A Safety and Efficacy Trial of Inhaled Mannitol in Adult Cystic Fibrosis Subjects

Long Term Administration of Inhaled Mannitol in Cystic Fibrosis - A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects

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

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Inhaled mannitol; Drug: Placebo Comparator: Arm B - Control

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.

• Study Type: Interventional
• Enrollment (Actual): 423
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Bahia Blanca, Argentina, 2401 (8001)
    • Hospital Interzonal General de Agudos Dr. Jose Penna
  • Buenos Aires, Argentina, 1750
    • Hospital del Tórax Cetrángolo
  • Buenos Aires, Argentina, 8000
    • Hospital Regional Español de Bahía Blanca
  • Cordoba, Argentina, 1900 (5000)
    • Hospital San Roque
  • Provincia De Mendoza
    • Mendoza, Provincia De Mendoza, Argentina, M5500CCG
      • INSARES
• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Mater Adult Hospital
• Belgium
  • Brussels, Belgium, B-1090
    • UZ VUB
  • Leuven, Belgium, B-3000
    • UZ Leuven
  • Liege, Belgium, 4000
    • CHR Citadelle
• Canada
  • Halifax, Canada, B3H 3A7
    • QEII Health Sciences Center
  • Montréal, Canada, H2X 2L0
    • Institut de recherches cliniques de Montreal
  • Ottawa, Canada, K1H 8L6
    • The Ottawa Hospital, General Campus
• Czechia
  • Brno, Czechia, 625 00
    • FN Brno
• Hungary
  • Budapest, Hungary, H-1125
    • Országos Korányi Tbc
  • Debrecen, Hungary, H-1031
    • Klinikai Farmakológiai Központ
  • Mosdós, Hungary, H-7257
    • Mosdós Tüdőgyógyintézet
  • Törökbálint, Hungary, H-2045
    • Törökbálint Tüdőgyógyintézet
• Israel
  • Haifa, Israel, 31096
    • Pediatrics Pulmonary Department Rambam Healthcare Campus
  • Petah-Tikva, Israel, 49202
    • Schneider Children's Medical Center of Israel
• Italy
  • Brescia, Italy
    • Spedali Civili Brescia
  • Milano, Italy
    • IRCCS Ca' Granda Ospedale Maggiore Policlinico Mil
  • Orbassano, Italy
    • AOU San Luigi Gonzaga
  • Parma, Italy
    • Aziendao Spedaliera Universitaria
  • Potenza, Italy
    • Cystic Fibrosis Center Hospital San Carlo
  • Roma, Italy
    • Centro Fibrosi Cistica Policlinico Umberto I
  • Verona, Italy
    • Azienda Ospedaliera Universitaria Integratadi Verona
• Mexico
  • Guadalajara, Mexico, 44220
    • Unidad Medica de Occidente
  • Guadalajara, Mexico, 44100
    • Instituto Jaliscience de Investigacion Clinica
  • Mexico City, Mexico, CP 6700
    • Arke Estudios Clinicos S.A
  • Monterrey, Mexico, 64460
    • CEPREP- Hospital Universitario
• New Zealand
  • Auckland, New Zealand
    • Greenlane Hospital
  • Christchurch, New Zealand, 8011
    • Canterbury Respiratory Research Group
  • Dunedin, New Zealand
    • Otago Respiratory Research Unit, Dunedin Hospital
• Poland
  • Gdańsk, Poland, 80-308
    • Szpital Dziecięcy Polanki im. M. Płażyńskiego w Gdańsku sp.
  • Karpacz, Poland, 58-540
    • Centrum Medyczne Karpacz SA
  • Kielce, Poland, 25-381
    • Wojewodzki Specjalistyczny Szpital Dzieciecy im. W. Buszkowskiego
  • Lodz, Poland, 93-513
    • Wojewodzki Szpital Specjalistyczny im.
  • Poznan, Poland, 60-569
    • Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu
  • Rabka Zdroj, Poland, 34-700
    • Sanatorium Cassia-Villa Medica S.C.
  • Rzeszow, Poland, 35-612
    • Podkarpacki Osrodek Pulmonologii i Alergologii
• Romania
  • Bucuresti, Romania, 020395
    • Institutul pentru Ocrotirea Mamei si Copilului "Alfred Rusescu"
  • Bucuresti, Romania, 050159
    • Institutul de Pneumoftiziologie "Marius Nasta" Bucuresti, Sectia Clinica Pneumologie V
  • Cluj - Napoca, Romania, 400371
    • Spitalul Clinic De Pneumoftiziologie "Leon Daniello" Cluj-Napoca
  • Lasi, Romania, 700115
    • Spitalul Clinic de Pneumoftiziologie Lasi
• Russian Federation
  • Barnaul, Russian Federation, 656045
    • Tatiana I. Martynenko
  • Moscow, Russian Federation, 105077
    • Pulmonology Research Institute
  • Saint-Petersburg, Russian Federation
    • Research and Clinical Center of interstitial and orphan lung diseases
  • Vladimir, Russian Federation, 600023
    • Mikhail Smirnov
  • Yaroslavl, Russian Federation, 150010
    • Clinical Hospital# 2
• Slovakia
  • Banská Bystrica, Slovakia, 975 17
    • Oddelenie pneumológie a ftizeológie
  • Bratislava, Slovakia, 825 56
    • Imuno-alergologická ambulancia
  • Košice, Slovakia, 040 11
    • Detska Fakultna nemocnica Kosice
• South Africa
  • Cape Town, South Africa, 7700
    • University of Cape Town Lung Institute
  • Durban, South Africa, 4001
    • St. Augustine's Medical Centre 2
• Spain
  • El Palmar, Spain
    • Hospital Universitario Virgen de la Arrixaca
  • Madrid, Spain, 28046
    • Hospital Universitaro La Paz
  • Oviedo, Spain, 33006
    • Hospital Universitario Central de Asturias
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocio Hospital Unidad de Fibrosis Quistica
  • Valencia, Spain, 46026
    • Hospital Universitario La Fe Neumología
• Ukraine
  • Dnipropetrovsk, Ukraine, 49044
    • Dnipropetrovsk State Medical Academy, Faculty Theraphy and Endocrinology Chair
  • Kherson, Ukraine, 73000
    • Municipal Institution "Kherson City Clinical Hospital n.a. Afanasiy and Olha Tropin
  • Kremenchuk, Ukraine, 396170
    • Kremenchuk First City Hospital n.a. O.T.Bogaevskyy
  • Kryvyy Rig, Ukraine, 50047
    • Department of Pulmonology and Thoracic Surgery of Public Institution " Kryvyy Rig City Clinical Hospital # 8
  • Zaporizhzhya, Ukraine, 69600
    • Hospital Department of Municipal Institution "Zaporizhzhya Regional Clinical Hospital"
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Dr Lawrence Sinde
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Long Beach, California, United States, 90806
      • Pediatric Pulmonology
    • Sacramento, California, United States, 95817
      • University of CA, Davis
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Florida
    • Jacksonville, Florida, United States, 32204
      • Dr Mitchell Rothstein
    • Miami, Florida, United States, 33136
      • University of Miami
    • Orlando, Florida, United States, 32803
      • Central Florida Pulmonary Group, P.A.
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Illinois
    • Glenview, Illinois, United States, 60025
      • Cystic Fibrosis Center of Chicago
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Peoria, Illinois, United States, 61537
      • Illinois Lung Institute
  • Kansas
    • Kansas City, Kansas, United States, 64081
      • University Of Kansas Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Charities Pediatric Clinical Research Unit
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 62114
      • Massachusetts General Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Offices of Research Administration
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63143
      • Dr Joseph Ojile
  • New Hampshire
    • Bedford, New Hampshire, United States, 03110
      • Dartmouth-Hitchcock Specialty Care
  • New York
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10003
      • The Cystic Fibrosis Center Beth Israel Medical Center
    • Valhalla, New York, United States, 10595
      • Dr Allen Dozor
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45267-0564
      • University of Cincinnati
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • The Children's Medical Center of Dayton
    • Toledo, Ohio, United States, 43606
      • The Toledo Hospital and Toledo Childrens Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Pediatric Pulmonary & CF Center
    • Oklahoma City, Oklahoma, United States, 73112
      • Dr Santiago Reyes
  • Oregon
    • Portland, Oregon, United States, 97227
      • Pediatric Clinic
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of SC
    • Columbia, South Carolina, United States, 29203
      • One Richland Medical Park
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Experimental arm A; Active treatment. Inhaled Mannitol	Drug: Inhaled mannitol; Inhaled mannitol 400 mg BD for 26 weeks
PLACEBO_COMPARATOR: Arm B - Control; Arm B	Drug: Placebo Comparator: Arm B - Control; Placebo Comparator: Arm B - Control BD for 26 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4).	The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits. Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period	To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control for improving lung function as measured by mean change from baseline forced vital capacity (FVC) (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF). The mean absolute change from baseline FVC (mL) over 26 weeks will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).	26 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Pulmonary Exacerbation Over the 26-week Treatment Period	To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control in increasing the time to first protocol defined pulmonary exacerbation over the 26-week treatment period in adult subjects with CF. Protocol defined pulmonary exacerbations are those where 4 or more symptoms are recorded and are treated with IV antibiotics	26 weeks
Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation	To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days on antibiotics due to protocol defined pulmonary exacerbations. Overlapping antibiotics are counted separately.	26 weeks
Number of Days in Hospital Due to Pulmonary Exacerbation	To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing the number of days in hospital due to protocol defined pulmonary exacerbation.	26 weeks
Rate of Pulmonary Exacerbations Over the 26-week Treatment Period	To determine whether inhaled mannitol (400 mg b.i.d.) decreases the rate of protocol defined pulmonary exacerbations over the 26-week treatment period compared to control in adult subjects with CF. Protocol defined pulmonary exacerbations defined by having 4 or more symptoms and treated with IV antibiotics.	26 weeks
The Incidence of Pulmonary Exacerbations	To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for decreasing incidence of protocol defined pulmonary exacerbations, where incidence is defined as the proportion of subjects with 1 or more exacerbation during the 26 week period.	26 weeks
Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks	To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for improving ease of expectoration. The visual analogue scale (VAS) was 10cm. The position marked by the subject was converted into a score from 0 to 100 where 0 was the worst possible outcome and 100 was the best possible outcome. The VAS was completed at baseline, 6, 14 and 26 weeks. The mean absolute change from baseline over 26 weeks (ie the average of the changes at 6,14 and 26 weeks) is the outcome measure and will be compared between the two treatment groups with a REML based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).	26 weeks
Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score	To determine whether in adult subjects with CF, inhaled mannitol (400 mg b.i.d.) is superior to control for improving respiratory symptoms measured by Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain. The CFQ-R respiratory domain score is a scale from 0 to 100. Higher scores are a more favourable response. The mean absolute change from baseline over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the change from baseline averaged over the treatment period (ie the average of the changes at 6 weeks, 14 weeks and 26 weeks). Missing values due to withdrawal for reasons related to safety or efficacy were imputed using a baseline observation carried forward approach (BOCF).	26 weeks

Collaborators and Investigators

• Sponsor: Pharmaxis
• Investigators: Principal Investigator: Moira Aitken, MD; Study Director: Brett Charlton, MD, Medical Director

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2014
• Primary Completion (ACTUAL): February 1, 2017
• Study Completion (ACTUAL): February 1, 2017

Study Registration Dates

• First Submitted: April 16, 2014
• First Submitted That Met QC Criteria: May 7, 2014
• First Posted (ESTIMATE): May 9, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 28, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: DPM-CF-303