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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the effect of of a twice daily dose of 100 mg AF-219 on cough reflex sensitivity in both healthy and chronic cough subjects |
|
E.2.2 | Secondary objectives of the trial |
To determine the effect of a twice daily dose of 100 mg AF 219 on cough severity VAS and urge-to-cough VAS in subjects with chronic cough
To determine the effect of a twice daily dose of 100 mg AF 219 on cough frequency in subjects with chronic cough
To assess the safety and tolerability of AF-219 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Both healthy and chronic cough subjects who meet all of the following criteria will be included in the study:
1. Be informed of the nature of the study and have provided written informed voluntary consent;
2. Be able to speak, read, and understand English;
3. Be males or females, of any race, between 18 and 80 years of age, inclusive;
4. Have a body mass index (BMI) ≥ 18 and < 35 kg/m2;
5. FEV1 ≥ 80% at Screening;
6. Be in good general health with no clinically relevant abnormalities based on the medical history, physical examination, clinical laboratory evaluations (hematology, clinical chemistry, and urinalysis), and 12 lead electrocardiogram;
7. Be non-smokers for at least 5 years;
8. If a female of child-bearing potential (i.e., have not undergone a hysterectomy or bilateral oophorectomy) or not post-menopausal (defined as no menses for at least 12 months), agree to use 2 forms of acceptable birth control from Screening through the Follow Up Visit; or if a male, they and/or their partner of child-bearing potential agree to use 2 forms of acceptable birth control from Screening through the Follow Up Visit;
9. Be able to communicate effectively with the Investigator and other study center personnel and agree to comply with the study procedures and restrictions.
10. Subjects with chronic cough must:
a. Have Treatment Refractory Cough for at least one year: a cough that is unresponsive to at least 8 weeks of targeted treatment for identified underlying triggers including reflux disease, asthma and post-nasal drip.
b. Have a cough for which no objective evidence of an underlying trigger can be determined after investigation.
c. Demonstrate significant cough symptoms by a score greater than 20/70 on the Hull Airway Reflux Questionnaire (HARQ)
d. Have a Cough Severity VAS ≥ 40 mm at Screening. |
|
E.4 | Principal exclusion criteria |
Subjects will be excluded if any of the following apply:
1. History of upper respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Baseline Visit (Day 0);
2. Have acute worsening of asthma;
3. Do not cough during the ATP or Capsaicin or Citric acid challenge at screening or only cough twice at the two highest concentrations of the test solution;
4. Demonstrate more than two coughs to inhalation of the normal saline solution during baseline challenge;
5. Treatment with an ACE-inhibitor as the potential cause of a subject‟s cough, or requiring treatment with an ACE-inhibitor during the study or within 4 weeks prior to Screening
6. History of opioid use within 1 week prior to the Baseline visit (Day 0);
7. Requiring concomitant therapy with prohibited medications (see Section 6.5);
8. History or symptoms of renal disease or renal obstructive disease:
a. History of kidney/bladder stones (nephro/uro-lithiasis) within 5 years of Screening.
b. 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.
c. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula [http://mdrd.com/]) at Screening.
9. History of concurrent malignancy or recurrence of malignancy within 2 years prior to Screening (not including subjects with <3 excised basal cell carcinomas);
10. History of a diagnosis of drug or alcohol dependency or abuse within approximately the last 3 years;
11. Any condition possibly affecting drug absorption (e.g., gastrectomy, gastroplasty, any type of bariatric surgery, vagotomy, or bowel resection);
12. Screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood pressure (DBP) >90 mm Hg;
13. Clinically significant abnormal electrocardiogram (ECG) at Screening, including any of the following:
a. QT (QTc) interval >450 milliseconds (msec) for males and >470 msec for females;
b. Atrial fibrillation or atrial flutter;
c. Heart rate <40 beats per minute (bpm) or >110 bpm;
d. Second degree or third degree (complete) AV block;
e. Left bundle branch block (including hemiblock);
f. Wolf-Parkinson-White Syndrome.
14. Personal or family history of congenital long QT syndrome or family history of sudden death;
15. Cardiac pacemaker;
16. Significantly abnormal laboratory tests at Screening, including:
a. Alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), aspartate aminotransferase (AST, SGOT), or total bilirubin >150% of the upper limit of normal (ULN);
b. Hemoglobin < 10 gm/dL, WBC count <2500 mm3, neutrophil count <1500 mm3, platelet count <100 × 103/ mm3;
c. Positive urine tests for drugs of abuse;
d. Positive tests at Screening for viral hepatitis (defined by positive immunoglobulin M (IgM) anti-hepatitis A virus (HAV), hepatitis B virus (HepB) sAg, anti-hepatitis C virus (HCV), or human immunodeficiency virus (HIV).
17. History of cutaneous adverse drug reaction to sulfonamides or signs and symptoms suggestive of anaphylaxis to sulfonamides;
18. Pregnant or breastfeeding;
19. Treatment with an investigational drug or biologic within 30 days preceding the first dose of study medication or plans to take another investigational drug or biologic within 30 days of study completion;
20. Blood donation within 56 days or plasma donation within 7 days prior to dosing;
21. 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 or Sponsor, would make the subject inappropriate for entry into this trial. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cough reflex sensitivity is measured by standard clinical methodology incorporating capsaicin, citric acid, ATP, and distilled water cough challenges. The standard end points measured in cough challenge testing are the concentrations of the challenge agents inducing 2 or more (C2) and 5 or more coughs (C5).
A logC5 is generally regarded as normally distributed within a population, so parametric comparison of paired observations will be made. In experiments where single paired observations are made two-tailed tests will be used. Where multiple comparisons are made, analysis of variance will be used. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoints are evaluated during entire treatment period |
|
E.5.2 | Secondary end point(s) |
Safety analysis: Clinical safety data from physical examinations, vital signs, 12 lead ECGs, clinical laboratory tests (hematology and clinical chemistry), and AEs/SAEs will be listed and summarized using descriptive statistics; urinalysis results will be listed and crystalluria will be described. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints are evaluated during entire treatment period |
|
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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | 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 | 2 |
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
|
|
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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |