| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate/ evaluate effects of revamilast on lung function in patients with chronic persistent asthma |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the safety and tolerability of revamilast in patients with chronic persistent asthma
•To investigate the pharmacokinetics of revamilast and its metabolite GRC 4037 in patients with asthma
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient provides written informed consent to participate in the
study
2. Male or female patient aged 18 to 65 years (inclusive)
3. Documented clinical diagnosis of asthma by a physician, based on
GINA (2009)
4. The following patients can be included in the study, based on GINA
(2009) stepwise therapy:
A. Patients who are currently on preferred or alternative Step 1 or Step 2
therapy. Patients on alternative step 1 therapy can enter a placebo run
in period only after appropriate washout criteria are met and after they
have been switched to as needed inhaled rapid acting beta 2 agonist,
upon consenting. Similarly, patients on alternative step 2 therapy can be
included in the study after giving proper wash out for their therapies and
switching them to low dose ICS (plus PRN salbutamol) upon consenting.
B. Patients who are currently on preferred or alternative step 3 therapy,
and for whom the PI, based on his clinical judgment and independent of
the intent to include patients in the study, feels that such patients can be
stepped down and switched to only low dose ICS (plus PRN salbutamol).
Such patients can be included in the study after giving proper wash out
for their therapies and switching them to low dose ICS (plus PRN
Salbutamol) upon consenting. However, in case the investigator has any
concern regarding stepping down patients from step 3, such patients
should not be enrolled in the study.
5. FEV1 between 50% and 85% (inclusive) of the predicted value for
their age, height and gender at screening and shown to be reversible
(not less than 12% increase in FEV1 with an absolute improvement in
FEV1 of at least 200 ml) not less than 15 minutes and up to 30 minutes after inhalation of 200 to 400 micrograms salbutamol via a spacer
Note: Reversibility should be determined at the time of Screening. At the investigator's discretion, if a patient fails to meet the not less than 12%m and 200 ml threshold, the reversibility tests may be repeated to a maximum of four measurements over one week. Once established, reversibility test need not be repeated in subsequent visits.
6. Patient judged by the investigator to be in otherwise good stable
health based on medical history, physical examination, and routine laboratory data
7. Female participants of child bearing potential must have a negative
pregnancy test at screening visit. In addition, female of child bearing
potential (FCBP) must agree to use TWO of the following contraceptive
measures from at least 14 days prior to the first dose of study
medication (i.e., 14 days prior to randomization) and continue until 28 days after dosing; combined oral contraceptive, hormonal intrauterine device, non hormonal intrauterine device, bilateral tubal ligation, barrier method of contraception (condom or occlusive cap [diaphragm/vault caps] with spermicidal foam/gel/film/cream/suppository); or vasectomized partner (sole partner). Female not of child bearing potential (i.e. are postmenopausal or permanently sterilized [e.g. tubal occlusion, hysterectomy, bilateral salpingectomy]) will not be required to use contraception. Female subject of child bearing potential must agree to have serum pregnancy tests during all visits while on study medication and until 2 weeks after taking the last dose of study medication.
8. Males (including those who have had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in reproductive sexual activity with FCBP while on study medication and for 90 days after taking the last dose of study medication.
Note:
* Documentation will involve availability of past prescriptions to
establish a clinical diagnosis of asthma. However, a prior spirometry
documentation of asthma is not required. Also, a cut-off date for
duration of asthma is not defined and not required, as long as patients fit
into other selection criteria. |
|
| E.4 | Principal exclusion criteria |
1. Patients currently on step 4 or 5 therapy as per GINA 2009
2. Pregnant or lactating women
3. Female subjects on hormone replacement therapy
4. Suffering from relevant lung diseases (other than asthma) causing
impairment in lung function (e.g. COPD [chronic bronchitis or
emphysema], obstructive sleep apnea requiring continuous positive
airway pressure)
5. Past history of Alpha 1 antitrypsin deficiency
6. History or suspected hypersensitivity to PDE4 inhibitors
7. Past smoker with a history of ≥10 packs per year or current smoker
(i.e. has smoked within the last 12 months prior to screening)
8. Recent (within 4 weeks prior to the enrolment visit) change in the patient's usual asthma treatment
9. Patients with risk factors for asthma exacerbation during the study,
including:
a) Current requirement for > 8 puffs per day of reliever medication
b) Hospitalisation for asthma
i. Within 1 month preceding screening and/or
ii. More than once in the 6 months preceding screening
c) Treatment with systemic (oral or parenteral corticosteroid therapy
within 1 month of screening or depot corticosteroid therapy within 3
months of screening) or receipt of more than 2 short courses of systemic
corticosteroid therapy in the preceding year
10. Evidence of current or recent neoplastic disease (other than patients
with basal or squamous cell skin cancer who are in remission /stable
who are eligible to enter the study)
11. Any 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
a. Any of the following clinically significant laboratory abnormalities:
• Significant renal insufficiency- Patients with serum creatinine
concentration >1.5 mg/dL
• Patients with a history of proteinuria >300 mg/day
• Patients with a clinically significant abnormal WBC count,
thrombocytopenia, or anaemia at screening
• Patients with evidence of clinically relevant hepatic disease (e.g.
values at screening or at randomization of more than 1.5 x ULN for
aspartate aminotransferase [AST], alanine aminotransferase [ALT],bilirubin or alkaline phosphatase; history of or current bleeding
oesophageal varices, ascites, encephalopathy)
• Positive serology for an infectious disease (including hepatitis B or C)
at screening and known case of human immunodeficiency virus [HIV]
b. Patients at risk for gastrointestinal haemorrhage (e.g. chronic peptic
ulceration)
c. Patients with a history of clinically significant cardiovascular disease
within the previous 6 months prior to screening (including, but not
limited to, unstable angina, myocardial infarction, stroke, peripheral
vascular disease, uncontrolled hypertension, ischemic changes on
resting ECG, Congestive cardiac failure of NYHF grade III and IV )
d. Patients who have been hospitalized for any psychiatric illness in the
past year, or are diagnosed with major depression
12. Baseline ECG QTc interval >450 ms or any other clinically significant
ECG abnormality
13. Patients with documented or suspected or current history of alcohol
or drug abuse
14. Patients who have undergone lung surgery in the previous year
15. Participation in an investigational drug trial during 30 days (or 9 half
lives) preceding screening |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change in morning pre-dose FEV1 from baseline to day 84 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline at days 7, 28, and 56 for morning pre-dose FEV1
- Change from baseline at days 7, 28, 56 and 84 in morning pre-dose
FVC, PEF, FEF25-75%
- Area under the curve of change from baseline morning pre-dose FEV1
measured at each visit to day 84
- Change from baseline in morning and evening PEF on days 7, 28, 56
and 84 (based on patient diary)
- Change from baseline at days 7, 28, 56 and 84 in morning pre-dose
FEV1, FVC, PEF, FEF25-75%, PEF for ICS and non ICS group
- Change in asthma day time symptom score from baseline at day 84
- Change in asthma night time symptom score from baseline at day 84
- Change in number of night time awakenings from baseline at day 84
- Frequency and the use of rescue (reliever) medication (salbutamol)
- Frequency and severity of asthma exacerbations
- Investigator global impression of change from baseline to day 84
- Patient global impression of change from baseline to day 84
- Plasma pharmacokinetics of revamilast and its metabolite GRC 4037
- Change from baseline in blood cell counts to day 84
o Differential cell count including eosinophils, neutrophils,
lymphocytes, monocytes, basophiles
o Total leukocyte count |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| India |
| Poland |
| Russian Federation |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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