| 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 | 17.1 |
| 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 |
| The primary objective of this study is to assess the PC20 response (concentration of methacholine required to cause at least a 20% fall in lung function) of two dose levels of AF-219 compared with placebo in subjects with asthma after provocation with methacholine. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess the safety and tolerability of a two dose levels of AF-219 compared with placebo after 3.5 days of treatment.
The exploratory objective is to assess the response of two dose levels of AF-219 compared with placebo in subjects with asthma after provocation with inhaled ATP. In addition, the relationship between AF-219 plasma concentrations and methacholine and ATP provocation will be explored. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following criteria will be included in the study:
1. Age between 18 and 65 years, inclusive.
2. Women of child bearing potential (i.e., women who are not surgically sterile, not having had hysterectomy, bilateral tubal occlusion or bilateral oophorectomy, or are not post-menopausal) must have a negative pregnancy test at Screening and prior to randomisation. Definition of postmenopausal status is having been naturally (spontaneously) amenorrhoeic for more than 12 months with an appropriate clinical profile, eg, age appropriate, history of vasomotor symptoms. Women of child-bearing potential must be using 2 forms of acceptable birth control method from Screening through the Follow-Up Visit. Acceptable birth control methods include (of which 2 must be used):
• established use of oral, injected or implanted hormonal methods of contraception;
• intrauterine device (IUD) or intrauterine system (IUS);
• Condom with spermicide
• Diaphragm with spermicide
Double-barrier method (diaphragm for female subject and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control.
When in line with the preferred life style of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
3. Male subjects with partners of child-bearing potential (as defined in Inclusion No. 2) must use 2 methods of acceptable birth control with their partner, 1 of which must be a barrier method. Contraception must start from screening and continue until 3 months after last dose of study drug
4. Non-smokers or former smokers, who stopped smoking 6 months prior to screening. Former smokers should not have a smoking history of more than 5pack years (1 pack of 20 cigarettes per day over 5 years).
5. Pre-bronchodilator (after abstaining from Short acting β2-agonist for ≥8 hrs) Forced Expiratory Volume (FEV1) ≥70% of the predicted normal value at the initial screening visit for the purposes of eligibility.
6. Pre-bronchodilator (after abstaining from Short acting β2-agonist for ≥8 hrs) Forced Expiratory Volume (FEV1) ≥70% of the predicted normal value OR if less than 70% must be within +/- 12 % of screening FEV1 prior to randomization. NB: This visit must not be rescheduled if criteria are not met.
7. Physician documented history or diagnosis of asthma for at least 6 months prior to screening according to the Global Initiative in Asthma guidelines (GINA, 2012).
8. Requires the use of Short acting β2-agonist therapy only (≤ 8 puffs per day) for at least 4 weeks prior to screening and prior to randomisation.
9. Positive response to methacholine challenge (PC20 ≤ 8 mg/mL) at screening.
10. Positive response to ATP challenge (PC20 ≤ 200 µmol/mL) at screening.
11. Have provided written informed consent
12. Are willing and able to comply with all aspects of the protocol
|
|
| E.4 | Principal exclusion criteria |
Subjects are NOT eligible for this study if they meet any of the following criteria:
1. Has been hospitalised or attended the emergency department for an asthma attack in the 12 months prior to screening.
2. Exacerbation of asthma or Lower respiratory tract infection during the 4 weeks before screening or prior to randomisation
3. Upper respiratory tract infection during the 4 weeks before screening or prior to randomization requiring treatment with antibiotics.
4. Inhaled or systemic corticosteroids (oral, intravenous, intramuscular) within 4 weeks prior to screening or prior to randomisation.
5. Short-acting or long-acting antihistamines within 48hrs or 7 days, respectively, prior to screening.
6. Body mass index (BMI) <18 kg/m2 or ≥ 35 kg/m2 at screening
7. History of kidney/bladder stones (nephro/uro-lithiasis) within 5 years of Screening
8. History of conditions or disorders that predispose to nephrolithiasis, such as Type 1 renal tubular acidosis, cystinuria, gout, hyperparathyroidism, inflammatory bowel disease (i.e., ulcerative colitis and crohn’s disease), short bowel syndrome, or bariatric surgery
9. History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with basal cell carcinomas or cervical carcinoma in situ that has been successfully treated surgically)
10. Personal or family history of congenital long QT syndrome
11. Presence of a cardiac pacemaker
12. History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years
13. Diagnosis of depression, psychosis, bipolar disorder, or schizoaffective disorder
14. In the opinion of the Investigator, in discussion with the Medical Monitor if required, an uncontrolled or unstable, clinically significant neurological, psychiatric, respiratory, cardiovascular, peripheral vascular, gastrointestinal, hepatic, pancreatic, endocrinological, hematological, or immunological disorder or an active infection
15. Patients with diabetes Type I or uncontrolled diabetes Type II or HbA1c > 8.0% at screening.
16. Any condition possibly affecting drug absorption e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection
17. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (using the(CKD EPI) formula (Levey, 2009) at screening
18. Systolic blood pressure >160 mm Hg or a diastolic blood pressure >90 mm Hg or Heart rate <40 bpm or >110 bpm at screening or prior to randomisation.
19. Clinically significant abnormal electrocardiogram (ECG) at Screening, including any of the following:
a. QTcB interval >450 milliseconds in males, >470 milliseconds in females
b. Atrial fibrillation or atrial flutter
c. Heart rate <40 bpm or >110 bpm
d. Second degree or third degree (complete) AV block
e. Left bundle branch block (including hemiblock)Wolf-Parkinson-White Syndrome
20. Significantly abnormal laboratory tests at Screening, including:
a) alkaline phosphatase (AP), alanine aminotransferase (SGPT, ALT), aspartate aminotransferase (AST, SGOT), or bilirubin >150% of the upper limit of normal (ULN)
b) hemoglobin < 11 gm/dL in males / < 10 gm/dL in females, white blood cell (WBC) count <2.5x109 /L, neutrophil count <1.5 x10^9 /L, platelet count <100 × 10^9/L
c) Positive tests for drugs of abuse at screening or prior to randomisation
d) Positive alcohol breath test at screening or prior to randomisation
e) Positive tests for human immunodeficiency virus (HIV) or viral hepatitis, defined by positive immunoglobulin M (IgM) anti-hepatitis A virus (HAV), hepatitis B surface antigen (HepB sAg), or anti-hepatitis C virus (HCV)
21. History of cutaneous adverse drug reaction to sulphonamides or signs or symptoms suggestive of anaphylaxis to sulfonamides.
22. Requiring concomitant therapy with prohibited medications at screening or prior to randomisation.
23. Pregnant or breastfeeding woman
24. Donation of sperm from Screening until 3 months after the last dose of study drug.
25. Male subjects with pregnant female partners
26. Treatment with an investigational drug within 30 days or five half lives preceding the first dose of study medication or plans to take another investigational drug within 30 days of study completion
36. Donation or loss of 400 ml or more of blood or donations of plasma within eight (8) weeks prior to initial dosing or longer if required by local regulation
37. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the Investigator after discussion with the medical monitor, if required, would make the subject inappropriate for entry into this trial
38. Failure to satisfy the investigator of fitness to participate for any other reason
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is methacholine PC20.
• This value will be normalised by means of a log (base 2) transformation,
• The primary comparison will be : AF-219 300 mg PO BID vs. placebo.
• Secondary comparisons are :
o AF-219 50 mg PO BID vs placebo
o AF-219 300 mg PO BID vs AF-219 50 mg PO BID
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Each methacholine challenge. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints include:
- Safety (AE, laboratory, Vital Signs, ECG) and PK parameters
- Change in FEV1 after methacholine challenge
Exploratory endpoints include:
- ATP PC20
- Change in FEV1 after ATP challenge
- Cough post ATP challenge
- Breathlessness (modified BORG scale) post methacholine and ATP challenge |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints:
From first drug administration to end of trial.
Exploratory endpoints:
Each methacholine and ATP challenge. |
|
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The last visit of the last subject on the study (LSLV). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
Print
