Effect of QVA149 Versus NVA237 and Tiotropium on Chronic Obstructive Pulmonary Disorder (COPD) Exacerbations (SPARK)

Novartis

Status and phase: Completed; Phase 3

Conditions: Chronic Obstructive Pulmonary Disease

Treatments: Drug: tiotropium; Drug: Salbutamol/albuterol; Drug: QVA149; Drug: NVA237

Study type: Interventional

Funder types: Industry

Identifiers

NCT01120691

2009-013256-69 (EudraCT Number)

CQVA149A2304

Details and patient eligibility

About

This study is designed to assess the effect of once-daily QVA149 on COPD exacerbations in patients with severe to very severe COPD.

Enrollment: 2,224 patients

Sex: All

Ages: 40+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria :

1. Male or female adults aged ≥40 years, who had signed an informed consent form prior to initiation of any study-related procedure.
2. Patients with severe to very severe Chronic Obstructive Pulmonary Disease COPD (Stage III or IV) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines 2008.
3. Current or ex-smokers with a smoking history of at least 10 pack years (Ten pack-years were defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years).
4. Patients with a post-bronchodilator Forced Expiratory Volume in one second ( FEV1) <50% of the predicted normal value, and post-bronchodilator FEV1/ Forced Vital Capacity (FVC) <0.70 at Visit 2 (day -14). (Post refers to 1 h after sequential inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol).
5. A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics.

Exclusion Criteria:

1. Pregnant women or nursing mothers (pregnancy confirmed by positive urine pregnancy test).

2. Women of child-bearing potential

3. Patients requiring long term oxygen therapy (> 15 h a day) on a daily basis for chronic hypoxemia.

4. Patients who had a COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization in the 6 weeks prior to visit 1 or between visit 1 (Day -21) and Visit 3 (Day 1).

5. Patients who developed a COPD exacerbation during a period between visit 1 and 3 were ineligible but were permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation.

6. Patients who had a respiratory tract infection within 4 weeks prior to visit 1 (Day -21)

   • Patients who developed an upper or lower respiratory tract infection during the screening period (up to visit 3 (Day 1) were not eligible, but were permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection

7. Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active), clinically significant bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension.

8. Patients with lung lobectomy, or lung volume reduction or lung transplantation.

9. Patients who, in the judgment of the investigator, have a clinically relevant laboratory abnormality or a clinically significant condition such as (but not limited to):

   • Unstable ischemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable Atrial Fibrillation (AF). Patients with such events not considered clinically significant by the investigator may be considered for inclusion in the study
   • history of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin
   • uncontrolled hypo- or hyperthyroidism, hypokalemia or hyper adrenergic state
   • narrow-angle glaucoma
   • Symptomatic prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. (Patients with a Transurethral Resection of Prostate (TURP) were excluded from the study. Patients who underwent full re-section of the prostate could be considered for the study, as well as patients who were asymptomatic and stable on pharmacological treatment for the condition).
   • any condition which might have compromised patient safety or compliance, interfered with evaluation, or precluded completion of the study

10. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count > 600/mm3 (at visit 2), or onset of symptoms prior to 40 years. Patients without asthma were excluded if their eosinophil count was >600/mm3 at visit 2.

11. Patients with allergic rhinitis who used H1 antagonists or intranasal corticosteroids intermittently (treatment with a constant dose was permitted).

12. Patients with eczema (atopic), known high immunoglobulin E (IgE) levels or a known positive skin prick test in the last 5 years.

13. Patients with known history and diagnosis of alpha-1 antitrypsin deficiency.

14. Patients who were participating in the active phase of a supervised pulmonary rehabilitation program.

15. Patients with Type I or uncontrolled Type II diabetes.

16. Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs or drugs of a similar class or any component thereof:

    • anticholinergic agents
    • long and short acting beta-2 agonists
    • sympathomimetic amines.

17. Patients with a history of long QT syndrome or whose corrected QT interval (QTc) measured at visit 2 (Day -14) (Fridericia method) was prolonged (>450 ms for males and females) as confirmed by the central ECG assessor.

18. Patients with a clinically significant abnormality on the screening or baseline ECG who in the judgment of the investigator would be at potential risk if enrolled into the study. (These patients could not be re-screened).

19. Patients who needed treatments for COPD and allied conditions after the start of the study (visit 1)

20. Patients who needed treatments for COPD and allied conditions (e.g. allergic rhinitis) unless they had been stabilized

21. Patients taking other prohibited medications

22. Patients unable to use a dry powder inhaler (e.g. single dose dry powder inhaler (SDDPI), HandiHaler® device, or pressurized Metered Dose Inhaler (MDI) (rescue medication).

23. Patients unable to use an electronic patient diary.

24. Patients who were, in the opinion of the investigator known to be unreliable or non-compliant.

25. Patients who used other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of visit 1 (day -21), whichever was longer.

26. Patients who had live attenuated vaccination within 30 days prior to the screening visit or during the run-in period. Inactivated influenza vaccination, pneumococcal vaccination or any other inactivated vaccine was acceptable provided it was not administered within 48 hours prior to screening and randomization visits.

No additional exclusions were applied by the investigator, in order to ensure that the study population was representative of all eligible patients.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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2,224 participants in 3 patient groups

QVA149

Experimental group

Description:

QVA149 110/50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.

Treatment:

Drug: QVA149

Drug: Salbutamol/albuterol

NVA237

Active Comparator group

Description:

NVA237 50 μg capsules for inhalation, once daily delivered via Novartis Single Dose Dry Powder Inhaler (SDDPI) for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.

Treatment:

Drug: Salbutamol/albuterol

Drug: NVA237

open-label tiotropium

Active Comparator group

Description:

Open-label tiotropium bromide 18 μg capsules for inhalation once daily delivered via HandiHaler® device for at least 64 weeks of double blind treatment period (study duration was up to 76 weeks). Salbutamol/albuterol was available for rescue medication use throughout the study.

Treatment:

Drug: tiotropium

Drug: Salbutamol/albuterol