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Investigation of the efficacy of generic and brand-name tiotropium bromide in the management of chronic obstructive pulmonary disease: A randomized comparative trial

Introduction: The beneficial effects of tiotropium bromide, a long acting anticholinergic bronchodilator, in the management of chronic obstructive pulmonary disease have been shown in previous studies. The present study aimed to compare the efficacy and safety of generic (Tiova®) and brand-name (Spiriva®) tiotropium preparations in patients with COPD. Methods and materials: In this randomized double-blind parallel-group trial, 79 patients with documented COPD were assigned to Tiova® or Spiriva® for a period of 4 weeks. Assessment of pulmonary function (using spirometry), quality-of-life (using St. George respiratory Questionnaire [SGRQ]) and severity of respiratory symptoms (using breathlessness, cough and sputum scale [BCSS]) was performed at baseline and at the end of treatment period. Results: There were significant increases in FEV1 and reductions in FVC by the end of study in both Tiova® and Spiriva® groups. FEV1/FVC ratio did not change significantly neither in the Tiova® nor in Spiriva® group. Overall SGRQ score as well as subscale scores of symptoms, activity and impacts were improved by both drugs. In the BCSS scale, the frequency and severity of three main symptoms (dyspnea, cough and sputum) was decreased by both drugs. Baseline as well as post-treatment values of spirometric parameters, SGRQ and BCSS scores was comparable between the groups, apart from a lower post-treatment frequency of cough and sputum in the Spiriva® versus Tiova® group. There was no report of adverse events in either of the study groups. Conclusion: The findings of this comparative trial showed equivalent efficacy and safety of Spiriva® and Tiova® in lessening the symptoms as well as improving the quality of life in patients with COPD. This finding has an important translational value given the significantly lower costs of generic versus brand-name products.


Introduction
Chronic obstructive pulmonary disease (COPD) is a pathologic state which is characterized by chronic, progressive and irreversible airflow obstruction, leading to impaired pulmonary function. Smoking is the major risk factor for COPD (Currie, 2010). According to WHO estimates, 65 million people had COPD in 2005 and more than 3 million people died because of COPD in this year, amounting to 5% of all deaths globally. COPD was the 5th cause of death in 2002 all over the world and currently it is the third cause of death, preceded by ischemic heart disease and stroke. Moreover, 90% COPDassociated deaths occur in low-and middle-income countries. In Iran, COPD was among the four main non-communicable diseases which led to death in 2012 (Semba et al., 2014).
COPD is a chronic state that is accompanied by symptoms such as productive coughs and dyspnea. By progression of COPD, exacerbations become more frequent and are often triggered by respiratory bacterial infections, predisposing to several life-threatening conditions such as left ventricular failure, cardiac arrhythmia, pneumothorax, pneumonia and pulmonary thromboembolism (Longo et al., 2011). Although complete control of COPD is difficult, pharmacotherapy can alleviate the symptoms, slow the disease progression, reduce the frequency and severity of exacerbations and also prevent mortality. Bronchodilators and inhaled corticosteroids are routinely administered medications for COPD management (Hanania and Sharafkhaneh, 2010). Bronchodilators have also been shown to be helpful in patients with increased airway hypersensitivity. Combination of a b 2 -agonist (e.g. salbutamol) and an anticholinergic (e.g. ipratropium bromide) has been found to be more effective than any of the other bronchodilators used alone (Balali-Mood and Hefazi, 2005).
Anticholinergic bronchodilators are widely used as standard treatments of COPD. Anticholinergics are indicated in all stages of COPD and are available in two forms: shortacting (ipratropium bromide) and long-acting (tiotropium bromide) (Vestbo et al., 2013). These bronchodilators block muscarinic receptors, resulting in relaxation and dilatation of airways and attenuation of mucus secretion (Kato et al., 2006). Tiotropium bromide is preferred over ipratropium bromide because of its specific inhibition of M3 receptors and longer duration of action (Vestbo et al., 2013). Tiotropium bromide is marketed under two trade names SpirivaÒ (manufactured by Boehringer-Ingelheim, Germany) and TiovaÒ (manufactured by Cipla, India). TiovaÒ is a generic product that is less expensive than the brand-name product (SpirivaÒ) (Tan and de Haan, 2014). Hitherto, only SpirivaÒ has been available and prescribed in Iran.
The present study aimed to compare the efficacy and safety of brand and generic products of tiotropium bromide in patients suffering from COPD.

Material and methods
This study was designed as a randomized double-blind clinical trial. Subjects were recruited from those referring to the Respiratory Clinic of the Baqiyatallah Hospital (Tehran, Iran). Inclusion criteria were documented history of COPD, age between 30 and 60 years, absence of spirometry contraindication, and a negative history of coagulopathy, prostate hypertrophy and glaucoma. Subjects with a history of hypersensitivity to tiotropium bromide, cigarette smoking, occupational exposure to toxic chemicals, allergic rhinitis or any other type of allergy, asthma, tuberculosis, lung cancer, systemic diseases with pulmonary complications (e.g. heart failure, renal dysfunction, hepatitis, cirrhosis and connective tissue disorders), anemia or polycythemia, and acute respiratory infection were excluded from the study.

Treatment
Eligible subjects were randomized to receive either SpirivaÒ (n = 33) or TiovaÒ (n = 46). Patients were instructed to take one capsule of either of the drugs daily at 12:00 a.m. Each capsule contained 18 lg of tiotropium bromide dry powder. Both study drugs were inhaled by the aid of appropriate apparatus i.e. RevolizerÒ (made by Cipla Ltd. For the use of TiovaÒ) and HandihalerÒ (made by Boehringer-Ingelheimmade Ltd. for the use of SpirivaÒ). During the study, all patients continued their standard COPD treatment regimen including SeretideÒ inhaler (containing Fluticasone and Salmeterol; one puff every 12 h), and N-acetylcysteine (600 mg every 12 h).

Assessments
Spirometric assessments were performed on a HI-801 Chest M.I. Spirometer (Tokyo, Japan), calibrated according to the manufacturer's instructions. Pulmonary function was assessed by measuring forced expiratory volume in the first second (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC ratio at baseline and at the end of trial.
Breathlessness, cough and sputum scale (BCSS) was used to assess the severity of three main symptoms of COPD that are most likely affected by standard COPD treatment. BCSS is a reliable and easy-to-use medical tool to explore the severity of respiratory symptoms and efficacy of treatment in clinical trials of COPD. Each item in BCSS is answered on a 5-point likert scale, representing the severity of symptoms (Leidy et al., 2003).
Evaluation of quality of life was performed using St. George's Respiratory Questionnaire (SGRQ) at baseline and at the end of treatment. After receiving instructions about how to fill the questionnaire, subjects were asked to answer SGRQ in a calm place independently, in the presence of an observer. SGRQ contains 76 items categorized in three subscales: ''Symptoms'' which asks about respiratory symptoms, their frequency and severity; ''Activity'' which asks about activities that cause or are limited by dyspnea; and ''Impacts'' which asks about social functioning and psychosocial disorders due to lung disease. The overall score ranges between 0 and 100, and higher scores indicate more severe impairment. SGRQ has been reported to be a sensitive, repeatable and numerical tool for evaluating a range of disorders affecting quality of life in patients with airway diseases (Jones et al., 1991).
The results of SGRQ and BCSS were analyzed by an internist or a lung subspecialist. The study protocol was approved by the institutional Ethics Committee and written informed consent was obtained from all participants.

Statistical analysis
Data were analyzed using SPSS software, version 16.0. Withingroup comparisons were made using paired samples t-test (for normally distributed data) or Wilcoxon signed-ranks test (for non-normally distributed data). Comparisons of baseline and post-treatment values between the study groups was carried out using independent samples t-test (for normally distributed data) or Mann-Whitney U test (for non-normally distributed data). Categorical variables were compared using McNemar's (within-group) or Fisher's exact (between-group) test. A two-sided p-value of <0.05 was considered as statistically significant.

Results
Out of the 79 eligible COPD patients (46 patients in the TiovaÒ and 33 patients in the SpirivaÒ group) who were initially recruited to the trial, 71 completed the study (n = 38 and 24 in the TiovaÒ and SpirivaÒ group, respectively). The reason for dropping from trial was not taking study medications due to personal reasons. Drop-out rate was not significantly different between the study groups (p > 0.05). The groups were comparable regarding age (48.78 ± 16.89 yrs and 46.69 ± 15.62 yrs in the TiovaÒ and SpirivaÒ group, respectively), gender (% males = 92.7% and 80% in the TiovaÒ and SpirivaÒ group, respectively) and BMI (24.12 ± 6.12 kg/m 2 and 24.38 ± 5.49 kg/m 2 in the TiovaÒ and SpirivaÒ group, respectively) (p > 0.05).

Spirometric findings
Spirometric findings in the study groups before and after the treatment are shown in Table 2. There were significant increases in FEV 1 by the end of study in both TiovaÒ (p = 0.048) and SpirivaÒ (p = 0.027) groups. In contrast, FVC values were significantly decreased in both groups (p < 0.001 and p < 0.05 in the TiovaÒ and SpirivaÒ group, respectively). FEV 1 /FVC ratio did not change significantly neither in the TiovaÒ nor SpirivaÒ group (p > 0.05). The impact of studied drugs on the spirometric parameters was comparable since baseline as well as post-treatment values for FEV 1 , FVC and FEV 1 /FVC was not significantly different between the groups (p > 0.05). Spirometric findings in the TiovaÒ and SpirivaÒ group are shown in Table 1.

SGRQ
In this study, the impact of administered medications on the quality of life was evaluated using SGRQ. Overall SGRQ score was significantly reduced after 4 weeks of treatment with either TiovaÒ (p = 0.002) or SpirivaÒ (p < 0.01). Subscale analysis revealed that both drugs improved activities (p < 0.001 in the TiovaÒ group and p < 0.01 in the SpirivaÒ group) and impacts (p = 0.002 in the TiovaÒ group and p < 0.001 in the SpirivaÒ group) scores, whilst the symptoms subscale score remained statistically unaltered in both groups (p > 0.05). Between-group comparisons indicated that total as well as subscale SGRQ scores did not significantly differ between the study groups, neither at baseline nor at the end of follow-up (p > 0.05). The effects of studied medications on the quality of life are summarized in Table 2.

BCSS
The severity of respiratory symptoms was evaluated using BCSS. The frequencies of cough, dyspnea, morning dyspnea and sputum were significantly reduced in both TiovaÒ and SpirivaÒ groups by the end of trial (p < 0.05). The frequency of none of the BCSS items (cough, dyspnea, morning dyspnea, sputum and hemoptysis) did significantly differ between the study groups at baseline (p > 0.05). However, a lower frequency of cough (p = 0.028) and sputum (p = 0.003) was observed with SpirivaÒ compared with TiovaÒ at the end of trial (Table 3).

Adverse events
Throughout the trial, both drugs were well tolerated and there was no report of typical anticholinergic side effects such as dry mouth, urinary retention and constipation in either of the groups.

Discussion
In pharmaceutical industry, generics are comparable with brand-name products in terms of safety and therapeutic efficacy, while they are significantly cheaper (20-90%) (Dunne et al., 2013;Keith et al., 1998). Because of cost-efficiency and wider availability, the policy of prescription of generic products instead of brand-name products has been accepted in many countries including Iran (since 1980) (Nelson et al., 2006;Zargarzadeh et al., 2007;Dupont and Heller, 2009). However, before a generic product could be regarded as a substitute for the original drug, its efficacy and safety are required to be demonstrated by bioequivalence (non-inferiority) trials (Heshmat et al., 2007;Aleyasin et al., 2012;Hadjibabaie et al., 2013;Beiraghdar et al., 2012a,b). With respect to COPD, the importance of developing generic drugs is more important, given the high burden of mortality that occurs in low-and middle-income countries, where access to brand-name medications may not be easy and affordable (Semba et al., 2014). Hence, decreasing treatment-associated costs should be considered as an important and determining factor in the pharmacotherapy of COPD. Tiotropium bromide is an inhaled long-acting anticholinergic bronchodilator which benefits patient with COPD including those with chronic bronchitis or emphysema. Long-term treatment with tiotropium bromide has been reported to improve exercise tolerance, health-related quality of life, and decrease dyspnea exacerbations and mortality (Tashkin et al., 2008;Balali-Mood and Hefazi, 2005). An important finding arising from the present study was the equivalent efficacy and safety of TiovaÒ, as a generic drug, compared with SpirivaÒ, as a brand name product. In spirometry, both TiovaÒ and SpirivaÒ improved FEV 1 significantly that is consistent with a meta-analysis of 22 randomized controlled trials on the efficacy of tiotropium bromide in the treatment of COPD (Karner et al., 2012). FEV 1 is a widely used measure for the assessment of the degree of airflow limitation, and its increase was comparable between SpirivaÒ and TiovaÒ. Our spirometric evaluations were complimented by assessment of quality of life and the frequency of symptoms. SGRQ is a reliable measure of health status in patients with COPD, and reflects the frequency of symptoms and the influence of breathlessness on daily activities as well as social functioning and psychological wellness. Our findings indicated that all three subscales of SGRQ (symptoms, activity and impacts) were significantly improved by both drugs, and that these improvements were equivalent between both groups. These findings are compliant with the results of two meta-analyses, including a Cochrane review, on the quality of life (assessed using SGRQ) in subjects receiving tiotropium bromide versus placebo. These studies indicated that tiotropium bromide improves quality of life in COPD patients (Karner et al., 2012;Yohannes et al., 2011). The positive effects of tiotropium bromide on quality of life were further confirmed by the results of BCSS, in which both studied drugs were found to reduce the severity of main COPD symptoms i.e. breathlessness, cough and sputum.
In summary, our comparative trial, being the first of its kind, showed comparable efficacy and safety of SpirivaÒ and TiovaÒ in lessening the symptoms as well as improving the quality of life in patients suffering from COPD. This finding has an important translational value for patients with COPD because of the lower cost of TiovaÒ versus SpirivaÒ (SpirivaÒ costs about three times as much as TiovaÒ), and the long-term nature of pharmacotherapy in COPD. In light of the present findings, TiovaÒ can be suggested as an effective and safe replacement for SpirivaÒ. However, since duration of follow-up in this pilot trial was relatively short, future large-scale studies are still required to compare the safety profile and quality of life-improving effects of TiovaÒ versus SpirivaÒ over longer-term periods.