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

Cystic Fibrosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02134353
• Other study ID #: DPM-CF-303
• Status: Completed
• Phase: Phase 3
• Start date: September 2014
• Est. completion date: February 2017

Study information

• Verified date: October 2020
• Source: Pharmaxis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 423
• Est. completion date: February 2017
• Est. primary completion date: February 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• Inhaled mannitol
Inhaled mannitol 400 mg BD for 26 weeks
• Placebo Comparator: Arm B - Control
Placebo Comparator: Arm B - Control BD for 26 weeks

Locations

Country	Name	City	State
Argentina	Hospital Interzonal General de Agudos Dr. Jose Penna	Bahia Blanca
Argentina	Hospital del Tórax Cetrángolo	Buenos Aires
Argentina	Hospital Regional Español de Bahía Blanca	Buenos Aires
Argentina	Hospital San Roque	Cordoba
Argentina	Insares	Mendoza	Provincia De Mendoza
Australia	Mater Adult Hospital	Brisbane	Queensland
Belgium	UZ VUB	Brussels
Belgium	UZ Leuven	Leuven
Belgium	CHR Citadelle	Liege
Canada	QEII Health Sciences Center	Halifax
Canada	Institut de recherches cliniques de Montréal	Montréal
Canada	The Ottawa Hospital, General Campus	Ottawa
Czechia	FN Brno	Brno
Hungary	Országos Korányi Tbc	Budapest
Hungary	Klinikai Farmakológiai Központ	Debrecen
Hungary	Mosdós Tüdogyógyintézet	Mosdós
Hungary	Törökbálint Tüdogyógyintézet	Törökbálint
Israel	Pediatrics Pulmonary Department Rambam Healthcare Campus	Haifa
Israel	Schneider Children's Medical Center of Israel	Petah-Tikva
Italy	Spedali Civili Brescia	Brescia
Italy	IRCCS Ca' Granda Ospedale Maggiore Policlinico Mil	Milano
Italy	AOU San Luigi Gonzaga	Orbassano
Italy	Aziendao Spedaliera Universitaria	Parma
Italy	Cystic Fibrosis Center Hospital San Carlo	Potenza
Italy	Centro Fibrosi Cistica Policlinico Umberto I	Roma
Italy	Azienda Ospedaliera Universitaria Integratadi Verona	Verona
Mexico	Instituto Jaliscience de Investigacion Clinica	Guadalajara
Mexico	Unidad Médica de Occidente	Guadalajara
Mexico	Arke Estudios Clinicos S.A	Mexico City
Mexico	CEPREP- Hospital Universitario	Monterrey
New Zealand	Greenlane Hospital	Auckland
New Zealand	Canterbury Respiratory Research Group	Christchurch
New Zealand	Otago Respiratory Research Unit, Dunedin Hospital	Dunedin
Poland	Szpital Dzieciecy Polanki im. M. Plazynskiego w Gdansku sp.	Gdansk
Poland	Centrum Medyczne Karpacz SA	Karpacz
Poland	Wojewodzki Specjalistyczny Szpital Dzieciecy im. W. Buszkowskiego	Kielce
Poland	Wojewodzki Szpital Specjalistyczny im.	Lodz
Poland	Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu	Poznan
Poland	Sanatorium Cassia-Villa Medica S.C.	Rabka Zdroj
Poland	Podkarpacki Osrodek Pulmonologii i Alergologii	Rzeszow
Romania	Institutul de Pneumoftiziologie "Marius Nasta" Bucuresti, Sectia Clinica Pneumologie V	Bucuresti
Romania	Institutul pentru Ocrotirea Mamei si Copilului "Alfred Rusescu"	Bucuresti
Romania	Spitalul Clinic de Pneumoftiziologie "Leon Daniello" Cluj-Napoca	Cluj - Napoca
Romania	Spitalul Clinic de Pneumoftiziologie Lasi	Lasi
Russian Federation	Tatiana I. Martynenko	Barnaul
Russian Federation	Pulmonology Research Institute	Moscow
Russian Federation	Research and Clinical Center of interstitial and orphan lung diseases	Saint-Petersburg
Russian Federation	Mikhail Smirnov	Vladimir
Russian Federation	Clinical Hospital# 2	Yaroslavl
Slovakia	Oddelenie pneumológie a ftizeológie	Banská Bystrica
Slovakia	Imuno-alergologická ambulancia	Bratislava
Slovakia	Detská fakultná nemocnica Košice	Košice
South Africa	University of Cape Town Lung Institute	Cape Town
South Africa	St. Augustine's Medical Centre 2	Durban
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar
Spain	Hospital Universitaro La Paz	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo
Spain	Hospital Virgen del Rocio Hospital Unidad de Fibrosis Quistica	Sevilla
Spain	Hospital Universitario La Fe Neumología	Valencia
Ukraine	Dnipropetrovsk State Medical Academy, Faculty Theraphy and Endocrinology Chair	Dnipropetrovsk
Ukraine	Municipal Institution "Kherson City Clinical Hospital n.a. Afanasiy and Olha Tropin	Kherson
Ukraine	Kremenchuk First City Hospital n.a. O.T.Bogaevskyy	Kremenchuk
Ukraine	Department of Pulmonology and Thoracic Surgery of Public Institution " Kryvyy Rig City Clinical Hospital # 8	Kryvyy Rig
Ukraine	Hospital Department of Municipal Institution "Zaporizhzhya Regional Clinical Hospital"	Zaporizhzhya
United States	Akron Children's Hospital	Akron	Ohio
United States	John Hopkins	Baltimore	Maryland
United States	Dartmouth-Hitchcock Specialty Care	Bedford	New Hampshire
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of SC	Charleston	South Carolina
United States	University of Cincinnati	Cincinnati	Ohio
United States	One Richland Medical Park	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	The Children's Medical Center of Dayton	Dayton	Ohio
United States	Cystic Fibrosis Center of Chicago	Glenview	Illinois
United States	Spectrum Health Offices of Research Administration	Grand Rapids	Michigan
United States	Hartford Hospital	Hartford	Connecticut
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Dr Mitchell Rothstein	Jacksonville	Florida
United States	University of Kansas Hospital	Kansas City	Kansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Pediatric Pulmonology	Long Beach	California
United States	Kosair Charities Pediatric Clinical Research Unit	Louisville	Kentucky
United States	Loyola University Medical Center	Maywood	Illinois
United States	University of Miami	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Dr Lawrence Sinde	Mobile	Alabama
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	The Cystic Fibrosis Center Beth Israel Medical Center	New York	New York
United States	Dr Santiago Reyes	Oklahoma City	Oklahoma
United States	Pediatric Pulmonary & CF Center	Oklahoma City	Oklahoma
United States	Central Florida Pulmonary Group, P.A.	Orlando	Florida
United States	Illinois Lung Institute	Peoria	Illinois
United States	Pediatric Clinic	Portland	Oregon
United States	University of CA, Davis	Sacramento	California
United States	Dr Joseph Ojile	Saint Louis	Missouri
United States	University of Washington	Seattle	Washington
United States	Tampa General Hospital	Tampa	Florida
United States	The Toledo Hospital and Toledo Childrens Hospital	Toledo	Ohio
United States	University of Arizona	Tucson	Arizona
United States	Dr Allen Dozor	Valhalla	New York

Sponsors (1)

Lead Sponsor	Collaborator
Pharmaxis

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  Czechia,  Hungary,  Israel,  Italy,  Mexico,  New Zealand,  Poland,  Romania,  Russian Federation,  Slovakia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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