Botulinum Toxin and Saliva Management in Tracheotomised Patients
Botulinum Toxin and Saliva Management in Tracheotomised Patients
TITLE

 A randomised placebo controlled trial to explore the effectiveness of Botulinum Toxin
 injection at reducing oral secretions and frequency of tracheal suctioning in tracheotomised
 patients.

 DESIGN

 Randomised controlled single blinded experimental design

 AIMS

 The purpose of this study is to determine if ultra-sounded guided injections of Botulinum
 Toxin into the salivary glands (Parotid and sub-mandibular glands) of patients with a
 tracheostomy tube in-situ assists in the reduction of oral secretions.

 OUTCOME MEASURES

 Amount of saliva production / frequency of tracheal suctioning / questionnaires.

 POPULATION

 In-patients at the Wellington Hospital based in London will be invited to participate within
 the study. Participants will be recruited from a range of wards which will include the
 Intensive Treatment Unit (ITU), acute medical wards and rehabilitation wards. All
 participants will have a tracheostomy tube in-situ and be breathing on room air, without the
 need for any mechanical ventilation. Participants will be receiving tracheal suctioning to
 assist in the clearance of saliva to maintain a clear airway.

 A total of 40 participants will be recruited to the study across a two year period.

 Each participant will have no prior history of the following:

 -  swallowing disorders

 -  stroke

 -  myocardial infarction

 -  head or neck surgery

 -  respiratory disease

 -  acute or progressive neurological disease

 -  structural abnormalities that could affect swallowing

 -  other medical conditions requiring medication that could affect swallowing.

 ELIGIBILITY

 Male and female adults over the age of 18 years

 TREATMENT

 Injection of Botulinum Toxin into both pairs of the parotid salivary glands and submandibular
 glands, using ultrasound guidance

 DURATION

 Data collection over a two year period / six weeks for each participant
A randomised placebo controlled trial to explore the effectiveness of Botulinum Toxin
 injection at reducing oral secretions and frequency of tracheal suctioning in tracheotomised
 patients.

 Protocol Number: Version 5, 20th July 2009

 HCA reference: CTO/09/032

 EudraCT reference: 2009-011204-27

 This protocol describes the Botulinum toxin and Saliva management study and provides
 information about procedures for entering participants. Every care was taken in its drafting,
 but corrections or amendments may be necessary. These will be circulated to investigators in
 the study. Problems relating to this study should be referred, in the first instance, to the
 Chief Investigator. This study will adhere to the principles outlined in the NHS Research
 Governance Framework for Health and Social Care (2nd edition). It will be conducted in
 compliance with the protocol, the Data Protection Act and other regulatory requirements as
 appropriate

 GLOSSARY OF ABBREVIATIONS

 AE Adverse Event AR Adverse Reaction CTA Clinical Trials Authorisation CTO Clinical Trials
 Office CRF Case Report Form CRGO Clinical Research Governance Office MHRA Medicines and
 Healthcare Regulatory Agency REC Research Ethics Committee SAE Serious Adverse Event SUSAR
 Suspected Unexpected Serious Adverse Reaction

 KEYWORDS Botulinum toxin, Saliva, Tracheostomy tube, Tracheal suctioning.

 STUDY SUMMARY

 TITLE A randomised placebo controlled trial to explore the effectiveness of Botulinum Toxin
 injection at reducing oral secretions and frequency of tracheal suctioning in tracheotomised
 patients.

 DESIGN Randomised controlled single blinded experimental design AIMS The purpose of this
 study is to determine if ultra-sounded guided injections of Botulinum Toxin into the salivary
 glands (Parotid and sub-mandibular glands) of patients with a tracheostomy tube in-situ
 assists in the reduction of oral secretions.

 OUTCOME MEASURES Amount of saliva production / frequency of tracheal suctioning /
 questionnaires.

 POPULATION In-patients at the Wellington Hospital based in London will be invited to
 participate within the study. Participants will be recruited from a range of wards which will
 include the Intensive Treatment Unit (ITU), acute medical wards and rehabilitation wards. All
 participants will have a tracheostomy in-situ and be breathing on room air, without the need
 for any mechanical ventilation. Participants will be receiving tracheal suctioning to assist
 in the clearance of saliva to maintain a clear airway.

 A total of 40 participants will be recruited to the study across a two year period.

 Each participant will have no prior history of the following: (a) swallowing disorders; (b)
 stroke; (c) myocardial infarction; (d) head or neck surgery; (e) respiratory disease; (f)
 acute or progressive neurological disease; (g) structural abnormalities that could affect
 swallowing and (h) other medical conditions requiring medication that could affect
 swallowing.

 ELIGIBILITY Adults over the age of 18 years

 TREATMENT Injection of Botulinum toxin injections into both pairs of salivary glands (parotid
 and submandibular glands), using ultrasound guidance DURATION Data collection over a two year
 period / six weeks for each participant

 1. INTRODUCTION

 1.1 BACKGROUND

 This Randomised Placebo Controlled trial will explore whether Botulinum Toxin injection
 into the salivary glands of tracheostomised patients is effective at reducing oral
 secretions and frequency of tracheal suctioning. The management of excess saliva ranges
 from conservative, such as postural changes and biofeedback to more aggressive such as
 medication, surgical and radiological intervention. Studies have shown that the use of
 medications, such as glycopyrrolate and scopolamine, are effective in reducing drooling,
 but have many adverse side effects, such as excessive dry mouth, constipation, urinary
 retention, decreased sweating and skin flushing 1-3. Recent research has shown that the
 long-term efficacy of intra-oral surgery for the management of sialorrhea to be
 minimally effective and that over two-thirds of patients had recurrence following
 surgery resulting in pharmacological or further surgical intervention 4. In contrast
 studies using radiation therapy in the management of sialorrhea, have shown initial
 satisfactory responses with up to 80% success rate, although there were some reported
 side effects, including oral candidiasis and mild skin reactions amongst participants 5

 Many studies have investigated the management of sialorrhea (drooling or excessive
 salivation) in both Parkinson's disease patients and in children with cerebral palsy,
 using Botulinum Toxin injected into the salivary glands 6-8. Several studies report on
 the use and efficacy of ultra-sound guided injection versus direct 'blind' injection
 into the salivary gland or glands 6 9-11, concluding that blind injections are as
 effective as ultra-sound guided injection, when solely injecting into the parotid gland.
 However, when injecting into both the parotid and submandibular glands use of guided
 injections as well as being a safe and effective technique in the treatment of
 sialorrhea 11 12. However to date there has been no application of Botulinum Toxin in
 patients who have a tracheostomy in-situ and who require regular tracheal suctioning due
 to excessive saliva and / or associated swallowing difficulties. This lack of knowledge
 may be of relevance given airway suctioning is associated with clinically significant
 complications, such as hypoxia microatelectasis (alveolar damage), laryngospasm and
 tracheal wall damage 13. Hooper suggested that the presence of a tracheostomy tube may
 cause irritation, resulting in an increased production of sputum 14.

 Patients have reported sensations of pain, pressure, crushing, choking and gagging,
 whereas in the hands of a skill practitioner, suctioning may not be more than a
 discomfort 15.

 Furthermore a study investigating knowledge and competence in performing tracheal
 suctioning in acute and within high dependency ward areas concluded that many staff
 members were unaware of recommended practice and a number demonstrated potentially
 unsafe practices 16.

 1.2 RATIONALE FOR CURRENT STUDY

 If ultra-sound guided Botulinum Toxin injection into the parotid and submandibular
 salivary glands is shown to be effective in reducing the amount of oral saliva and
 subsequently reducing for the need to perform tracheal suctioning, this can ultimately
 make tracheal suctioning unnecessary, reduce the time to extubation and normalise
 airflow through the larynx. This in turn may normalise swallowing physiology, with the
 ultimate outcome of removal of the tracheostomy tube.

 A reduction in salivary secretions may also significantly reduce the likelihood of
 aspiration pneumonia which may have a positive impact on length of stay as well as a
 reduction in healthcare costs.

 Given the wide-range of clinical competencies necessary for the safe and effective
 administration of tracheal suctioning, any pharmacologically induced benefit could
 attenuate the incidence of secondary complications as well as the likelihood of
 associated malpractice litigation.

 The current study will also aid in producing guidelines in the management of saliva in
 this patient population.

 2. STUDY OBJECTIVES

 To determine whether Botulinum Toxin is effective at reducing oral secretions in
 tracheotomised patients.

 To determine whether Botulinum Toxin is effective at reducing the frequency of tracheal
 suctioning in tracheotomised patients.

 To investigate self-perceptions by patients in the management of oral / tracheal
 secretions

 To investigate nursing perceptions on amount oral secretions and frequency of tracheal
 suctioning

 3. STUDY DESIGN

 The design will be a randomised, placebo-controlled single-blinded experimental study.
 Eligible patients will be randomly assigned to receive either active treatment or a
 placebo. Randomisation will be performed by matching consecutive eligible patients to a
 list of random numbers, generated via a computerised programme, allocating to either
 group.

 Each participant will be recruited for durations of six weeks in total. The treatment
 (injections of Botulinum toxin into the salivary glands) will be given one-week post
 after initial baseline measurements have been taken. Each participant will be
 followed-up at one week, two weeks and four weeks post injection. The patient will also
 continue to be reviewed throughout the study by the Speech and Language Therapist.

 3.1 STUDY OUTCOME MEASURES

 Primary Outcome measure

 To determine whether Botulinum Toxin is more effective than placebo at reducing oral
 secretions, as measured in milligrams at one week, two weeks and at four weeks follow up
 visits.

 Secondary Outcome measures

 To determine whether there is a difference in the frequency of tracheal suctioning
 performed, across a 12-hour period, between the treatment and placebo controlled group,
 as measured by the volume of secretions suctioned at one week, two weeks and four weeks
 follow up visits.

 To investigate the self-perceived patient outcomes of amount of oral secretions and
 frequency of tracheal suctioning required, using a self-perception questionnaire, to be
 completed at one week, two weeks and at four weeks follow up visits.

 To investigate nursing perceptions on the amount of oral secretions and frequency
 tracheal suctioning required by individual patients, using a questionnaire, to be
 completed at one week, two weeks and at four weeks follow up visits.

 4. PARTICIPANT ENTRY

 4.1 PRE-RANDOMISATION EVALUATIONS

 All participants will be referred to the speech and language therapy department by their
 primary Consultant, for assessment of their tracheostomy, communication and / or
 swallowing.

 The patient will be assessed by the Speech and Language Therapist, using a Clinical
 Bedside Evaluation (CBE), as to whether they are able to safely swallow their own saliva
 or require tracheal suctioning to assist in clearing secretions that are falling into
 their airway.

 4.2 INCLUSION CRITERIA

 Patients must meet all of the following inclusion criteria to be eligible for enrolment
 into the study;

 Male or female participants over the age of 18 years

 Participants who have a tracheostomy tube in-situ

 Participants who are breathing on room air, without the need for any mechanical
 ventilation

 Participants who require tracheal suctioning in order to maintain a clear airway

 4.3 EXCLUSION CRITERIA

 Patients presenting with any of the following exclusion criteria will not be included in
 the study;

 Contra-indications to the use of Botulinum Toxin

 Receiving medications that may react with Botulinum Toxin, such as aminoglycosides
 (e.g., gentamicin), anticholinesterase medicines (e.g., neostigmine), lincosamides
 (e.g., clindamycin), magnesium, neuromuscular blockers (e.g., atracurium), polymyxin, or
 quinidine because the risk of toxic effects may be increased

 Receiving anticoagulants medication (e.g., warfarin)

 Expectant mothers

 Previous history of;

 Swallowing disorders Stroke Myocardial Infarction Heart Disease Head or neck surgery
 Acute or progressive neurological disease Structural abnormalities that may affect
 swallowing

 4.4 WITHDRAWAL CRITERIA

 Patients will be able to withdraw from the study at any time and will continue to
 receive therapy intervention / treatment as is required. Subjects may be withdrawn from
 the study for any of the following reasons;

 Personal reasons: as stated in the informed consent form, subjects may withdraw from the
 study at any time

 Subject withdraws consent

 Clinical judgement of the Investigator: a subject may be withdrawn from the study, if
 the opinion of the Investigator, it is not in the subject's best interest to continue

 Loss to follow-up

 If the patient withdraws from the study and also withdraws consent for disclosure of
 future information, no further evaluations will be performed and no additional data
 collected. The investigator will retain and continue to use any data collected before
 such withdrawal of consent.

 Withdrawal due to an adverse event should be distinguished from that due to patient
 perceived lack of treatment response or any other reason for withdrawal and recorded on
 the appropriate adverse event Case Report Form.

 If a patient withdraws due to a serious adverse event, the serious adverse event will be
 reported in accordance with the reporting requirements defined in Section 7,
 Pharmacovigilence.

 5. RANDOMISATION AND ENROLMENT PROCEDURE

 5.1 RANDOMISATION OR REGISTRATION PRACTICALITIES

 From the 40 participants who will be enrolled within the study, 20 will be randomly
 assigned to the treatment group and the other 20 will be randomly allocated to the
 placebo-control group.

 All participants will be randomised to either the treatment or placebo-controlled group
 using a computerised randomisation generator (www.Randomization.com). This process will
 be co-ordinated by the CTO administrator who will advise the Chief Investigator to which
 group consecutive participants are allocated.

 5.2 UNBLINDING

 All participants and Nursing staff will be blinded to which group each participant has
 been allocated to. In the event where patients become unwell during the study or where
 there is a SAE, where the treatment would affect future management, unblinding will
 occur and all parties involved in the participants care will be informed as to which
 group the participant was allocated, as well as informing the patient and their carers.

 6. TREATMENTS

 Dr. V P Misra, Consultant Neurophysiologist, will be responsible for prescribing the
 study medication, for patients receiving the Botulinum Toxin within the treatment arm of
 the study.

 6.1 TREATMENT ARMS

 The dosage given is as follows:

 Botulinum Toxin type-A (Dysport, Ipsen Ltd, Slough, Berkshire) will be reconstituted
 with 1.0ml of sodium chloride injection B.P. (0.9%) to yield a solution containing 500
 units per ml of Dysport.

 Each parotid salivary gland will be injected with 75MU of Botulinum Toxin type-A
 (Dysport, Ipsen Ltd, Slough, Berkshire), 0.15mls in total, with 0.09mls into the mass of
 the gland and another 0.06mls into the adjacent part above the masseter muscle, as
 described by Pal 17, using a 1ml syringe and a 30 gauge needle.

 Each submandibular salivary gland will be injected with 15MU of Botulinum Toxin A
 (Dysport, Ipsen Ltd, Slough, Berkshire), administering 0.03mls, using a 1ml syringe and
 a 30 gauge needle.

 Each injection will be performed using ultrasound guidance using the Philips iU22
 ultrasound system to landmark the site of each of the glands. The drug will be obtained
 from Ipsen Ltd and funding application for the drug will be made to Ipsen Ltd, as well
 as via The Wellington Hospital.

 Placebo Participants will receive a pin-pick using a 1ml syringe and a 30 gauge needle,
 filled with sodium chloride (0.9%) at the sites of the parotid and submandibular
 salivary glands, using ultrasound guidance to landmark the sites.

 6.2 INTERACTION WITH OTHER DRUGS

 According to the summary of product characteristics produced by Ipsen limited, drugs
 which affect neuromuscular transmission, such as aminoglycoside antibiotics, should be
 used with caution. Other medications that may interact with Botulinum Toxin are
 anticholinesterase medicines (e.g., neostigmine), lincosamides (e.g., clindamycin),
 magnesium, neuromuscular blockers (e.g., atracurium), polymyxin, or quinidine because
 the risk of toxic effects may be increased.

 6.3 DISPENSING AND ACCOUNTABILITY

 The shelf-life of Botulinum toxin- type A is 15 months, when stored at a temperature of
 2-8oC. The product can be stored for up to 8 hours, following reconstitution at a
 temperature of 2-8oC. The drug will be stored with the Wellington Hospitals Pharmacy
 department and be prepared by the Consultant Neurophysiologist prior to administration.
 Once used, any remaining Botulinum Toxin will be inactivated with dilute hypochlorite
 solution and thereafter be disposed of using the hospitals' policy on disposal of unused
 drugs; any out-of-date vials of the drug will also be inactivated with dilute
 hypochlorite and disposed using the hospitals practice policy on disposal of medication
 / drugs.

 7. PHARMACOVIGILANCE

 7.1 DEFINITIONS

 Adverse Event (AE):

 Any untoward medical occurrence in a patient or clinical trial subject administered a
 medicinal product and which does not necessarily have a causal relationship with this
 treatment. An AE can therefore be any unfavourable and unintended sign (including an
 abnormal laboratory finding), symptom, or disease temporally associated with the use of
 an investigational medicinal product (IMP), whether or not considered related to the
 IMP.

 Adverse Reaction (AR):

 All untoward and unintended responses to an IMP related to any dose administered. All
 AEs judged by either the reporting investigator or the sponsor as having reasonable
 causal relationship to a medicinal product qualify as adverse reactions. The expression
 reasonable causal relationship means to convey in general that there is evidence or
 argument to suggest a causal relationship.

 Unexpected Adverse Reaction: an AR, the nature or severity of which is not consistent
 with the applicable product information (e.g. investigator's brochure for an unapproved
 investigational product or summary of product characteristics (SmPC) for an authorised
 product). When the outcome of the adverse reaction is not consistent with the applicable
 product information this adverse reaction should be considered as unexpected. Side
 effects documented in the SmPC which occur in a more severe form than anticipated are
 also considered to be unexpected.

 Serious Adverse Event (SAE) or Serious Adverse Reaction:

 Any untoward medical occurrence or effect that at any dose Results in death

 Is life-threatening - refers to an event in which the subject was at risk of death at
 the time of the event; it does not refer to an event which hypothetically might have
 caused death if it were more severe

 Requires hospitalisation, or prolongation of existing inpatients' hospitalisation

 Results in persistent or significant disability or incapacity

 Is a congenital anomaly or birth defect

 Medical judgement should be exercised in deciding whether an AE/AR is serious in other
 situations. Important AE/ARs that are not immediately life-threatening or do not result
 in death or hospitalisation but may jeopardise the subject or may require intervention
 to prevent one of the other outcomes listed in the definition above, should also be
 considered serious.

 Suspected Unexpected Serious Adverse Reaction (SUSAR):

 Any suspected adverse reaction related to an IMP that is both unexpected and serious.

 7.2 CAUSALITY

 Most adverse events and adverse drug reactions that occur in this study, whether they
 are serious or not, will be expected treatment-related toxicities due to the drugs used
 in this study. The assignment of the causality should be made by the investigator
 responsible for the care of the participant using the definitions in the table below.

 If any doubt about the causality exists the local investigator should inform the study
 coordination centre who will notify the Chief Investigators. The pharmaceutical
 companies and/or other clinicians may be asked to advise in some cases.

 In the case of discrepant views on causality between the investigator and others, all
 parties will discuss the case. In the event that no agreement is made, the MHRA will be
 informed of both points of view.

 Relationship Description Unrelated There is no evidence of any causal relationship
 Unlikely There is little evidence to suggest there is a causal relationship (e.g. the
 event did not occur within a reasonable time after administration of the trial
 medication). There is another reasonable explanation for the event (e.g. the
 participant's clinical condition, other concomitant treatment).

 Possible There is some evidence to suggest a causal relationship (e.g. because the event
 occurs within a reasonable time after administration of the trial medication). However,
 the influence of other factors may have contributed to the event (e.g. the participant's
 clinical condition, other concomitant treatments).

 Probable There is evidence to suggest a causal relationship and the influence of other
 factors is unlikely.

 Definitely There is clear evidence to suggest a causal relationship and other possible
 contributing factors can be ruled out.

 Not assessable There is insufficient or incomplete evidence to make a clinical judgement
 of the causal relationship.

 7.3 REPORTING PROCEDURES

 All adverse events will be reported. Depending on the nature of the event the reporting
 procedures below should be followed. Any questions concerning adverse event reporting
 should be directed to the study coordination centre in the first instance. A flowchart
 is given below to aid in the reporting procedures.

 7.3.1 Non serious AR / AEs

 All such toxicities, whether expected or not, will be recorded in the toxicity section
 of the relevant case report form and sent to the study coordination centre within one
 month of the form being due.

 7.3.2 Serious AR / AEs

 Fatal or life threatening SAEs and SUSARs will be reported on the day that the local
 site is aware of the event. The SAE form asks for nature of event, date of onset,
 severity, corrective therapies given, outcome and causality (i.e. unrelated, unlikely,
 possible, probably, definitely). The responsible investigator should sign the causality
 of the event. Additional information should be sent within 5 days if the reaction has
 not resolved at the time of reporting.

 SAEs

 An SAE form should be completed and faxed to the study coordination centre for all SAEs
 within 24 hours. Please refer to the product SMPC for details of adverse events, if not
 included within these guidelines then any adverse effects will be reported to the
 Clinical Trials Office

 SUSARs

 In the case of serious, unexpected and related adverse events, the staff at the site
 should:

 Complete the SAE case report form & send it immediately (within 24 hours, preferably by
 fax), signed and dated to the study coordination centre together with relevant treatment
 forms and anonymised copies of all relevant investigations.

 Or

 Contact the study coordination centre by phone and then send the completed SAE form to
 the study coordination centre within the following 24 hours as above.

 The study coordination centre will notify the MHRA and REC of all SUSARs occurring
 during the study according to the following timelines; fatal and life-threatening within
 7 days of notification and non-life threatening within 15 days. All investigators will
 be informed of all SUSARs occurring throughout the study.

 Local investigators should report any SUSARs and /or SAEs as required by their Local
 Research Ethics Committee and/or Research & Development Office.

 Contact details for reporting SAEs and SUSARs

 Fax: 020 7034 8402, for the immediate attention Rasmi Pillai

 Please send SAE forms to:

 Rasmi Pillai 79 Harley Street London W1G 8PZ

 Tel: 0207 034 8403 (Mon to Fri 09:00 - 17:00 hours)

 8. ASSESSMENT AND FOLLOW-UP

 Participants will continue to be followed-up at one week, two week and at four week
 intervals post intervention and thereafter as long as they have their tracheostomy tube
 in-place and continue to benefit from ongoing intervention from Speech and Language
 Therapy for swallowing and / or communication difficulties. Assessment will focus on
 weaning from the tracheostomy tube, ability to safely swallow and recordings of tracheal
 suctioning and amount of oral saliva. Assessments will also be made of the patients /
 carers perceptions of saliva management.

 8.1 LOSS TO FOLLOW-UP

 Patients who may be lost to follow-up will not have their data included and will be
 followed-up locally by their local services.

 8.2 TRIAL CLOSURE

 Participants will continue to receive Speech and Language Therapy intervention and
 ongoing assessment, whilst they remain an inpatient at the hospital. They will be
 removed from the trial if and when they are swallowing and managing their own saliva,
 without any need for any tracheal suctioning and if the tracheostomy tube is removed.
 The end of trial date will be six weeks from inclusion date.

 9. STATISTICS AND DATA ANALYSIS

 A power calculation has been performed to determine the sample size, which has been
 based on previous studies using Botulinum Toxin type A and treatment of drooling /
 excessive saliva management.

 Once entered into Statistical Package for the Social Sciences (SPSS) the data will be
 examined for extreme values and transcription errors. Data analysis will commence
 following data base lock, which will occur four to six weeks following the last patient
 data collection and resolution of all outstanding data queries. Data will be analysed
 using Multiple Regression.

 Data and all appropriate documentation will be stored for a minimum of 5 years after the
 completion of the study, including the follow-up period.

 10. MONITORING

 10.1 RISK ASSESSMENT

 This study is considered low risk as this drug dosage has been shown to be a safe and
 effective treatment for Parkinson's disease patients with excess saliva (sialorrhea).

 10.2 MONITORING AT STUDY COORDINATION CENTRE

 During study conduct, HCA's CTO will conduct periodic monitoring visits to the
 investigator site to ensure that the protocol and GCP are being followed. The monitors
 may review source documents to confirm that the data recorded on the CRF is accurate.
 The investigator and institution will allow HCA' CTO and appropriate regulatory
 authorities direct access to source documents to perform this verification.

 The study site may be subject to quality assurance audits performed by HCA's CTO.

 It is important that the investigator(s) and their relevant personnel are available
 during the monitoring visits and audits or inspections and that sufficient time is
 devoted to the process.

 11. REGULATORY ISSUES

 11.1 CTA

 This study is being conducted under a Clinical Trial Authorisation issued by the UK
 Competent Authority; the Medicines and Healthcare products Regulatory Agency (MHRA);
 EudraCT No. 2009-011204-2742

 11.2 ETHICS APPROVAL

 This protocol will be submitted to the Ethics Committee (EC), whose approval will be
 obtained before the start of the study. The investigators will inform the EC of
 subsequent protocol amendments and any serious adverse events which occur during the
 study.

 11.3 CONSENT

 THE INVESTIGATOR OR DELEGATED PHYSICIAN MUST INFORM PATIENTS ABOUT THE BACKGROUND TO,
 AND PRESENT KNOWLEDGE OF THE IMP WITH SPECIAL REFERENCE TO KNOWN ACTIVITY AND ADVERSE
 DRUG REACTION. THE INVESTIGATORS MUST ALSO ENSURE THE FOLLOWING POINTS ARE MADE:

 The patient must be provided with the Patient Information Sheet and Informed Consent
 form consistent with the protocol version used and approved by EC.

 Before the patient is entered into the study, the patient's written consent must be
 obtained using the Informed Consent form described above (according to HCA SOP
 RD.CTS.UK.001). The patient will retain a copy of the signed informed consent form and
 the original will be filed in the Trial Master file.

 The patient may refuse treatment either before or at any time during the study. Refusal
 to participate will involve no penalty or loss of benefits to which the patient is
 otherwise entitled.

 An explanation on whom to contact for answers to pertinent questions about the research
 and research subject's rights, and who to contact in the event of a research-related
 injury to the subject must be given.

 All participants are free to withdraw at any time from the protocol treatment without
 giving reasons and without prejudicing further treatment.

 11.4 CONFIDENTIALITY

 Participants' identification data will be required for the registration process. The
 Study Coordination Centre will preserve the confidentiality of participants taking part
 in the study and is registered under the Data Protection Act.

 11.5 INDEMNITY

 HCA International Ltd. holds negligent harm insurance policies which apply to this
 study.

 11.6 SPONSOR

 HCA International Ltd, The Clinical Trials Office will act as the main sponsor for this
 study.

 11.7 FUNDING

 HCA International Ltd

 11.8 AUDITS AND INSPECTIONS

 The study may be subject to inspection and audit by HCA international. Under their remit
 as a Department of Health recognised Sponsor HCA will ensure adherence to GCP and the
 Research Governance Framework for Health and Social Care (2nd edition). The study will
 be monitored for Research Governance compliance in accordance with HCA SOP No
 RD.RG.UK.001.

 12. STUDY MANAGEMENT

 The day-to-day management of the study will be co-ordinated through the Clinical Trials
 Office.
Inclusion Criteria:

 -  Patients must meet all of the following inclusion criteria to be eligible for
 enrollment into the study

 -  Male or female participants over the age of 18 years

 -  Participants who have a tracheostomy tube in-situ

 -  Participants who are breathing on room air, without the need for any mechanical
 ventilation

 -  Participants who require tracheal suctioning in order to maintain a clear airway

 Exclusion Criteria:

 -  Patients presenting with any of the following exclusion criteria will not be included
 in the study

 -  Contra-indications to the use of Botulinum Toxin

 -  Receiving medications that may react with Botulinum Toxin, such as aminoglycosides
 (e.g., gentamicin), anticholinesterase medicines (e.g., neostigmine), lincosamides
 (e.g., clindamycin), magnesium, neuromuscular blockers (e.g., atracurium), polymyxin,
 or quinidine because the risk of toxic effects may be increased

 -  Receiving anticoagulants medication (e.g., warfarin)

 -  Expectant mothers

 -  Previous history of:

 -  Swallowing disorders

 -  Stroke

 -  Myocardial Infarction

 -  Heart Disease

 -  Head or neck surgery

 -  Acute or progressive neurological disease

 -  Structural abnormalities that may affect swallowing