D DAVID PUBLISHING. 1. Introduction

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1 Journal of Health Science 2 (2014) doi: / / D DAVID PUBLISHING Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA pmdi in Patients with Chronic Obstructive Pulmonary Disease (COPD) Rajendra Mehta 1, Salil Bhargava 2, Santhalingam Balamurugan 3, Nazma Morde 4, Juliet Rebello 4, Jaideep Gogtay 4, Geena Malhotra 4 and Shrinivas Purandare 4 1. Department of Allergy and Chest diseases, Super Specialty Research Centre for Asthma, Indore , Madhya Pradesh, India 2. Department of Respiratory, Gyanpushp Research Center for Chest & Allergy Diseases, Indore , Madhya Pradesh, India 3. Chest Research Centre, Chennai , Tamil Nadu, India 4. Clinical Research Department, Cipla Ltd., Mumbai , Maharashtra, India Received: November 26, 2014 / Accepted: December 29, 2014 / Published: December 30, Abstract: Ipratropium bromide (IB) is an effective treatment for reversible bronchospasm associated with COPD. Cipla Ltd. has developed a formulation of Ipratropium bromide pmdi (Test IB) which is designed to be equivalent to the originator product Atrovent HFA pmdi (Reference IB) as a cost effective alternative for the treatment of COPD. The objective of the study was to establish non-inferiority of the Test IB to Reference IB in patients with stable COPD. In this multicenter, randomized, double-blind, double dummy, parallel group study, patients aged 40 years were randomized to receive 2 puffs three times daily (TID) of either the Test IB or Reference IB for 12 weeks. The primary endpoint was the change from pre dose to post dose FEV 1 at 90 min at the end of 12 weeks. Secondary endpoints included FVC, symptom score, rescue medication use and St. George's Respiratory Questionnaire (SGRQ). Safety and tolerability included evaluation of adverse events (AEs), vital signs assessments, physical examination and any change in concomitant medications. A total of 395 patients were randomized to either the Test IB (n = 199) or the Reference IB (n = 196); the majority of patients were male with a mean pre-bronchodilator FEV 1 (% predicted) of 60%. The per protocol set comprised of 258 patients (n = 129 in each treatment group). The mean treatment difference between the Test IB and Reference IB for the primary endpoint (mean change in FEV 1 from pre-dose to 90 min post dose at 12 weeks) was L and the lower limit of the 95% confidence interval (CI) for the difference between the two products was L which is greater than the predefined non inferiority limit of L. No significant difference was seen between the Test IB and Reference IB for any secondary efficacy variables. The AE profile was also comparable between the two treatments. The results indicate that the Test IB (Ipratropium Bromide HFA pmdi, Cipla Ltd.) is non inferior to the Reference IB. Key words: Efficacy, safety, ipratropium bromide, MDI, patients, COPD. 1. Introduction Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes of disability worldwide and is the only disease for which the prevalence and mortality rates continue to rise. Recent estimates suggest that there are approximately more than 52 million COPD patients around the world. Worldwide, Corresponding author: Nazma Morde, research fields: pharmacy and clinical research. nazma.syed@cipla.com. cigarette smoking is the most commonly encountered risk factor for COPD, although in many countries, air pollution resulting from the burning of wood and other biomass fuels has also been identified as a COPD risk factor [1]. Bronchodilators are the first line therapy for patients with COPD [2]. Bronchodilator such as anticholinergics plays an important role as both rescue and maintenance therapy for COPD patients [1]. With increasing prevalence and cost of care, there is a need

2 592 Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA for more effective and cost effective inhalation therapies. This is particularly relevant for countries and organizations with the least financial resources. Ipratropium bromide delivered by hydrofluoroalkane (HFA) pressurised metered dose inhaler (pmdi) (Atrovent ; Boehringer Ingelheim, Reference IB) has been in widespread use for the treatment of Chronic Obstructive Pulmonary Disease (COPD) for many years without apparent ill consequences. Cipla Ltd. has also developed ipratropium bromide HFA pmdi which is comparable to Atrovent HFA pmdi in vitro, thus offering an alternative cost effective anticholinergic treatment to COPD patients. For patients with COPD whose conditions are not sufficiently controlled by monotherapy, current international guidelines for the management of COPD recommend combination therapy with an inhaled anticholinergic and a short-acting β 2 -adrenoceptor agonist [1]. This approach recognizes that anticholinergics and β 2 -adrenoceptor agonists achieve their bronchodilating effects via different mechanisms that may involve different sites within the airways. Since Combivent CFC pmdi (combination of ipratropium bromide/salbutamol) has been withdrawn worldwide due to the CFC phaseout, the introduction of a new ipratropium HFA pmdi of Cipla Ltd. also provides a cost effective combination with salbutamol HFA pmdi for such group of COPD patients. To our knowledge this is the first study to evaluate the efficacy and safety two ipratropium bromide HFA pmdi formulations in COPD patients. 2. Materials and Methods 2.1 Patients The objective of the present study was to evaluate if ipratropium bromide HFA pmdi, Cipla Ltd. (Test IB) is non-inferior to Atrovent HFA pmdi (Reference IB) in stable COPD patients. Patients with GOLD (2003) stage 2 COPD were recruited into the study. Specifically, male or female subjects aged years, with a diagnosis of COPD were recruited in the study. Subjects were required to be on regular treatment with Ipratropium bromide alone or in combination with a β 2 -agonist for the past 2 weeks prior to screening, had a pre bronchodilator FEV 1 50% and 80% of predicted normal value, pre-bronchodilator FEV 1 /FVC ratio < 70% and a smoking history of 10 pack years to be eligible for the study. Patients were excluded if they were hypersensitive to ipratropium bromide; had a history of asthma, allergic rhinitis, atopy or had a total eosinophil count > 600/µL; demonstrated increase in FEV 1 12% of the pre-dose value after inhalation of salbutamol 400 g, were using > 8 puffs/day of salbutamol 100 mcg/actuation for immediate symptomatic relief; had any concomitant pulmonary disease; had symptomatic prostatic hypertrophy or narrow angle glaucoma, pulmonary hypertension, clinical signs of right heart failure, unstable angina, myocardial infarction, acute exacerbation requiring hospitalisation or any change in COPD therapy, respiratory infection requiring antibiotics and had used systemic corticosteroids in the past 3 months before the screening visit. 2.2 Study Design and Interventions This was a 12-week randomised, double-blind, double-dummy, multicentre study with a baseline run-in period of 2-weeks. A total of 25 investigational sites in India participated in this study. Following written informed consent, eligible patients with a confirmed diagnosis of COPD as per the GOLD criteria entered a screening period of one week during which the patients were trained on the filling of the diary card to record the rescue use and symptom scores and the laboratory reports were reviewed for eligibility. Certain medications such oral and parenteral corticosteroids, long acting β 2 -agonist (LABA) alone or in combination with Inhaled corticosteroids (ICS), tiotropium bromide, ipratropium bromide alone or in combination salbutamol, beta blockers and certain herbal medications were not permissible throughout

3 Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA 593 the study. Theophylline, ICS and mucolytic agents were permitted as long as the dose remained constant throughout the study. A COPD exacerbation was permitted to be treated with oral or parenteral prednisolone. Patients with more than one COPD exacerbation which required treatment with oral or parenteral prednisolone or required hospitalization were withdrawn from the study. In addition, salbutamol was provided as a rescue medication for immediate symptomatic relief throughout the study. After screening, all subjects entered a 2 week run-in period during which the patients continued to record the symptom scores and β 2 -agonist use. Patients were required to demonstrate the correct technique in the use of the pmdi, have no change in COPD treatment and no COPD-related hospital visits, were able to perform acceptable pulmonary function tests (PFT) with FEV 1 50% and 80%, and had to complete the study diary correctly in order to be randomised. Theophylline treatment was withheld for at least 48 h, and treatment with β 2 -adrenergic bronchodilators for at least 12 h prior to each PFT throughout the study. All pulmonary function tests were conducted in triplicate, from which the best values were recorded and used for analysis. Spirometry was conducted as per American Thoracic Standards guidelines [14]. All eligible patients were randomised (1:1) to a 12 week active treatment period with either test ipratropium bromide HFA pmdi (Test IB) or Atrovent HFA pmdi (containing Ipratropium bromide) of Boehringer Ingelheim (Reference IB) (Fig. 1). All patients inhaled 2 puffs thrice daily of either the Test IB (20 µg/actuation) or Reference IB (20 µg/actuation) for 12 weeks. After randomization, each patient entered a 12-week treatment period. FEV 1 and FVC were measured prior to dosing and at 15 min and 90 min post-dose at week 0, week 4, week 8 and week 12. The intake of study drug was withheld for at least 12 h prior to PFT at all treatment visits. The study drug was administered after baseline PFT had been performed. Subjects recorded symptom scores, rescue medication use, study medication use, and any adverse events on the diary cards throughout the treatment period. The severity of COPD symptoms (breathlessness, cough, sputum production and wheezing) were rated using a 4-point scale: none (0), mild (1), moderate (2), and severe (3). Quality of life (QoL) was evaluated at baseline and after 12 weeks of randomization using the St. George s Respiratory Questionnaire (SGRQ). Compliance was assessed by checking adequacy of the inhalation technique and through patient diary cards. A patient was considered to be compliant to the study medication if the % compliance for that patient was greater than or equal to 50%. Fig. 1 Study design.

4 594 Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA 2.3 Statistical Analysis The primary endpoint in this study was change from pre dose to post dose FEV 1 at 90 min at 12 weeks. Previous studies indicated that a reasonable assumption for the SD of FEV 1 is 300 ml. Assuming a treatment difference not greater than -100 ml, the sample size was calculated to be 143 patients per treatment group in order to detect this difference with a power of 80% at a significance level of (one sided). The primary endpoint (change from pre dose to post dose FEV 1 at 90 min at 12 weeks) was assessed using ANCOVA (Analysis of covariance) including center & treatment as factors. Secondary endpoints (FVC, symptom scores, use of rescue medication, SGRQ score) and safety endpoints (adverse events, vital signs, physical examination and change in concomitant medication) were summarized descriptively by formulation. 3. Results 3.1 Subject Disposition, Demographics and Baseline Characteristics A total of 395 subjects were randomized into the study (199 in the Test IB group and 196 in the Reference IB Group (Table 1). Demographic characteristics, pulmonary function and medication use at baseline was similar for the 2 treatment groups (Table 2). 3.2 Efficacy The compliance with the study medication was similar in the two treatment groups. Out of 395 randomized patients, 171 patients in the Reference IB group and 178 patients in the Test IB group were compliant with the study medication use. The mean change from pre dose to post dose FEV 1 at 90 min at 12 weeks in the PP population was L (0.199) in the Reference IB group and L (0.122) in the Test IB group. The 2-sided 95% CI (equivalent to one-sided 97.5% CI) ) for the least square mean [LSM] difference (Test IB-Reference IB) of L was , A non-inferiority limit of L which is clinically relevant (associated with a noticeable change in symptoms (dyspnoea) as assessed by the COPD patients) for change FEV 1 was used in this study. The lower limit of the 2-sided 95% CI (equivalent to the 1-sided 97.5% CI) was above the predefined non-inferiority limit of L. This suggests that the Test IB is non inferior to Reference IB. The results of the ITT population were similar to the results of the PP Population (Fig. 2). On all treatment visits (T0, T4, T8 and T12), the Test IB was comparable to the Reference IB for both FEV 1 and FVC (Fig. 3). The overall symptom scores, the use of salbutamol and the SGRQ scores at week 12 was similar between the Test IB and Reference IB group (Table 3). 3.3 Safety The adverse event (AE) profile of the Test IB group was similar to that of the Reference IB group. 58 AEs were reported by 36 (18.37%) patients in the Reference IB group and 45 AEs were reported by 30 (15.08%) patients in the Test IB group. Most of the events reported were of mild severity. The most common adverse event was pyrexia, followed by COPD cough and headache. Most AEs were not related to the study medication. A total of 8 patients reported 14 AEs that were related to the study medication (Table 4). There were 4 patients who reported 4 SAEs during the study. Table 1 Populations analysed. Population for analysis Treatment Group Reference IB (N) Test IB (N) Total (N) Safety & ITT PP

5 Table 2 Summary of demographics and baseline characteristics (ITT Population). Treatment Group ITT set Age (Years) Ethnic Origin Gender Weight (Kg) Height (cm) Baseline COPD medications Asian Female Male Salbutamol Theophylline ICS N (%) N (%) N (%) N (%) N (%) N (%) Baseline FEV 1 (L) %Predicted FEV 1 FVC (L) %FEV 1 /FV C ratio Reference IB n= (10) 196 (100%) 196 (100) 56 (13) 163 (7) 19 (9.6) 16(8.1) 18(9.1) (0.372) (9.199) (0.553) (8.974) Test IB n= (10) 195 (100%) 1 (0.5) 197 (99.5) 57 (12) 164 (7) 16 (8.0) 19(9.5) 19(9.5) (0.433) (10.088) (0.616) (9.036)

6 596 Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA pmdi in Patients with Chronic Obstructive Pulmonary Disease (COPD) Change in FEV1 (L) from pre dose to 90 min post dose at 12 weeks PP set ITT set Reference IB Test IB Fig. 2 Primary end point change in FEV 1 from pre dose to 90min post dose at 12 weeks in the per protocol (PP) and intent-to-treat (ITT) populations for Atrovent pmdi and Cipla ipratropium bromide. 3 FVC (L) at 90 min post dose Reference IB Test IB 0 T0 T4 T8 T12 FEV1 at 90 min post dose T0 T4 T8 T12 (a) Reference IB Test IB (b) Fig. 3 a: FVC at 90min post dose at all treatment visits (T0 baseline, T4 week 4, T8 week 8 and T12 week 12) for ITT population; b: FEV 1 at 90min post dose at all treatment visits (T0 baseline, T4 week 4, T8 week 8 and T12 week 12) for ITT population.

7 Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA 597 Table 3 Baseline/ change from baseline at endpoint in patient rated variables: ITT population. Variables Reference IB Test IB COPD symptom scores Baseline change Salbutamol use (puffs/day) Baseline change SGRQ scores Baseline change Table 4 Summary of adverse events related to study drug. Reference IB n = 196 Test IB n = 199 Number of patients experiencing at least one related Adverse Event 5 3 Total Adverse events 7 7 Ventricular extrasystoles 1. Constipation. 1 Mouth ulceration 1. Peptic ulcer. 1 Rectal prolapse. 1 Chest pain. 1 Nasopharyngitis 1. Tremor. 1 Urinary retention. 1 Chronic obstructive pulmonary disease 1. Cough 2. Dyspnoea 1 1 One patient (in the Test IB group) had severe retention of urine along with severe constipation leading to hardening of stool and bleeding per rectum prolapse and the SAE was considered to be related to the study treatment. The other three patients (2 in the Test IB group and 1 in the Reference IB) had severe COPD exacerbations which were not related to the study treatment. Three patients who had SAEs were withdrawn from the study (2 in Test IB group and one in Reference IB group). However, none of the other adverse events led to withdrawal from the study. This suggests that both that the two treatments were well tolerated. 4. Discussion and Conclusions The two treatment groups were balanced at screening, for all demographic and baseline characteristics including baseline lung function parameters, thereby enabling meaningful comparison of the study data between the treatments. However all except one patient in the study were male. The most common cause of COPD is smoking (NICE Clinical Guideline); gender is not relevant either to the development or the treatment of the disease [3]. This study was conducted in India and the predominance of men in the study population is more likely to reflect differences in smoking habits between the sexes (due to Indian culture) than in the prevalence of COPD. However, there are no differences between the sexes in the pathophysiology of the disease or the recommended treatment for COPD and so the low number of women in the study population does not affect the applicability of the study findings. Based on the primary measure of efficacy (change

8 598 Comparative Efficacy and Safety of Two Formulations of Ipratropium Bromide (IB) HFA from predose to 90 min post dose FEV 1 at 12 weeks of treatment) in COPD patients, it can be seen that ipratropium bromide HFA pmdi by Cipla Ltd. was non inferior to Atrovent HFA pmdi in both the PP and ITT populations. The lower limit of the 2-sided 95% CI (equivalent to the 1-sided 97.5% CI) for the difference between the treatments was above the predefined non-inferiority limit of -100 ml. It is interesting to note that both the upper and lower 95% CI were also well within 40 ml, which is reassuring that even if more stringent equivalence limits of 50 ml were used, equivalence of Test IB to Reference IB would have been concluded. The improvement in FEV 1 at 90 min post dose reported in the current study (110 ml with Reference IB and 107 ml with Test IB) was comparatively lesser than that reported in published literatures, which is attributed to the selection of patients with mild to moderate severity and exclusion of patients who demonstrated 12% reversibility in FEV 1 [4, 5, 6]. The two formulations were similar for secondary efficacy measures such as FVC, symptom scores, use of rescue medication and the SGRQ scores. Most adverse events were of mild severity. The incidence of AEs was low and was similar in the two treatment groups. There were no deaths reported in the study. Four SAEs were reported during the study which were resolved over time. In the Test IB group, two patient were withdrawn from the study because of COPD exacerbation. The percentage of patients with adverse events was low and was comparable between the two treatment groups. The most common adverse event in both treatment groups was pyrexia. In summary, this study confirms that ipratropium bromide HFA pmdi by Cipla Ltd., provides similar clinical benefit as Atrovent HFA pmdi in improving lung function and symptoms of COPD, and has a comparable tolerability profile, and thus provides an alternative cost effective treatment to patients with COPD. References [1] Global initiative for chronic obstructive lung disease: NHLBI/WHO Workshop. Updated Available at: (cited 08/2003a). [2] Siafakas, N. M., Vermeire, P., Pride, N. B., Paoletti, P., Gibson, J., Howard, P., Yernault, J. C., Decramer, M., Higenbottam, T., Postma, D. S., Rees, J., on behalf of the Task Force Optimal Assessment and Management of Chronic Obstructive Pulmonary Disease (COPD): a Consensus Statement of the European Respiratory Society. Eur. Respir. J. 8: [3] National Institute for Clinical Excellence Chronic obstructive pulmonary disease. Management of chronic obstructive pulmonary disease in adults in primary and secondary care. Clinical Guideline 12. [4] Van Noord, J. A., Bantje, Th. A., Eland, M. E., Korducki, L., Cornelissen, P. J. G., on behalf of Dutch Tiotropium study group A Randomized Controlled Comparison of Tiotropium and Ipratropium in the Treatment of Chronic Obstructive Pulmonary Disease. Thorax 55: [5] Voshaar, T., Lapidus, R., Maleki-Yazdi, R., Timmer, W., Rubin, E., Lowe, L., and Bateman, E A Randomized Study of Tiotropium Respimat Soft Mist TM Inhaler vs. Ipratropium pmdi in COPD. Respiratory Medicine 102: [6] Brazinsky, S. A., Lapidus, R. J., Weiss, L. A., Ghafouri, M., Fagan, N. M., Witek, T. J., The ATROVENT HFA Study Group One Year Evaluation of Safety and Efficacy of Ipratropium Bromide HFA and CFC Inhalation Aerosols in Patients with COPD. Clin. Drug Invest. 23 (3):