Study of the Safety and Effectiveness of BC1036 Capsules to Treat Frequent Long-Term Cough

A Multicentre, Double-Blind, Placebo-Controlled, Adaptive Pivotal Study of the Efficacy and Safety of Oral BC1036 in the Management of Cough

The purpose of this study is to investigate the effect of BC1036 (theobromine) on cough-related quality of life and cough severity following 2 weeks' treatment.

Study Overview

• Status: Completed
• Conditions: Cough
• Intervention / Treatment: Drug: BC1036

Detailed Description

Cough is a common and disabling symptom. At any one time 20% of the population have a troublesome cough and sufferers consume 75 million doses of over-the-counter anti-tussive (anti-cough) medication annually. Chronic cough can be the presenting symptom of almost all respiratory conditions; it can also occur in the absence of overt lung pathology. The only study to grade cough severity found 7% of a general population had cough sufficient to interfere with activities of daily living on at least a weekly basis in the UK. Cross sectional studies have consistently shown that chronic cough is particularly prevalent in middle aged females.

The investigational medicinal product BC1036 (theobromine) is being developed as a non-codeine, non-narcotic treatment for persistent cough. Theobromine is a well characterised molecule with a long history of safe use both as a medicine and as a food product. As a member of the xanthine family, it bears structural and pharmacological similarity to caffeine and theophylline, both of which have long been approved for medicinal use.

This is a placebo-controlled, double-blind, parallel group study of BC1036 in subjects with persistent cough (chronic or sub-acute), treatment resistant after a routine clinical assessment as outlined in the BTS Recommendations for the Management of Cough in Adults and despite adequate treatment of any associated potential aggravating factors or without the continuance of any obvious precipitating factors. The objective is to investigate the effect of BC1036 on cough-related quality of life and cough severity following 2 weeks' treatment. It is planned to recruit 288 evaluable subjects from cough clinics, secondary and primary care centres in the UK. Subjects will receive either BC1036 or placebo over a period of 14 days.

Eligible subjects will be required to attend the clinic on five occasions: screening, baseline, days 7, 14, and a follow up visit at day 28. At every visit the subjects will complete the Leicester Cough Questionnaire (LCQ), and a cough Visual Analogue Score (VAS). Spirometry will be performed for measurement of lung function. Blood samples will be drawn for safety clinical laboratory parameters and physical examinations and ECG will be performed. Subjects should be seen for all visits on the designated day ± 1 day, except Day 28 ± 2 days.

• Study Type: Interventional
• Enrollment (Anticipated): 288
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Belfast, United Kingdom, BT7 2EB
    • Ormeau Road Health Centre
  • Belfast, United Kingdom
    • The Queen's University of Belfast
  • Cottingham, United Kingdom, HU16 5JQ
    • Castle Hill Hospital
  • East Horsely, United Kingdom, KT24 6QT
    • The Medical Centre
  • Garston, Watford, United Kingdom, WD25 0EA
    • Sheepcot Medical Centre
  • Leicester, United Kingdom, LE3 9QP
    • Glenfield Hospital
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • London, United Kingdom, SW3 6LY
    • Royal Brompton Hospital
  • Mortimer, United Kingdom, RG7 3SQ
    • Mortimer Surgery
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Sheffield, United Kingdom, S35 9XQ
    • Ecclesfield Group Practice
  • Soham, Ely, United Kingdom, CB7 5JD
    • Staploe Medical Centre
  • Wellingborough, Northampton, United Kingdom, NN8 4RW
    • Albany House Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged 18 to 75 years.
• Confirmed diagnosis of a persistent cough.
• Leicester Cough Questionnaire score of ≤ 17 at baseline.
• FEV ≥ 70% of predicted normal, at screening. See protocol Appendix 4 for formula for calculating predicted values.
• Willing to use effective contraception for the duration of the study. Female subjects who are neither surgically sterilized nor post-menopausal (defined as no menses for one year or an FSH value > 40 mIU/L) will be required to use two methods throughout the study and for 30 days after. Besides abstinence the following contraceptive methods are acceptable: hormonal (e.g. oral, injection, transdermal patch, implant, cervical ring), barrier (e.g. condom or diaphragm with spermicidal agent) or intrauterine device. If hormonal contraceptives are used they must be used from 6 weeks before the first administration of test product. Male subjects must agree to use condoms for the duration of the study and for 30 days after.
• Willing and able to give informed consent and of complying with the trial assessments and any other trial procedures.

Exclusion Criteria:

• Pregnant or lactating females.
• Major surgery within the 30 days preceding the screening visit.
• Any serious infections within the 30 days prior to the screening visit.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, renal or hepatic disease or psychiatric illness/social situations that would limit compliance with study requirements.
• Known hepatitis B or C or human immunodeficiency virus (HIV) or syphilis seropositivity.
• A history of serious adverse allergic reaction to any medication.
• Treatment with another investigational medicinal product within the 30 days prior to enrollment.

• Treatment with:

  • Systemic oral steroids within 7 days prior to randomisation at Visit 2.
  • Theophylline and theophylline-like agents within 7 days prior to randomisation.
  • Opiates or opioids e.g. codeine, dextromethorphan, within 7 days prior to randomisation.
  • ACE inhibitors within one month prior to the screening visit.
• Depot injection of corticosteroids within 6 weeks of the screening visit.
• History suggestive of febrile illness within the last 7 days prior to the screening visit.
• Subjects with significant sputum production (defined as more than 5 ml (~one teaspoon)/day on any three days in the screening period).
• Current smokers or past smokers who have a smoking history of > 20 pack years or stopped smoking ≤ 12 months prior to screening.
• Any pulmonary co-morbidity such as COPD, recurrent lower respiratory tract infections (≥ 2 in the 12 months prior to screening) and bronchiectasis where cough suppression may lead to sputum retention and infection.
• Any pulmonary abnormality on chest X-ray or CT scan performed in the twelve months prior to enrolment indicative of COPD, bronchiectasis etc.
• Subjects diagnosed with asthma who have suffered an exacerbation requiring hospitalisation within 4 weeks prior to screening.
• A history of cancer within the previous five years (excluding carcinoma in situ or nonmelanoma skin cancer treated by surgical excision).
• Uncontrolled hypertension (resting systolic BP > 170mmHg or resting diastolic BP > 95 mm Hg).
• A corrected QT interval of > 470ms for female subjects or of > 450ms for male subjects, calculated using the QTcF correction formula, or second degree or higher heart block on an ECG recording, at screening.
• Subjects known to have a sensitivity to methylxanthines and related compounds, or known to have exhibited an allergic response or sensitivity to cocoa-based products.
• History or presence of alcohol or substance abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: BC1036; BC1036 300 mg capsule capsule by mouth, twice daily, for 14 days.	Drug: BC1036; Other Names: Theobromine; CAS number 83-67-0; EV Substance code SUB15511MIG
PLACEBO_COMPARATOR: Sugar Pill; Sugar placebo capsule by mouth, twice daily, for 14 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leicester Cough Questionnaire (LCQ)	Cough-related quality of life assessed using the Leicester Cough Questionnaire (LCQ). The baseline-adjusted total LCQ score at Day 14 will be used as the primary endpoint.	Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adapted 7-day Leicester Cough Questionnaire (LCQ)	Adapted 7-day LCQ to measure quality of life over the previous 7 days.	Day 7
Leicester Cough Questionnaire (LCQ)	LCQ at Day 28 will measure quality of life over the previous 14 days.	Day 28
Cough visual analogue scale (VAS)	VAS scores on a 100 mm scale fixed at both ends by 'no cough' and 'worst cough ever'. Assessment made at every visit.	From screening to Day 28
Airway sensitivity using capsaicin challenge	Subgroup of approximately 100 subjects will be challenged with capsaicin at Day 0 and Day 14.	Day 0 and Day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary function tests	Pulmonary function will be measured at all visits using a calibrated spirometer. This includes Forced Expiratory Volume (FEV), Forced Vital Capacity (FVC) and peak flow.	From screening to day 28

Collaborators and Investigators

• Sponsor: Respicopea Limited
• Investigators: Principal Investigator: Alyn Morice, BA(Hons) MB.B.Chir MA FRCP, Castle Hill Hospital; Principal Investigator: Fan Chung, MB, BS, MD, FRCP, DSc (PI), Royal Brompton & Harefield NHS Foundation Trust; Principal Investigator: Warwick Coulson, BSc, MBBS, DipRCOG, MRCGP, Albany House Medical Centre; Principal Investigator: Alun George, MA MBBS, DRCOG, DCH, MRCGP, Staploe Medical Centre; Principal Investigator: Bernard Higgins, MB ChB, MRCP, MD, Freeman Health System; Principal Investigator: Alan Jackson, MB, BS, Sheepcot Medical Centre; Principal Investigator: Philip Marazzi, MB, BS, The Medical Centre; Principal Investigator: Ian Pavord, MB BS, MRCP, FRCP, DM, Glenfield Hospital; Principal Investigator: Surinder Birring, BSc,MBChB(Hons),MRCP,MD(PI), King's College Hospital NHS Trust; Principal Investigator: Lorcan McGarvey, MBBCh,BAOHons,MRCP,MD,CCST(PI), The Queen's University of Belfast; Principal Investigator: Richard Oliver, MB ChB, MRCGP, Ecclesfield Group Practice; Principal Investigator: Chris Strang, MB BS, D. Obst, RCOG M, Mortimer Surgery; Principal Investigator: Damien McNally, MB,BCh,BAO,DRCOG,DMH,MRCGP, Ormeau Road Health Centre

Publications and helpful links

General Publications

• Morice AH, McGarvey L, Pavord ID, Higgins B, Chung KF, Birring SS. Theobromine for the treatment of persistent cough: a randomised, multicentre, double-blind, placebo-controlled clinical trial. J Thorac Dis. 2017 Jul;9(7):1864-1872. doi: 10.21037/jtd.2017.06.18.

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (ACTUAL): August 1, 2013
• Study Completion (ACTUAL): August 1, 2013

Study Registration Dates

• First Submitted: July 27, 2012
• First Submitted That Met QC Criteria: August 2, 2012
• First Posted (ESTIMATE): August 3, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): August 2, 2013
• Last Update Submitted That Met QC Criteria: August 1, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: Persistent; Cough; Chronic; Acute; Longterm
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Cough; Physiological Effects of Drugs; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Theobromine
• Other Study ID Numbers: BC1036-001