Study of Fluticasone Propionate MDPI Compared With Fluticasone/Salmeterol MDPI in Adolescent and Adult Patients With Persistent Asthma

Asthma Clinical Trial

Official title:

A 12-Week, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone/Salmeterol Multidose Dry Powder Inhaler in Adolescent and Adult Patients With Persistent Asthma Symptomatic Despite Low-dose or or Mid-dose Inhaled Corticosteroid Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02139644
• Other study ID #: FSS-AS-301
• Secondary ID: 2014-001149-25
• Status: Completed
• Phase: Phase 3
• Start date: June 2014
• Est. completion date: September 2015

Study information

• Verified date: November 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study was to evaluate the efficacy of fluticasone propionate multidose dry powder inhaler (Fp MDPI) and fluticasone propionate/salmeterol xinafoate multidose dry powder inhaler (FS MDPI) when administered over 12 weeks in patients 12 years of age and older with persistent asthma.

Study drug and placebo was supplied in Teva multidose dry powder inhaler (MDPI) devices and provided for participants to use at home. Participants performed spirometry at every visit. Each participant was given a diary at each visit for use until the next visit. Rescue medication (albuterol/salbutamol) was dispensed at each visit, if needed, as determined by the investigational center personnel.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 787
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

1. Best pre-bronchodilator forced expiratory volume in 1 second (FEV1) of 40 to 85% of their predicted normal value.

2. Current Asthma Therapy: Patients must have a short-acting ß2-agonist (for rescue use) for a minimum of 8 weeks before the Screening Visit (SV) and a low-dose inhaled corticosteroid (ICS). The low-dose ICS may be either as ICS monotherapy or as an ICS/long-acting beta agonist (LABA) combination. The ICS component of the patient's asthma therapy should be stable for a minimum of 1 months before providing consent.

3. Reversibility of Disease: Patients must have at least 15% reversibility (all patients) and at least a 200 mL increase from baseline FEV1 (patients age 18 and older) within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol at the SV. Note: Patients who do not qualify for the study due to failure to meet reversibility will be permitted to perform a retest once within 7 days.

4. Patients must provide written informed consent/assent. For minor patients (ages 12 to 17 years, or as applicable per local regulations), the written ICF must be signed and dated by the parent/legal guardian and the written assent form must be signed and dated by the patient (if applicable). Note: Age requirements are as specified by local regulations.

5. Outpatient >= 12 years of age on the date of consent/assent. In countries where the local regulations permit enrollment of adult patients only, patients must be 18 years of age and older.

6. Asthma diagnosis: The patient has a diagnosis of asthma as defined by the National Institutes of Health (NIH). The asthma diagnosis has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in asthma medication) for at least 30 days.

7. The patient is able to perform acceptable and repeatable spirometry.

8. The patient is able to perform peak expiratory flow (PEF) with a handheld peak flow meter.

9. The patient is able to use a MDI device without a spacer device and a MDPI device.

10. The patient is able to withhold (as judged by the investigator) his or her regimen of ICS or study drug, and rescue medication for at least 6 hours before the SV and before all treatment visits.

11. The patient/parent/legal guardian/caregiver is capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements.

12. SABAs: All patients must be able to replace their current SABA with albuterol/salbutamol HFA MDI inhalation aerosol for the duration of the study.

13. Female patients may not be pregnant, breastfeeding, or attempting to become pregnant.

• other criteria may apply, please contact the investigator for more information

Exclusion Criteria:

1. A history of a life-threatening asthma exacerbation (an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures).

2. The patient is pregnant or lactating, or plans to become pregnant during the study period or for 30 days after the study.

3. The patient has participated as a randomized patient in any investigational drug study within 30 days of the SV.

4. The patient has previously participated as a randomized patient in a study of Fp MDPI or FS MDPI.

5. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the study drug or rescue medication formulation (ie, lactose).

6. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, azole antifungals, ritonavir, or clarithromycin) within 30 days before the SV.

7. The patient has been treated with any of the prohibited medications during the prescribed (per protocol) washout periods before the SV.

8. The patient currently smokes or has a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). The patient must not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).

9. The patient has a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the SV.

10. The patient has a history of alcohol or drug abuse within 2 years preceding the SV.

11. The patient has had an asthma exacerbation requiring systemic corticosteroids within 30 days before the SV, or has had any hospitalization for asthma within 2 months before the SV.

12. Initiation or dose escalation of immunotherapy (administered by any route) is planned during the study period. However, patients on stable immunotherapy may be considered for inclusion.

13. The patient has used immunosuppressive medications within 4 weeks before the SV.

14. The patient is unable to tolerate or unwilling to comply with the appropriate washout periods and withholding of all applicable medications.

15. The patient has untreated oral candidiasis at the SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the study.

16. The patient has a history of a positive test for human immunodeficiency virus (HIV), active hepatitis B virus, or hepatitis C infection.

17. The patient is either an employee or an immediate relative of an employee of the clinical investigational center.

18. A member of the patient's household is participating in the study at the same time. However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened.

19. The patient has a disease/condition that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study.

• other criteria may apply, please contact the investigator for more information

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• FS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) and salmeterol xinafoate (Sx) dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to either 100/12.5 mcg Fp/Sx or 50/12.5 mcg Fp/Sx in the morning and evening for a total daily dose of 200/25 mcg or 100/25 mcg Fp/Sx. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
• Fp MDPI
Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to either 100 mcg or 50 mcg of Fp one inhalation twice a day for a total daily dose of 200 mcg or 100 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
• Placebo MDPI
Placebo administered via a multidose dry powder inhaler (MDPI) one puff in the morning and one puff in the evening for 12 weeks.
• albuterol/salbutamol
A short-acting ß2-adrenergic agonists (SABA), albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
• Beclomethasone dipropionate
QVAR (beclomethasone dipropionate) 40 mcg inhalation aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI) for the duration of the Run-in Period (14-21 days) and prior to randomization. A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.

Locations

Country	Name	City	State
Canada	Teva Investigational Site 11067	Montreal	Quebec
Canada	Teva Investigational Site 11065	Toronto	Ontario
Canada	Teva Investigational Site 11068	Vancouver	Quebec
Czechia	Teva Investigational Site 54084	Neratovice
Czechia	Teva Investigational Site 54088	Praha
Czechia	Teva Investigational Site 54087	Rokycany
Hungary	Teva Investigational Site 51134	Budapest
Hungary	Teva Investigational Site 51143	Budapest
Hungary	Teva Investigational Site 51144	Budapest
Hungary	Teva Investigational Site 51140	Debrecen
Hungary	Teva Investigational Site 51142	Deszk
Hungary	Teva Investigational Site 51165	Dombovar
Hungary	Teva Investigational Site 51145	Kiskunhalas
Hungary	Teva Investigational Site 51141	Miskolc
Hungary	Teva Investigational Site 51133	Mosdós
Hungary	Teva Investigational Site 51136	Nyíregyháza
Hungary	Teva Investigational Site 51139	Nyíregyháza
Hungary	Teva Investigational Site 51163	Sopron
Hungary	Teva Investigational Site 51137	Szeged
Hungary	Teva Investigational Site 51164	Szigetvár
Hungary	Teva Investigational Site 51138	Szombathely
Poland	Teva Investigational Site 53182	Bialystok
Poland	Teva Investigational Site 53183	Bialystok
Poland	Teva Investigational Site 53185	Bialystok
Poland	Teva Investigational Site 53191	Bialystok
Poland	Teva Investigational Site 53187	Bienkówka
Poland	Teva Investigational Site 53219	Bydgoszcz
Poland	Teva Investigational Site 53217	Debica
Poland	Teva Investigational Site 53188	Krakow
Poland	Teva Investigational Site 53178	Kraków
Poland	Teva Investigational Site 53180	Kraków
Poland	Teva Investigational Site 53220	Lodz
Poland	Teva Investigational Site 53235	Lodz
Poland	Teva Investigational Site 53221	Lódz
Poland	Teva Investigational Site 53237	Lublin
Poland	Teva Investigational Site 53194	Poznan
Poland	Teva Investigational Site 53234	Poznan
Poland	Teva Investigational Site 53233	Strzelce Opolskie
Poland	Teva Investigational Site 53179	Tarnów
Poland	Teva Investigational Site 53218	Tarnów
Poland	Teva Investigational Site 53193	Warszawa
Poland	Teva Investigational Site 53181	Wroclaw
Poland	Teva Investigational Site 53189	Wroclaw
Russian Federation	Teva Investigational Site 50236	Chelyabinsk
Russian Federation	Teva Investigational Site 50226	Ekaterinburg
Russian Federation	Teva Investigational Site 50227	Kazan
Russian Federation	Teva Investigational Site 50234	Moscow
Russian Federation	Teva Investigational Site 50238	Moscow
Russian Federation	Teva Investigational Site 50230	Novosibirsk
Russian Federation	Teva Investigational Site 50231	Saint Petersburg
Russian Federation	Teva Investigational Site 50224	St. Petersburg
Russian Federation	Teva Investigational Site 50233	Voronezh
Russian Federation	Teva Investigational Site 50237	Yaroslavl
South Africa	Teva Investigational Site 90002	Cape Town
South Africa	Teva Investigational Site 90008	Cape Town
South Africa	Teva Investigational Site 90005	Centurion
South Africa	Teva Investigational Site 90001	Johannesburg
South Africa	Teva Investigational Site 90003	Middelburg
South Africa	Teva Investigational Site 90007	Pretoria
Ukraine	Teva Investigational Site 58125	Kharkiv
Ukraine	Teva Investigational Site 58126	Kharkiv
Ukraine	Teva Investigational Site 58127	Kyiv
Ukraine	Teva Investigational Site 58128	Kyiv
Ukraine	Teva Investigational Site 58129	Vinnytsya
United States	Teva Investigational Site 12399	Baltimore	Maryland
United States	Teva Investigational Site 12391	Bethesda	Maryland
United States	Teva Investigational Site 12397	Birmingham	Alabama
United States	Teva Investigational Site 12587	Brooklyn	New York
United States	Teva Investigational Site 12374	Canton	Ohio
United States	Teva Investigational Site 12379	Centennial	Colorado
United States	Teva Investigational Site 12386	Centennial	Colorado
United States	Teva Investigational Site 12480	Cincinnati	Ohio
United States	Teva Investigational Site 12492	Cincinnati	Ohio
United States	Teva Investigational Site 12493	Clearwater	Florida
United States	Teva Investigational Site 12596	Colorado Springs	Colorado
United States	Teva Investigational Site 12589	Columbia	Maryland
United States	Teva Investigational Site 12395	Cypress	California
United States	Teva Investigational Site 12990	Cypress	Texas
United States	Teva Investigational Site 12373	Dallas	Texas
United States	Teva Investigational Site 12997	Decatur	Georgia
United States	Teva Investigational Site 12377	Edmond	Oklahoma
United States	Teva Investigational Site 12402	El Paso	Texas
United States	Teva Investigational Site 12476	Encinitas	California
United States	Teva Investigational Site 12396	Fall River	Massachusetts
United States	Teva Investigational Site 12586	Fountain Valley	California
United States	Teva Investigational Site 12591	Fresno	California
United States	Teva Investigational Site 12375	Glendale	Arizona
United States	Teva Investigational Site 12389	Greenville	South Carolina
United States	Teva Investigational Site 12475	Huntersville	North Carolina
United States	Teva Investigational Site 12372	Huntington Beach	California
United States	Teva Investigational Site 12991	Knoxville	Tennessee
United States	Teva Investigational Site 12992	Largo	Florida
United States	Teva Investigational Site 12483	Lenexa	Kansas
United States	Teva Investigational Site 12584	Longmont	Colorado
United States	Teva Investigational Site 12365	Los Angeles	California
United States	Teva Investigational Site 12381	Los Angeles	California
United States	Teva Investigational Site 12401	Los Angeles	California
United States	Teva Investigational Site 12368	Medford	Oregon
United States	Teva Investigational Site 12376	Miami	Florida
United States	Teva Investigational Site 12390	Miami	Florida
United States	Teva Investigational Site 12487	Middleburg Heights	Ohio
United States	Teva Investigational Site 12378	Milwaukee	Wisconsin
United States	Teva Investigational Site 12394	Mission Viejo	California
United States	Teva Investigational Site 12594	Missoula	Montana
United States	Teva Investigational Site 12580	Mount Pleasant	South Carolina
United States	Teva Investigational Site 12478	Murray	Utah
United States	Teva Investigational Site 12582	New Braunfels	Texas
United States	Teva Investigational Site 12384	North Dartmouth	Massachusetts
United States	Teva Investigational Site 12585	North Dartmouth	Massachusetts
United States	Teva Investigational Site 12385	Ocean City	New Jersey
United States	Teva Investigational Site 12398	Orangeburg	South Carolina
United States	Teva Investigational Site 12583	Orlando	Florida
United States	Teva Investigational Site 12400	Pittsburgh	Pennsylvania
United States	Teva Investigational Site 12382	Portland	Oregon
United States	Teva Investigational Site 12364	Raleigh	North Carolina
United States	Teva Investigational Site 12490	Rancho Mirage	California
United States	Teva Investigational Site 12393	Riverside	California
United States	Teva Investigational Site 12369	Rockville	Maryland
United States	Teva Investigational Site 12485	Rockville Centre	New York
United States	Teva Investigational Site 12366	Rolling Hills Estates	California
United States	Teva Investigational Site 12494	Saint Louis	Missouri
United States	Teva Investigational Site 12595	Saint Louis	Missouri
United States	Teva Investigational Site 12363	San Antonio	Texas
United States	Teva Investigational Site 12482	San Antonio	Texas
United States	Teva Investigational Site 12383	San Diego	California
United States	Teva Investigational Site 12370	San Jose	California
United States	Teva Investigational Site 12392	Savannah	Georgia
United States	Teva Investigational Site 12592	Shiloh	Illinois
United States	Teva Investigational Site 12380	Skillman	New Jersey
United States	Teva Investigational Site 12388	South Burlington	Vermont
United States	Teva Investigational Site 12371	Stockton	California
United States	Teva Investigational Site 12488	Sylvania	Ohio
United States	Teva Investigational Site 12481	Tallahassee	Florida
United States	Teva Investigational Site 12473	Upland	Pennsylvania
United States	Teva Investigational Site 12579	Upland	California
United States	Teva Investigational Site 12477	Waco	Texas
United States	Teva Investigational Site 12484	Waterbury	Connecticut
United States	Teva Investigational Site 12590	Waterbury	Connecticut
United States	Teva Investigational Site 12491	Winter Park	Florida
United States	Teva Investigational Site 12588	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products R&D, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Czechia,  Hungary,  Poland,  Russian Federation,  South Africa,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours Postdose (FEV1 AUEC0-12h) at Week 12	A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Data from these assessments were used to analyze the primary endpoint of baseline adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement.; The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value.	Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours
Primary	Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12	Trough FEV1 was a morning spirometry taken predose and pre-rescue bronchodilator. If the patient inadvertently administered asthma medication/study drug at home on the AM of the visit, or if the patient took rescue medication within 6 hours of testing, the visit was rescheduled.; The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1).	Day 1 (predose, baseline), Week 12
Secondary	Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment	Morning PEF tests were performed before administration of study drug or rescue medications (data were excluded if the time of PEF measurement was more than 5 minutes after the dose time). The patient recorded the highest value of 3 measurements obtained in the patient diary. The baseline PEF was the average value of recorded (nonmissing) morning assessments over the 7 days prior to randomization on Day 1. For efficacy analyses of weekly average morning PEF measurements, values were the averages based on available data for that week.	Days -6 to Day 1 (predose), Day 1 (postdose) daily until Week 12
Secondary	Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period	The total daily asthma symptom score is the average of the daytime and nighttime scores as recorded in the patient diary (range 0-9).; Daytime Symptom Score: 0=No symptoms; Symptoms for 1 short period; Symptoms for 2+ short periods; Symptoms for most of the day - did not affect normal daily activities; Symptoms for most of the day - did affect normal daily activities; Symptoms so severe that I could not go to work or perform normal daily activities; Nighttime Symptom Score (determined in the AM): 0=No symptoms; Symptoms causing me to wake once (or wake early); Symptoms causing me to wake twice or more (including waking early); Symptoms causing me to be awake for most of the night; Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM).	Days -6 to Day 1 (predose, baseline) to Week 12
Secondary	Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period	Patients recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each AM and PM in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value. The weekly average was based on the available data for the 7 days before each analysis week. The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using a mixed model for repeated measures.	Days -6 to Day 1 (predose, baseline), up to week 12
Secondary	Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12	The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma, defined as the number of days elapsed from the date of randomization to the date of withdrawal due to worsening asthma. Patients who were lost to follow-up, who had not withdrawn due to worsening asthma by week 12, or who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.	up to Week 12 of the Treatment Period
Secondary	Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old	The AQLQ(S) (September 2010 version; patients aged =18 years) was self-administered by the patients at the investigational center at the randomization visit and at Week 12 or end of trial. The questionnaire is a tool to measure the impact of asthma on a patient's quality of life (physical, emotional, social, and occupational) with a recall period of 2 weeks. The AQLQ(S) was administered only to patients 18 years and older. The 32 individual questions in the AQLQ were equally weighted. The overall AQLQ score was the mean of the responses to each of the 32 questions, and ranged from 1 to 7. A score of 7.0 indicated that the patient had no impairments due to asthma and a score of 1.0 indicated severe impairment.; Positive change from baseline scores indicate improved quality of life.	Day 1 (predose, baseline), end of trial (up to week 12)
Secondary	Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1	A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Baseline FEV1 was the average of 2 FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, baseline was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment.; Values of 9999 indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.	Day 1 of the Treatment Period (predose and postdose)
Secondary	Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period	An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.	Day 1 to Week 12 of the Treatment Period