A Study of the Effect of 20 mg Ambroxol Hydrochloride on Acute Cough.

Cough is the 5th most common presenting complaint in adults. Cough results from the stimulation of two types of afferent pathways whose receptors are located within the airway epithelium. These include rapidly adapting receptors (RARs) and C-fibre receptors. Acute as well as chronic, non-productive cough, which often follow viral upper respiratory tract infection, may result from increased sensitivity of the cough reflex. Relatively little research has been done to gain insight into the mechanisms of cough in health and disease, and to properly evaluate potential antitussive therapies. Indeed, little consensus exists regarding the optimal treatment of acute cough because of the lack of standardised outcome measures for cough. Possibly the most significant clinical need in terms of cough therapy is for the cough associated with an acute upper respiratory tract infection (URTI). Although the cough associated with URTI is often self-limiting and resolves within several days, it undoubtedly accounts for a major proportion of huge worldwide expenditure of over-the-counter (OTC) cough and cold products where patients are still struggling to find an effective medication.

This exploratory study will enable us to identify the cough challenge agent (CCA) that is most sensitive to the effect of ambroxol on cough reflex. This is expected to provide a reproducible response, to use in future studies.

This will be an open label, study in subjects with acute cough associated with URTI.

There will be a Screening/Baseline and combined Treatment visit. Subjects will return approximately 1-4 weeks after their treatment once all symptoms have subsided and the subject is no longer suffering from URTI, for a Follow-up Visit.

Up to 14 subjects with acute cough in relation to a URTI and who meet all entry criteria will be assigned to:

Treatment p.o 20 mg ambroxol lozenge (Lysopain Ambr MintM)

At Baseline and post treatment, cough sensitivity will be measured by standard clinical methodology incorporating a series of four cough challenges (citric acid, capsaicin, ATP and distilled water).

Screening/baseline visit 1a The Screening and Baseline visit will ensure that each subject meets all the specified inclusion and none of the exclusion criteria.

Treatment phase visit 1b Subjects who satisfy all entry criteria at baseline will be administered 20 mg ambroxol in the form of a lozenge which must be sucked until fully dissolved in the mouth.

The treatment will be administered in the afternoon of the same visit day as the screening/baseline assessments.

The series of abbreviated cough challenges will be conducted at 30 min and 90 min post dose.

Telephone contact Patients will be contacted by telephone once a week to determine if all symptoms associated with URTI have abated. Once this is confirmed patient will be booked in for the follow-up visit.

Follow-Up Phase Subjects will return within 4 weeks after treatment for a Follow-Up Visit once symptoms of URTI have abated. A series of full cough challenges will be performed at this vist to determine reduction in cough hypersensitivity.

Inclusion criteria

• Be informed of the nature of the study and have provided written informed voluntary consent;
• Be able to speak, read, and understand English;
• Be males or females, of any race, between 18 and 80 years of age, inclusive;
• Subject has an acute cough and other symptoms consistent with a common cold or an acute upper respiratory tract infection (URTI) diagnosis deemed by the investigator based on findings from medical history review, full physical examination and vital signs;
• The onset of symptoms must be within 72 h of study enrolment;
• Have a Cough Severity VAS ≥ 40 mm at Screening;
• Be in good general health (other than URTI) with no clinically relevant abnormalities based on the medical history, physical examination, and 12 lead electrocardiogram;
• Cough at least twice to all cough challenge Agents - citric acid, capsaicin, ATP and distilled water cough challenges at baseline.
• 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 to 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;
• Be able to communicate effectively with the Investigator and other study centre personnel and agree to comply with the study procedures and restrictions.

-

Exclusion criteria

• History of asthma or other respiratory related disease
• Symptoms of runny nose, stuffy nose, sore throat, or sneezing due to any condition other than URTI or common cold (e.g., seasonal or perennial allergic rhinitis, sinusitis, strep throat, vasomotor rhinitis, etc.) as established by the investigator
• Clinical features of a complication of the common cold during the physical examination at screening (e.g., otitis media, sinusitis, or pneumonia) with or without the need for systemic antibiotics
• History of a severe cutaneous adverse reaction to any treatment;
• Evidence of a possible bacterial infection i.e. sinus pain, purulent nasal discharge or pleuritic pain.
• Evidence of chest infection or pneumonia
• Fever greater than 39ºC (102ºF oral temperature) at the time of screening if, in the judgment of the investigator, the individual is too ill to participate in the study or the fever is due to reasons other than URTI
• Demonstrate more than two coughs to inhalation of the normal saline solution during baseline challenge
• Current smoker or individuals who have given up smoking within the past 6 months or those with >20 pack-year smoking history;
• Treatment with an ACE-inhibitor during the study or within 4 weeks prior to Screening
• History of opioid use within 1 week prior to baseline;
• Requiring concomitant therapy with prohibited medications
• History of known or suspected allergy or hypersensitivity reactions to ambroxol (e.g., asthma, urticaria or allergic type) or any of the non-medicinal ingredients contained in the study investigational product.
• Clinically significant abnormal electrocardiogram (ECG) at Screening;
• Personal or family history of congenital long QT syndrome or family history of sudden death;
• Pregnant or breastfeeding;
• 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;
• 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 -