A Study of the Effectiveness and Safety of Different Doses of Fluticasone Propionate Taken From a Dry Powder Inhaler (Puffer) in Adolescents and Adults Who Have Asthma That is Not Controlled by High Dose Inhaled Corticosteroid Asthma Medications

Phase 2

Completed

Conditions: Asthma

Interventions: Drug: Fp MDPI
Other: Placebo MDPI
Drug: Flovent Diskus
Drug: albuterol/salbutamol

Registration Number: NCT01576718

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

Brief Summary: The primary objective of this study is to evaluate the dose response, efficacy and safety of 4 different doses of fluticasone propionate (50, 100, 200, and 400mcg) delivered as Fluticasone Spiromax® Inhalation Powder (Fp Spiromax) when administered twice daily in subjects 12 years of age and older with severe persistent asthma who are uncontrolled on high dose ICS therapy.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 889

Inclusion Criteria

Written informed consent/assent signed and dated by the subject and/or parent /legal guardian before conducting any study related procedure.
Male or female 12 years and older, as of the Screening Visit. Male or female 18 years and older, as of the Screening Visit, in countries where local regulations or the regulatory status of study medication permit enrollment of adults only.
General good health, and free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the subject at increased risk during the study.
Asthma Diagnosis: Asthma as defined by the National Institutes of Health (NIH).
Severity of Disease:

• A best forced expiratory volume in one second (FEV1) of 40%-85% of the predicted normal value during the Screening Visit. NHANES III predicted values will be used for subjects aged ≥12 years and adjustments to predicted values will be made for African American subjects. ATS/ERS 2005 criteria for acceptability, reproducibility, and end of test must be met for spirometry
Reversibility of Disease: Demonstrated a ≥12% reversibility of FEV1 within 30 minutes following 2 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers are permitted for reversibility testing only) at the Screening Visit. If a subject fails to demonstrate an increase in FEV1 ≥12% then the subject is not eligible for the study and will not be allowed to re-screen. Reversibility values of 11.50 - 11.99 will be rounded to 12. Documented historical reversibility of ≥ 12 % within 3 months of the Screening Visit will be accepted.
Current Asthma Therapy: Subjects will be required to be on a short acting β2 agonist and inhaled corticosteroid for a minimum of 8 weeks before the Screening Visit and have been maintained on a stable dose of inhaled corticosteroids for four weeks prior to the Screening Visit at one of the following doses:
- Fluticasone propionate HFA MDI ≥ 880 mcg/day
- Fluticasone propionate DPI≥ 1000 mcg/day
- Beclomethasone dipropionate DPI ≥ 2000 mcg/day
- Beclomethasone dipropionate HFA (QVAR)≥ 640 mcg/day
- Beclomethasone dipropionate HFA (Clenil Modulite)≥ 2000 mcg/day
- Budesonide DPI ≥ 1600 mcg/day
- Budesonide MDI ≥ 1600 mcg/day
- Flunisolide ≥ 2000 mcg/day
- Triamcinolone acetonide ≥ 2000 mcg /day
- Mometasone furoate DPI ≥ 880 mcg/day
- Ciclesonide HFA MDI ≥ 640 mcg/day
Exception 1: Based upon the investigator's judgment that there is no inherent harm in changing the subject's current ICS/LABA therapy and the subject provides consent, subjects on inhaled Fluticasone propionate/salmeterol DPI ≥ 1000 mcg/day, or Fluticasone propionate/salmeterol HFA ≥ 880 mcg/day, or Fluticasone propionate/Formoterol ≥ 1000 mcg/day,or Beclomethasone dipropionate/Formoterol ≥ 400 mcg/day, or Budesonide/formoterol HFA ≥ 640 mcg/day, or Budesonide/formoterol DPI ≥ 800 mcg/day, or Mometasone furoate/formoterol MDI ≥ 800 mcg/day or subjects on a qualifying ICS dose plus a long-acting β2-agonists (LABA) administered via separate inhalers, may be switched to a qualifying dose of fluticasone propionate provided the subjects will not participate in the PK portion of the study.

Exception 2: Subjects on a qualifying dose of fluticasone propionate who wish to participate in the PK portion of the study and who provide consent may have their fluticasone propionate switched to a different qualifying ICS (non-fluticasone propionate) at a pre-screening visit. The subject will be required to return to the clinic to complete the Screening Visit following a 1-week washout period.
Short-Acting β2-Agonists: All subjects must be able to replace their current short-acting β2-agonists with albuterol/salbutamol inhalation aerosol at the Screening Visit for use as needed for the duration of the study. The use of spacer devices with the metered dose inhaler (MDI) will not be allowed during the study with exception of it's use during reversibility testing at the Screening Visit. Nebulized albuterol/salbutamol will not be allowed at any time during the study. Subjects must be able to withhold all inhaled short-acting β2 sympathomimetic bronchodilators for at least 6 hours prior to all study visits.
If female, is currently not pregnant, breast feeding, or attempting to become pregnant, has a negative serum pregnancy test, and is of
- Non-childbearing potential, defined as:
  - Before menarche, or
  - 1 year post-menopausal, or
  - Surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy), or
  - Congenital sterility, or
  - Diagnosed as infertile and not undergoing treatment to reverse infertility or is of
- Child-bearing potential, willing to commit to using a consistent and acceptable method of birth control as defined below for the duration of the study:
  - Systemic contraception used for 1 month prior to screening, including birth control pills, transdermal patch (Ortho Evra®), vaginal ring (NuvaRing®), levonorgesterel (Norplant®), or injectable progesterone (Depo-Provera®), or
  - Double barrier methods (condoms, cervical cap, diaphragm, and vaginal contraceptive film with spermicide), or
  - Intrauterine device (IUD) or
  - Monogamous with a vasectomized male partner or is of
- Child-bearing potential and not sexually active, willing to commit to using a consistent and acceptable method of birth control as defined above for the duration of the study, in the event the subject becomes sexually active
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 (visits, record-keeping, etc).

Exclusion Criteria

History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures.
Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 2 weeks of the Screening Visit. In addition, the subject must be excluded if such infection occurs between the Screening Visit and the Randomization Visit.
Any asthma exacerbation requiring oral corticosteroids within 1 month of the Screening Visit. A subject must not have had any hospitalization for asthma within 2 month prior to the Screening Visit.

Note: An exacerbation of asthma is defined as any worsening of asthma requiring any treatment other than rescue albuterol/salbutamol HFA MDI and/or the subject's regular inhaled corticosteroid maintenance treatment. This includes requiring the use of systemic corticosteroids and/or emergency room visit or hospitalization, a change in the subject's regular inhaled corticosteroid maintenance treatment, or the addition of other asthma medications.
Presence of glaucoma, cataracts, ocular herpes simplex, or malignancy other than basal cell carcinoma.
Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular (e.g., congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary heart disease), hepatic, renal, hematological, neuropsychological, endocrine (e.g., uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison's disease, Cushing's syndrome), gastrointestinal (e.g., poorly-controlled peptic ulcer, GERD), or pulmonary (e.g., chronic bronchitis, emphysema, bronchiectasis with the need for treatment, cystic fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which could affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
Have any of the following conditions that, in the judgment of the investigator, might cause participation in this study to be detrimental to the subject, including, but not limited to:
- Current malignancy excluding basal cell carcinoma; History of malignancy is acceptable only if the subject has been in remission for one year prior to the Screening Visit. (Remission is defined as no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to the Screening Visit)
- Current or untreated tuberculosis; History of tuberculosis is acceptable only if a subject has received an approved prophylactic treatment regimen or an approved active treatment regimen and has had no evidence of active disease for a minimum of 2 years
- Uncontrolled hypertension (systolic BP ≥160 or diastolic BP >100)
- Stroke within 3 months prior to the Screening Visit
- Immunologic compromise
History of a positive test for HIV, hepatitis B or hepatitis C infection.
Untreated oral candidiasis at the Screening Visit. Subjects with clinical visual evidence of oral candidiasis and who agree to receive treatment and comply with appropriate medical monitoring may enter the study
History of any adverse reaction to any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the dry powder inhalers (Spiromax or Diskus) used in the study (i.e., lactose).
History of severe allergy to milk protein.
Use of systemic, oral or depot corticosteroids within 4 weeks prior to the Screening Visit
- Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological disease is permitted
- Use of intranasal corticosteroids or ocular corticosteroids at a stable dose for at least 4 weeks prior to the Screening Visit and throughout the study is permitted
Use of immunosuppressive medications within 4 weeks prior to the Screening Visit and during the study.
Immunotherapy for the treatment of allergy at a stable maintenance dose for at least 90 days prior to the Screening Visit and which will remain at a stable dose without escalation throughout the study is permitted.
Use of Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, ketoconazole, itraconazole) within 4 weeks prior to the Screening Visit. Strong and moderate CYP3A4 inhibitors are prohibited and weak CYP3A4 are allowed.
History of alcohol or drug abuse within two years preceding the Screening Visit.
Current smoker or a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). A subject may not have used tobacco products within the past one year (e.g., cigarettes, cigars, chewing tobacco, or pipe tobacco).
Study participation by clinical investigator site employees and/or their immediate relatives.
Study participation by more than one subject from the same household at the same time. However, after the study completion or discontinuation by one subject another subject from the same household may be screened.
Participation in any investigational drug study within the 30 days (starting at the final follow-up visit) preceding the Screening Visit or planned participation in another investigational drug study at any time during this study.
Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for in vitro fertilization during the study period or for 30 days following the subject's last study related visit (for eligible subjects only - if applicable). Eligible female subjects unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fp MDPI 200 mcg	albuterol/salbutamol	Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 50 mcg	albuterol/salbutamol	Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 200 mcg	Fp MDPI	Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 50 mcg	Fp MDPI	Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 100 mcg	Fp MDPI	Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 100 mcg	albuterol/salbutamol	Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 400 mcg	Fp MDPI	Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Fp MDPI 400 mcg	albuterol/salbutamol	Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Placebo MDPI	Placebo MDPI	Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Placebo MDPI	albuterol/salbutamol	Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Flovent Diskus 250mcg	Flovent Diskus	Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
Flovent Diskus 250mcg	albuterol/salbutamol	Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

Primary Outcome Measures

Name	Time	Method
Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period	Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12	Trough FEV1 was measured electronically by spirometry at morning (AM) investigational site visits, before administration of the AM dose of study drug, and before albuterol/salbutamol administration. The highest FEV1 value from 3 acceptable and 2 reproducible maneuvers was used. All FEV1 data were submitted to a central reading center for evaluation. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period	Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12	Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Maximum Observed Plasma Concentration (Cmax)	Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Time Of Maximum Observed Plasma Concentration (Tmax)	Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12	Day 1 to Week 12	The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma. Worsening asthma was defined as: 1. clinic visit FEV1 below the FEV1 stability limit value calculated on Day 1. 2. any 7-day run-in or treatment window (using information from the patient diary) during which the subject experienced: * 3 or more days in which the highest PEF has fallen below the PEF stability limit calculated on Day 1 * 3 or more days in which ≥12 inhalations/day of albuterol/salbutamol was used * 2 or more days in which the subject experienced a nighttime asthma symptom score of \>2 3. clinical asthma exacerbation, defined as worsening asthma requiring any treatment other than study drug or rescue albuterol/salbutamol including the use of systemic corticosteroids and/or ER visit or hospitalization. Patients who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.
Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t)	Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods	Baseline (Day -6 to Day 1 predose), Treatment (Day 1 to Week 12)	The change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model, with the response being the proportion of rescue-free 24-hour periods. The model included 2 time points of measurement for each subject: the baseline (the last 7 days before the treatment period) and the treatment period. The model contained covariates for sex, age, and treatment. Rescue-free days were as indicated in patient diaries. Data values are estimated means.
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period	Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12	Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (non-missing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period	Day 1 to Week 12	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.
24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint	Baseline (Day 1), Week 12, Endpoint	24-hour urinary cortisol excretion was determined from 24-hour pooled-urine samples; urine was refrigerated until return to the investigational site after each 24-hour collection period. Urine was collected within 7 days of Day 1 and within 7 days of Week 12. Urine cortisol sample collection was not required at endpoint visit for subjects who terminated early from the study.
Patients With Positive Swab Test Results for Oral Candidiasis	Screening (Days -21 to -14), Randomization (Day 1), Weeks 1, 2, 3, 4, 6, 8, 10, 12	Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at each visit. Any visual evidence of oral candidiasis during the oropharyngeal exam was evaluated by obtaining and analyzing a swab of the suspect area. This outcomes indicates how many patients had positive swab test results. The total number of patients who had oropharyngeal exams at each timepoint are specified in the timepoint field. Appropriate therapy was to be initiated immediately at the discretion of the investigator and was not to be delayed for culture confirmation. Subjects with a culture-positive infection could continue participation in the study on appropriate anti-infective therapy, provided this therapy was not prohibited by the protocol.

Trial Locations

Locations (300): Teva Investigational Site 85502
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Zagreb, Croatia
Teva Investigational Site 85533
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Athens, Greece
Teva Investigational Site 85532
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Larissa, Greece
Teva Investigational Site 36510
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Siofok, Hungary
Teva Investigational Site 48505
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Bydgoszcz, Poland
Teva Investigational Site 70512
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Moscow, Russian Federation
Teva Investigational Site 70508
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Ryazan, Russian Federation
Teva Investigational Site 80502
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Kharkiv, Ukraine
Teva Investigational Site 70509
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Samara, Russian Federation
Teva Investigational Site 80501
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Dnipropetrovsk, Ukraine
Teva Investigational Site 11527
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Goodyear, Arizona, United States
Teva Investigational Site 10573
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Bakersfield, California, United States
Teva Investigational Site 10516
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Tucson, Arizona, United States
Teva Investigational Site 11518
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Costa Mesa, California, United States
Teva Investigational Site 10590
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Fountain Valley, California, United States
Teva Investigational Site 11520
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Huntington Beach, California, United States
Teva Investigational Site 10551
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Granada Hills, California, United States
Teva Investigational Site 11545
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Huntington Beach, California, United States
Teva Investigational Site 10547
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Long Beach, California, United States
Teva Investigational Site 10503
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Mission Viejo, California, United States
Teva Investigational Site 11549
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Los Angeles, California, United States
Teva Investigational Site 10540
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Orange, California, United States
Teva Investigational Site 10536
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Newport Beach, California, United States
Teva Investigational Site 10578
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Palmdale, California, United States
Teva Investigational Site 10585
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Redwood City, California, United States
Teva Investigational Site 11551
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Orange, California, United States
Teva Investigational Site 11538
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Rolling Hills Estates, California, United States
Teva Investigational Site 10563
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San Jose, California, United States
Teva Investigational Site 11556
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Santa Monica, California, United States
Teva Investigational Site 10529
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Walnut Creek, California, United States
Teva Investigational Site 10506
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Stockton, California, United States
Teva Investigational Site 10572
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Colorado Springs, Colorado, United States
Teva Investigational Site 10545
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Centennial, Colorado, United States
Teva Investigational Site 11569
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Wheat Ridge, Colorado, United States
Teva Investigational Site 10528
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Waterbury, Connecticut, United States
Teva Investigational Site 10556
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Boynton Beach, Florida, United States
Teva Investigational Site 11513
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Brandon, Florida, United States
Teva Investigational Site 11507
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Clearwater, Florida, United States
Teva Investigational Site 11546
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Fort Myers, Florida, United States
Teva Investigational Site 11526
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Hialeah, Florida, United States
Teva Investigational Site 11525
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Kissimmee, Florida, United States
Teva Investigational Site 11537
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Sarasota, Florida, United States
Teva Investigational Site 10593
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South Miami, Florida, United States
Teva Investigational Site 10571
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Ocala, Florida, United States
Teva Investigational Site 11555
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Tallahassee, Florida, United States
Teva Investigational Site 10554
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Tamarac, Florida, United States
Teva Investigational Site 10525
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Valrico, Florida, United States
Teva Investigational Site 11510
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Columbus, Georgia, United States
Teva Investigational Site 11572
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Columbus, Georgia, United States
Teva Investigational Site 11504
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Albany, Georgia, United States
Teva Investigational Site 10586
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Lilburn, Georgia, United States
Teva Investigational Site 11539
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Savannah, Georgia, United States
Teva Investigational Site 10543
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Stockbridge, Georgia, United States
Teva Investigational Site 10584
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Iowa City, Iowa, United States
Teva Investigational Site 10527
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South Bend, Indiana, United States
Teva Investigational Site 10513
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Metairie, Louisiana, United States
Teva Investigational Site 10564
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Bangor, Maine, United States
Teva Investigational Site 10510
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Largo, Maryland, United States
Teva Investigational Site 11548
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Baltimore, Maryland, United States
Teva Investigational Site 10577
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Wheaton, Maryland, United States
Teva Investigational Site 10538
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Brockton, Massachusetts, United States
Teva Investigational Site 10546
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North Dartmouth, Massachusetts, United States
Teva Investigational Site 10575
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Saint Louis, Missouri, United States
Teva Investigational Site 10589
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Saint Louis, Missouri, United States
Teva Investigational Site 10531
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Plymouth, Minnesota, United States
Teva Investigational Site 11562
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Columbia, Missouri, United States
Teva Investigational Site 10552
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Saint Louis, Missouri, United States
Teva Investigational Site 11563
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Columbia, Missouri, United States
Teva Investigational Site 10518
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Bellevue, Nebraska, United States
Teva Investigational Site 11532
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Saint Louis, Missouri, United States
Teva Investigational Site 10559
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Cherry Hill, New Jersey, United States
Teva Investigational Site 10501
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Hillsborough, New Jersey, United States
Teva Investigational Site 11566
🇺🇸
Edison, New Jersey, United States
Teva Investigational Site 11550
🇺🇸
Ocean City, New Jersey, United States
Teva Investigational Site 10588
🇺🇸
West Orange, New Jersey, United States
Teva Investigational Site 10520
🇺🇸
New York, New York, United States
Teva Investigational Site 10532
🇺🇸
Newburgh, New York, United States
Teva Investigational Site 10587
🇺🇸
Brooklyn, New York, United States
Teva Investigational Site 10567
🇺🇸
North Syracuse, New York, United States
Teva Investigational Site 10522
🇺🇸
Canton, Ohio, United States
Teva Investigational Site 10544
🇺🇸
Columbus, Ohio, United States
Teva Investigational Site 11505
🇺🇸
Middleburg Heights, Ohio, United States
Teva Investigational Site 11521
🇺🇸
Dayton, Ohio, United States
Teva Investigational Site 11544
🇺🇸
Tulsa, Oklahoma, United States
Teva Investigational Site 10598
🇺🇸
Ashland, Oregon, United States
Teva Investigational Site 11543
🇺🇸
Medford, Oregon, United States
Teva Investigational Site 10509
🇺🇸
Altoona, Pennsylvania, United States
Teva Investigational Site 10566
🇺🇸
Pittsburgh, Pennsylvania, United States
Teva Investigational Site 10521
🇺🇸
Upland, Pennsylvania, United States
Teva Investigational Site 10562
🇺🇸
Providence, Rhode Island, United States
Teva Investigational Site 10581
🇺🇸
Lincoln, Rhode Island, United States
Teva Investigational Site 10583
🇺🇸
Orangeburg, South Carolina, United States
Teva Investigational Site 10517
🇺🇸
Spartanburg, South Carolina, United States
Teva Investigational Site 10519
🇺🇸
Boerne, Texas, United States
Teva Investigational Site 11515
🇺🇸
Spartanburg, South Carolina, United States
Teva Investigational Site 10541
🇺🇸
Dallas, Texas, United States
Teva Investigational Site 10542
🇺🇸
Dallas, Texas, United States
Teva Investigational Site 10548
🇺🇸
El Paso, Texas, United States
Teva Investigational Site 11552
🇺🇸
El Paso, Texas, United States
Teva Investigational Site 11512
🇺🇸
Fort Worth, Texas, United States
Teva Investigational Site 11560
🇺🇸
Waco, Texas, United States
Teva Investigational Site 11528
🇺🇸
Layton, Utah, United States
Teva Investigational Site 10576
🇺🇸
Provo, Utah, United States
Teva Investigational Site 10534
🇺🇸
South Burlington, Vermont, United States
Teva Investigational Site 10502
🇺🇸
Fairfax, Virginia, United States
Teva Investigational Site 10595
🇺🇸
Manassas, Virginia, United States
Teva Investigational Site 10524
🇺🇸
Spokane, Washington, United States
Teva Investigational Site 11561
🇺🇸
Bellingham, Washington, United States
Teva Investigational Site 10530
🇺🇸
Tacoma, Washington, United States
Teva Investigational Site 11511
🇺🇸
Tacoma, Washington, United States
Teva Investigational Site 10570
🇺🇸
Greenfield, Wisconsin, United States
Teva Investigational Site 11559
🇺🇸
Greenfield, Wisconsin, United States
Teva Investigational Site 85570
🇦🇺
Bedford Park, Australia
Teva Investigational Site 85571
🇦🇺
Parkville, Australia
Teva Investigational Site 59507
🇧🇬
Burgas, Bulgaria
Teva Investigational Site 59503
🇧🇬
Lovech, Bulgaria
Teva Investigational Site 59501
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 59506
🇧🇬
Pleven, Bulgaria
Teva Investigational Site 59504
🇧🇬
Ruse, Bulgaria
Teva Investigational Site 59508
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 59502
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 59505
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 59509
🇧🇬
Varna, Bulgaria
Teva Investigational Site 11595
🇨🇦
Etobicoke, Ontario, Canada
Teva Investigational Site 11592
🇨🇦
Sarnia, Ontario, Canada
Teva Investigational Site 11590
🇨🇦
Toronto, Ontario, Canada
Teva Investigational Site 85504
🇭🇷
Zagreb, Croatia
Teva Investigational Site 11591
🇨🇦
Newmarket, Canada
Teva Investigational Site 85501
🇭🇷
Zagreb, Croatia
Teva Investigational Site 70561
🇩🇪
Berlin, Germany
Teva Investigational Site 70564
🇩🇪
Bonn, Germany
Teva Investigational Site 85503
🇭🇷
Zagreb, Croatia
Teva Investigational Site 70553
🇩🇪
Delitzsch, Germany
Teva Investigational Site 70557
🇩🇪
Cottbus, Germany
Teva Investigational Site 70558
🇩🇪
Frankfurt, Germany
Teva Investigational Site 70562
🇩🇪
Hamburg, Germany
Teva Investigational Site 70560
🇩🇪
Hanover, Germany
Teva Investigational Site 70555
🇩🇪
Leipzig, Germany
Teva Investigational Site 70554
🇩🇪
Munchen, Germany
Teva Investigational Site 70556
🇩🇪
Magdeburg, Germany
Teva Investigational Site 70550
🇩🇪
Munchen, Germany
Teva Investigational Site 70552
🇩🇪
Munster, Germany
Teva Investigational Site 70563
🇩🇪
Nurnberg, Germany
Teva Investigational Site 70559
🇩🇪
Wiesbaden, Germany
Teva Investigational Site 70551
🇩🇪
Rudersdorf, Germany
Teva Investigational Site 85534
🇬🇷
Athens, Greece
Teva Investigational Site 85531
🇬🇷
Heraklion, Greece
Teva Investigational Site 85530
🇬🇷
Thessaloniki, Greece
Teva Investigational Site 36504
🇭🇺
Budapest, Hungary
Teva Investigational Site 36507
🇭🇺
Balassagyarmat, Hungary
Teva Investigational Site 36505
🇭🇺
Budapest, Hungary
Teva Investigational Site 36516
🇭🇺
Erd, Hungary
Teva Investigational Site 36515
🇭🇺
Kaposvar, Hungary
Teva Investigational Site 36513
🇭🇺
Kaba, Hungary
Teva Investigational Site 36514
🇭🇺
Csoma, Hungary
Teva Investigational Site 36503
🇭🇺
Miskolc, Hungary
Teva Investigational Site 36502
🇭🇺
Nyiregyhaza, Hungary
Teva Investigational Site 36517
🇭🇺
Szarvas, Hungary
Teva Investigational Site 36508
🇭🇺
Szazhalombatta, Hungary
Teva Investigational Site 36506
🇭🇺
Szeged, Hungary
Teva Investigational Site 36509
🇭🇺
Szeged, Hungary
Teva Investigational Site 36501
🇭🇺
Szombathely, Hungary
Teva Investigational Site 36512
🇭🇺
Veszprem, Hungary
Teva Investigational Site 59550
🇮🇪
Dublin, Ireland
Teva Investigational Site 59551
🇮🇪
Dublin, Ireland
Teva Investigational Site 72511
🇮🇱
Ashkelon, Israel
Teva Investigational Site 72501
🇮🇱
Haifa, Israel
Teva Investigational Site 72512
🇮🇱
Haifa, Israel
Teva Investigational Site 72502
🇮🇱
Jerusalem, Israel
Teva Investigational Site 72504
🇮🇱
Jerusalem, Israel
Teva Investigational Site 72509
🇮🇱
Kfar Saba, Israel
Teva Investigational Site 72506
🇮🇱
Petach Tikva, Israel
Teva Investigational Site 72510
🇮🇱
Tel Aviv, Israel
Teva Investigational Site 72507
🇮🇱
Ramat-Gan, Israel
Teva Investigational Site 72503
🇮🇱
Rehovot, Israel
Teva Investigational Site 72508
🇮🇱
Tel-Aviv, Israel
Teva Investigational Site 72505
🇮🇱
Zerifin, Israel
Teva Investigational Site 81571
🇳🇿
Auckland, New Zealand
Teva Investigational Site 81572
🇳🇿
Christchurch, New Zealand
Teva Investigational Site 81573
🇳🇿
Tauranga, New Zealand
Teva Investigational Site 81570
🇳🇿
Wellington, New Zealand
Teva Investigational Site 48507
🇵🇱
Bialystok, Poland
Teva Investigational Site 48501
🇵🇱
Lodz, Poland
Teva Investigational Site 48506
🇵🇱
Grodzisk Mazowiecki, Poland
Teva Investigational Site 48509
🇵🇱
Lodz, Poland
Teva Investigational Site 48513
🇵🇱
Lublin, Poland
Teva Investigational Site 48508
🇵🇱
Poznan, Poland
Teva Investigational Site 48512
🇵🇱
Poznan, Poland
Teva Investigational Site 48503
🇵🇱
Tarnow, Poland
Teva Investigational Site 48502
🇵🇱
Strzelce Opolskie, Poland
Teva Investigational Site 48504
🇵🇱
Wroclaw, Poland
Teva Investigational Site 81534
🇷🇴
Brasov, Romania
Teva Investigational Site 81539
🇷🇴
Brasov, Romania
Teva Investigational Site 81533
🇷🇴
Bucharest, Romania
Teva Investigational Site 81535
🇷🇴
Bucharest, Romania
Teva Investigational Site 81537
🇷🇴
Bucharest, Romania
Teva Investigational Site 81531
🇷🇴
Cluj-Napoca, Romania
Teva Investigational Site 81536
🇷🇴
Cluj-Napoca, Romania
Teva Investigational Site 81530
🇷🇴
Targu Mures, Romania
Teva Investigational Site 81532
🇷🇴
Timisoara, Romania
Teva Investigational Site 81538
🇷🇴
Timisoara, Romania
Teva Investigational Site 70505
🇷🇺
Barnaul, Russian Federation
Teva Investigational Site 70502
🇷🇺
Kazan, Russian Federation
Teva Investigational Site 70511
🇷🇺
Moscow, Russian Federation
Teva Investigational Site 70507
🇷🇺
Smolensk, Russian Federation
Teva Investigational Site 70501
🇷🇺
St. Petersburg, Russian Federation
Teva Investigational Site 70504
🇷🇺
St. Petersburg, Russian Federation
Teva Investigational Site 70503
🇷🇺
Yaroslavl, Russian Federation
Teva Investigational Site 70510
🇷🇺
St. Petersburg, Russian Federation
Teva Investigational Site 81501
🇷🇸
Belgrade, Serbia
Teva Investigational Site 36552
🇿🇦
Cape Town, South Africa
Teva Investigational Site 70506
🇷🇺
Tomsk, Russian Federation
Teva Investigational Site 36553
🇿🇦
Thabazimbi, South Africa
Teva Investigational Site 36551
🇿🇦
Bloemfontein, South Africa
Teva Investigational Site 36555
🇿🇦
Cape Town, South Africa
Teva Investigational Site 36554
🇿🇦
Witbank, South Africa
Teva Investigational Site 34501
🇪🇸
Badalona, Spain
Teva Investigational Site 34507
🇪🇸
Aranjuez, Spain
Teva Investigational Site 36550
🇿🇦
Port Elizabeth, South Africa
Teva Investigational Site 34505
🇪🇸
Madrid, Spain
Teva Investigational Site 34506
🇪🇸
Lleida, Spain
Teva Investigational Site 34502
🇪🇸
Barcelona, Spain
Teva Investigational Site 34510
🇪🇸
Barcelona, Spain
Teva Investigational Site 34509
🇪🇸
Bilbao, Spain
Teva Investigational Site 34511
🇪🇸
Vitoria, Spain
Teva Investigational Site 34504
🇪🇸
Santiago de Compostela, Spain
Teva Investigational Site 34508
🇪🇸
Valencia, Spain
Teva Investigational Site 34503
🇪🇸
Salt, Spain
Teva Investigational Site 80513
🇺🇦
Dnipropetrovsk, Ukraine
Teva Investigational Site 80511
🇺🇦
Donetsk, Ukraine
Teva Investigational Site 80503
🇺🇦
Kharkiv, Ukraine
Teva Investigational Site 80504
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80505
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80506
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80509
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80508
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80507
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80517
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80520
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80519
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80514
🇺🇦
Odesa, Ukraine
Teva Investigational Site 80521
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 80515
🇺🇦
Yalta, Ukraine
Teva Investigational Site 80522
🇺🇦
Zaporizhia, Ukraine
Teva Investigational Site 80516
🇺🇦
Simferopol, Ukraine
Teva Investigational Site 80512
🇺🇦
Vinnytsya, Ukraine
Teva Investigational Site 80510
🇺🇦
Zaporizhzhia, Ukraine
Teva Investigational Site 80518
🇺🇦
Zaporizhzhya, Ukraine
Teva Investigational Site 34584
🇬🇧
London, United Kingdom
Teva Investigational Site 34582
🇬🇧
Cottingham, United Kingdom
Teva Investigational Site 34585
🇬🇧
Penzance, United Kingdom
Teva Investigational Site 34580
🇬🇧
Torpoint, United Kingdom
Teva Investigational Site 34581
🇬🇧
Watford, United Kingdom
Teva Investigational Site 11565
🇺🇸
Houston, Texas, United States
Teva Investigational Site 11568
🇺🇸
Houston, Texas, United States
Teva Investigational Site 11541
🇺🇸
Seattle, Washington, United States
Teva Investigational Site 10537
🇺🇸
Miami, Florida, United States
Teva Investigational Site 10553
🇺🇸
Miami, Florida, United States
Teva Investigational Site 11508
🇺🇸
Miami, Florida, United States
Teva Investigational Site 11514
🇺🇸
Miami, Florida, United States
Teva Investigational Site 11516
🇺🇸
Miami, Florida, United States
Teva Investigational Site 11530
🇺🇸
Miami, Florida, United States
Teva Investigational Site 11570
🇺🇸
Miami, Florida, United States
Teva Investigational Site 11558
🇺🇸
Indianapolis, Indiana, United States
Teva Investigational Site 11571
🇺🇸
Las Vegas, Nevada, United States
Teva Investigational Site 10582
🇺🇸
San Diego, California, United States
Teva Investigational Site 11554
🇺🇸
San Diego, California, United States
Teva Investigational Site 10507
🇺🇸
Cincinnati, Ohio, United States
Teva Investigational Site 10523
🇺🇸
Cincinnati, Ohio, United States
Teva Investigational Site 10515
🇺🇸
San Antonio, Texas, United States
Teva Investigational Site 10569
🇺🇸
San Antonio, Texas, United States
Teva Investigational Site 11519
🇺🇸
San Antonio, Texas, United States
Teva Investigational Site 11517
🇺🇸
San Antonio, Texas, United States
Teva Investigational Site 11501
🇺🇸
Overland Park, Kansas, United States
Teva Investigational Site 10504
🇺🇸
Birmingham, Alabama, United States
Teva Investigational Site 10579
🇺🇸
Oklahoma City, Oklahoma, United States
Teva Investigational Site 10533
🇺🇸
Denver, Colorado, United States
Teva Investigational Site 11531
🇺🇸
Denver, Colorado, United States
Teva Investigational Site 11542
🇺🇸
Denver, Colorado, United States
Teva Investigational Site 10560
🇺🇸
Oklahoma City, Oklahoma, United States
Teva Investigational Site 10574
🇺🇸
Oklahoma City, Oklahoma, United States
Teva Investigational Site 11557
🇺🇸
Portland, Oregon, United States
Teva Investigational Site 10550
🇺🇸
Omaha, Nebraska, United States
Teva Investigational Site 11529
🇺🇸
Omaha, Nebraska, United States
Teva Investigational Site 10555
🇺🇸
Philadelphia, Pennsylvania, United States
Teva Investigational Site 10565
🇺🇸
Homewood, Alabama, United States
Teva Investigational Site 11522
🇺🇸
Roseville, California, United States
Teva Investigational Site 10539
🇺🇸
Tampa, Florida, United States
Teva Investigational Site 11567
🇺🇸
Louisville, Kentucky, United States
Teva Investigational Site 10591
🇺🇸
Lexington, Kentucky, United States
Teva Investigational Site 11503
🇺🇸
Albuquerque, New Mexico, United States
Teva Investigational Site 10580
🇺🇸
Bronx, New York, United States
Teva Investigational Site 10526
🇺🇸
Charleston, South Carolina, United States
Teva Investigational Site 11547
🇺🇸
Charleston, South Carolina, United States
Teva Investigational Site 10508
🇺🇸
Richmond, Virginia, United States
Teva Investigational Site 10512
🇺🇸
Rochester, New York, United States
Teva Investigational Site 10511
🇺🇸
Columbus, Georgia, United States
Teva Investigational Site 11594
🇨🇦
Burlington, Ontario, Canada
Teva Investigational Site 10568
🇺🇸
Lawrenceville, Georgia, United States
Teva Investigational Site 11502
🇺🇸
Troy, Michigan, United States