A Phase I/II randomised, placebo-controlled, double blind trial to assess the safety, tolerability, pharmacodynamics and exploratory efficacy of heparin 25 mg inhalation powder in adults with Cystic Fibrosis (CF) - VR496/005- Orally inhaled heparin in adults with Cystic Fibrosis

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2007-006276-11-IE
• Date of registration: 11/02/2008
• Prospective Registration: Yes
• Primary sponsor: Vectura Limited
• Public title: A Phase I/II randomised, placebo-controlled, double blind trial to assess the safety, tolerability, pharmacodynamics and exploratory efficacy of heparin 25 mg inhalation powder in adults with Cystic Fibrosis (CF) - VR496/005- Orally inhaled heparin in adults with Cystic Fibrosis
• Scientific title: A Phase I/II randomised, placebo-controlled, double blind trial to assess the safety, tolerability, pharmacodynamics and exploratory efficacy of heparin 25 mg inhalation powder in adults with Cystic Fibrosis (CF) - VR496/005- Orally inhaled heparin in adults with Cystic Fibrosis
• Date of first enrolment: 11/11/2008
• Target sample size: 64
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-006276-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Ireland, Italy

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female = 18 years;
2. Non-smoker;
3. Written informed consent obtained prior to any trial specific procedures;
4. Confirmed diagnosis of CF lung disease (i.e., respiratory clinical symptoms and positive sweat test or disease inducing mutations) by CF expert / Investigator;
5. FEV1 40 - 80% of predicted value for age, sex and height; during 6 months prior to Screening;
6. FEV1 within 10% of best value during 6 months prior to Screening);
7. Regular mucus production due to CF;
8. Ease of sputum expectoration (i.e., clearability) VAS score of ? 80 mm;
9. Neutrophil elastase and / or IL-8 levels above detectable levels and/or upper limit of normal range for specified laboratory;
10. Adequate contraceptive measures (the subject [and his/her partner] should use
adequate contraceptive measures, consisting of two forms of contraception, at
least one of which must be a barrier method);
11. Able to comply with all the requirements of the protocol;
12. Able to use inhaler satisfactorily.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Known sensitivity to any preparation of inhaled or parenteral heparin or the excipient leucine;
2.Any contra indication to Monoparin® considered clinically relevant;
3.Increased bleeding risk defined as any of :
a.Evidence of clinically significant haemoptysis (i.e., bright red blood or substantial blood clot in sputum);or an increased risk of developing haemoptysis by virtue of previous clinical history of clinically significant haemoptysis
b.Haemorrhage of any major organ 6 months prior to Baseline (Day 1);
c.Patients with active gastrointestinal ulcer / bleeding during 6 months prior to Baseline (Day 1);
d.History of heparin-induced thrombocytopaenia;
e.Patients with bleeding diathesis defined by: i) aPTT > 25% above normal (26-36 seconds) and / or; ii) Platelet count < 100 x 106 cells/mL and / or; iii) Prothrombin time (PT) > 25% above the upper limit of normal (ULN) (i.e., 18.8s);
f. Evidence of portal hypertension (e.g., hypersplenism or known Grade III/IV oesophageal varices;
4. Clinically significant liver disease (e.g., known severe liver disease or cirrhosis, raised serum transaminases [ALT, AST] more than 2 x ULN), which in the opinion of the Investigator would impose a significant clinical risk;
5. Clinically significant serious disease or organ system disease not currently controlled / stable on present therapy;
6. Patients with a history of clinically or radiologically diagnosed aspergilloma;
7.Pregnancy at Screening; or lactation;
8. Planned hospitalisations which could interfere with trial compliance;
9. Previous thoracic or scheduled major surgery during trial period;
10. Any vaccination within 1 month of Screening;
11. Previous or current regular use of proscribed medication defined as:
a. Chronic / regular non-steroidal anti-inflammatory drug (NSAID) use (i.e., more than 3 times per week);
b. Any regular anti coagulant therapy (e.g., warfarin, aspirin) in the 2 weeks prior to Screening;
c. Any previous use of inhaled heparin;
d. Use of parenteral heparin 1 month prior to Screening;
e. Use of other investigational drugs 1 month prior to Screening;
f. Chronic / regular corticosteroid (1 month prior to Screening) use except for:
i)inhaled corticosteroids = 1 mg/day of beclometasone dipropionate (BDP) or equivalent (e.g., 500 mg/day Seretide); Note: It is acceptable for the dose to be reduced 1 month prior to and during Screening as long as this lower dose subsequently remains stable. ii) systemic doses of = 5 mg/day of oral prednisolone or equivalent; iii) limited dermatological use (a maximum of 3 times per week);
g. Any regular inhaled tobramycin (Tobi®) or other antibiotic use for oral, inhaled or parenteral treatment to be stable for at least 1 month prior to Screening and during the course of the trial (e.g., erythromycin, clarithromycin; azithromycin; colistin). (Note: If dosing changes between Screening and Baseline (Day 1), the patient can not be entered in the trial);
h.Modification of medication to treat respiratory disease between Screening and Baseline (Day 1): i) administration of additional medication for a respiratory infection such as antibiotics (e.g., any inhaled antibiotic such as Tobi® and colistin or any oral or parenteral antibiotic); ii) use of mucolytics (e.g., Pulmozyme®, erdosteine). Patients must be off Pulmozyme® for 1 month prior to Baseline (Day 1) and during the treatment period; iii) concomitant use of hypertonic saline treatment (Note: Patients treated with Pulmozym

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cystic Fibrosis
MedDRA version: 9.1 Level: LLT Classification code 10011763 Term: Cystic fibrosis lung

Intervention(s)

Product Name: Heparin 25mg inhalation powder, hard capsule
Pharmaceutical Form: Inhalation powder, hard capsule
INN or Proposed INN: HEPARIN SODIUM
CAS Number: 9041081
Concentration unit: IU/mg international unit(s)/milligram
Concentration type: not less then
Concentration number: 150-
Pharmaceutical form of the placebo: Inhalation powder, hard capsule
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Main Objective: To investigate the safety and tolerability of heparin 25 mg, inhalation powder, hard capsules in adults with CF.

Secondary Objective: Pharmacodynamic investigation of: Expectorated mucus (rheological). Effects on sputum inflammatory markers (neutrophil elastase, IL-6, -8, total cell count, %neutrophils,%macrophages); effect on pH in exhaled breath condensate may be measured; on inflammatory blood markers(neutrophil elastase, neutrophil elastase / alpha-1 antitrypsin complex, IL-6, -8, neutrophil count, C reactive protein); coagulation (aPTT, platelets). Evaluate efficacy by VAS based on change in symptoms: cough resolution; expectorated sputum clearability, thickness, volume, colour, viscoelasticity; breathlessness; general well being. Microbiology of sputum for effects on bacterial growth, density, antibiotic sensitivity (ID, culture, density, sensitivity of P aeruginosa, B cepacia, H influenzae and S aureus). Pulmonary function ;FEV1, FVC, forced mid-expiratory flow (FEF25-75), arterial oxygen saturation (SaO2). Response to the CF Questionnaire; Exercise performance.

Primary end point(s): Pharmacodynamic Endpoints
The PD variables are:
Expectorated mucus measurement parameters (i.e., rheological viscoelasticity / physicochemical measurement parameters) (in accordance with advised tests) (expectorated sputum samples must be collected after standard physiotherapy regime);
Induced sputum markers (neutrophil elastase, interleukins [IL-6, IL-8 and IL-10]) and cell counts (i.e., neutrophils, macrophages) (induced samples collected at all centres; pre-dose and 1 hour post treatment and at selected centres; 1 hour post treatment and at 4 hours post treatment for inflammatory markers);
EBC levels of pH and superoxide (and / or 8-isoprostane);
Blood markers, neutrophil elastase, neutrophil elastase / AAT complex, neutrophil count, IL-6, IL-8, IL-10 and CRP levels;
aPTT and platelet count.
Evaluation of Efficacy Endpoints
The efficacy variables are:
VAS parameters, i.e., cough resolution; expectorated sputum clearability, thickness, volume, colour, viscoelasticity (stickiness); breathlessness; general well being (including feeling, energy, physical activity, appetite and sleep);
Microbiology assays of expectorated sputum (i.e., analysis of bacterial growth, density, antibiotic sensitivity of the following organisms are included: Pseudomonas aeruginosa [mucoid and other types], Burkholderia cepacia, Haemophilus influenzae, Staphylococcus aureus;
Pulmonary function parameters FEV1, FVC and FEF25-75, and SaO2 by finger oximetry at rest, post physiotherapy and before induced sputum;
Response to the CFQ: responses to the questionnaire are to be measured by a six point Likert scale which are then transformed into values of between 0 and 100. Transformed scores of less than 50 represent negative scores, suggesting that the individuals may be experiencing difficulties within that particular domain;
Response to 10-metre shuttle exercise test (Singh et al 1994; Serisier et al 2006).

Secondary ID(s)

VR496/005