The VESUTO® study is a randomized, double-blind, active-controlled, 2-way crossover clinical study to assess the efficacy of once-daily administration of orally inhaled tiotropium/olodaterol FDC or tiotropium monotherapy on pulmonary function (lung hyperinflation), exercise capacity [6-min walk test (6MWT)], and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD (NCT02629965). Patient follow-up in the study includes Visit 0 (informed consent), Visit 1 (screening), Visit 2 (randomization), Visit 3 to Visit 4 (assessment after crossover with 6-week treatment period), and Visit 5 (follow-up) (Fig. 1). This study protocol was finalized on October 30, 2015 as version 1.0. The study began in February 2016 in Japan.
The study will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki in accordance with the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), relevant Boehringer Ingelheim Standard Operating Procedures, and the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997). The study was initiated only after all required legal documentation had been reviewed and approved by the respective Institutional Review Board and competent authority according to regulations in Japan. The detailed information of each Institutional Review Board is included in Supplementary Table S1. For inclusion, all patients must sign a written informed consent prior to participation in the study, which includes medication washout and restrictions. Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the responsibility of the treating physician of the patient. Study data will be collected, analyzed, and published without personal identifiable information. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist is provided in Supplementary Table S2.
Study Population and Setting
Men or women outpatients, aged ≥40 years with a diagnosis of COPD and stable airway obstruction, will be invited to participate in the study. Patients will be required to perform the 6MWT on several occasions during the study. Patients with any contraindication to exercise as stipulated in the European Respiratory Society (ERS) guidelines , and supported by the American Thoracic Society (ATS)/American College of Chest Physician guidelines will be excluded from participation . The VESUTO® study has been planned to be conducted mainly at respiratory medicine centers of general clinics and hospitals located in major cities in Japan.
Inclusion and Exclusion Criteria
Patients will be required to have a diagnosis of COPD and stable airway obstruction with post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%, post-bronchodilator FEV1 <80% of predicted normal, and GOLD grade 2–4 at Visit 1. Patients must be current or ex-smokers with a smoking history of >10 pack-years. Patients must also have a score of ≥1 on the modified Medical Research Council (mMRC) scale, 6MWD <400 m, and have a breathing discomfort on the modified Borg scale ≥4 measured just after the 6MWT at Visit 2. The criterion of the 6MWD <400 m is referred to in studies that evaluated the combination therapy of tiotropium and formoterol compared to tiotropium  and the ECLIPSE study which considered the relation of 6MWD with survival rate .
Main exclusion criteria are presence of a significant disease other than COPD; clinically relevant abnormal baseline hematology, blood chemistry, urinalysis, or creatinine more than twice the upper limit of normal; and current documented diagnosis of asthma. The main exclusion criteria are listed in Table 1.
A patient may be withdrawn from the study before completion if the patient withdraws consent or is no longer able to participate due to medical reasons [e.g., pregnancy, surgery, adverse events (AEs), or other diseases requiring discontinuation], or contraindications for exercise testing have occurred. Patients may also be withdrawn for administrative reasons (continuous protocol violations or persistent non-compliance of treatment administration).
Eligible patients who consent to participate in the study will be randomized in a 1:1 ratio to two sequential groups at Visit 2 and will receive one of two treatments: tiotropium/olodaterol FDC 5/5 μg inhalation solution (2.5/2.5 μg per actuation) or tiotropium 5 μg inhalation solution (2.5 μg per actuation). These medications will be provided by Nippon Boehringer Ingelheim (Tokyo, Japan) and will be administered using the RESPIMAT® inhaler (Boehringer Ingelheim). The 6-week crossover treatment period does not include any washout period.
Patients will be advised to self-administer the study medication at the hospital (study site) approximately at the same time at each clinic visit (Visit 2 ± 30 min and between 7:00 am and 10:00 am). Throughout the study, patients will self-administer the study medication at home, in the morning, in a seated position. Detailed written instructions and training for the use of the RESPIMAT® inhaler will be given to the patient at Visit 1 and repeated at Visits 2 and 3. The investigator or qualified study personnel will observe the inhalation procedure and will reinforce a correct inhalation technique. Salbutamol is permitted as rescue medication throughout the study.
Patients will complete a patient diary confirming that study medication was taken and record both the weather conditions and the number (puffs) of rescue medication use. The study medication compliance will be emphasized to be within 80–120% compliance rate.
For performing pulmonary function tests (PFTs), unified spirometers (Flowscreen; eResearch Technology GmbH; Estenfeld, Germany) will be provided by Boehringer Ingelheim at all investigational sites throughout the study. Spirometers and their use, including daily calibration, must meet ATS/ERS criteria . The 6MWT will be performed according to the methodology described by ATS guidelines , and investigators and delegated qualified personnel are required to be trained for the 6MWT procedure before recruiting patients in order to control the variability of measurement by unifying the conduct of the procedure at each center.
At Visit 1, patients will be trained on the 6MWT before the PFT is performed. At Visit 2, the 6MWT for confirming eligibility and baseline measurement will be performed before administration of the first study medication. The 6MWT will be performed at the hospital at Visit 3 and Visit 4, starting 90 min (allowance +15 min) after administration of the study medication. During the 6MWT, oxygen saturation and heart rate will be monitored using a mobile pulse oximeter. Just after the end of the 6MWT, the intensity of breathing discomfort and leg discomfort will be assessed using a modified Borg Scale.
A physical activity monitor (HJA-750C; OMRON, Kyoto, Japan) will be used for assessment of physical activity. This is a 3-axis accelerometer that is used to measure the overall movement of a patient. Patients will wear the physical activity monitor every day for 2 weeks each prior to Visit 2 for baseline assessment, and prior to Visit 3 and Visit 4 for assessment of 6-week treatment. Patients will wear the physical activity monitor all day, except during bathing or water sport activities. Investigators will request patients to avoid extreme activities (e.g., extreme exercise) which are not a part of their normal daily routine in order to facilitate proper functioning of the equipment.
Rationale for Comparator, Dose, and Duration of the Treatments
Tiotropium/olodaterol is the FDC of tiotropium plus olodaterol, and we would like to know the additional effect to tiotropium, so we selected tiotropium monotherapy as comparator. The doses of both tiotropium/olodaterol FDC (5/5 µg) and tiotropium monotherapy (5 µg) were assessed in previous studies [10,11,12,13, 15, 16], and those doses were approved worldwide including Japan. The 6-week treatment period is the same period used in the previous studies assessing IC.
The primary endpoint is IC at rest, measured 60 min post-dose, and after 6-week treatment using FlowScreen from ERT®. The secondary endpoints include 6MWD (90 min post-dose), FVC (30 min post-dose), slow vital capacity (SVC) (60 min post-dose), and physical activity [average number of steps per day (steps/day); average daily duration (min) of ≥4 metabolic equivalents (METs); average daily duration (min) of ≥3 METs; average daily duration (min) of ≥2 METs; and average daily active strength (METs min) of ≥3 METs] after 6 weeks treatment.
Other efficacy endpoints are described in Table 2. Safety assessments will include heart rate, blood pressure, and oxygen saturation in conjunction during the 6MWT, and AEs will be monitored throughout the study.
Data which are planned to be collected at each visit are shown in Table 3.
Randomization and Blinding
Interactive Response Technology (IRT) will be used for randomization (ratio 1:1) to a treatment sequential group and for assignment of appropriate medications to eligible patients at Visit 2. Randomization will not be stratified. The IRT-assigned medication number, determined by a computer-generated random sequence, and the corresponding medication kit will be given to patients at Visit 2. Patients, investigators, and everyone involved in study conduct or analysis or with any other interest will remain blinded using this procedure.
The randomized set will comprise all randomized patients, and the treated set (TS) will comprise patients who are documented to have taken any dose of study medication. The full analysis set (FAS), which will be used for primary endpoint analysis, will include TS patients with complete data at baseline Visit 2 and complete post-dose measurements of IC at rest. Assignment to the FAS will be done after implementation of any data handling rules, which set measurements to “missing”.
The per-protocol set (PPS) will contain a subset of patients for whom serious protocol deviations have not been identified. This subset will be defined under blinded review based on the magnitude and potential impact of any serious protocol violations.
Sample Size Calculation
For the primary endpoint, the difference in IC at rest after 6 weeks treatment between the two treatment groups is estimated to be 0.1 L. To detect a difference of 0.1 L with the standard deviation of 0.41 L (based on the previously conducted replicate studies ) in the IC at rest between the two treatments with 90% power at the 2-sided alpha of 0.05, 180 patients will be required. nQuery Advisor® + nTerim v.2.0 (MOT0-1, 1-sample t test) was used for the sample size calculation.
Primary and Secondary Endpoint Analyses
A mixed-effects model repeated measures (MMRM; SAS procedure MIXED) approach with treatment and period as categorical fixed effects, study baseline (Visit 2) as a covariate, and patient as a random effect will be used for primary endpoint analysis (IC at rest, measured at 60 min post-dose after 6 weeks treatment). Adjusted mean values, as well as treatment contrasts, will be presented with the 95% confidence intervals and values. If the number of patients in the PPS is <90% of the number of patients in the FAS, the primary analysis will also be performed on the PPS. These will be supportive analyses to assess the robustness of the primary analysis using the FAS. All secondary and further endpoints will be analyzed using a similar MMRM model. Descriptive statistics will be provided for each of the two treatment groups. Additionally, the analysis that the data generated during rainy weather is excluded will be performed as the sensitivity analysis to assess the impact of climate on the activity monitor .
Safety analyses will be conducted using the TS and will be mostly descriptive in nature. No hypothesis testing is planned prospectively. AEs will be coded using the Medical Dictionary for Regulatory Activities. The number of patients with AEs during the treatment period will be summarized, and the incidence will be compared across the treatment groups. Frequency, severity, seriousness, and causal relationship of AEs will be tabulated by system organ class and preferred term.
Data Acquisition and Handling of Missing Data
Data will be collected and captured through an electronic case report form. Missing data due to worsening of COPD symptoms leading to discontinuation of study medication will be imputed by the baseline data. In other cases, missing data will not be imputed.