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Completed

NCT Number: NCT02134353

A Safety and Efficacy Trial of Inhaled Mannitol 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

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Key information

Conditions

Cystic Fibrosis Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Diseases Genetic Diseases, Inborn Infant, Newborn, Diseases Lung Diseases Pancreatic Diseases Respiratory Tract Diseases

Age range

18 year–99 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Insares, Mendoza, Mendoza Province, Argentina

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Have given written informed consent to participate in this trial in accordance with local regulations;
  • 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);
  • Be aged at least 18 years old;
  • Have FEV1 > 40 % and < 90% predicted (using NHanes III [1]);
  • Be able to perform all the techniques necessary to measure lung function;
  • 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
  • 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

  • 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;
  • Be considered "terminally ill" or eligible for lung transplantation;
  • Have had a lung transplant;
  • Be using maintenance nebulized hypertonic saline in the 2 weeks prior to visit 1;
  • Have had a significant episode of hemoptysis (> 60 mL) in the three months prior to Visit 0;
  • Have had a myocardial infarction in the three months prior to Visit 0;
  • Have had a cerebral vascular accident in the three months prior to Visit 0;
  • Have had major ocular surgery in the three months prior to Visit 0;
  • Have had major abdominal, chest or brain surgery in the three months prior to Visit 0;
  • Have a known cerebral, aortic or abdominal aneurysm;
  • Be breast feeding or pregnant, or plan to become pregnant while in the trial;
  • Be using an unreliable form of contraception (female subjects at risk of pregnancy only);
  • Be participating in another investigative drug trial, parallel to, or within 4 weeks of screening (Visit 0);
  • Have a known allergy to mannitol;
  • Be using non-selective oral beta blockers;
  • Have uncontrolled hypertension -i.e. systolic BP > 190 and / or diastolic BP > 100;
  • 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
  • Have a failed or incomplete MTT at trial entry (as evaluated in Section 8.1.1.1).
  • The subject must not commence treatment with rhDNase or maintenance antibiotics during the trial.

Treatment and study plan

Inhaled mannitol

Drug

Inhaled mannitol 400 mg BD for 26 weeks

Placebo Comparator: Arm B - Control

Drug

Placebo Comparator: Arm B - Control BD for 26 weeks

Primary outcomes

  1. Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4).

    Time frame: 26 weeks

    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).

Secondary outcomes

  1. Mean Change From Baseline FVC (mL) Over the 26-week Treatment Period

    Time frame: 26 weeks

    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).

Other outcomes

  1. Time to First Pulmonary Exacerbation Over the 26-week Treatment Period

    Time frame: 26 weeks

    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

  2. Number of Days on Antibiotics (Oral, Inhaled or IV) Due to Pulmonary Exacerbation

    Time frame: 26 weeks

    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.

  3. Number of Days in Hospital Due to Pulmonary Exacerbation

    Time frame: 26 weeks

    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.

  4. Rate of Pulmonary Exacerbations Over the 26-week Treatment Period

    Time frame: 26 weeks

    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.

  5. The Incidence of Pulmonary Exacerbations

    Time frame: 26 weeks

    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.

  6. Mean Change From Baseline in Ease of Expectoration Measured Using a Visual Analogue Scale (VAS) Over 26 Weeks

    Time frame: 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).

  7. Change From Baseline Over 26 Weeks in CFQ-R Respiratory Domain Score

    Time frame: 26 weeks

    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).

Sponsors and collaborators

Lead sponsor

Syntara

Industry

Registry information

Official study title

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

Important dates

Study start
2014
Primary completion
2017
Study completion
2017
First posted
May 9, 2014
Registry last updated
Oct 28, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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