathogenic microorganisms or reduction below pathogenic criteria of opportunistic microorganisms susceptible to levofloxacin identified at baseline, as assessed through bacteriological culture and antibiotic susceptibility testing at the final visit (Day 7-9).	At the Final visit (Day 7-9)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
By-pathogen microbiological eradication rate of levofloxacin-susceptible bacteria	Proportion of levofloxacin-susceptible pathogenic bacteria at baseline that are eradicated at the final visit (Day 7-9).	At baseline that are eradicated at the final visit (Day 7-9)
Overall per-patient microbiological eradication rate of bacteria intermediate or resistant to levofloxacin	Proportion of patients (pooling both treatment groups) with microbiological eradication (i.e., absence/no growth of pathogenic microorganisms or reduction below pathogenic criteria of opportunistic microorganisms) of bacteria intermediate or resistant to levofloxacin at baseline (as assessed through bacteriological culture and antibiotic susceptibility testing), at the final visit (Day 7-9).	At the final visit (Day 7-9)
Overall by-pathogen microbiological eradication rate of bacteria intermediate or resistant to levofloxacin	Proportion of pathogenic bacteria intermediate or resistant to levofloxacin at baseline (pooling both treatment groups) that are eradicated at the final visit (Day 7-9).	At baseline that are eradicated at the final visit (Day 7-9)
Proportion of patients with clinical cure	Absence or at least one-unit improvement vs. baseline of all cardinal signs of bacterial conjunctivitis (conjunctival discharge, bulbar conjunctival injection and palpebral conjunctival injection) at OT visit (Day 3-4) and final visit (Day 7-9).	At Day 3-4 and final visit (Day 7-9)
Time to clinical cure	Absence or at least one-unit improvement vs. baseline of all cardinal signs of bacterial conjunctivitis (conjunctival discharge, bulbar conjunctival injection and palpebral conjunctival injection), assessed through photographs taken every 12 ± 1 hours from Day 0 to Day 7-9, using the study smartphone and eyePRO.net.	Every 12 ± 1 hours from Day 0 to Day 7-9
Time to resolution (absence) of bacterial conjunctivitis symptoms	Time to resolution (absence) of bacterial conjunctivitis symptoms (i.e. pain, burning/stinging, itching, tearing, foreign body sensation, photophobia and discomfort) recorded by the patient every 12 ± 1 hours from Day 0 to Day 7-9 through the electronic patient diary.	Every 12 ± 1 hours from Day 0 to Day 7-9

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Adverse events throughout the study	The number of patients with adverse events, and the number and types of events will be recorded throughout the study	Throughout the study, from Day 0 to Day 7-9
Local tolerability: Ocular itching/burning or discomfort related to study drug instillation	Ocular itching/burning or discomfort related to study drug instillation, assessed by a Numeric Rating Scale (NRS) (0 = no itching/burning or discomfort to 10 = unbearable itching/burning or discomfort), through the electronic patient diary.	Twice a day, from Day 0 to Day 5
Compliance: Assessment of the number of instillations	Number of study drug instillations, assessed through the electronic patient diary from Day 1 to Day 5	From Day 1 to Day 5
Feasibility: Microbiological eligibility rate	The proportion of screened patients with positive culture for levofloxacin-sensitive bacteria.	At the Final visit (Day 7-9)
Feasibility: Patient confidence in using the study smartphone and eyePRO.net	Taking photographs of the study eye, as well as in following the picture-capturing procedure as per Investigator's instructions. The confidence of the patient in using the study smartphone and eyePRO.net is assessed through a questionnaire on the final visit (Day 7-9) by means of NRSs of 'Ease of using the smartphone', 'Ease of use of eyePRO.net', and 'Ease of following the picture-capturing procedures' (range 0-10, where 0 indicates 'very difficult' and 10 indicates 'very easy').	At the Final visit (Day 7-9)
Feasibility part 1: Assessment of the mean number of pictures uploaded at a time through eyePRO.net	Mean timing of picture upload for each patient deemed suitable for clinical evaluation by the central team of blinded assessors.	At the Final visit (Day 7-9)
Feasibility part 2: Assessment of the mean number of pictures uploaded at a time through	Mean the percentage of timely picture uploads for each patient deemed suitable for clinical evaluation by the central team of blinded assessors.	At the Final visit (Day 7-9)
Feasibility part 3: Assessment of the mean number of pictures uploaded at a time through	Mean the percentage of uploaded pictures for each patient deemed suitable for clinical evaluation by the central team of blinded assessors.	At the Final visit (Day 7-9)
Feasibility: Accuracy of photographic assessments of clinical cure against the gold standard direct ocular examination	Sensitivity, specificity, positive predictive value and negative predictive value of photographic assessments of clinical cure against the gold standard direct ocular examination at both the on-therapy and final visits	At the Final visit (Day 7-9)

Collaborators and Investigators

• Sponsor: NTC srl
• Investigators: Principal Investigator: Francesco Bandello, Prof., Ospedale San Raffaele IRCCS S.r.l.

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2021
• Primary Completion (Actual): June 14, 2023
• Study Completion (Actual): September 19, 2023

Study Registration Dates

• First Submitted: September 20, 2024
• First Submitted That Met QC Criteria: September 25, 2024
• First Posted (Actual): September 27, 2024

Study Record Updates

• Last Update Posted (Actual): September 27, 2024
• Last Update Submitted That Met QC Criteria: September 25, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Levofloxacin; RD03/2016
• Additional Relevant MeSH Terms: Infections; Eye Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Conjunctival Diseases; Eye Infections, Bacterial; Eye Infections; Conjunctivitis; Conjunctivitis, Bacterial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Ketorolac; Ophthalmic Solutions; Pharmaceutical Solutions; Levofloxacin; Ofloxacin
• Other Study ID Numbers: LEVOKETO_02-2020

Drug and device information, study documents

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