A Clinical Trial to Study the Effects of Revamilast in Patients With Chronic Persistent Asthma

• Change in morning pre-dose Forced Vital Capacity (FVC) from baseline to week 12 [ Time Frame: baseline to 12 weeks ] [ Designated as safety issue: No ]
• Area under the curve of Forced Expiratory Volume in One Second (FEV1) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Change in asthma day time symptom score from baseline to week 12 [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
• Frequency and severity of asthma exacerbations during treatment period [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
• Change in investigator global impression from baseline to week 12 [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
  An investigator-rated test measured on a 7-point scale, used to rate change in a patient's condition over the course of the study.
• Change in patient global impression from baseline to week 12 [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
  A patient-rated test measured on a 7-point scale, used to rate change in a patient's condition over the course of the study.
• Change in morning pre-dose Peak Expiratory Flow (PEF) from baseline to week 12 [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]
• Change in morning pre-dose PEF25-75% (Forced expiratory flow 25-75%) from baseline to week 12 [ Time Frame: Baseline to 12 weeks ] [ Designated as safety issue: No ]

Asthma is a common, chronic inflammatory disease of the bronchial airways, with a reported prevalence in most industrialized countries of between 5 to 10 % of the adult population. Asthma is clinically characterized by repeated episodes of wheezing, breathlessness, chest tightness, and coughing; usually in the presence of variable airflow obstruction that is often reversible either spontaneously or with treatment (The Global Initiative for Asthma (GINA), 2009).

Drug treatment of asthma has focused on anti-inflammatory therapy in all but the mildest, intermittent cases. Inhaled corticosteroids have been shown to be anti-inflammatory in asthma, but chronic use of these agents may be associated with a range of side effects, especially at high doses. In asthma, there remains a need for the development of novel anti-inflammatory therapies that are at least equally effective and possess a superior safety profile in comparison to corticosteroids.

This is a randomized, double-blind, triple dummy, placebo controlled, parallel group, dose ranging study. The study will be conducted in adult patients with a diagnosis of chronic persistent asthma with an Forced Expiratory Volume in one second(FEV1) of 50% to 80% of the predicted value. Study will enroll 448 patients globally (278 from India) across different centers.

Patients will be recruited after providing written informed consent. After screening and run in period, patient will be randomized (patient meeting randomization criteria) in 1:1:1:1 ratio to receive either one of the three dose regimens of revamilast or placebo.

The primary objective of the study is to evaluate the effect of revamilast on lung function as assessed by Forced Expiratory Volume in one second (FEV1) after the therapy (12 weeks). Secondary objective includes area under curve for FEV1, Change in asthma symptoms, patient / investigator's global assessments and safety. Patients will be followed for safety and efficacy assessment at week 1, 4, 8 12 and 14 after start of therapy.

• Drug: Revamilast
  Tablet. Low dose, Once daily for 12 weeks
• Drug: Revamilast
  Medium dose, Once daily for 12 weeks
• Drug: Revamilast
  High dose, Once daily for 12 weeks
• Drug: Placebo
  Placebo tablet in triple dummy format, Once daily for 12 weeks

• Experimental: Low dose
  Low dose revamilast
  Intervention: Drug: Revamilast
• Experimental: Medium dose
  Medium dose Revamilast
  Intervention: Drug: Revamilast
• Experimental: High dose
  High dose Revamilast
  Intervention: Drug: Revamilast
• Placebo Comparator: Placebo
  Matching placebo in triple dummy format
  Intervention: Drug: Placebo

Inclusion Criteria:

1. The patient provides written informed consent to participate in the study
2. Male or female patient aged 18 to 65 years
3. Documented diagnosis of asthma
4. Forced Expiratory Volume in One Second (FEV1) between 50% and 80% of the predicted value
5. Patient judged by the investigator to be in otherwise good stable health based on medical history, physical examination, and routine laboratory data
6. Female participants must have a negative pregnancy test at screening visit
7. Males must agree to use barrier contraception while on study medication and for 90 days after taking the last dose of study medication

Exclusion Criteria:

1. Pregnant or lactating women
2. Female subjects on hormone replacement therapy or hormonal contraceptives
3. Suffering from relevant lung diseases (other than asthma) causing impairment in lung function
4. Past smoker with a history of ≥10 pack per year or current smoker
5. Recent change in the patient's usual asthma treatment

6. Patients with risk factors for asthma exacerbation during the study, including (any of the following):

   • Current requirement for > 8 puffs per day of reliever medication.
   • Hospitalization for asthma
   • Treatment with systemic corticosteroid therapy within 3 months
7. Evidence of current or recent neoplastic disease
8. Clinically significant cardiovascular, haematological, endocrine, neurological, gastrointestinal, psychiatric, metabolic, immunologic, infectious, hepatic, renal, gynaecological disease or other condition that the investigator considers detrimental to the patient's participation in the study or that may prevent the successful completion of the study
9. Positive serology for an infectious disease (including hepatitis B or C) at screening and known case of human immunodeficiency virus [HIV]
10. Patients who have been hospitalized for any psychiatric illness in the past year, or are diagnosed with major depression
11. Clinically significant ECG Abnormality at baseline
12. Patients with documented or suspected or current history of alcohol and drug abuse
13. Patients who have undergone lung surgery in the previous year
14. Participation in an investigational drug trial during 30 days preceding screening