COPD
Conditions
Brief summary
The purpose of this study is to investigate the dose response of RPL554 in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE that are still symptomatic despite treatment with a stable background of tiotropium over 4 weeks of treatment. This study is intended to support optimal dose selection for a Phase III program evaluating RPL554 as an add-on treatment to standard of care therapy.
Detailed description
This is a Phase IIb, randomized, double-blind, placebo controlled, multiple dose, parallel group study to investigate the effects of 4 weeks of treatment with nebulized RPL554 (at different dose levels) compared to placebo in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE on a stable background therapy of open-label tiotropium. The study comprises seven visits: Pre-screening (Visit 0), Screening (Visit 1) and then a Treatment Period consisting of Randomization (Visit 2), and weekly visits for 4 weeks (Visit 3 to Visit 6).
Interventions
DRUGEnsifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium
Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 0.375 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.
DRUGEnsifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium
Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 0.75 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.
DRUGEnsifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium
Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 1.5 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.
DRUGEnsifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium
Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 3.0 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.
DRUGEnsifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium
Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● Placebo twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication.
Sponsors
Iqvia Pty Ltd
LGC Limited
Verona Pharma plc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Sign an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study. * Male or female aged between 40 and 80 years inclusive, at the time of informed consent. * Must agree to meet the following from the first dose up to 1 month after the last dose of study medication: * If male: * Not donate sperm * Either: be sexually abstinent in accordance with a patient's usual and preferred lifestyle (but agree to abide by the contraception requirements below should their circumstances change) * Or: use a condom with all sexual partners. If the partner is of childbearing potential the condom must be used with spermicide and a second reliable form of contraception must also be used (e.g., diaphragm/cap with spermicide, established hormonal contraception, intra-uterine device) * If female: * be of non-childbearing potential or use a highly effective form of contraception * Have a 12-lead ECG recording at Screening showing the following (and no changes in the pre-dose value at the first treatment deemed clinically significant by the Investigator): * Heart rate between 45 and 90 beats per minute * QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec for males, and ≤ 470 msec for females * QRS interval ≤ 120 msec * No clinically significant abnormality including morphology (e.g., left bundle branch block, atrio-ventricular nodal dysfunction, ST segment abnormalities consistent with ischemia) * Capable of complying with study restrictions and procedures, including ability to use the nebulizer correctly. * Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of 45 kg. * COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to Screening. * Ability to perform acceptable and reproducible spirometry. * Post-bronchodilator (four puffs of albuterol) spirometry at Screening demonstrating the following: * FEV1/ FVC ratio of ≤0.70 * FEV1 ≥30% and ≤70% of predicted normal\* \*National Health and Nutrition Examination Survey (NHANES) III (Hankinson et al, 1999) will be used as the reference for normal predicted values. * Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) and during the period between Visits 1 and 2. * A score of ≥2 on the modified Medical Research Council (mMRC) dyspnea scale at Screening. * A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening showing no clinically significant abnormalities unrelated to COPD. * Meet the concomitant medication restrictions and be expected to do so for the rest of the study. * Current and former smokers with smoking history of ≥10 pack years. * Capable of withdrawing from long acting bronchodilators (other than tiotropium) for the duration of the study, and short acting bronchodilators for 6 hours prior to dosing.
Exclusion criteria
* A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation. * COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, within 3 months of Screening or prior to the first treatment. * A history of one or more hospitalizations for COPD or pneumonia within 6 months of Screening or prior to the first treatment. * Intolerance or hypersensitivity to albuterol, tiotropium or other muscarinic receptor antagonists. * Other respiratory disorders: Patients with a current diagnosis of asthma, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung diseases, uncontrolled or unstable sleep apnea, known alpha-1 antitrypsin deficiency, core pulmonale, clinically significant pulmonary hypertension or other active pulmonary diseases. * Previous lung resection or lung reduction surgery. * Pulmonary rehabilitation, unless such treatment has been stable from 4 weeks prior to Screening and remains stable during the study. * Oral therapies for COPD (e.g. oral steroids, theophylline, and roflumilast) or antibiotics within 3 months prior to Screening, or ICS therapy within 4 weeks prior to Screening * Prior exposure to RPL554. * History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years. * Received an experimental drug within 30 days or five half-lives, whichever is longer. * Women who are pregnant or breast-feeding. * Patients with uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, hematological, urological, immunological, psychiatric, or ophthalmic diseases that the Investigator believes are clinically significant. This includes any hepatic disease or moderate to severe renal impairment. * Documented clinically significant cardiovascular disease such as: any history of arrhythmias, angina, recent (\<1 year) or suspected myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or diagnosis of hypertension within 3 months prior to Screening. * Use of non-selective oral β-blockers. * Major surgery (requiring general anesthesia) within 6 weeks prior to Screening, lack of full recovery from surgery at Screening, or planned surgery through the end of the study. * Required use of oxygen therapy, even on an occasional basis. * History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell). * Clinically significant abnormal values for laboratory safety tests (hematology, blood chemistry, viral serology or urinalysis) at Screening, as determined by the Investigator. In particular, alanine aminotransferase or aspartate aminotransferase cannot be more than twice the upper limit of normal. * Patients with conditions which are sensitive to antimuscarinic effects such as narrow angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction. * Current marijuana use (all forms). * A disclosed history or one known to the Investigator, of significant non-compliance in previous investigational studies or with prescribed medications. * Any other reason that the Investigator considers makes the patient unsuitable to participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | Baseline and Week 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Baseline and Weeks 1, 2, 3 and 4 | The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary). |
| LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Baseline, Weeks 2 and 4 | Patients completed the SGRQ-C consisting of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits. |
| LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Weeks 2 and 4 | The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. |
| LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Weeks 2 and 4 | The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, Compared with prior to the study start, how do you feel your breathing is? on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome. |
| LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
| Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Pre-dose on Day 1 and Week 2 | Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554. |
| Steady-State Plasma Concentrations of RPL554 at Week 2 | Pre-dose at Week 2 | Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554. |
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) | TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. | An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events. |
| LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Baseline and Weeks 1, 2, 3 and 4 | Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded). |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 49 study centers in the United States of America between 01 May 2019 and 15 November 2019. Overall, 416 adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) on a stable background therapy of open-label tiotropium were randomized and 413 patients received double-blind study treatment.
Pre-assignment details
Following Screening on Visit 1, eligible patients entered a 14-day run-in period, where they received tiotropium once daily. At Visit 2, patients were re-assessed for eligibility according to randomization criteria. Patients were randomized equally across 5 double-blind treatment groups (4 doses of RPL554 or placebo).
Participants by arm
| Arm | Count |
|---|---|
| RPL554 0.375 mg Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. | 83 |
| RPL554 0.75 mg Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. | 85 |
| RPL554 1.5 mg Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. | 82 |
| RPL554 3.0 mg Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. | 82 |
| Placebo Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. | 84 |
| Total | 416 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 5 | 6 | 4 | 3 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 5 | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | RPL554 0.75 mg | RPL554 1.5 mg | RPL554 3.0 mg | RPL554 0.375 mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 45 Participants | 37 Participants | 41 Participants | 39 Participants | 37 Participants | 199 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 45 Participants | 41 Participants | 44 Participants | 47 Participants | 217 Participants |
| Age, Continuous | 65.5 years STANDARD_DEVIATION 8.33 | 63.8 years STANDARD_DEVIATION 7.67 | 64.5 years STANDARD_DEVIATION 7.92 | 64.2 years STANDARD_DEVIATION 7.86 | 63.6 years STANDARD_DEVIATION 8.41 | 64.3 years STANDARD_DEVIATION 8.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 84 Participants | 81 Participants | 80 Participants | 82 Participants | 81 Participants | 408 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 9 Participants | 6 Participants | 10 Participants | 9 Participants | 41 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 78 Participants | 73 Participants | 76 Participants | 73 Participants | 75 Participants | 375 Participants |
| Sex: Female, Male Female | 48 Participants | 51 Participants | 45 Participants | 51 Participants | 44 Participants | 239 Participants |
| Sex: Female, Male Male | 37 Participants | 31 Participants | 37 Participants | 32 Participants | 40 Participants | 177 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 83 | 0 / 81 | 0 / 83 | 0 / 84 |
| other Total, other adverse events | 6 / 82 | 9 / 83 | 4 / 81 | 8 / 83 | 5 / 84 |
| serious Total, serious adverse events | 0 / 82 | 1 / 83 | 0 / 81 | 2 / 83 | 0 / 84 |
Outcome results
Primary
Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines.
Time frame: Baseline and Week 4
Population: The Full Analysis Set (FAS) included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Only patients with valid values at baseline and Week 4 are included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RPL554 0.375 mg | Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | 0.1963 liters | Standard Error 0.02639 |
| RPL554 0.75 mg | Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | 0.2100 liters | Standard Error 0.02676 |
| RPL554 1.5 mg | Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | 0.2260 liters | Standard Error 0.02647 |
| RPL554 3.0 mg | Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | 0.2431 liters | Standard Error 0.02631 |
| Placebo | Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | 0.1188 liters | Standard Error 0.02589 |
Comparison: Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo.p-value: 0.000895% CI: [0.0517, 0.1968]MMRM
Comparison: Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo.p-value: 0.00495% CI: [0.0344, 0.18]MMRM
Comparison: Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo.p-value: 0.014895% CI: [0.018, 0.1643]MMRM
Comparison: Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo.p-value: 0.036895% CI: [0.0048, 0.1501]MMRM
Secondary
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Day 1 | 0.0795 liters | Standard Error 0.01767 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Week 4 | 0.0359 liters | Standard Error 0.02455 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Day 1 | 0.0909 liters | Standard Error 0.0177 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Week 4 | 0.0630 liters | Standard Error 0.02486 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Day 1 | 0.1020 liters | Standard Error 0.0179 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Week 4 | 0.0640 liters | Standard Error 0.02451 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Week 4 | 0.0969 liters | Standard Error 0.02426 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Day 1 | 0.1374 liters | Standard Error 0.01777 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Day 1 | 0.0282 liters | Standard Error 0.01756 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Week 4 | 0.0096 liters | Standard Error 0.02413 |
Secondary
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1156 liters | Standard Error 0.02323 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Day 1 | 0.1533 liters | Standard Error 0.016 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1095 liters | Standard Error 0.02538 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1118 liters | Standard Error 0.02129 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1154 liters | Standard Error 0.02308 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1243 liters | Standard Error 0.02364 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1309 liters | Standard Error 0.02338 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1301 liters | Standard Error 0.02144 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1305 liters | Standard Error 0.02574 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Day 1 | 0.1614 liters | Standard Error 0.01602 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1433 liters | Standard Error 0.02334 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Day 1 | 0.1810 liters | Standard Error 0.0162 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1308 liters | Standard Error 0.02143 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1444 liters | Standard Error 0.02343 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1394 liters | Standard Error 0.02544 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1626 liters | Standard Error 0.0253 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Day 1 | 0.2017 liters | Standard Error 0.01609 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1385 liters | Standard Error 0.02324 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1651 liters | Standard Error 0.02321 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1526 liters | Standard Error 0.02149 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 2 | 0.0304 liters | Standard Error 0.02285 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 3 | 0.0294 liters | Standard Error 0.02297 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Day 1 | 0.0654 liters | Standard Error 0.0159 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 4 | 0.0369 liters | Standard Error 0.02488 |
| Placebo | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Week 1 | 0.0246 liters | Standard Error 0.02107 |
Secondary
LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 1 | -0.0088 liters | Standard Error 0.02038 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 2 | -0.0278 liters | Standard Error 0.02183 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 3 | -0.0385 liters | Standard Error 0.02185 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 4 | -0.0201 liters | Standard Error 0.02296 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 1 | -0.0354 liters | Standard Error 0.02058 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 4 | -0.0348 liters | Standard Error 0.02356 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 2 | -0.0696 liters | Standard Error 0.02243 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 3 | -0.0630 liters | Standard Error 0.02254 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 4 | -0.0141 liters | Standard Error 0.02311 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 2 | -0.0070 liters | Standard Error 0.02212 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 3 | -0.0413 liters | Standard Error 0.02222 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 1 | -0.0451 liters | Standard Error 0.02056 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 1 | -0.0216 liters | Standard Error 0.02081 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 2 | 0.0136 liters | Standard Error 0.0222 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 4 | 0.0054 liters | Standard Error 0.02306 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 3 | -0.0232 liters | Standard Error 0.02205 |
| Placebo | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 4 | -0.0218 liters | Standard Error 0.02256 |
| Placebo | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 3 | -0.0533 liters | Standard Error 0.02162 |
| Placebo | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 2 | -0.0377 liters | Standard Error 0.02169 |
| Placebo | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Week 1 | -0.0520 liters | Standard Error 0.02024 |
Secondary
LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3
Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Day 1 | 0.2353 liters | Standard Error 0.01926 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 1 | 0.1860 liters | Standard Error 0.02305 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 2 | 0.1963 liters | Standard Error 0.02453 |
| RPL554 0.375 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 3 | 0.1987 liters | Standard Error 0.02503 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Day 1 | 0.2426 liters | Standard Error 0.0193 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 3 | 0.2006 liters | Standard Error 0.02544 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 1 | 0.2026 liters | Standard Error 0.02322 |
| RPL554 0.75 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 2 | 0.2121 liters | Standard Error 0.02483 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 3 | 0.2277 liters | Standard Error 0.02526 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 1 | 0.2116 liters | Standard Error 0.02321 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 2 | 0.2191 liters | Standard Error 0.02481 |
| RPL554 1.5 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Day 1 | 0.2610 liters | Standard Error 0.01951 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Day 1 | 0.2852 liters | Standard Error 0.01938 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 1 | 0.2353 liters | Standard Error 0.02326 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 3 | 0.2197 liters | Standard Error 0.02505 |
| RPL554 3.0 mg | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 2 | 0.2421 liters | Standard Error 0.02466 |
| Placebo | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 3 | 0.1072 liters | Standard Error 0.02476 |
| Placebo | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 2 | 0.1098 liters | Standard Error 0.02429 |
| Placebo | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Week 1 | 0.1041 liters | Standard Error 0.02277 |
| Placebo | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Day 1 | 0.1469 liters | Standard Error 0.01914 |
Secondary
LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.2744 liters | Standard Error 0.03512 |
| RPL554 0.375 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.3463 liters | Standard Error 0.02857 |
| RPL554 0.375 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.2706 liters | Standard Error 0.03724 |
| RPL554 0.375 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.2839 liters | Standard Error 0.03281 |
| RPL554 0.375 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.2597 liters | Standard Error 0.03401 |
| RPL554 0.75 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.3177 liters | Standard Error 0.0357 |
| RPL554 0.75 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.3282 liters | Standard Error 0.03446 |
| RPL554 0.75 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.3199 liters | Standard Error 0.03302 |
| RPL554 0.75 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.3198 liters | Standard Error 0.03775 |
| RPL554 0.75 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.3775 liters | Standard Error 0.02858 |
| RPL554 1.5 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.3070 liters | Standard Error 0.0344 |
| RPL554 1.5 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.3852 liters | Standard Error 0.02892 |
| RPL554 1.5 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.3065 liters | Standard Error 0.03302 |
| RPL554 1.5 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.3176 liters | Standard Error 0.03544 |
| RPL554 1.5 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.2951 liters | Standard Error 0.03729 |
| RPL554 3.0 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.3414 liters | Standard Error 0.03707 |
| RPL554 3.0 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.4035 liters | Standard Error 0.02874 |
| RPL554 3.0 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.3008 liters | Standard Error 0.03513 |
| RPL554 3.0 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.3343 liters | Standard Error 0.03417 |
| RPL554 3.0 mg | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.3545 liters | Standard Error 0.03311 |
| Placebo | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1524 liters | Standard Error 0.03368 |
| Placebo | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1626 liters | Standard Error 0.03475 |
| Placebo | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.2241 liters | Standard Error 0.0284 |
| Placebo | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1736 liters | Standard Error 0.03647 |
| Placebo | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1717 liters | Standard Error 0.03242 |
Secondary
LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Day 1 | 0.0838 liters | Standard Error 0.02543 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Week 4 | 0.0152 liters | Standard Error 0.03486 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Day 1 | 0.1294 liters | Standard Error 0.02543 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Week 4 | 0.0838 liters | Standard Error 0.03529 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Day 1 | 0.1187 liters | Standard Error 0.02574 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Week 4 | 0.0438 liters | Standard Error 0.03478 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Week 4 | 0.0982 liters | Standard Error 0.03443 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Day 1 | 0.1514 liters | Standard Error 0.02558 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Day 1 | 0.0344 liters | Standard Error 0.02527 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Week 4 | -0.0030 liters | Standard Error 0.03425 |
Secondary
LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1431 liters | Standard Error 0.03318 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.2165 liters | Standard Error 0.0239 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1350 liters | Standard Error 0.03606 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1460 liters | Standard Error 0.03045 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1362 liters | Standard Error 0.03261 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1860 liters | Standard Error 0.03372 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.2010 liters | Standard Error 0.03302 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1890 liters | Standard Error 0.03065 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1928 liters | Standard Error 0.03654 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.2397 liters | Standard Error 0.0239 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.1783 liters | Standard Error 0.03296 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.2519 liters | Standard Error 0.02419 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.1691 liters | Standard Error 0.03064 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1798 liters | Standard Error 0.03346 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.1623 liters | Standard Error 0.0361 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.2134 liters | Standard Error 0.03594 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.2715 liters | Standard Error 0.02404 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.1739 liters | Standard Error 0.03321 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.2104 liters | Standard Error 0.03279 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.2039 liters | Standard Error 0.03074 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 2 | 0.0217 liters | Standard Error 0.03228 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 3 | 0.0252 liters | Standard Error 0.03281 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Day 1 | 0.0864 liters | Standard Error 0.02375 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 4 | 0.0382 liters | Standard Error 0.03533 |
| Placebo | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Week 1 | 0.0323 liters | Standard Error 0.03014 |
Secondary
LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4
Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.
Time frame: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 1 | -0.0159 liters | Standard Error 0.03028 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 2 | -0.0647 liters | Standard Error 0.0319 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 3 | -0.0966 liters | Standard Error 0.03354 |
| RPL554 0.375 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 4 | -0.0390 liters | Standard Error 0.03323 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 1 | -0.0650 liters | Standard Error 0.03053 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 4 | -0.0347 liters | Standard Error 0.03408 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 2 | -0.0744 liters | Standard Error 0.03275 |
| RPL554 0.75 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 3 | -0.0936 liters | Standard Error 0.03456 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 4 | -0.0570 liters | Standard Error 0.03344 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 2 | -0.0458 liters | Standard Error 0.03231 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 3 | -0.0857 liters | Standard Error 0.0341 |
| RPL554 1.5 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 1 | -0.0887 liters | Standard Error 0.03053 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 1 | -0.0624 liters | Standard Error 0.03092 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 2 | -0.0045 liters | Standard Error 0.03245 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 4 | -0.0217 liters | Standard Error 0.03336 |
| RPL554 3.0 mg | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 3 | -0.0690 liters | Standard Error 0.03383 |
| Placebo | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 4 | -0.0198 liters | Standard Error 0.03264 |
| Placebo | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 3 | -0.0969 liters | Standard Error 0.03318 |
| Placebo | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 2 | -0.0614 liters | Standard Error 0.0317 |
| Placebo | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Week 1 | -0.0617 liters | Standard Error 0.03008 |
Secondary
LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4
Patients completed the SGRQ-C consisting of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits.
Time frame: Baseline, Weeks 2 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 2 | -1.808 units on a scale | Standard Error 1.196 |
| RPL554 0.375 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 4 | -4.387 units on a scale | Standard Error 1.3087 |
| RPL554 0.75 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 2 | -1.132 units on a scale | Standard Error 1.2583 |
| RPL554 0.75 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 4 | -2.400 units on a scale | Standard Error 1.3732 |
| RPL554 1.5 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 2 | -3.465 units on a scale | Standard Error 1.2311 |
| RPL554 1.5 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 4 | -4.870 units on a scale | Standard Error 1.348 |
| RPL554 3.0 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 4 | -4.163 units on a scale | Standard Error 1.3479 |
| RPL554 3.0 mg | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 2 | -3.618 units on a scale | Standard Error 1.2491 |
| Placebo | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 2 | -0.249 units on a scale | Standard Error 1.2277 |
| Placebo | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Week 4 | -0.116 units on a scale | Standard Error 1.3195 |
Secondary
LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4
The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary).
Time frame: Baseline and Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 1 | -0.978 units on a scale | Standard Error 0.3375 |
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 2 | -0.873 units on a scale | Standard Error 0.3916 |
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 3 | -0.950 units on a scale | Standard Error 0.383 |
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 4 | -1.690 units on a scale | Standard Error 0.4337 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 1 | -0.669 units on a scale | Standard Error 0.3375 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 4 | -0.593 units on a scale | Standard Error 0.4412 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 2 | -0.471 units on a scale | Standard Error 0.3932 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 3 | -0.338 units on a scale | Standard Error 0.3865 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 4 | -1.226 units on a scale | Standard Error 0.4346 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 2 | -0.597 units on a scale | Standard Error 0.3921 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 3 | -1.091 units on a scale | Standard Error 0.3843 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 1 | -0.617 units on a scale | Standard Error 0.3403 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 1 | -1.142 units on a scale | Standard Error 0.3405 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 2 | -0.598 units on a scale | Standard Error 0.3952 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 4 | -1.071 units on a scale | Standard Error 0.4357 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 3 | -1.097 units on a scale | Standard Error 0.3827 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 4 | -0.228 units on a scale | Standard Error 0.432 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 3 | -0.287 units on a scale | Standard Error 0.3832 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 2 | -0.102 units on a scale | Standard Error 0.3908 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | Week 1 | -0.319 units on a scale | Standard Error 0.3397 |
Secondary
LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication
Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded).
Time frame: Baseline and Weeks 1, 2, 3 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 1 | -0.510 number of rescue medication puffs | Standard Error 0.1384 |
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 2 | -0.325 number of rescue medication puffs | Standard Error 0.1822 |
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 3 | -0.302 number of rescue medication puffs | Standard Error 0.1726 |
| RPL554 0.375 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 4 | -0.412 number of rescue medication puffs | Standard Error 0.1753 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 1 | -0.580 number of rescue medication puffs | Standard Error 0.1407 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 4 | -0.510 number of rescue medication puffs | Standard Error 0.1799 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 2 | -0.360 number of rescue medication puffs | Standard Error 0.1847 |
| RPL554 0.75 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 3 | -0.139 number of rescue medication puffs | Standard Error 0.1765 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 4 | -0.784 number of rescue medication puffs | Standard Error 0.1766 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 2 | -0.388 number of rescue medication puffs | Standard Error 0.1828 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 3 | -0.647 number of rescue medication puffs | Standard Error 0.1736 |
| RPL554 1.5 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 1 | -0.539 number of rescue medication puffs | Standard Error 0.1395 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 1 | -0.629 number of rescue medication puffs | Standard Error 0.1412 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 2 | -0.379 number of rescue medication puffs | Standard Error 0.185 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 4 | -0.506 number of rescue medication puffs | Standard Error 0.1777 |
| RPL554 3.0 mg | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 3 | -0.558 number of rescue medication puffs | Standard Error 0.1742 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 4 | -0.671 number of rescue medication puffs | Standard Error 0.1741 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 3 | -0.504 number of rescue medication puffs | Standard Error 0.1724 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 2 | -0.544 number of rescue medication puffs | Standard Error 0.1812 |
| Placebo | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Week 1 | -0.556 number of rescue medication puffs | Standard Error 0.1386 |
Secondary
LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4
The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, Compared with prior to the study start, how do you feel your breathing is? on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome.
Time frame: Weeks 2 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 3.512 units on a scale | Standard Error 0.0867 |
| RPL554 0.375 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 3.553 units on a scale | Standard Error 0.0922 |
| RPL554 0.75 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 3.522 units on a scale | Standard Error 0.0895 |
| RPL554 0.75 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 3.543 units on a scale | Standard Error 0.0944 |
| RPL554 1.5 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 3.456 units on a scale | Standard Error 0.0876 |
| RPL554 1.5 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 3.536 units on a scale | Standard Error 0.0932 |
| RPL554 3.0 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 3.577 units on a scale | Standard Error 0.0922 |
| RPL554 3.0 mg | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 3.523 units on a scale | Standard Error 0.0889 |
| Placebo | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 3.427 units on a scale | Standard Error 0.0876 |
| Placebo | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 3.506 units on a scale | Standard Error 0.0909 |
Secondary
LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4
The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome.
Time frame: Weeks 2 and 4
Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 1.682 units on a scale | Standard Error 0.3183 |
| RPL554 0.375 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 2.089 units on a scale | Standard Error 0.3423 |
| RPL554 0.75 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 1.285 units on a scale | Standard Error 0.3263 |
| RPL554 0.75 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 1.484 units on a scale | Standard Error 0.3496 |
| RPL554 1.5 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 1.582 units on a scale | Standard Error 0.3229 |
| RPL554 1.5 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 2.055 units on a scale | Standard Error 0.3475 |
| RPL554 3.0 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 2.063 units on a scale | Standard Error 0.3437 |
| RPL554 3.0 mg | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 1.589 units on a scale | Standard Error 0.3255 |
| Placebo | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 2 | 1.421 units on a scale | Standard Error 0.3202 |
| Placebo | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | Week 4 | 1.766 units on a scale | Standard Error 0.3381 |
Secondary
Number of Patients With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events.
Time frame: TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks.
Population: The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious drug-related TEAE | 0 Participants |
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 Participants |
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to drug discontinuation | 2 Participants |
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 12 Participants |
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE leading drug discontinuation | 0 Participants |
| RPL554 0.375 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any drug-related TEAE | 1 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any drug-related TEAE | 3 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE leading drug discontinuation | 1 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 1 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 15 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious drug-related TEAE | 0 Participants |
| RPL554 0.75 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to drug discontinuation | 3 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 14 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to drug discontinuation | 0 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any drug-related TEAE | 2 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious drug-related TEAE | 0 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE leading drug discontinuation | 0 Participants |
| RPL554 1.5 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any drug-related TEAE | 2 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious drug-related TEAE | 0 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to drug discontinuation | 0 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE leading drug discontinuation | 0 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 18 Participants |
| RPL554 3.0 mg | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 2 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any drug-related TEAE | 4 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE leading drug discontinuation | 0 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious drug-related TEAE | 0 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to drug discontinuation | 1 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 17 Participants |
| Placebo | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | Any serious TEAE | 0 Participants |
Secondary
Steady-State Plasma Concentrations of RPL554 at Week 2
Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554.
Time frame: Pre-dose at Week 2
Population: The PK analysis set included all randomized patients who had blood sampling performed and quantitative values of study treatment concentrations determined. Patients were classified according to actual treatment received for PK analysis set. Number of patients with values available at the specific visit were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RPL554 0.375 mg | Steady-State Plasma Concentrations of RPL554 at Week 2 | 37.3 pg/mL | Standard Deviation 58.84 |
| RPL554 0.75 mg | Steady-State Plasma Concentrations of RPL554 at Week 2 | 53.7 pg/mL | Standard Deviation 51.71 |
| RPL554 1.5 mg | Steady-State Plasma Concentrations of RPL554 at Week 2 | 107.9 pg/mL | Standard Deviation 92.98 |
| RPL554 3.0 mg | Steady-State Plasma Concentrations of RPL554 at Week 2 | 170.6 pg/mL | Standard Deviation 154.3 |
| Placebo | Steady-State Plasma Concentrations of RPL554 at Week 2 | NA pg/mL | — |
Secondary
Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2
Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554.
Time frame: Pre-dose on Day 1 and Week 2
Population: The Pharmacokinetic (PK) analysis set included all randomized patients who had blood sampling performed and quantitative values of study treatment concentrations determined. Patients were classified according to actual treatment received for PK analysis set. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Number of patients with values available at the specific visit were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RPL554 0.375 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Day 1 | 2.8 picogram per milliliter (pg/mL) | Standard Deviation 1.18 |
| RPL554 0.375 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Week 2 | 2.2 picogram per milliliter (pg/mL) | Standard Deviation 3.85 |
| RPL554 0.75 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Day 1 | 2.1 picogram per milliliter (pg/mL) | Standard Deviation 2.98 |
| RPL554 0.75 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Week 2 | 2.3 picogram per milliliter (pg/mL) | Standard Deviation 3.56 |
| RPL554 1.5 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Day 1 | 1.9 picogram per milliliter (pg/mL) | Standard Deviation 1.4 |
| RPL554 1.5 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Week 2 | 1.9 picogram per milliliter (pg/mL) | Standard Deviation 1.58 |
| RPL554 3.0 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Week 2 | 2.0 picogram per milliliter (pg/mL) | Standard Deviation 2.22 |
| RPL554 3.0 mg | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Day 1 | 2.4 picogram per milliliter (pg/mL) | Standard Deviation 3.56 |
| Placebo | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Day 1 | 2.4 picogram per milliliter (pg/mL) | Standard Deviation 3.06 |
| Placebo | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Week 2 | 2.2 picogram per milliliter (pg/mL) | Standard Deviation 2.13 |