Clinical trial NCT02134353: A Safety and Efficacy Trial of Inhaled Mannitol in Adult Cystic Fibrosis Subjects
Official title: Long Term Administration of Inhaled Mannitol in Cystic Fibrosis - A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cystic Fibrosis
Lead sponsor: Syntara
Sponsor class: INDUSTRY
First posted: 2014-05-09
Enrollment: 423
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial aims to provide prospective evidence of the safety and efficacy of mannitol 400 mg b.i.d. in subjects aged 18 years and above.

We hypothesize that inhaled mannitol 400 mg b.i.d. will increase the mean change from baseline FEV1 (mL) compared to control over the 26-week treatment period in adult subjects with cystic fibrosis. Any improvement in FEV1 is considered clinically meaningful, however, this trial has set a threshold of 80 mL for the purposes of determining an appropriate sample size for statistical power while retaining trial feasibility in an orphan disease population

Detailed description: This is a double-blind, randomized, parallel arm, controlled, multicenter, and interventional clinical trial. Potential subjects will sign the informed consent form (ICF) and be assessed for eligibility. After satisfying all inclusion \& exclusion criteria, subjects will be given a mannitol tolerance test (MTT). Those subjects that pass the MTT will be randomized to receive inhaled mannitol (400 mg b.i.d.) or control b.i.d. for a period of 26-weeks.

Eligibility criteria: Inclusion Criteria:

1. Have given written informed consent to participate in this trial in accordance with local regulations;
2. Have a confirmed diagnosis of cystic fibrosis (positive sweat chloride value ≥ 60 mEq/L) and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype);
3. Be aged at least 18 years old;
4. Have FEV1 \> 40 % and \< 90% predicted (using NHanes III \[1\]);
5. Be able to perform all the techniques necessary to measure lung function;
6. Be adherent with maintenance therapies (antibiotics and or rhDNase), if used, for at least 80% of the time in the two weeks prior to visit 1 and
7. If rhDNase and/or maintenance antibiotic are being used treatment must have been established at least 1 month prior to screening (Visit 0). The subject should remain on the rhDNase and / or maintenance antibiotics for the duration of the trial. The subject should not commence treatment with rhDNase or maintenance antibiotics during the trial

Exclusion Criteria:

1. Be investigators, site personnel directly affiliated with this trial, or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biologically or legally adopted;
2. Be considered "terminally ill" or eligible for lung transplantation;
3. Have had a lung transplant;
4. Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1;
5. Have had a significant episode of hemoptysis (\> 60 mL) in the three months prior to Visit 0;
6. Have had a myocardial infarction in the three months prior to Visit 0;
7. Have had a cerebral vascular accident in the three months prior to Visit 0;
8. Have had major ocular surgery in the three months prior to Visit 0;
9. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0;
10. Have a known cerebral, aortic or abdominal aneurysm;
11. Be breast feeding or pregnant, or plan to become pregnant while in the trial;
12. Be using an unreliable form of contraception (female subjects at risk of pregnancy only);
13. Be participating in another investigative drug trial, parallel to, or within 4 weeks of screening (Visit 0);
14. Have a known allergy to mannitol;
15. Be using non-selective oral beta blockers;
16. Have uncontrolled hypertension -i.e. systolic BP \> 190 and / or diastolic BP \> 100;
17. Have a condition or be in a situation which in the Investigator's opinion may put the subject at significant risk, may confound results or may interfere significantly with the subject's participation in the trial;or
18. Have a failed or incomplete MTT at trial entry (as evaluated in Section 8.1.1.1).
19. The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial.

Primary outcomes:
measure: Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4).
timeFrame: 26 weeks
Secondary outcomes:
measure: Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period
timeFrame: 26 weeks
Other outcomes:
measure: Time to First Pulmonary Exacerbation Over the 26-week Treatment Period
timeFrame: 26 weeks
measure: Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation
timeFrame: 26 weeks
measure: Number of Days in Hospital Due to Pulmonary Exacerbation
timeFrame: 26 weeks
measure: Rate of Pulmonary Exacerbations Over the 26-week Treatment Period
timeFrame: 26 weeks
measure: The Incidence of Pulmonary Exacerbations
timeFrame: 26 weeks
measure: Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks
timeFrame: 26 weeks
measure: Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score
timeFrame: 26 weeks
Locations:
city: Mobile
country: United States
facility: Dr Lawrence Sinde
state: Alabama
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Long Beach
country: United States
facility: Pediatric Pulmonology
state: California
city: Sacramento
country: United States
facility: University of CA, Davis
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: Dr Mitchell Rothstein
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group, P.A.
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Glenview
country: United States
facility: Cystic Fibrosis Center of Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Peoria
country: United States
facility: Illinois Lung Institute
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Hospital
state: Kansas
city: Louisville
country: United States
facility: Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: Baltimore
country: United States
facility: John Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Grand Rapids
country: United States
facility: Spectrum Health Offices of Research Administration
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Dr Joseph Ojile
state: Missouri
city: Bedford
country: United States
facility: Dartmouth-Hitchcock Specialty Care
state: New Hampshire
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: The Cystic Fibrosis Center Beth Israel Medical Center
state: New York
city: Valhalla
country: United States
facility: Dr Allen Dozor
state: New York
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: The Children's Medical Center of Dayton
state: Ohio
city: Toledo
country: United States
facility: The Toledo Hospital and Toledo Childrens Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: Pediatric Pulmonary & CF Center
state: Oklahoma
city: Oklahoma City
country: United States
facility: Dr Santiago Reyes
state: Oklahoma
city: Portland
country: United States
facility: Pediatric Clinic
state: Oregon
city: Charleston
country: United States
facility: Medical University of SC
state: South Carolina
city: Columbia
country: United States
facility: One Richland Medical Park
state: South Carolina
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Mendoza
country: Argentina
facility: Insares
state: Provincia De Mendoza
city: Bahia Blanca
country: Argentina
facility: Hospital Interzonal General de Agudos Dr. Jose Penna
city: Buenos Aires
country: Argentina
facility: Hospital del Tórax Cetrángolo
city: Buenos Aires
country: Argentina
facility: Hospital Regional Español de Bahía Blanca
city: Cordoba
country: Argentina
facility: Hospital San Roque
city: Brisbane
country: Australia
facility: Mater Adult Hospital
state: Queensland
city: Brussels
country: Belgium
facility: UZ VUB
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liege
country: Belgium
facility: CHR Citadelle
city: Halifax
country: Canada
facility: QEII Health Sciences Center
city: Montréal
country: Canada
facility: Institut de recherches cliniques de Montréal
city: Ottawa
country: Canada
facility: The Ottawa Hospital, General Campus
city: Brno
country: Czechia
facility: FN Brno
city: Budapest
country: Hungary
facility: Országos Korányi Tbc
city: Debrecen
country: Hungary
facility: Klinikai Farmakológiai Központ
city: Mosdós
country: Hungary
facility: Mosdós Tüdőgyógyintézet
city: Törökbálint
country: Hungary
facility: Törökbálint Tüdőgyógyintézet
city: Haifa
country: Israel
facility: Pediatrics Pulmonary Department Rambam Healthcare Campus
city: Petah-Tikva
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Brescia
country: Italy
facility: Spedali Civili Brescia
city: Milano
country: Italy
facility: IRCCS Ca' Granda Ospedale Maggiore Policlinico Mil
city: Orbassano
country: Italy
facility: AOU San Luigi Gonzaga
city: Parma
country: Italy
facility: Aziendao Spedaliera Universitaria
city: Potenza
country: Italy
facility: Cystic Fibrosis Center Hospital San Carlo
city: Roma
country: Italy
facility: Centro Fibrosi Cistica Policlinico Umberto I
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integratadi Verona
city: Guadalajara
country: Mexico
facility: Instituto Jaliscience de Investigacion Clinica
city: Guadalajara
country: Mexico
facility: Unidad Médica de Occidente
city: Mexico City
country: Mexico
facility: Arke Estudios Clinicos S.A
city: Monterrey
country: Mexico
facility: CEPREP- Hospital Universitario
city: Auckland
country: New Zealand
facility: Greenlane Hospital
city: Christchurch
country: New Zealand
facility: Canterbury Respiratory Research Group
city: Dunedin
country: New Zealand
facility: Otago Respiratory Research Unit, Dunedin Hospital
city: Gdańsk
country: Poland
facility: Szpital Dziecięcy Polanki im. M. Płażyńskiego w Gdańsku sp.
city: Karpacz
country: Poland
facility: Centrum Medyczne Karpacz SA
city: Kielce
country: Poland
facility: Wojewodzki Specjalistyczny Szpital Dzieciecy im. W. Buszkowskiego
city: Lodz
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im.
city: Poznan
country: Poland
facility: Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
city: Rabka Zdroj
country: Poland
facility: Sanatorium Cassia-Villa Medica S.C.
city: Rzeszow
country: Poland
facility: Podkarpacki Osrodek Pulmonologii i Alergologii
city: Bucuresti
country: Romania
facility: Institutul pentru Ocrotirea Mamei si Copilului "Alfred Rusescu"
city: Bucuresti
country: Romania
facility: Institutul de Pneumoftiziologie "Marius Nasta" Bucuresti, Sectia Clinica Pneumologie V
city: Cluj - Napoca
country: Romania
facility: Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca
city: Lasi
country: Romania
facility: Spitalul Clinic de Pneumoftiziologie Lasi
city: Barnaul
country: Russian Federation
facility: Tatiana I. Martynenko
city: Moscow
country: Russian Federation
facility: Pulmonology Research Institute
city: Saint-Petersburg
country: Russian Federation
facility: Research and Clinical Center of interstitial and orphan lung diseases
city: Vladimir
country: Russian Federation
facility: Mikhail Smirnov
city: Yaroslavl
country: Russian Federation
facility: Clinical Hospital# 2
city: Banská Bystrica
country: Slovakia
facility: Oddelenie pneumológie a ftizeológie
city: Bratislava
country: Slovakia
facility: Imuno-alergologická ambulancia
city: Košice
country: Slovakia
facility: Detská fakultná nemocnica Košice
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute
city: Durban
country: South Africa
facility: St. Augustine's Medical Centre 2
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Madrid
country: Spain
facility: Hospital Universitaro La Paz
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio Hospital Unidad de Fibrosis Quistica
city: Valencia
country: Spain
facility: Hospital Universitario La Fe Neumología
city: Dnipropetrovsk
country: Ukraine
facility: Dnipropetrovsk State Medical Academy, Faculty Theraphy and Endocrinology Chair
city: Kherson
country: Ukraine
facility: Municipal Institution "Kherson City Clinical Hospital n.a. Afanasiy and Olha Tropin
city: Kremenchuk
country: Ukraine
facility: Kremenchuk First City Hospital n.a. O.T.Bogaevskyy
city: Kryvyy Rig
country: Ukraine
facility: Department of Pulmonology and Thoracic Surgery of Public Institution " Kryvyy Rig City Clinical Hospital # 8
city: Zaporizhzhya
country: Ukraine
facility: Hospital Department of Municipal Institution "Zaporizhzhya Regional Clinical Hospital"
Study officials:
name: Moira Aitken, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical Director
name: Brett Charlton, MD
role: STUDY_DIRECTOR
References:
citation: Flume PA, Amelina E, Daines CL, Charlton B, Leadbetter J, Guasconi A, Aitken ML. Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study. J Cyst Fibros. 2021 Nov;20(6):1003-1009. doi: 10.1016/j.jcf.2021.02.011. Epub 2021 Mar 11.