More COPD patients than you may realise need1...

inhealability

Some COPD inhalers require more inspiratory
effort than others.1*

SPIOLTO® RESPIMAT® was designed with inhaleability
in mind and to make it easy for your patients to inhale.2

References:

1. Ghosh S et al. Int J Chron Obstruct Pulmon Dis. 2019;14:585-595.

2. Anderson P et al. Int J Chron Pulmon Dis. 2006;1(3):251-259.

 
 

TOVITO® Clinical Trial Programme

 

01/03/2019

Author: Boehringer Ingelheim


TOVITO® is a clinical trial programme with >16,000 patients that evaluates the effect of Spiolto® Respimat® on lung function, quality of life, exacerbation, exercise and other important clinical outcomes related to the daily life of a COPD patient.
 

TOVITO® is the >16,000 patient Phase III Clinical Trial Programme investigating the efficacy and safety of Spiolto® Respimat® in COPD

TOVITO® evaluates the effect of Spiolto® Respimat® on lung function, quality of life, exacerbations, exercise tolerance and other important clinical outcomes related to the daily life of patients with COPD

Endpoints:

  • Lung function
  • Quality of life
  • Exercise
  • Physical activity
  • Breathlessness
  • Lung function vs ICS/LABA
  • Exacerbations
  • Breathlessness on walking
  • Number of patients
  • Length of trial (weeks)

Phases:

  • Pivotal trial
  • Phase IIIa trial
  • Phase IIIb trial
  • Phase IV

Endpoints

  • Lung function

Lung function is an assessment of how well a COPD patient’s lungs work. Measures used include:

  • FEV1 (forced expiratory volume in one second)
  • FEV1 AUC0-3 (area under the curve), FEV1 AUC0-24, FEV1 AUC12-24
  • Trough FEV1 (FEV1 measured at the -10 minute time point at the end of the dosing interval)
  • Quality of life

Quality of life improvements in COPD patients are measured by the St. George’s Respiratory Questionnaire (SQRG) total score

  • The SGRQ is a 50-item questionnaire designed to measure impact on health status (quality of life) in patients with obstructive airways disease, including COPD1
  • Jones PW, et al. The St George’s respiratory questionnaire. Respir Med 1991;85(Suppl B):25–31.
  • Lung function vs ICS/LABA

Lung function vs ICS/LABA is a measure to assess the efficacy of LAMA/LABA vs LABA/ICS in reducing moderate-to-severe exacerbations1 and at improving lung function and quality of life1

  • Horita N, et al. Cochrane Database Syst Rev 2017; 2:CD012066.
  • Breathlessness

Breathlessness in COPD is caused by limited airflow in and out of the lungs, which makes it difficult to breathe1

  • Calverley P. Review COPD: what is the unmet need? Br J Pharmacol 2008;115:487–93.
  • Exercise

Exercise capacity is the amount of exercise patients are physically capable of doing1

Measures used include:

  • Constant work rate cycle ergometry: to assess effectiveness of therapy in improving exercise capacity in patients with COPD2
  • The Endurance Shuttle Walking Test (ESWT): to assess the amount of activity a COPD patient can endure. The ESWT measures how far someone can walk at a standard speed without stopping for a rest3
  • Goldstein RE. Exercise Capacity. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 8.
  • Andrianopoulos V, et al. Characteristics and determinants of endurance cycle ergometry and six-minute walk distance in patients with COPD. BMC Pulmonary Medicine 2014;14:97.
  • Holland AE, et al. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J 2014;44:1428–46.
  • Physical activity

'Physical activity' reflects the amount of activity and the difficulty patients have in their activities in daily life. Measures used include:

  • Functional Performance Inventory - Short Form: to allow patients to self-report the ease or difficulties with which they carry out day-to-day activities to meet their basic needs, fulfill usual roles, and maintain their health and well-being1
  • Borg scale: to decide the amount of shortness of breath that a patient experiences during exercise or tasks2
  • Leidy NK. Functional Performance Inventory. ATS. Available at: http://qol.thoracic.org/sections/instruments/fj/pages/fpi.html [Last accessed: August 2018].
  • Kendrick K, et al. Usefulness of the modified 0-10 Borg scale in assessing the degree of dyspnea in patients with COPD and asthma. J Emerg Nurs 2000;26(3):216–22.
  • Breathlessness on walking

Breathlessness on walking means people with COPD adapt their lifestyles by decreasing their physical activity. Decreased activity results in patients experiencing further breathlessness during even lower levels of physical activity, leading to their condition further worsening and increasing the risk of disability and death1

  • Exacerbations

A sudden worsening of symptoms or ‘flare ups’, that may be triggered by a bacterial or viral infection and typically lasts for several days1

  • Number of patients

The total number of participants in the study

  • Length of trial (weeks)

The total duration of the trial

Phases

  • Pivotal trial

A phase III trial that allows a regulatory authority to decide whether or not to approve a drug

  • Phase IIIa trial

A trial conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission

  • Phase IIIb trial

A trial conducted after regulatory submission, but prior to the medicine’s approval and launch

  • Phase IV

A phase IV trial that assesses the safety, efficacy, or optimal use of a drug after it has been granted regulatory approval

tonado 1+21,2

Two pivotal Phase III replicate studies that assessed the efficacy and safety of Spiolto® Respimat® (tiotropium+olodaterol) versus Spiriva® Respimat® (tiotropium) or Striverdi® Respimat® (olodaterol) alone in 5,162 patients with moderate to very severe COPD (GOLD Stage 2-4)1,2

In the 52-week TONADO® 1&2 trials:

  • Spiolto® Respimat® also provided significant improvements in lung function – right from the initial disease stages when patients first need maintenance therapies for their COPD (GOLD stage 2)1
  • Spiolto® Respimat® demonstrated significant improvements in breathlessness2 and quality of life1 beyond Spiriva® Respimat®1,2
  • A post-hoc analysis from TONADO® showed Spiolto® Respimat® more than doubles the improvement in lung function* compared to Spiriva® Respimat® in patients who had no prior COPD maintenance therapy at baseline1
  • Data also showed that Spiolto® Respimat® was well tolerated with a comparable safety profile to Spiriva® Respimat® or Striverdi® Respimat® alone2
  • Although the TONADO® trials were not specifically designed to evaluate the effect of treatments on COPD exacerbations, there was a trend towards benefit in the reduction of moderate to severe exacerbations with Spiolto® Respimat® beyond that found with Spiriva® Respimat®2

The primary endpoints for the TONADO® trials were: lung function as measured by trough FEV1, FEV1 AUC0-3 and health-related quality of life, as measured by St George’s Respiratory Questionnaire (SGRQ) total score, after 24 weeks of treatment2

Secondary endpoints included breathlessness, as measured by Transitional Dyspnoea Index (TDI) focal score at 24 weeks2

* Improvement in trough FEV1 after 24 weeks of treatment

References
  • Ferguson F, et al. Efficacy of tiotropium+olodaterol in patients with COPD by initial disease severity and treatment intensity: a post hoc analysis. Adv Ther 2015;32(6):523–6.
  • Buhl R, et al. Tiotropium and olodaterol fixed dose combination versus mono-components in COPD (GOLD2-4). Eur Respir J 2015; 45(4):969–79.
  • Lung function
  • Quality of life
  • Length of trial (weeks)
  • Number of patients
vivacito1

A Phase IIIa study that investigated the 24-hour bronchodilator profile of once-daily Spiolto® Respimat® (tiotropium+olodaterol) in 219 patients with moderate to very severe COPD (GOLD stage 2-4)1

In the 6-week VIVACITO® trial:

  • Spiolto® Respimat® improved lung function of COPD patients to levels significantly above those achieved with Spiriva® Respimat® (tiotropium) or Strivedi® Respimat® (olodaterol) monotherapies, or with placebo1

The primary endpoint of the VIVACITO® trial was: lung function as measured by FEV1 AUC0-24 after 6 weeks of treatment

Secondary end points included lung function over 24 hours as measured by trough FEV11

References
  • Beeh KM, et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2015;32:53–9.
  • Lung function
  • Length of trial (weeks)
  • Number of patients
moracto 1+21

Two Phase IIIa replicate studies that investigated the effects of Spiolto® Respimat® (tiotropium+olodaterol) on inspiratory capacity and exercise endurance in 586 patients with moderate to severe COPD (GOLD stage 2-3)1

In the 6-week MORACTO® 1&2 trials:

  • Once-daily Spiolto® Respimat® yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies. Spiolto® Respimat® also showed improvements in breathing discomfort and exercise tolerance versus placebo but not consistently versus monotherapies1

The primary endpoints of the MORACTO® 1&2 trials were: inspiratory capacity at rest before constant work rate cycle ergometry and exercise endurance, measured by endurance time during constant work rate cycle ergometry, after 6 weeks of treatment1

The secondary end points included intensity of breathing discomfort on physical activity as measured by the Borg scale, and lung function, as measured by FEV1, after 6 weeks of treatment

References
  • O’Donnell DE, et al. Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD. Eur Respir J 2017;49:1601348.
  • Exercise
  • Length of trial (weeks)
  • Number of patients
torracto1

A Phase IIIa study that evaluated the effects Spiolto® Respimat® (tiotropium+olodaterol) on exercise endurance in 404 patients with GOLD stage 2-3 COPD1

In the 12-week TORRACTO® trial:

  • Spiolto® Respimat® improved patients’ endurance time during exercise versus placebo1

Endpoints for the TORRACTO® trial were: cycle ergometry (primary endpoint) and included an Endurance Shuttle Walk Test (secondary endpoint). All measured at 12 weeks1

References
  • Maltais F, et al. Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease. Ther Adv Respir Dis 2018; 12:1753465818755091.
  • Exercise
  • Length of trial (weeks)
  • Number of patients
otemto 1+21,2

Two Phase IIIb replicate studies that investigated the effects of Spiolto® Respimat® (tiotropium+olodaterol) on lung function and health-related quality of life compared to placebo in 1,621 patients with moderate to severe COPD (GOLD stage 2-3)1,2

In the 12-week OTEMTO® 1&2 trials:

  • Spiolto® Respimat® demonstrated a significant improvement in both lung function and health-related quality of life versus placebo, but not consistently versus Spiriva® Respimat® (tiotropium) monotherapy2
  • A post-hoc analysis of the OTEMTO® 1&2 trials showed that Spiolto® Respimat® provided a clinically meaningful 4 point improvement in quality of life compared to placebo right from the initial disease stages when patients first need maintenance therapies for their COPD (GOLD 2)1
  • In the same patient group (GOLD 2), 13% more patients achieved a clinically meaningful improvement in quality of life with Spiolto® Respimat® compared to Spiriva® Respimat® (52.8% compared to 39.2%)1

The primary endpoints of the OTEMTO® 1&2 trials were: lung function as measured by FEV1 AUC0-3, trough FEV1, and health-related quality of life as measured by St George’s Respiratory Questionnaire (SGRQ) total score, after 12 weeks of treatment1,2

References
  • Singh D, et al. Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO® studies. Respir Res 2016;17:73.
  • Singh D, et al. Tiotropium+olodaterol shows clinically meaningful improvements in quality of life. Respir Med 2015;109:1312–9.
  • Lung function
  • Quality of life
  • Length of trial (weeks)
  • Number of patients
energito1

A Phase IIIb study that evaluated effects of once-daily Spiolto® Respimat® (tiotropium+olodaterol) on lung function compared to twice-daily salmeterol/fluticasone propionate in 229 patients with moderate to severe COPD (GOLD stage 2-3)1

In the 6-week ENERGITO® trial:

  • Spiolto® Respimat® showed superior lung function compared to a LABA*/ICS** fixed dose combination (salmeterol/fluticasone propionate) in patients with moderate to severe COPD.1 Optimising lung function is the primary treatment goal from the start of maintenance therapy (GOLD stage 2)2

The primary endpoint of the ENERGITO® study was: lung function as measured by FEV1 AUC0-12, FEV1 AUC0-24 and FEV1 AUC12-24 after 6 weeks of treatment

Secondary endpoints included lung function as measured by trough FEV1 at 6 weeks1

* Long-acting beta2-agonist

** Inhaled corticosteroids

References
  • Beeh KM et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study). Int J COPD 2016;11:193–205.
  • World Health Organization. COPD management.
    Available at: http://www.who.int/respiratory/copd/management/en [Last Accessed August 2018].
  • Lung function
  • Length of trial (weeks)
  • Number of patients
physacto1,2,3

A Phase IIIb trial assessed the effect of Spiolto® Respimat® (tiotropium+olodaterol) alone or in combination with supervised exercise training on exercise capacity and physical activity outcomes compared to placebo, including the amount of physical activity and perceived difficulties1,2,3

A 12-week self-management behaviour modification programme was included for all four groups to provide an optimal environment for translating improvements in exercise capacity into increases in daily activity2

In the 12-week PHYSACTO® trial:

  • Spiolto® Respimat® with and without exercise training and behaviour modification significantly increased exercise capacity compared to placebo1
  • Spiolto® Respimat® also showed improvements in shortness of breath associated with physical activity for people taking Spiolto® Respimat® compared to placebo1

The primary endpoint of the PHYSACTO® trial was: exercise capacity measured by endurance time during an Endurance Shuttle Walk Test (ESWT) to symptom limitation, after 8 weeks of treatment (to reflect the 8-week duration of the exercise training programme)1

A series of secondary endpoints included assessments of patient’s levels of physical activity as measured by an activity monitor, patient’s reports of the ease or difficulty with which they perform daily activities as quantified by the Functional Performance Inventory - Short Form, and a daily activity diary3

References
  • Troosters T, et al. Effect of Bronchodilation and Exercise Training with Behavior Modification on Exercise Tolerance and Downstream Effects on Symptoms and Physical Activity in COPD. Am J Respir Crit Care Med 2018; 201706-1288OC.
  • Bourbeau J, et al. Behaviour-change intervention in a multicentre, randomised, placebo controlled COPD study: Methodological considerations and implementation. BMJ Open 2016;6:e010109.
  • Troosters T, et al. Enhancing exercise tolerance and physical activity in COPD with combined pharmacological and nonpharmacological interventions: PHYSACTO randomised, placebo controlled study design. BMJ Open 2016;6:e010106.
  • Physical activity
  • Length of trial (weeks)
  • Number of patients
dynagito1

A landmark study that investigated the effect of Spiolto® Respimat® (tiotropium+olodaterol) in reducing the rate of moderate-to-severe COPD exacerbations compared with Spiriva® Respimat® (tiotropium)1

In the 52-week study, over 7,800 patients with moderate-to-severe COPD and at least one moderate-to- severe exacerbation in the previous 12 months were included, from >50 countries worldwide. The primary endpoint was annualised rate of moderate-to-severe COPD exacerbations

Data from the DYNAGITO® trial showed:

  • Spiolto® Respimat® lowers the rate of moderate-to-severe COPD exacerbations compared with Spiriva® Respimat® (p=0.0498‡)1
    o The pre-specified significance level of p<0.01 for the primary endpoint of DYNAGITO® was not met
  • Fewer exacerbations with Spiolto® Respimat® that required intervention with systemic steroids or with systemic steroids plus antibiotics1 compared with Spiriva® Respimat®‡
  • There was no difference in exacerbation rate between Spiolto® Respimat® and Spiriva® Respimat® in exacerbations treated with antibiotics only (p=0.2062‡)1
  • No new side effects or safety concerns were identified in DYNAGITO®1
  • Spiolto® Respimat® has a similar safety profile to Spiriva® Respimat®1

‡ The primary endpoint was not met

References
  • Calverley P, et al. Lancet Respir Med 2018;6(5):337–44.
  • Exacerbations
  • Length of trial (weeks)
  • Number of patients
otivato1,2

A Phase IV study that evaluated the effect of Spiolto® Respimat® (tiotropium+olodaterol) compared with Spiriva® Respimat® (tiotropium) on breathlessness during walking in 106 patients with COPD over a 6 week period1

In the 6-week OTIVATO® trial:

  • Spiolto® Respimat® significantly reduced the intensity of breathlessness during walking compared with Spiriva® Respimat® alone2
References
  • OTIVATO clinical trial. NCT02853123. Effect of tiotropium + olodaterol on breathlessness in COPD patients. Available at: https://clinicaltrials.gov/ct2/show/NCT02853123?term=OTIVATO&rank=1 [Last accessed: April 2018].
  • Maltais F, et al. The effect of tiotropium/olodaterol vs tiotropium on breathlessness during the 3-minute constant speed shuttle test in patients with chronic obstructive pulmonary disease. Poster presented at ATS May 20 2018.
  • Breathlessness on walking
  • Length of trial (weeks)
  • Number of patients

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Respimat® Device Assembly - Preparation for First Use
 

References

1. Pitcairn G et al. J Aerosol Med 2005;3:264-272.
2. Anderson A. Int J Chron Obstruct Pulmon Dis 2006;1:251-259.
3. Dalby R et al. Med Devices: Evidence and Research 2011;4:145-155.

 
 
PC-SG-100210
Production date: Mar 2019

What is Spiolto® Respimat® (tiotropium/olodaterol)?

Tiotropium/olodaterol is approved as once daily maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. It is built on tiotropium, the active ingredient in Spiriva® and is enhanced by olodaterol which was specifically designed to complement the efficacy of tiotropium. Tiotropium/olodaterol provides significant improvements in lung function, COPD symptoms and quality of life over tiotropium – right from the initial stages when suitable patients need maintenance therapy.[1-4]

Tiotropium/olodaterol is administered via Respimat®, the only inhaler available that actively delivers a unique mist. This means the patient just needs to take a slow deep breath to get the medication deep into the lungs.*[5-9]
 

What is the safety profile of Spiolto® Respimat® (tiotropium/olodaterol)?

Spiolto® Respimat® (tiotropium/olodaterol) has a comparable adverse event profile to the component monotherapies.[10]

Adverse event incidence was generally balanced across all treatment groups, with the majority being mild to moderate in severity.[10]

Spiolto® Respimat® safety and tolerability profile was established in patients treated for up to 52 weeks.[10]

The proportion of patients who discontinued due to adverse events with Spiolto® Respimat® was comparable to that of Spiriva® (tiotropium) and Striverdi® (olodaterol).[10]

The percentage of patients reporting an adverse event with Spiolto® Respimat® was comparable to that of Spiriva®.[10]

For full safety profile, please refer to the Local Prescribing Information.

What are the contraindications of Spiolto® Respimat® (tiotropium/olodaterol)?[4]

Spiolto® Respimat® is contraindicated in patients with hypersensitivity to tiotropium or olodaterol or to any of the excipients.

Spiolto® Respimat® is also contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, e.g. ipratropium or oxitropium.

For information on warnings and precautions, please refer to the Local Prescribing Information.
 
References

[1] Maltais F et al. Effects of 12 weeks of once-daily tiotropium and olodaterol fixed-dose combination on exercise endurance in patients with COPD. Thorax 2014;69:A186-A187

[2] Ferguson F et al. Efficacy of tiotropium+olodaterol in patients with COPD by initial disease severity and treatment intensity: a post hoc analysis. Adv Ther. 2015; 32(6): 523-526

[3] Singh D et al. Tiotropium+olodaterol shows clinically meaningful improvements in quality of life. Respir Med. 2015; 10: 1312-1319

[4] Spiolto® Respimat® Summary of Product Characteristics, February 2017

[5] Newman SP et al. Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: Comparison of Respimat® with conventional metered-dose inhalers with and without spacer devices. Chest 1998; 113: 957-963

[6] Pitcairn G et al. Deposition of corticosteroid aerosol in the human lung by Respimat® Soft Mist™ Inhaler compared to deposition by metered dose inhaler or by Turbuhaler® dry powder inhaler. J Aerosol Med 2005; 18(3): 264-272

[7] Dalby R et al. A review of the development of Respimat® Soft Mist™ Inhaler. Int J Pharm 2004; 283: 1-9

[8] Dalby RN et al. Development of Respimat® SoftMist™ inhaler and its clinical utility in respiratory disorders. Med Devices (Auckl) 2011; 4: 145-155

[9] Anderson P. Use of Respimat Soft Mist Inhaler in COPD patients. Int J Chron Obstruct Pulmon Dis 2006; 1(3): 251–259

[10] Buhl R, et al. Eur Respir J. 2015;45:969-979.

[11] Spiriva® Respimat® Summary of Product Characteristics January 2017.

[12] Striverdi® Respimat® Summary of Product Characteristics March 2016.