Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

Brief Title

Inhaled Mannitol as a Mucoactive Therapy for Bronchiectasis

Official Title

: A Phase III Multicenter, Randomized, Parallel Group, Controlled, Double Blind Study to Investigate the Safety and Efficacy of Inhaled Mannitol Over 12 Months in the Treatment of Bronchiectasis.

Brief Summary

      No gold standard therapy exists for clearing mucus from the airways of patients with
      bronchiectasis. While rhDNase has a proven place in the treatment of cystic fibrosis (CF), it
      failed to improve Forced expiratory volume in one second (FEV1) in a short-term non-CF
      bronchiectasis study and has been shown to be detrimental after 6 months therapy in non CF
      bronchiectasis, moreover it has no proven effect on mucociliary clearance. Hypertonic saline
      has been shown to have a comparable mode of action to inhaled mannitol, but has yet to be
      examined as a long term treatment option in bronchiectasis.

      The purpose of this study is to examine the efficacy and safety of 52 weeks treatment with
      inhaled mannitol in subjects with non-cystic fibrosis bronchiectasis. Previous studies with
      inhaled mannitol have demonstrated improvement in mucociliary clearance; mucus rehydration;
      improvement in quality of life and respiratory symptoms in patients with bronchiectasis and
      pulmonary function in cystic fibrosis. The results of this current study in combination with
      a recently completed 3 month study seek to confirm these early findings and to extend the
      evidence to support its use as a mucoactive therapy in subjects with bronchiectasis.

      We hypothesize that mannitol will improve the overall health and hygiene of the lung through
      regular and effective clearing of the mucus load. As a consequence of the reduction in mucus
      load and inflammatory process, the frequency of bronchiectasis related pulmonary
      exacerbations and the need for exacerbation related antibiotic treatment should fall. Days in
      hospital and community health care costs are expected to change in line with improvements in
      respiratory health.

      Finally, we plan to demonstrate that inhaled mannitol is safe and well tolerated over a 52
      week period. We will test these hypotheses using 400 mg mannitol twice daily (BD) against
      control.
    

Study Phase

Phase 3

Study Type

Interventional

Primary Outcome

Rate of Graded Pulmonary Exacerbations

Secondary Outcome

 Quality of Life as Measured by the St. Georges Respiratory Questionnaire (SGRQ) Total Score

Condition

Bronchiectasis

Intervention

Inhaled mannitol

Study Arms / Comparison Groups

 Mannitol

Description:  Inhaled mannitol 400mg

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Status

Drug

Estimated Enrollment

485

Start Date

November 2009

Completion Date

January 2014

Primary Completion Date

January 2014

Eligibility Criteria

        Inclusion Criteria

          1. Have given written informed consent to participate in this study in accordance with
             local regulations

          2. Have documented evidence of confirmed diagnosis of (non-cystic fibrosis)
             bronchiectasis by computed tomography (CT), High resolution computed tomography (HRCT)
             or bronchogram

          3. Be aged 18 - 85 years inclusive, male and female

          4. Have FEV1 (Forced expiratory volume in one second) ≥ 40% and ≤85% predicted* and ≥1.0L
             (*according to NHANES III predicted tables) measured at Visit 0A (V0A)

          5. Clinician documented history of at least 2 pulmonary exacerbations, each requiring
             antibiotic therapy, in the last 12 months prior to Visit 0A (V0A) and a total of at
             least 4 in the last 2 years prior to Visit 0A

          6. Have a total SGRQ (St George's respiratory questionnaire) score of ≥30 at Visit 0B
             (V0B)

          7. Have a production of ≥10g of sputum at Visit 0B Have reported chronic sputum
             production of ≥1 tablespoon (15mL) per day on the majority of days in the 3 months
             prior to Visit 0A

          8. Be able to perform all the techniques necessary to measure lung function

          9. Have FEV1 ≥40% predicted* and ≥1.0L (*according to NHANES III 1999 predicted tables)
             measured at V0B (Baseline result prior to MTT (Mannitol Tolerance Test)
             administration)

        Exclusion Criteria

          1. Be investigators, site personnel directly affiliated with this study, or their
             immediate families. Immediate family is defined as a spouse, parent, child or sibling,
             whether biologically or legally adopted.

          2. Have bronchiectasis as a consequence of cystic fibrosis or focal endobronchial lesion
             or otherwise curable causes (e.g. foreign body aspiration)

          3. Be considered "terminally ill" or listed for transplantation

          4. Be using hypertonic saline in the 14 days prior to commencing Visit 0B or thereafter
             at any time during the study

          5. Have previously used inhaled mannitol (Bronchitol) for more than a day

          6. Have had a significant episode of hemoptysis (>60 mL) in the previous 6 months

          7. Have had rescue antibiotics in the 4 weeks prior to V0B (chronic background antibiotic
             therapy accepted)

          8. Have smoked within the last 3 months and must not smoke during their participation in
             the study

          9. Have had a myocardial infarction in the three months prior to Visit 0A

         10. Have had a cerebral vascular accident in the three months prior to Visit 0A

         11. Have had major ocular surgery in the three months prior to Visit 0A

         12. Have had major abdominal, chest or brain surgery in the three months prior to Visit 0A

         13. Have a known cerebral, aortic or abdominal aneurysm

         14. Have actively treated Mycobacterium tuberculosis

         15. Have actively treated or unstable nontuberculous mycobacterial (NTM)infection or be
             under consideration for NTM treatment in the next 12 months

         16. Have unstable Allergic bronchopulmonary aspergillosis (ABPA) requiring steroid therapy
             (≤5mg dose oral steroids in stable ABPA accepted)

         17. Have end stage interstitial lung disease

         18. Have active malignancy including melanoma (other skin carcinomas exempted). Remissions
             from any malignancy ≥2 years also exempted

         19. Be breast feeding or pregnant, or plan to become pregnant while in the study

         20. Be using an unreliable form of contraception (female subjects at risk of pregnancy
             only)

         21. Be participating in another investigational drug study, parallel to, or within 4 weeks
             of Visit 0A

         22. Have a known intolerance to mannitol or β2-agonists

         23. Have uncontrolled hypertension - e.g. for adults: systolic blood pressure (BP) > 190
             and or diastolic BP > 100

         24. Subject has a condition or is 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 patient's participation in the study

         25. Have previously been screen failed for the study (exceptions - see section 3.3.2
             Eligibility Criteria - Rescreening)
      

Gender

All

Ages

18 Years - 85 Years

Accepts Healthy Volunteers

No

Contacts

Diana Bilton, MD, , 

Location Countries

Argentina

Location Countries

Argentina

NCT ID

NCT00669331

Organization ID

DPM-B-305

Responsible Party

Sponsor

Study Sponsor

Pharmaxis

Study Sponsor

Diana Bilton, MD, Principal Investigator, Brompton Hospital London UK

Verification Date

March 2016