Therapeutic Efficacy of Tiludronic Acid on Inner Ear Involvement in Advanced Otosclerosis (OTOPHOS)

The aim of this study is to assess the efficacy of a biphosphonate (tiludronic acid, Skelid®, Sanofi-Aventis) in the treatment of inner ear involvement in advanced otosclerosis

Study Overview

• Status: Terminated
• Conditions: Otosclerosis
• Intervention / Treatment: Drug: tiludronic acid; Drug: Placebo

Detailed Description

Otosclerosis is a bone dystrophy localized to middle and inner ears with unknown etiology. It principally concerns adult patients between 30 and 50 years of age. Women present with this disease 2 times more frequently than men. Family cases are observed in 50% with a dominant autosomal transmission and low penetrance (40%). In its early stages, the disease is mainly located at the stapediovestibular joint leading to its ankylosis and a conductive hearing loss. In its advanced stages, the lesions extend around the cochlea and vestibule, induce a sensorineural hearing loss which can progress to severe and profound deafness, and prolonged balance disorders. On CT-scan, disease foci show a demineralization. Their density is inversely correlated to the hearing loss. In early stage, hearing function is currently rehabilitated by conventional hearing aids or surgery. In advanced forms, cochlear involvement is not accessible to surgery, and rehabilitation is insured by he hearing aids or cochlear implants. Vestibular dysfunction is dealt with by physiotherapy or symptomatic treatment. Drugs with anabolic activity in bone, such as sodium fluoride and etidronate (first generation bisphosphonate, Didronel ®), appear to reduce the hearing loss and to increase the radiological density of disease foci. However, their efficacy is low and poorly documented. Their effect on vestibular function is unknown.

Moreover, ototoxicity has been reported for etidronate. New biphosphonates such as tiludronic acid (Skelid ®) have a significantly more potent inhibition of bone resorption and do not have an ototoxic effect. They have been used for the treatment or the prevention of postmenopausal osteoporosis and in Paget's disease with mild to moderate adverse effects in the majority of cases.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France, 92118
    • Beaujon Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 and 75 years
• French citizen
• Signed consent for participation
• No dental infection
• No programmed dental surgery during the treatment
• Effective contraception for women of childbearing potential
• Patient with advanced otosclerosis defined by:
• Slowly progressive uni or bilateral hearing loss
• No past medical history of chronic otitis media
• No past medical history of other causes of cochlear damage (significant surgical trauma with a 30 dB deterioration of bone conduction at 4000 Hz in postoperative period, sound trauma, barotrauma, ototoxic drugs)
• Normal tympanic membranes
• A conductive or mixed hearing loss
• A moderate to severe hearing loss on at least one ear (average of thresholds at 500, 1000, 2000 and 4000 Hz) on air conduction between 30 and 90 dB.
• Normal tympanometry or with a decreased peak
• Absent ipsilateral stapedial reflex
• As possible, intraoperative confirmation of stapediovestibular ankylosis
• radiological confirmation if CT-scan before inclusion available

Exclusion Criteria:

• Individuals not covered by the french public health insurance
• Pure-tone average < 30 dB ou > 90 dB
• Programmed stapes surgery during the observation period
• Previous treatment by biphosphonate
• Known intolerance to tiludronate
• Other contraindications to tiludronate treatment:
• allergy to biphosphonates
• hypersensitivity to one of the excipients
• severe renal failure (creatinine clearance < 30 mL/min)
• juvenile Paget's disease
• pregnancy and breastfeeding
• galactose intolerance, lactase insufficiency, glucose-galactose malabsorption
• Ongoing chemotherapy or radiotherapy or patient achieves of a cancer
• Long-term systemic steroid treatment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Placebo	Drug: Placebo; 400 mg / day for 3 month
Experimental: Skelid; tiludronic acid	Drug: tiludronic acid; 400 mg / day for 3 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hearing preservation on pure-tone audiometry at 2 years	Effect on hearing preservation as assessed by air conduction pure-tone average at 2 years. Hearing deterioration is defined by a deterioration of pure-tone average by air conduction >20 dB at 500, 1000, 2000 and 4000 Hz between inclusion and the end of the observation period.	year 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hearing preservation at one year	Effect on hearing preservation as assessed by air conduction pure-tone average at 1 year	year 1
cochlear function	Effect on cochlear function preservation as evaluated by bone conduction pure-tone average (500, 1000, 2000 and 4000 Hz) at 1 and 2 years.	years 1 and 2
Stapedial reflex preservation	Percentage of stapedial reflex preservation on the controlateral ear if unilateral otosclerosis at 1 and 2 years.	years 1 and 2
Speech reception threshold and speech discrimination score	Effect on speech reception threshold ans speech discrimination score at 1 and 2 years.	years 1 and 2
Tinnitus and balance disorders	Effect on the prevalence and the intensity of tinnitus and balance disorders as evaluated by questionnary at 1 and 2 years.	years 1 and 2
Radiological bone density	Effect on radiological bone density at fissula ante fenestram as assessed on high resolution temporal bone CT-scans before and after treatment by calculation of fissula ante fenestram / temporal bone squama cortex bone density ration on axial views.	year 2
Tolerance	Clinical tolerance during treatment	month 3

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Alexis BOZORG-GRAYELI, Pr, Hôpital Général, CHU de Dijon

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2012
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: June 8, 2012
• First Submitted That Met QC Criteria: June 8, 2012
• First Posted (Estimate): June 12, 2012

Study Record Updates

• Last Update Posted (Actual): November 6, 2017
• Last Update Submitted That Met QC Criteria: November 3, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: inner ear; otosclerosis; tiludronic acid
• Additional Relevant MeSH Terms: Otorhinolaryngologic Diseases; Ear Diseases; Otosclerosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Tiludronic acid
• Other Study ID Numbers: P081235

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No