Evaluation of Tolerability and Pharmacokinetics of Roflumilast, 250μg and 500μg, as add-on to Standard COPD Treatment to Treat Severe COPD

Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial

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Official title:

A Multicenter, Randomized, Double-blind Phase 3 Study to Evaluate Tolerability and Pharmacokinetics of 500 μg Roflumilast Once Daily With an Up-titration Regimen in COPD, Including an Open-label Down-titration Period Evaluating Tolerability and Pharmacokinetics of 250 μg Roflumilast Once Daily in Subjects Not Tolerating 500 μg Roflumilast Once-daily

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02165826
• Other study ID #: RO-2455-302-RD
• Secondary ID: U1111-1150-24772
• Status: Completed
• Phase: Phase 3
• First received: May 2, 2014
• Last updated: October 22, 2015
• Start date: May 2014
• Est. completion date: September 2015

Study information

• Verified date: October 2015
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Health authority: Bulgaria: Bulgarian Drug AgencyBulgaria: Ministry of HealthGermany: Ethics CommissionGermany: German Institute of Medical Documentation and InformationGreece: Ethics CommitteeGreece: National Organization of MedicinesHungary: National Institute of PharmacyPoland: Ministry of HealthPoland: Office for Registration of Medicinal Products, Medical ProductsDevices and BiocidalRomania: National Medicines AgencyRomania: Ministry of Public HealthRussia: Ministry of Health of the Russian FederationRussia: Pharmacological Committee, Ministry of HealthRussia: Ethics CommitteeSlovakia: State Institute for Drug ControlSouth Africa: Department of HealthSouth Africa: Medicines Control CouncilSouth Africa: National Health Research Ethics CouncilSpain: Ethics CommitteeUkraine: The Ministry of Health of UkraineUkraine: The State Pharmacological Center of Ministry of Health of UkraineUkraine: The Ethics Commission at Treatment and Prevention InstitutionsUnited Kingdom: Department of HealthUnited Kingdom: Food Standards AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: National Health ServiceUnited Kingdom: Research Ethics CommitteePhilippines: Department of HealthPhilippines: Bureau of Food and DrugsSouth Korea: Institutional Review BoardSouth Korea: Korea Food and Drug Administration (KFDA)Thailand: Ethical CommitteeThailand: Food and Drug AdministrationThailand: Khon Kaen University Ethics Committee for Human ResearchThailand: Ministry of Public Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate discontinuation rates of roflumilast using an up-titration regimen for the first 4 weeks of treatment compared with continuous treatment of 500 μg one daily (OD) during the entire 12-week main period, and to evaluate if participants who do not tolerate roflumilast 500 μg OD have a drug exposure with 250 μg roflumilast OD similar to that observed in other participants with the 500 μg OD dose.

Description:

Roflumilast is a product which has been approved for the treatment of severe chronic obstructive lung disease (COPD) and its approved dose is 500μg once daily. This study is primarily designed to see whether alternation in this dose can improve tolerability of Roflumilast in COPD patients. Therefore one in three patients will start roflumilast therapy at a lower dose of 250μg once daily, another one in three will only take the 500μg tablet every other day (and one placebo every other day). Rest of them will start the regular dose of 500μg once daily right away and see whether starting with a lower dose of Roflumilast will lead to better tolerability. Furthermore, the study will see if patients who do not tolerate roflumilast should be given a lower dose of 250μg once daily.

Lastly, the study will investigate what the body does to roflumilast. Patients with a history of COPD for at least last 12 months and a former smoker or current smoker with history of at least 10 pack years will be invited to participate.

The main study period lasts for a maximum of 15 weeks and patients will have to visit the study site up to 6 times. If patients are not tolerating roflumilast, the investigators may switch them to the down titration period where they may be on a lower dose for rest of the study. Then patients will remain in the down titration period for additional 8 weeks and will have to visit the study site 4 times. Most of the visits will take approximately 1 to 2 hours. However, one visit in the main period and 1 or 2 visits in the down titration period will take approximately 6 to 7 hours. These visits are longer to allow time to conduct blood taking.

The Randomization visit is considered the Baseline visit and for participants that discontinue the Main Period and continue into the Down-Titration Period Day 1 of Down Titration is considered BaselineDT.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1323
• Est. completion date: September 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Has a history of chronic obstructive pulmonary disease (COPD) (according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013) for at least 12 months prior to Screening (Visit V0) associated with chronic productive cough for 3 months in each of the 2 years prior to Screening (Visit V0, with other causes of productive cough excluded).

4. Shows a post-bronchodilator forced expiratory volume in 1 second (FEV1) of =50% of predicted.

5. Shows an FEV1/forced vital capacity (FVC) ratio (post-bronchodilator) <70%.

6. Has at least one documented COPD exacerbation within one year prior to Screening (Visit V0).

7. Is on standard of care COPD maintenance treatment including Long Acting ß2-Agonist (LABAs), long-acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0).

8. Must be a former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 10 pack years.11

9. Is male or female and aged 40 or older.

10. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.

Exclusion Criteria:

Criteria affecting the read-out parameters of the study

1. Has a COPD exacerbation ongoing at the Screening (Visit V0), or has a COPD exacerbation between V0 and V1.

2. Has a lower respiratory tract infection not resolved 4 weeks prior to Screening (Visit V0).

3. Has a diagnosis of asthma and/or other relevant lung disease (eg, history of primary bronchiectases, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [eg, fibrosis, silicosis, sarcoidosis], or active tuberculosis).

4. Has a known a1-antitrypsin deficiency.

5. Has taken roflumilast within 6 months of Screening (Visit V0).

Criteria within ethical considerations in terms of general health

6. Has clinically relevant abnormal laboratory values suggesting an undiagnosed disease requiring further clinical evaluation (as assessed by the investigator).

7. Has a history of severe psychiatric or neurological disorders.

8. Has a history of depression associated with suicidal ideation or behavior.

9. Has congestive heart failure severity grade IV according to New York Heart Association (NYHA) Functional Classification.

10. Has hemodynamically significant cardiac arrhythmias or heart valve deformations.

11. Has computed tomography (CT) or chest x-ray findings indicating an acute pulmonary disease other than COPD (eg, tuberculosis, severe bronchiectasis, tumors).

12. Has severe immunological diseases (eg, known human immune deficiency virus (HIV) infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy).

13. Has liver impairment Child-Pugh B or C and/or active viral hepatitis.

14. Has severe acute infectious diseases (eg, tuberculosis, or acute hepatitis).

15. Has a history of malignant disease (except basal cell carcinoma) within 5 years before Screening (Visit V0).

16. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within one year before Screening (Visit V0).

17. Has a history of hypersensitivity or allergies to roflumilast or rescue medication or ingredients thereof, or any other contraindication for the use thereof.

18. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 12 weeks after participating in this study; or intending to donate ova during such time period.

19. Intends to donate blood, organs, or bone marrow during the course of the study.

20. Has received any investigational compound within 30 days prior to Screening (Visit V0), is currently participating in another interventional clinical study, or has been previously enrolled in this study.

21. Is suspected to be unable or unwilling to comply with study procedures (eg, language problems, psychological disorders, number and timing of visits at the center).

22. Suffers from any concomitant disease that might interfere with study procedures or evaluations.

23. Is required to take excluded medications.

24. Is an immediate family member, study center employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease (COPD)
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• Roflumilast
Roflumilast tablets
• Roflumilast Placebo
Roflumilast placebo-matching tablets
• Standard of Care COPD Treatment
The participant is on standard of care COPD maintenance treatment including LABAs, long-acting anticholinergics, or any combination thereof taken on a constant daily dose within 12 weeks prior to Screening (Visit V0) Examples of LABA containing products are: Formoterol, Salmeterol, Indacaterol, Formoterol/Budesonide, Salmeterol/Fluticasone, Treatment including lon-acting anticholinergics: Tiotropium, Aclidinium.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Country where clinical trial is conducted

Slovakia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Prematurely Discontinuing Study Treatment due to any Reason	The primary endpoint is the percentage of participants prematurely discontinuing study treatment for any reason during the main period from V1 to Vend. Discontinuation is defined as permanently stopping randomized treatment; subjects who resume randomized treatment after an interval will not be counted as having discontinued. The analysis will use discontinuations occurring during the main period, irrespective of whether a participant subsequently enters into the down-titration period.	Baseline to week 12 (main period)	No
Secondary	Percentage of Participants with Adverse Events of Interest	Adverse events of interest to evaluate tolerability are defined as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain.	Baseline to week 12 (main period)	No
Secondary	Change in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) during the down titration period	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing will be performed using spirometry prior to taking study medication.	Baseline DT (Day 1 of Down titration period) to week 8 (down-titration period)	No
Secondary	Percentage of Participants Prematurely Discontinuing Study Treatment due to Any Reason During Down-titration Period		Baseline DT (Day 1 of Down titration period) to week 8 (down-titration period)	No
Secondary	Change in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing will be performed using spirometry prior to taking study medication.	Baseline up to Week 12 (main period) and Baseline DT to week 8 (down-titration period)	No
Secondary	Change in Pre-bronchodilator Forced Vital Capacity (FVC)	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing will be performed using spirometry prior to taking study medication.	Baseline up to Week 12 (main period) and Baseline DT to week 8 (down-titration period.	No
Secondary	Change in Treatment Satisfaction Scores	Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied.	Baseline up to Week 12 (main period) and Baseline DT to week 8 (Down-titration period and also Baseline to week 8 (down-titration period)	No
Secondary	Pharmacokinetics (PK) Profiles of Roflumilast and Roflumilast N-oxide	Typical PK parameters like clearance, absorption rates, and volume of distribution, will be derived.	Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8.Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at week 2 and pre-dose at Baseline DT, weeks 4 and 8	No
Secondary	Individual and population PK parameters for roflumilast and roflumilast N-oxide and total PDE4 inhibitory activity (tPDE4i)4 of both active moieties	Individual and population PK parameters for roflumilast and roflumilast N-oxide and total PDE4 inhibitory activity (tPDE4i)4 of both active moieties including covariate effects on these parameters.	Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8.Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at week 2 and pre-dose at Baseline DT, weeks 4 and 8	No
Secondary	Relationship between PK and relevant safety (adverse events of interest to evaluate tolerability ie, diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain) and efficacy (FEV1) parameters	Relationship between PK and relevant safety (adverse events of interest to evaluate tolerability ie, diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain) and efficacy (FEV1) parameters.	Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8.Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at week 2 and pre-dose at Baseline DT, weeks 4 and 8	No