hbcbs journal club - tiotropium + olodaterol fixed dose combination (fdc) in chronic obstructive...

JOURNAL CLUB

Sandeepkumar Balabbigari, Pharm.D Candidate 2016

Ernest Mario School of Pharmacy, Rutgers University

Cycle 3 2016, Horizon Blue Cross Blue Shield of New Jersey

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TIOTROPIUM AND OLODATEROL FIXED-DOSE COMBINATION VERSUS MONO-COMPONENTS IN COPD

Background Chronic obstructive pulmonary disease (COPD) is a chronic, progressive disease associated with worsening

airflow limitation and chronic inflammation in the airways and lungs. Long-term exposure to cigarette smoke

and/or air-borne pollutants, and the subsequent inflammatory reactions that follow are the common causes of the

disease. COPD involves both the reversible symptoms (smooth muscle contraction, mucus secretion) and

irreversible symptoms (fibrosis/narrowing of the airways, destruction of alveoli). Adequate treatment primarily

involves pharmacological therapy; current options include muscarinic antagonists, β2-agonists, inhaled and oral

corticosteroids, or a combination the aforementioned options. The fixed dose combination (FDC) of inhaled

tiotropium, an established long-acting muscarinic antagonist (LAMA), and olodaterol, a novel selective, long-

acting β2-agonist (LABA), offers a long-acting option for COPD patients whose condition cannot be managed by

short-acting agents. The combination of these complementary agents works to reduce inflammation in the airways

and lungs and prevent bronchial smooth muscle contraction. Currently, tiotropium and olodaterol FDCs are

available as once-daily Stiolto™ Respimat® Inhalation Spray from Boehringer Ingelheim Pharma GmbH.

Previous trials

Beeh KM, Westerman J, Kirsten AM, 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;32:53–59.

- Double-blind, placebo-controlled, multicenter, phase III, incomplete crossover study

- Patients received four of the following six treatments as a once daily inhalation. Each treatment was given for

6 weeks with a 3 week washout period between each treatment. Pulmonary function tests were conducted at

preset times for each treatment phase.

Placebo Tiotropium 2.5 µg Tiotropium + olodaterol FDC 2.5/5 µg

Olodaterol 5 µg Tiotropium 5 µg Tiotropium + olodaterol FDC 5/5 µg

- Patient inclusion and exclusion criteria are similar to that of the pivotal trials for Stiolto™ Respimat®

Inhalation Spray. However, baseline patient population characteristics differed in some criteria, particularly in

the percentage of current smokers vs. ex-smokers

- Primary endpoint: Forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 24 hours

(AUC0–24) response

- FDCs of tiotropium + olodaterol had statistically significant (p< 0.0001) greater improvements in COPD

patients’ lung function profiles than monotherapy with the separate components and placebo.

- Limitations: Only 219 patients were randomized. No follow-up study was conducted to determine long-term

efficacy and safety differences between the FDC treatments and their individual components.

ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R. Efficacy and safety of combining olodaterol

Respimat® and tiotropium HandiHaler® in patients with COPD: results of two randomized, double-blind,

active-controlled studies. Int J COPD. 2014;9:1133–1144.

- Two replicate, double-blind, randomized, 12-week studies

- Patients received one of two treatments as a once daily inhalation for 12 weeks. Spirometry, vital sign testing,

and SGRQ administration were conducted at random and at preset times during treatment.

Tiotropium 18 µg (via HandiHaler®) and olodaterol 5 µg (via Respimat®)

Tiotropium 18 µg (via HandiHaler®) and placebo (via Respimat®)

- Patient inclusion and exclusion criteria are similar to that of the pivotal trails for Stiolto™ Respimat®

Inhalation Spray. However, baseline patient population characteristics differed in some criteria, particularly in

the percentage of current smokers vs. ex-smokers.

- Primary endpoints: Forced expiratory volume in 1second (FEV1) area under the curve from 0 to 3 hours

(AUC0–3) response and trough FEV1 response (defined as change from baseline) after 12 weeks of treatment

- The administration of both tiotropium and olodaterol as once daily inhalations yielded statistically significant

(p< 0.01) greater bronchodilatory effects in COPD patients than the administration of tiotropium alone.

- Limitations: These studies were only conducted for 12 weeks. Due to the short length of the study, some of

the long term safety, efficacy, and health status effects could not be determined.

Why this study?

Both tiotropium and olodaterol are currently available as separate inhalation products for use in patients suffering

from COPD. Stiolto™ Respimat® Inhalation Spray is a combination product that delivers both a LAMA and

LABA once daily. This can potentially increase adherence and improve symptom control in a disease state that

requires daily medication for adequate control.

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GENERAL STUDY OVERVIEW

Title/Citation Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD

Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-

components in COPD (GOLD 2–4) Eur Respir J. 2015;45(4):969–979.

Funding The clinical trials mentioned in this study were supported by Boehringer Ingelheim Pharma GmbH. Medical

writing was also contracted and compensated by Boehringer Ingelheim Pharma GmbH.

Trial design This study consisted of two clinical trials. Both were multinational, replicate, phase III, multicenter, randomized,

double-blind, active-controlled, five-arm, parallel-group studies.

Objectives To determine the safety and efficacy of fixed-dose combination therapy with tiotropium and olodaterol compared

to monotherapy of the separate components in patients with moderate to very severe COPD (GOLD state 2-4).

METHODS

Inclusion

criteria

- Outpatients at least 40 years old and a history of moderate to very severe COPD (GOLD stage 2-4)

- Post-bronchodilator FEV1 < 80% of predicted normal and FEV1/FVC < 70%

- Current or ex-smokers with a smoking history of > 10 pack-years

Exclusion

criteria

- Significant diseases other than COPD - Clinically relevant abnormal baseline lab values

- History of asthma - Known active tuberculosis

- Clinically evident bronchiectasis - Cystic fibrosis

- Life-threatening pulmonary obstruction - Regular use of daytime oxygen

- Currently enrolled in pulmonary rehabilitation program or completed program within six weeks of screening

Interventions

Patients received one of the following treatments:

Olodaterol Respimat 5 µg once daily Tiotropium + olodaterol FDC Respimat 2.5/5 µg once daily

Tiotropium Respimat 2.5 µg once daily Tiotropium + olodaterol FDC Respimat 5/5 µg once daily

Tiotropium Respimat 5 µg once daily

Inhaled corticosteroid (ICS) use was allowed as required for the individual patient. Albuterol inhalers

(100mcg/actuation) were also provided as rescue inhalers for as needed use. Oral steroid and theophylline use was

also permitted while patients received treatment, but pulmonary function tests were not conducted within seven

days of the last dose.

Outcome

measures

Primary Outcome: three primary end points were evaluated in each trial after 24 weeks of treatment

- Forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0–3) response

- Trough FEV1 response (defined as change from baseline (mean of the values of 1 h and 10 min prior to the

first dose of treatment))

- St George’s Respiratory Questionnaire (SGRQ) total score (SGRQ was analyzed in a pre-specified combined

analysis of data from both studies)

Pulmonary function tests were performed on day 1 and at weeks 2, 6, 12, 18, 24, 32, 40 and 52. SGRQ was

completed on day 1 and after 12, 24 and 52 weeks, prior to any pulmonary function tests or other procedures

Secondary Outcomes:

- Mahler Transition Dyspnea Index focal score at 24 weeks

- Trough FVC

- FVC AUC0-3

- FVC AUC0-12 and FEV1 AUC0-12 response in a 12 hour PFT sub-set of patients

- FVC peak0-3 and FEV1 peak0-3

- FVC and FEV1 at 5, 15, and 30 minutes, and 1, 2, and 3 hours after inhalation of treatment

Statistical

analyses

Be prepared to discuss the appropriateness of each statistical test and result

- 2-sided alpha: 0.05

- Power: 90%

- Sample sizes calculated using a 2-sample t-test with equal numbers using Query Advisor 6.0

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- Estimated standard deviations to calculate sample size:

FEV1 AUC0–3: 226 mL Through FEV1: 225 mL Total SGRQ: 13 units

- Calculated sample sizes to achieve power: 500 patients to detect a difference of 46 mL for FEV1 AUC0–3 and

through FEV1; 1000 patients to detect a difference of 1.885 in SGRQ total score

- Mean changes from baseline for all primary endpoints and the key secondary endpoint (Mahler Transition

Dyspnea Index focal score) were analyzed using REML-based mixed-effect model repeated measures

approach.

RESULTS

Enrollment

Study 1

3369 patients screened; 2624 randomized into treatment group

- Olodaterol Respimat 5 µg once daily: n = 528; completed = 431

- Tiotropium Respimat 2.5 µg once daily: n = 525; completed = 448

- Tiotropium Respimat 5 µg once daily: n = 527; completed = 455

- Tiotropium + olodaterol FDC Respimat 2.5/5 µg once daily: n = 522; completed = 462

- Tiotropium + olodaterol FDC Respimat 5/5 µg once daily: n = 522; completed = 466

2262 patients (86.2%) completed the study; 362 patients were discontinued.

Study 2

3518 patients screened; 2539 randomized into treatment group

- Olodaterol Respimat 5 µg once daily: n = 510; completed = 412

- Tiotropium Respimat 2.5 µg once daily: n = 507; completed = 409

- Tiotropium Respimat 5 µg once daily: n = 506; completed = 410

- Tiotropium + olodaterol FDC Respimat 2.5/5 µg once daily: n = 508; completed = 445

- Tiotropium + olodaterol FDC Respimat 5/5 µg once daily: n = 507; completed = 430

2106 patients (83.0%) completed the study; 432 patients were discontinued.

For both studies, adverse events, non-compliance, lost to follow-up, and withdrawn consent not due to an adverse

event were the most common reasons for discontinuation.

Baseline

characteristics

Notable baseline characteristics of each treatment group from both study populations combined

Olodaterol

5 µg

Tiotropium

2.5 µg

Tiotropium

5 µg

Tiotropium +

olodaterol

2.5/5 µg

Tiotropium

+ olodaterol

5/5 µg

Male (%)

73.6 73.0 73.1 73.5 71.2

Age (years) 64.2 ± 8.2 64.0 ± 8.7 63.9 ± 8.6 64.1 ± 7.8 63.8 ± 8.3

Ex / Current

Smoker (%)

63.6 / 36.4 62.4 / 37.6 64.2 / 35.8 63.9 / 36.1 61.1 / 38.9

Co-morbidities (%) 86.4 85.7 87.3 86.3 86.5

GOLD Stage

2 / 3 / 4 (%)

51.3 / 36.4

/ 12.3

50.2 / 39.6 /

10.0

50.0 / 37.5 /

12.4

50.4 / 39.5 /

10.0

48.8 / 39.7 /

11.6

Baseline LAMA /

LABA Use (%)

35.2 / 47.3 33.7 / 46.0 33.5 / 43.6 39.1 / 47.7 36.7 / 47.2

Efficacy

Primary endpoint analysis at the end of 24 weeks included all randomized patients who had baseline

measurements, received at least one treatment dose, and had at least measurement post-dose.

Combined Data from Study 1 and 2

FEV1 AUC0-3 Trough FEV1

Response

SGRQ

Responder Rate

Olodaterol 5 µg 134.5 mL 55.5 mL 44.8 %

Tiotropium 2.5 µg 136.5 mL 72.5 mL 49.6 %

Tiotropium 5 µg 152 mL 80.5 mL 48.7 %

Tiotropium + olodaterol FDC 2.5/5 µg 248.5 mL 118 mL 53.2 %

Tiotropium + olodaterol FDC 5/5 µg 262 mL 140.5 mL 57.5 %

FEV1 AUC0-3: data presented as mean FEV1 AUC0-3 responses from all treatment arms in both studies.

Improvements with FDC treatments were statistically significant over the individual components (p< 0.0001).

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Trough FEV1 Response: data presented as mean trough FEV1 responses from all treatment arms in both studies.

Improvements with FDC treatments were statistically significant over the individual components (p< 0.05).

SGRQ Responder Rate: Data is presented as (n %) and is cumulative of both studies. Increases in responder rate

for tiotropium + olodaterol FDC 5/5 µg over its individual components were statistically significant (p< 0.05). For

tiotropium + olodaterol FDC 2.5/5 µg, there was a significant improvement in responder rate versus olodaterol 5

µg and tiotropium 5 µg (p < 0.05) but not tiotropium 2.5 µg (p = 0.1071).

Adverse events

Treatment-

related ADRs

ADRs Requiring

Hospitalization

ADR’s Leading To

Discontinuation

Olodaterol 5 µg 6.6% 15.6 % 9.9 %

Tiotropium 2.5 µg 6.0% 14.0 % 8.7 %

Tiotropium 5 µg 6.1% 15.0 % 9.0 %

Tiotropium + olodaterol

FDC 2.5/5 µg

6.0% 14.5 % 5.5 %


FDC 5/5 µg

7.1% 14.9 % 7.4 %

Data is presented as (n %) and is cumulative of both studies.

COPD

Exacerbations

Infection Gastrointestinal

Disorders

Olodaterol 5 µg 35.6% 37.9 % 15.9 %

Tiotropium 2.5 µg 34.1% 35.2 % 14.7 %

Tiotropium 5 µg 32.9% 33.7 % 14.9 %


FDC 2.5/5 µg

29.2% 38.3 % 14.2 %


FDC 5/5 µg

32.3% 36.3 % 13.9 %

Data is presented as (n %) and is cumulative of both studies.

A subset analysis was conducted on patients with cardiac history; overall incidence of adverse events in this subset

was comparable across treatment arms.

AUTHORS’ CONCLUSIONS

The two trials evaluated in this study show that once daily tiotropium + olodaterol FDCs have statistically significant improvements in

lung function and symptoms in patients with moderate to very-severe COPD. These improvements, at both the beginning and end of

the dosing interval, were demonstrated by greater increases in FEV1 AUC0-3, trough FEV1, and improved SGRQ scores with

tiotropium + olodaterol FDCs than with monotherapy of the separate components. There were no significant differences in the adverse

events experienced by the various treatment groups, regardless of whether patients were receiving 2.5 µg or 5 µg of tiotropium.

However, the authors did recognize that the lack of a placebo group limits the strength of this study. They also note that, despite no

specific design in the trials to examine COPD exacerbations, the limited exacerbation data they were able to collect reflects that of

other studies concerning the use of LAMA + LABA FDC in COPD patients.

GENERALIZABILITY/CRITIQUE/DISCUSSION

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Patient

Population

- The trials were multi-center and international, which allows for the generalizability of study results to multiple

patient populations. At the same time, the randomization of the study populations yielded treatment groups of

similar sizes and baseline patient characteristics, allowing for the different treatment groups to be directly

compared.

- Smoking and exposure to cigarette smoke are the most common risk factors for developing COPD and the

progression of the disease. By including only current smokers and ex-smokers in the trials, the study was able

to simulate the majority of real-world patient population that is affected by COPD. Compared to other trials

involving tiotropium and olodaterol FDCs, these pivotal trails included a larger proportion of patients who are

ex-smokers. Because ex-smokers have been shown to have less progressive COPD than current smokers, the

results of these pivotal trials may report higher efficacy than other similarly-designed trials.

It is also important to recognize that some patients may develop COPD through occupational or other

environmental exposures and thus are not represented in these trials.

In addition, a subset analysis of the differences in endpoint outcomes between current smokers and ex-

smokers would be ideal in determining the degree of benefit a patient will receive from tiotropium and/or

olodaterol therapy given their current smoking status.

- Patients in these trials ranged from moderate to very severe COPD (GOLD Stage 2-4), representing the

typical patients who are often initiated on combination inhalation therapy. A subset analysis of the differences

in endpoint outcomes between the patients of the various GOLD stages would be ideal in determining the

degree of benefit a patient will receive given their current severity of COPD.

- The majority of patients included in the trials were male, which does not reflect the current rising trend of the

incidence of COPD in women almost equaling that of males.

Intervention

- Both trials in the study were replicate double-blind and active-controlled. Although placebo trials are the

preferred method for randomized clinical trials, the researchers justified their choice to forgo a placebo

treatment arm by stating that it is unethical to withhold treatment in COPD patients for 52 weeks.

- Use of LAMA, LABA, or FDC of both agents as well as an as-needed rescue inhaler reflects current clinical

guidelines for the maintenance treatment of moderate to very severe COPD. Although patients were allowed

to continue inhaled corticosteroid as required, randomization ensured the percentage of patients in each

treatment arm requiring ICS was not significantly different. It was later determined that the use of ICS did not

affect long-term decline in FEV1 and thus did not alter the primary endpoints of the trials.

- The length of the study, 52 weeks, provides enough data to allow researcher to adequately assess the long-

term effects of each treatment. Although the trials did not collect data to specifically assess the effect of the

treatments on exacerbation risk, a 52 week trial is an adequate length of time to determine exacerbation risk in

COPD patients as the risk determined by the number of exacerbations in the past 12 months.

- To fully determine the value of tiotropium + olodaterol FDC in the real-world, clinical setting, it should be

studied against other inhalation combination products indicated for COPD to determine its benefit, both

clinically and economically, over already established treatments.

- Stiolto™ Respimat® Inhalation Spray has only been approved as 2.5 mcg tiotropium + 2.5 mg olodaterol and

recommended to be administered as two inhalations once daily. This deviates from the original studied

treatment and brings into question whether two successive inhalations of a lower dose FDC (2.5 mcg

tiotropium + 2.5 mg olodaterol) would yield the same drug delivery and benefits as one inhalation of a higher

dose FDC (5 mcg tiotropium + 5 mg olodaterol).

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Endpoints

- Primary and secondary endpoints focus solely on lung function rather than lung volume. Although FEV1 and

FVC testing remain the gold standard in COPD, some literature indicates that improvements in lung volume

measurements, such as forced residual capacity (FRC) and residual volume (RV), are also associated with

better COPD patient outcomes.

- By assessing both FEV1 AUC0-3 and through FEV1, researchers are able to determine both the peak effects and

the extent of the bronchodilation effects of 24 hour dosing.

- Primary endpoints measured both quantitative (FEV1 AUC0-3 and through FEV1) and qualitative (SGRQ)

changes in patient outcomes. The quantitative measures are able to track improvements in disease

progression, while qualitative measures are able to track improvements in patients’ quality of life.

- Measurement of FEV1 after the administration of the treatment allows researchers to determine presence and

any improvements in airflow limitations. However, another common measurement of airflow limitation,

FEV1/FVC, was not included in these trials.

- Reporting of specific adverse events was only descriptive. With no documentation of the severity of a specific

adverse event, it is difficult to determine the clinical relevance of the reported adverse events.

Statistics

- Statistical significance was not reported for adverse events. Knowing whether the occurrence of an adverse

event is statistically significant or not, helps clinicians determine whether the adverse event was due to chance

or related to the treatment given to the patient.

- Data regarding the endpoints was derived from the intend-to-treat patient population, which promotes

generalizability to clinical practice. However, had data from the per-protocol patient population been used, it

would have ensured that changes in primary endpoints responses was due to drug efficacy rather than patient

drop out.

- The sponsor collected data and performed statistical analysis

RECOMMENDATION

Stiolto™ Respimat® Inhalation Spray (2.5 mcg tiotropium + 2.5 mg olodaterol) has been FDA-approved as a once-daily maintenance

treatment for COPD. The recommended dose is two inhalations at the same time daily. Currently, several combination inhalation

products are already available in the market for the same indication. These products are only available as brand-name medications and

include Combivent Respimat® (albuterol + ipratropium), Symbicort® (budesonide + formoterol), Breo Ellipta® (fluticasone +

vilanterol), Advair® (fluticasone + salmeterol), and Anoro™ Ellipta® (umeclidinium + vilanterol). Tiotropium + olodaterol FDC was

not compared head-to-head against any of the other combination inhalation products currently available in the market. Given that

many COPD patients achieve adequate maintenance therapy using less costly treatments, I recommended placing Stiolto™ Respimat®

Inhalation Spray under Medicare Tier 4 and Commercial Tier 3 (non-preferred brand) with a dispensing limit of one package per

month. After similar safety and efficacy to other combination inhalation products is demonstrated, I would recommend moving

Stiolto™ Respimat® Inhalation Spray to Medicare Tier 3 and Commercial Tier 2 (preferred brand) with a dispensing limit of one

package per month , the same tier and dispensing criteria the other combination inhalers indicated for COPD are currently under.

References:

1. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD

(GOLD 2–4) Eur Respir J. 2015;45(4):969–979.

2. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease

(COPD) and asthma. Am Rev Respir Dis 1987;136:225–244.

3. Marion, DW. Chronic Obstructive Pulmonary Disease (COPD), including emphysema (Beyond the Basics). In: UpToDate,

Post TW (Ed), UpToDate, Waltham, MA. (Accessed on August 10, 2015.)

4. Tiotropium. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at:

http://www.micromedexsolutions.com. Accessed August 10, 2015.

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5. Deng. "On Biostatistics and Clinical Trials." Using Area Under the Curve (AUC) as Clinical Endpoints. N.p., 14 Oct. 2012.

Web. Accessed August 10, 2015.

6. "Chronic Obstructive Pulmonary Disease (COPD)." WHO. N.p., Jan. 2015. Web. Accessed September 02, 2015.

7. M. Cazzola, W. MacNee, F.J. Martinez, K.F. Rabe, L.G. Franciosi, P.J. Barnes, et al., Outcomes for COPD pharmacological

trials: from lung function to biomarkers, Eur. Respir. J. 31 (2008) 416e469

8. Beeh KM, Westerman J, Kirsten AM, 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;32:53–59.

9. ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R. Efficacy and safety of combining olodaterol Respimat®and

tiotropium HandiHaler® in patients with COPD: results of two randomized, double-blind, active-controlled studies. Int J

COPD. 2014;9:1133–1144.

10. Rice KL, Kunisaki KM, Niewoehner DE. Role of tiotropium in the treatment of COPD. Int J Chron Obstruct Pulmon Dis.

2007;2:95-105.

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