Clinical trial: Comparative Study of Umeclidinium/Vilanterol (UMEC/VI) in a Fixed Dose Combination With Indacaterol Plus Tiotropium (NCT02257385)

Eligibility criteria:
Inclusion Criteria:

          -  Type of subject: Outpatient

          -  Informed Consent: A signed and dated written informed consent prior to study
             participation.

          -  Participants 40 years of age or older at Visit 1.

          -  Gender: Male or female participants. A female is eligible to enter and participate in
             the study if she is of: Non-child bearing potential (i.e., physiologically incapable
             of becoming pregnant, including any female who is post-menopausal or surgically
             sterile). Surgically sterile females are defined as those with a documented
             hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females
             are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical
             profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement
             therapy.OR Child bearing potential, has a negative pregnancy test at screening, and
             agrees to one of the following acceptable contraceptive methods used consistently and
             correctly (i.e., in accordance with the approved product label and the instructions of
             the physician for the duration of the study screening to follow-up contact):
             Abstinence, Oral Contraceptive, either combined or progestogen alone, Injectable
             progestogen, Implants of levonorgestrel, Estrogenic vaginal ring, Percutaneous
             contraceptive patches, Intrauterine device (IUD) or intrauterine system (IUS) that
             meets the Standard Operating Procedure (SOP) effectiveness criteria as stated in the
             product label, Male partner sterilization (vasectomy with documentation of
             azoospermia) prior to the female subject's entry into the study, and this male is the
             sole partner for that subject. For this definition, "documented" refers to the outcome
             of the investigator's/designee's medical examination of the subject or review of the
             subject's medical history for study eligibility, as obtained via a verbal interview
             with the subject or from the subject' s medical records. Double barrier method: condom
             and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal
             agent (foam/gel/film/cream/suppository)

          -  Diagnosis: An established clinical history of COPD in accordance with the definition
             by the American Thoracic Society/European Respiratory Society.

          -  Smoking History: Current or former cigarette smokers with a history of cigarette
             smoking of >=10 pack-years. Former smokers are defined as those who have stopped
             smoking for at least 6 months prior to Visit 1.

          -  Severity of Disease: A pre and post-albuterol/salbutamol Forced Expiratory Volume in
             One Second/ Forced Vital Capacity (FEV1/ FVC) ratio of <0.70 and a pre and
             post-albuterol/salbutamol FEV1 of <=70% predicted normal value at Visit 1, calculated
             using Quanjer reference equations.

          -  Dyspnoea: A score of >= 2 on the Modified Medical Research Council Dyspnoea Scale
             (mMRC) at Visit 1.

          -  QT interval corrected (QTc) Criteria: QTc <450 milliseconds (msec) or QTc <480 msec
             for patients with bundle branch block The QTc is the QT interval corrected for heart
             rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or
             another method, machine or manual overread. For subject eligibility and withdrawal,
             QTcF will be used. For purposes of data analysis, QTcF will be used as primary. The
             QTc should be based on single or averaged QTc values of triplicate Electrocardiogram
             (ECGs) obtained over a brief recording period.

          -  French participants: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant
             during the study.

          -  Asthma: A current diagnosis of asthma.

          -  Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung
             infections (such as tuberculosis), and lung cancer are absolute exclusionary
             conditions. A subject who, in the opinion of the investigator, has any other
             significant respiratory conditions in addition to COPD should be excluded. Examples
             may include clinically significant bronchiectasis, pulmonary hypertension,
             sarcoidosis, or interstitial lung disease. Allergy rhinitis is not exclusionary.

          -  Other Diseases/Abnormalities: Participants with historical or current evidence of
             clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
             immunological, endocrine (including uncontrolled diabetes or thyroid disease) or
             hematological abnormalities that are uncontrolled and/or a previous history of cancer
             in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has
             been resected for cure is not exclusionary). 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 would affect the efficacy or safety analysis if the
             disease/condition exacerbated during the study.

          -  Contraindications: A history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or
             magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic
             hypertrophy or bladder neck obstruction that, in the opinion of the study physician,
             contraindicates study participation or use of an inhaled anticholinergic or beta 2
             agonist.

          -  Hospitalisation: Hospitalisation for COPD or pneumonia within 12 weeks prior to Visit
             1.

          -  Lung Resection: Participants with lung volume reduction surgery within the 12 months
             prior to Screening (Visit 1).

          -  12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at
             Visit 1. Specific ECG findings that preclude subject eligibility will be listed in
             protocol The study investigator will determine the medical significance of any ECG
             abnormalities not listed.

          -  Screening labs: Significantly abnormal finding from clinical chemistry or haematology
             tests at Visit 1 as determined by the study investigator.

          -  Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour
             period required prior to spirometry testing at each study visit.

          -  Medications prior to Screening: Use of the following medications according to the
             following defined time intervals prior to Visit 1: Depot corticosteroids (12 weeks);
             Oral or parenteral corticosteroids (6 weeks); Antibiotics (for lower respiratory tract
             infection) (6 weeks); Cytochrome P450 3A4 strong inhibitors ( 6 weeks); Long Acting
             Beta-Agonist (LABA)/ inhaled corticosteroids (ICS) combination products (e.g.
             fluticasone/salmeterol, mometasone, furoate/formoterol fumarate,
             budesonide/formoterol, fumarate), If LABA/ICS therapy is discontinued completely (30
             days); If discontinuing LABA therapy and switching to ICS monotherapy (48 hours for
             salmeterol or formoterol, 14 days for Olodaterol, Indacaterol or, Vilanterol); Use of
             ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent (30 days);
             Initiation or discontinuation of ICS use (30 days); Inhaled long acting beta2-agonists
             (LABA): Salmeterol, Formoterol (48 hours), Olodaterol, Indacaterol and Vilanterol (14
             days); Long acting muscarinic antagonists (LAMA) (Tiotropium, Aclidinium,
             Glycopyrronium, Umeclidinium) (7 days); LABA/LAMA combination products (Whichever mono
             component has the longest washout); Roflumilast (14 days); Oral beta-agonists-
             Long-acting (48 hours), Short-acting(12 hours); Theophyllines (48 hours); Oral
             leukotriene inhibitors (zafirlukast, montelukast, zileuton) (48 hours); Inhaled sodium
             cromoglycate or nedocromil sodium (24 hours); Inhaled short acting beta2-agonists (4
             hours); Inhaled short-acting anticholinergic (short acting muscarinic antagonist
             [SAMA]) products eg ipratropium (4 hours); Inhaled short-acting
             anticholinergic/short-acting beta2-agonist combination products (SAMA/Short Acting
             beta2-agonists [SABA]) (4 hours); Any other investigational medication (30 days or
             within 5 drug half-lives)

          -  Oxygen: Use of Long Term Oxygen Therapy (LTOT).This is defined as oxygen therapy
             prescribed for greater than 12 hours per day. As needed oxygen use (i.e. <=12 hours
             per day) is not exclusionary.

          -  Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use)
             of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulized therapy.

          -  Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary
             rehabilitation program within 12 weeks prior to Visit 1. Participants who are in the
             maintenance phase of a pulmonary rehabilitation program are not excluded.

          -  Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2
             years prior to Visit 1.

          -  Affiliation with Investigator Site: Is an investigator, sub-investigator, study
             coordinator, employee of a participating investigator or study site, or immediate
             family member of the aforementioned that is involved in this study.

          -  Inability to read: In the opinion of the investigator, any subject who is unable to
             read and/or would not be able to complete a questionnaire.

          -  Participants who are pre-screen or screen failures cannot be re-screened.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 40 Years old.


Patient description (medical language): A 30-year-old man who is a computer scientist came to the clinic with the lab result stating azoospermia.  The patient is sexually active with his wife and does not use any contraception methods.  They have been trying to conceive for the past year with no success.  The patient has a past medical history of recurrent pneumonia, shortness of breath, and  persistent cough that produces large amounts of thick sputum. The patient had multiple lung infections during childhood. He does not smoke, use illicit drugs or alcohol.  The patient has no history of other medical conditions including allergies or any kind of surgery.  On physical examination, the digits show clubbing.  An ultrasound shows bilateral absence of the vas deferens, and FEV1 was 75% on the respiratory function test.

Patient description (patient's own words): I'm a 30-year-old computer scientist. I did some lab tests that came back quite alarming, stating that I have azoospermia?! I'm sexually active with my wife and we don't use contraception. We've been trying to have a child for the past year. I have a medical history of pneumonia and shortness of breath and regular wet cough. I had several lung infections when I was a kid. That's why I'm very careful and don't smoke, do drugs, or drink. I don't have other medical conditions including allergies or any kind of surgery. The doctor did the clubbing test on my fingers, which was positive. I also did an ultrasound and it showed that I'm missing the tubes that carry sperm around. I also had a 75% for my respiratory function test.

Does the patient match the trial criteria? Contradiction