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Trial registered on ANZCTR


Registration number
ACTRN12610000464066
Ethics application status
Approved
Date submitted
3/06/2010
Date registered
8/06/2010
Date last updated
28/01/2024
Date data sharing statement initially provided
28/01/2024
Date results information initially provided
28/01/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of sertraline for palliative management of refractory breathlessness
Scientific title
A randomised double-blind multi-site parallel arm controlled trial to assess relief of refractory breathlessness in palliative care patients taking oral sertraline versus a placebo.
Secondary ID [1] 251967 0
013/09
Universal Trial Number (UTN)
Trial acronym
Sertraline for dyspnoea
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intractable dyspnoea 257517 0
Condition category
Condition code
Respiratory 257677 257677 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Sertraline/placebo 25-100mg in the morning via oral capsule.
Days 1-3 Sertraline/placebo 25mg each morning, Days 4-6, sertraline/placebo 50mg each morning, Days 7-28 sertraline/placebo 100mg each morning. Dose modification is included in the protocol. After the 28 day intervention period the dose is titrated downwards with the medication ceasing after day 34, or, participant can remain on blinded medication if experiencing benefit from the medication.
Intervention code [1] 256611 0
Treatment: Drugs
Comparator / control treatment
Placebo comprised of micro crystalline celllose in a gelatine capsule.
Control group
Placebo

Outcomes
Primary outcome [1] 258582 0
Change in the current sensation of breathlessness using a 100mm Visual Analogue Scale and a 4 point likert scale.
Timepoint [1] 258582 0
Assessed at baseline (morning and evening), daily in the morning and evening of days 26, 27 and 28, and at study exit. Average of morning and evening scores over the last three days (day 26, 27 and 28) will determine response.
Secondary outcome [1] 264449 0
Performance status using the Australia - modified Karnofsky Performance Status (AKPS)
Timepoint [1] 264449 0
Baseline, day 9 and at study conclusion (day 28)
Secondary outcome [2] 264450 0
Medication compliance using nurse kept medication chart.
Timepoint [2] 264450 0
Daily and through to Day 28
Secondary outcome [3] 264451 0
Physiological parameters; spirometry, arterial blood gases, changes in pulse oximetry, changes in resting respiratory rate
Timepoint [3] 264451 0
Baseline, day 9 and at study conclusion (day 28)
Secondary outcome [4] 264452 0
Serum sodium levels
Timepoint [4] 264452 0
Baseline, and days 9, 28, any day treatment is ceased, and followup days each month for as long as participant is taking blinded medication.
Secondary outcome [5] 264453 0
Safety assessments of vital signs, National Cancer Institutes Common Terminology for Adverse Events (Version 4.0), specific questions to the participant for problems and changes to medications,
Timepoint [5] 264453 0
Baseline, days 9, 28 and day 3 of dose titration time point (clinic or home visits) and days 3, 6, 14, 21 and day 6 downward titration (be telephone), any day that treatment is ceased, every two weeks by telephone or direct visit during blinded continuation of intervention, and 4 weeks of follow-up.
Secondary outcome [6] 264454 0
Modified Medical Council dyspnoea score
Timepoint [6] 264454 0
Baseline assessment, evening participant diaryof days 26, 27 and 28.
Secondary outcome [7] 264455 0
Participant and caregiver quality of life using the European Organisation for Research and Treatment of Cancer (EORTC) Cancer subscale (C15), the Chronic Respiratory Questionnaire (CRQ) Dyspnoea subscale, and the Caregiver Quality of Life Index - Cancer (CQOLC).
Timepoint [7] 264455 0
Baseline, day 9 and at study conclusion (day 28), any day that treatment is ceased, monthly during blinded continuation of intervention and at week 4 of follow-up.
Secondary outcome [8] 264456 0
Measures of life space using the Life Space QUestionnaire.
Timepoint [8] 264456 0
Baseline, day 9, and at study conclusion (day 28) and any day that treatment is ceased.
Secondary outcome [9] 264457 0
Descriptors of breathlessness using a list of 15 descriptors developed by Simon PM, Schwartzstein RM et all.
Timepoint [9] 264457 0
Baseline, day 9, at study conclusion (day 28) and any day that treatment is ceased.
Secondary outcome [10] 264458 0
Hospital Anxiety and Depression Scale (HADS) scores
Timepoint [10] 264458 0
Baseline, at study conclusion (day 28) and any day that treatment is ceased.
Secondary outcome [11] 264459 0
Health service utilisation collected by asking participants specific questions about their admissions, medical visits and changes to medications during follow-up telephone calls and visits.
Timepoint [11] 264459 0
Every two weeks from Day 34 until the participant ceases blinded continuation of treatment, and completes 2 fortnightly follow-up assessments.

Eligibility
Key inclusion criteria
Adults (age >18)
Refractory dyspnoea where the underlying cause of the dyspnoea has been maximally treated. Refractory dyspnoea does not have a minimum duration and can have been present for any period of time. A medical specialist must document that all identified reversible causes of the dyspnoea are being optimally managed
Breathlessness of a level 3 or higher on the Modified Medical Research Council (MRC) dyspnoea scale
On stable medications for breathlessness over the prior week except routine “as needed” medications
Prognosis of at least 2 months in the opinion of the treating clinician
English-speaking and able to read study questionnaires (5th grade level)
Able to provide informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous adverse reaction to sertraline
2. History of severe hepatic impairment defined as Childs Pugh Class of ‘C’ (score of 11 to 15)
3. Gastro-intestinal bleeding within the previous six months
4. Serum sodium less than 128mmol/l
5. Recent difficulty with seizure control
6. Evidence of respiratory depression with resting respiratory rate <8
7. Active respiratory or cardiac event in the previous week, not including upper respiratory tract infections. Illness must be resolved for at least 1 week prior to baseline evaluation, as judged by a doctor involved in the care of the person
8. Documented previous respiratory failure induced by any opiate medication
9. Pregnant or breastfeeding
10. Unable to give informed consent or complete diary entries
11. Depressive symptomology or suicidality (HADS depression subscale >16)
12. Current therapy with any one of the following medications due to the risk of serotonin syndrome: any selective serotonin reuptake inhibitor (SSRI); any serotonin-norepinephrine reuptake inhibitor (SNRI); noradrenergic and specific serotonergic antidepressant (NaSSA); any serotonin receptor agonist; any tricyclic antidepressant; any monoamine oxidase inhibitor (MAOI) or who have been taking non-reversible monoamine oxidase inhibitors within 4 weeks prior to study entry or reversible MAOIs within 2 days of study entry; Buspirone; Lithium; Carbamazepine; Linezolid; Imatinib; Amphetamine type drugs (dexamphetamine, methylphenidate); Weight loss drugs (phenteramine, diethylpropion, sibutramine); Over the counter medications (dextromethorphan, chlorpheniramine, and bropheniramine); Complementary medicines- St Johns Wort, tryptophan, S-adenosyl-methionine (SAME);

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
At each site, participants will be sequentially allocated a unique identifying number (ID) on referral to the study. This ID number will be used for all subsequent study documentation for that participant.
On notification of a participant, the pharmacist at each site will consult the strata table according to the strata determined by the HADS anxiety and depression subscales and will allocate the next code available according to the supplied strata table and dispense the active or inactive medicine delivered in a labeled starter pack. The participant ID, allocation code, dates of request, preparation, and dispensing will be recorded in a log maintained by the pharmacist.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation schedules have been developed by an organisation not involved in this study. Treatment for each participant will be allocated according to a block randomisation schedule, held by the Central Registry Clinical trials Pharmacist, in a 1:1 ratio for each treatment arm. Block randomisation will ensure even allocation to each code.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/07/2010
Actual
24/01/2011
Date of last participant enrolment
Anticipated
Actual
29/09/2016
Date of last data collection
Anticipated
Actual
16/01/2017
Sample size
Target
150
Accrual to date
Final
160
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 1790 0
Repatriation Hospital - Daw Park
Recruitment hospital [2] 1791 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 1792 0
Flinders Private Hospital - Bedford Park
Recruitment hospital [4] 1793 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 1794 0
Braeside Hospital - Prairiewood
Recruitment hospital [6] 1795 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [7] 1796 0
Sacred Heart Hospice - Darlinghurst
Recruitment hospital [8] 1797 0
Calvary Health Care Sydney Ltd - Kogarah
Recruitment hospital [9] 1798 0
Barwon Health - McKellar Centre campus - North Geelong
Recruitment hospital [10] 1799 0
The Prince Charles Hospital - Chermside
Recruitment postcode(s) [1] 7611 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 7609 0
2176 - Prairiewood
Recruitment postcode(s) [3] 7612 0
2217 - Kogarah
Recruitment postcode(s) [4] 7610 0
2298 - Waratah
Recruitment postcode(s) [5] 7608 0
3084 - Heidelberg
Recruitment postcode(s) [6] 7613 0
3215 - North Geelong
Recruitment postcode(s) [7] 7614 0
4032 - Chermside
Recruitment postcode(s) [8] 2979 0
5041
Recruitment postcode(s) [9] 2980 0
5042

Funding & Sponsors
Funding source category [1] 257104 0
Government body
Name [1] 257104 0
Commonwealth Department of Health and Ageing
Country [1] 257104 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
Flinders Drive
Bedford Park,
SA 5042
Country
Australia
Secondary sponsor category [1] 256364 0
Government body
Name [1] 256364 0
Commonwealth Department of Health and Ageing
Address [1] 256364 0
PO Box 9848
Canberra ACT, 2601
Country [1] 256364 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259145 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 259145 0
Locked Bag 1
Lookout Road
NEW LAMBTON NSW 2305
Ethics committee country [1] 259145 0
Australia
Date submitted for ethics approval [1] 259145 0
25/01/2010
Approval date [1] 259145 0
Ethics approval number [1] 259145 0
EC00403
Ethics committee name [2] 259146 0
Southern Adelaide Health Service / Flinders University Human Research Ethics Committee
Ethics committee address [2] 259146 0
Human Research Ethics Room 2A221
Flinders Medical Centre,
Flinders Drive,
Level 2, Flinders Medical Centre
BEDFORD PARK SA 5042
Ethics committee country [2] 259146 0
Australia
Date submitted for ethics approval [2] 259146 0
01/07/2010
Approval date [2] 259146 0
Ethics approval number [2] 259146 0
EC00188
Ethics committee name [3] 290258 0
Austin Health Human Research Ethics Committee
Ethics committee address [3] 290258 0
Office for Research Harold Stokes Building 145 Studley Rd HEIDELBERG VIC 3084
Ethics committee country [3] 290258 0
Australia
Date submitted for ethics approval [3] 290258 0
29/06/2010
Approval date [3] 290258 0
15/10/2010
Ethics approval number [3] 290258 0
EC00204
Ethics committee name [4] 290259 0
Barwon Health Human Research Ethics Committee
Ethics committee address [4] 290259 0
Human Research Ethics Committee Office for Research Barwon Health PO Box 281 GEELONG VIC 3220
Ethics committee country [4] 290259 0
Australia
Date submitted for ethics approval [4] 290259 0
06/10/2010
Approval date [4] 290259 0
19/11/2010
Ethics approval number [4] 290259 0
EC00208
Ethics committee name [5] 290260 0
The Prince Charles Hospital HREC
Ethics committee address [5] 290260 0
Building 12 The Prince Charles Hospital Rode Road Lower Ground Floor, Administration Building CHERMSIDE QLD 4032
Ethics committee country [5] 290260 0
Australia
Date submitted for ethics approval [5] 290260 0
24/11/2011
Approval date [5] 290260 0
19/04/2012
Ethics approval number [5] 290260 0
EC00168

Summary
Brief summary
Breathlessness continues to be a major clinical problem for many people with advanced progressive illnesses such as cancer, end-stage cardiac failure or chronic obstructive pulmonary disease even when they are receiving the best treatment for the underlying disease. Although there are some interventions that may offer benefit (oxygen therapy, sustained release low dose morphine), there is still a need for a wider range of interventions to meet the needs of people with refractory breathlessness.

Sertraline, an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, is primarily used to treat major depression as well as obsessive–compulsive, panic, and social anxiety disorders. Previous research has suggested that treatment of concomitant mood or anxiety symptoms can improve dyspnoea however studies are needed to further clarify its potential benefits for the treatment of breathlessness.

The research team has conducted a Phase II double blind, titrated dose, multi-site placebo controlled pilot study of sertraline (ACTRN12608000253303) using the proposed inclusion and exclusion criteria and the measures proposed in this study design. The pilot study has demonstrated acceptability and feasibility of this study, however further Phase III data is needed in order to ensure that this is a well tolerated and effective intervention suitable for a broad range of people with refractory breathlessness.

This study will evaluate critically a new but theoretically useful therapy whose role needs to be carefully defined. Although sertraline has been used in small uncontrolled studies, the evidence for a net clinical benefit is inadequate.

Aim: The primary aim is to test the efficacy of sertraline compared with placebo in relieving the sensation of intractable breathlessness. Secondary aims focus on the impact of the sertraline on improving quality of life (QOL), dyspnoea-related anxiety and depression, adverse effects, function and clinical predictors of benefit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31259 0
Prof David Currow
Address 31259 0
Flinders University Flinders Centre for Clinical Change, Flinders University Institute of Palliative and Supportive Care Research Flinders Drive Bedford Park SA 5042
Country 31259 0
Australia
Phone 31259 0
+61 8 7221 8235
Fax 31259 0
Email 31259 0
david.currow@flinders.edu.au
Contact person for public queries
Name 14506 0
Prof David Currow
Address 14506 0
Flinders University
Flinders Centre for Clinical Change,
Flinders University Institute of Palliative and Supportive Care Research
Flinders Drive
Bedford Park
SA 5042
Country 14506 0
Australia
Phone 14506 0
+61 8 7221 8235
Fax 14506 0
+61 8 8374 4018
Email 14506 0
david.currow@flinders.edu.au
Contact person for scientific queries
Name 5434 0
Prof David Currow
Address 5434 0
Flinders University
Flinders Centre for Clinical Change,
Flinders University Institute of Palliative and Supportive Care Research
Flinders Drive
Bedford Park
SA 5042
Country 5434 0
Australia
Phone 5434 0
+61 8 7221 8235
Fax 5434 0
+61 8 8374 4018
Email 5434 0
david.currow@flinders.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in the primary publication, after de-identification (text, tables, figures and appendices). Medicare and all other administrative data will not be available.
When will data be available (start and end dates)?
Data is available from the date of publication, for a period of 15 years.
Available to whom?
Other researchers who have specifically applied to the Principal Investigator and whose projects have appropriate Human Research Ethics committee approval. To be decided on a case by case basis by the Principal Investigator.
Available for what types of analyses?
Data will be available for analysis to achieve the aims in the approved proposal.
How or where can data be obtained?
Anyone who wishes to access the data should submit a proposal to for approval, data requestors will need to sign a data access agreement. After that, the Data Center will transfer the data and other documents to data requestors.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21500Study protocoldoi:10.1136/bmjopen-2016-013177  
21501Statistical analysis plan  itcc@uts.edu.au
21502Informed consent form  itcc@uts.edu.au
21503Clinical study report  itcc@uts.edu.au
21504Ethical approval  itcc@uts.edu.au


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Sertraline in symptomatic chronic breathlessness: ... [More Details]
Plain language summaryNo Chronic breathlessness generates suffering late in... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStudy protocol: A phase III randomised, double-blind, parallel arm, stratified, block randomised, placebo-controlled trial investigating the clinical effect and cost-effectiveness of sertraline for the palliative relief of breathlessness in people with chronic breathlessness.2016https://dx.doi.org/10.1136/bmjopen-2016-013177
N.B. These documents automatically identified may not have been verified by the study sponsor.