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Trial registered on ANZCTR


Registration number
ACTRN12610000481077
Ethics application status
Approved
Date submitted
3/06/2010
Date registered
11/06/2010
Date last updated
10/12/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
The effectiveness of guideline driven antiemetic therapy versus single agent antiemetic therapy in patients with cancer and nausea not related to cancer therapy.
Scientific title
A two-stage trial of response to antiemetic therapy in patients with cancer and nausea not related to anticancer therapy.

Study 1: A randomised open label study of guideline driven targeted antiemetic therapy versus single agent antiemetic therapy.
Secondary ID [1] 1289 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nausea in the setting of advanced cancer not related to anticancer therapy 256546 0
Condition category
Condition code
Cancer 256721 256721 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-centre, open label randomised parallel arm trial to determine whether guideline driven (targeted) aetiology based antiemetic therapy is more effective than single agent therapy with haloperidol in patients with cancer and nausea not related to anticancer therapy.
Participants will be randomised to active treatment arms 1 or 2.

In each trial arm, the duration of each step is 24 hours and the overall duration of treatment is 72 hours (3 days) after administration of the first study antiemetic. The mode of administration will be a clinician decision based on patient characteristics.

Abbreviations: subcutaneous (sc), po (orally), bd (twice daily), iv (intravenously), tds (three dimes/day), qid (four times /day), Q4/6h (every 4/6 hours), prn (as required).

Rescue medication for all patients will be metoclopramide (10mg po, sc, iv, prn q4h). If this dose is already delivered in the standard treatment (Arm 1), haloperidol (0.5mg po, sc, prn to q6h) will be administered.

Patients will have access to laxatives according to clinician practice.

Arm 1 Clinical Practice Guideline (CPG) driven antiemetic therapy, given orally or parenterally (subcutaneous or intravenous), according to the presumed cause of nausea, using freely available Pharmaceutical Benefits Scheme (PBS) listed antiemetics, in a 3 step dose escalation schedule. The duration of each step is 24 hours. Overall duration of treatment is 72 hours.

Treatment drugs are prochlorperazine, haloperidol, dexamethasone, promethazine, metoclopramide, hyoscine butylbromide, ranitidine.

CPG dosing schedule and drug selection by cause: If there are multiple causes, the most likely cause is chosen from the following schedule. Note: sc drug delivery can be in a 24hr infusion, except for Dexamethasone which is not given as an infusion.

Dominant Cause A: Central/Chemoreceptive Trigger Zone (CTZ) stimulation
Step 1 Prochlorperazine 5mg tds po
or 25mg PR followed by 5mg tds po
or 12.5mg bd iv
Step 2: Haloperidol 1.5mg/24hrs po or sc
Step 3: Haloperidol 3mg/24hrs po or sc

Dominant Cause B: Central Nervous System (CNS) disease
Step 1 Dexamethasone 8mg/24hrs po/sc/iv
Step 2 Dexamethasone 12mg/24hrs po/sc/iv
Step 3 Dexamethasone 16mg/24hrs po/sc/iv

Dominant Cause C: Vestibular involvement (nausea related to abnormalities of the middle ear or motion and/or positional nausea)
Step 1 Prochlorperazine 5mg tds po
or 25mg per rectum (PR) followed by 5mg tds po
or 12.5mg bd iv
Step 2 Prochlorperazine 10mg tds po
or 25mg PR followed by 10mg tds po
or 12.5mg tds iv
Step 3 Promethazine 25 mg tds po
or 12.5mg sc followed by 10mg tds po

Dominant Cause D: Gastric stasis
Step 1 Metoclopramide 10mg qid po/sc/iv
Step 2 Metoclopramide 10mg Q4h po/sc/iv
(patients must receive at least 5 doses of 4 hourly metoclopramide/24hours)
Step 3 Metoclopramide 10mg Q4h po/sc/iv,
Dexamethasone 8mg/24hrs po/sc/iv

Dominant Cause E: Ileus
Step 1 Metoclopramide 10mg qid po/sc/iv
Step 2 Metoclopramide 10mg Q4h po/sc/iv
Step 3 Metoclopramide 10mg Q4h po/sc/iv,
Dexamethasone 8mg/24hrs po/sc/iv

Dominant Cause F: Mechanical obstruction
Step 1 Haloperidol 1.5mg/24hrs po/sc,
Dexamethasone 8mg/24hrs
Step 2 Haloperidol 3mg/24hrs po/sc,
Dexamethasone 8mg/24hrs
Step 3 Haloperidol 3mg/24hrs po/sc,
Dexamethasone 8mg/24hrs po/sc/iv,
Hyoscine butlybromide 80mg/24hrs sc or Ranitidine 200mg/24hrs sc (in patients where there is a realistic chance of bowel obstruction).

Dominant Cause G: Gastritis
Step 1 Metoclopramide10mg qid po/sc/iv, Proton Pump Inhibitors (PPI) min dose
Step 2 Metoclopramide 10mg qid po/sc/iv, PPI max dose
Step 3 Metoclopramide 10mg Q4h po/sc/iv, PPI max dose
(PPI choice according to local policy)

Dominant Cause H: Cause undetermined (or multifactorial)
Step 1 Metoclopramide 10mg qid po/sc/iv
Step 2 Metoclopramide 10mg qid po/sc/iv,
Haloperidol 1.5mg/24hrs po/sc
Step 3 Metoclopramide 10mg Q4h po/sc/iv,
Haloperidol 3mg/24hrs sc

Arm 2 Haloperidol, in a 3 step dose escalation schedule from 1mg/24 hours to 3mg/24 hours orally or parenterally (subcutaneously).

Participants with intolerable nausea despite maximum breakthrough doses can proceed to Study 2 prior to the next 24 hour assessment. Participants already on Step 3 should be considered for Study 2.

Treatment after the 72 hour trial period should be at the clinicians’ discretion if the patient does not continue to study 2.

For all study participants, secondary outcomes and collection of data for safety will occur until the end of 4 weeks after the primary endpoint, unless consent is withdrawn.
Intervention code [1] 255822 0
Treatment: Drugs
Comparator / control treatment
Antiemetic CPG driven (targeted) therapy according to the presumed cause of nausea, using freely available PBS listed antiemetics
Control group
Active

Outcomes
Primary outcome [1] 257667 0
Response to treatment at 72 hours. Response is defined as an improvement of at least two points in average nausea score from baseline and final score less than 3, measured for the previous 24 hours on an 11-point (0-10) numeric rating scale (NRS).
Timepoint [1] 257667 0
Average nausea: Baseline, 24, 48 and 72 hours after first study antiemetic administered
Response: At 24, 48 and 72 hours after first study antiemetic administered.
Secondary outcome [1] 262936 0
Best nausea score measured on an 11-point (0-10) NRS.
Timepoint [1] 262936 0
At baseline, 24, 48 and 72 hours after first study antiemetic administered.
Secondary outcome [2] 262937 0
Worst nausea score measured on an 11-point (0-10) NRS.
Timepoint [2] 262937 0
At baseline, 24, 48 and 72 hours after first study antiemetic administered.
Secondary outcome [3] 263066 0
Number of rescue doses delivered, obtained from medical records of drug and dose recorded by treating nurse.
Timepoint [3] 263066 0
At each 24 hour assessment after first study antiemetic administered until final assessment 24 hours after last antiemetic administered (i.e. 24, 48 and 72 hours after first antiemetic administered).
Secondary outcome [4] 264403 0
Number of patients treated at each dose level determined from medical records kept by treating nurse.
Timepoint [4] 264403 0
When drugs are administered: At baseline, 24 and 48 hours after first study antiemetic administered.
Secondary outcome [5] 264404 0
Number of patients with nausea who were not eligible for study 1 and proceeded to study 2, determined as those who have received appropriate antiemetics at sufficient dose (equivalent to step 3 in the antiemetic guidelines) and report refractory nausea (defined as an average nausea score greater than or equal to 3).
Timepoint [5] 264404 0
At recruitment.
Secondary outcome [6] 264405 0
Number of participants with nausea refractory to either targeted or single agent therapy. Refractory nausea is defined as an average nausea score greater than or equal to 3, measured for the previous 24 hours on an 11-point (0-10) NRS.
Timepoint [6] 264405 0
At 24, 48 and 72 hours after first study antiemetic administered.
Secondary outcome [7] 264406 0
Number of participants with refractory nausea (nausea score greater than or equal to 3) who proceeded to study 2 after completion of study 1, 72 hours after the first study antiemetic was administered.
Timepoint [7] 264406 0
On completion of study, 72 hours after first study antiemetic administered.
Secondary outcome [8] 264407 0
Number of episodes of vomiting experienced, patient self-reported on nurse-held records.
Timepoint [8] 264407 0
At each 24 hour assessment after first antiemetic administered until final assessment 24 hours after last antimetic administered (i.e., 24, 48 and 72 hours after first antiemetic administered).
Secondary outcome [9] 264408 0
Toxicity identified by the National Cancer Institute Adverse Events Criteria (V4.0)
Timepoint [9] 264408 0
At each 24 hour assessment after first antiemetic administered until final assessment 24 hours after last antimetic administered (i.e., 24, 48 and 72 hours after first antiemetic administered).
Secondary outcome [10] 264409 0
Number of patients randomised to the guideline therapy arm who comply with the antiemetic guidelines, patient reported on nurse-held records.
Timepoint [10] 264409 0
At each 24 hour assessment after first antiemetic administered until final assessment 24 hours after last antimetic administered (i.e., 24, 48 and 72 hours after first antiemetic administered).

Eligibility
Key inclusion criteria
Patients who: are 18 years or over, have a clinical diagnosis of cancer, have nausea with an average score over the last 24 hours of greater than or equal to 3 on an 11 point numerical rating scale (NRS) anchored at 0 (no nausea) and 10 (worst possible nausea), are not currently receiving antiemetics or are already receiving antiemetics but these are inappropriate as defined by the antiemetic guidelines or are at a suboptimal dose, are able to comply with all trial requirements, are able to provide fully informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who: have nausea related to the treatment of cancer (i.e. surgery, chemotherapy, radiotherapy) where acute treatment with 5HT3 antagonists is indicated (i.e. within 5 days of anticancer therapy), have nausea for which a specific antiemetic is indicated and randomisation to haloperidol would not be appropriate (e.g. dexamethasone for acutely raised ICP), have undergone a procedure or intervention with the potential to affect nausea within 2 days prior to study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period, if on corticosteroids, the dose has changed within 48 hours prior to study, have a definite contraindication to any of the drugs listed in the guidelines (e.g. Parkinson’s disease, QTc prolongation on most recent ECG (>450msecs in men, >470msecs in women), uncontrolled seizures), have had a prior serious adverse event following use of any of the drugs listed in the guidelines (e.g. dystonic reaction, neuroleptic malignant syndrome), are pregnant or breastfeeding

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)
All patients under the care or shared care of the palliative care team and all potential participants attending clinic will be screened by the study nurse for their suitability to enter the study in consultation with the treating clinician and nursing staff. The study nurse will ask the clinician in charge for permission to approach potentially eligible participants. This referral will be recorded within both the Case Report Form (CRF) and the participant clinical file. After checking with the clinical team to make sure the person meets the broad criteria for consideration of eligibility, that the person has given explicit permission to be seen by a researcher, and is well enough to be approached, the study nurse will introduce themself to the person and explain the study. If participants are suitable for entry and prepared to consent to the study, they will undergo baseline assessments and assessment of eligibility criteria. On notification of a participant, the site co-ordinator will consult the central registry to obtain the next code available. The Principal Investigator will then chart and order the allocated medication according to the code. A screening log will be kept of all potentially eligible participants including the reasons for non-entry.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation schedules will be developed for each site using random numbers generated by computer at an independent centre. Treatment for each patient will be allocated according to a block randomisation schedule held by the central registry at the Queensland University of Technology. Site coordinators will contact the central registry to obtain random allocation once consent has been obtained. Block randomisation within the centre will ensure even allocation to each code in each site. Sites will not be informed of the block size in order to minimise bias in patient allocation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
None
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/06/2010
Actual
19/10/2010
Date of last participant enrolment
Anticipated
Actual
29/04/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
216
Accrual to date
Final
185
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 1074 0
St Vincent's Hospital Brisbane - Kangaroo Point
Recruitment hospital [2] 1075 0
Sacred Heart Hospice - Darlinghurst
Recruitment hospital [3] 1076 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 6934 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 2513 0
2164
Recruitment postcode(s) [3] 2962 0
2217
Recruitment postcode(s) [4] 2512 0
2310
Recruitment postcode(s) [5] 2964 0
3002
Recruitment postcode(s) [6] 6935 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [7] 2396 0
3065
Recruitment postcode(s) [8] 2977 0
3181
Recruitment postcode(s) [9] 2978 0
3215
Recruitment postcode(s) [10] 2976 0
4101
Recruitment postcode(s) [11] 6933 0
4169 - Kangaroo Point
Recruitment postcode(s) [12] 2963 0
5041

Funding & Sponsors
Funding source category [1] 256314 0
Government body
Name [1] 256314 0
National Health and Medical Research Council (NHMRC)
Country [1] 256314 0
Australia
Primary sponsor type
Individual
Name
Professor Patsy Yates
Address
Queensland University of Technology
School of Nursing and Midwifery
Victoria Park Road
Kelvin Grove QLD 4059
Country
Australia
Secondary sponsor category [1] 255724 0
Other Collaborative groups
Name [1] 255724 0
Palliative Care Clinical Studies Collaborative
Address [1] 255724 0
Flinders University
700 Goodwood Rd
Daw Park SA 5041
Country [1] 255724 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258429 0
Mater Adult Hospital
Ethics committee address [1] 258429 0
Raymond Terrace
South Brisbane QLD 4101
Ethics committee country [1] 258429 0
Australia
Date submitted for ethics approval [1] 258429 0
14/04/2010
Approval date [1] 258429 0
25/06/2010
Ethics approval number [1] 258429 0
1517A
Ethics committee name [2] 259116 0
Southern Adelaide Palliative Services
Ethics committee address [2] 259116 0
700 Goodwood Road
Daw Park SA 5041
Ethics committee country [2] 259116 0
Australia
Date submitted for ethics approval [2] 259116 0
21/07/2010
Approval date [2] 259116 0
17/02/2011
Ethics approval number [2] 259116 0
388.10
Ethics committee name [3] 259117 0
Peter MacCallum Cancer Centre
Ethics committee address [3] 259117 0
St Andrew's Place
East Melbourne VIC 3002
Ethics committee country [3] 259117 0
Australia
Date submitted for ethics approval [3] 259117 0
09/07/2010
Approval date [3] 259117 0
03/02/2011
Ethics approval number [3] 259117 0
HREC/10/Alfred/22 SSA/10/PMCC/19
Ethics committee name [4] 259118 0
St Vincent's Hospital
Ethics committee address [4] 259118 0
PO Box 2900
Fitzroy VIC 3065
Ethics committee country [4] 259118 0
Australia
Date submitted for ethics approval [4] 259118 0
01/07/2010
Approval date [4] 259118 0
22/11/2010
Ethics approval number [4] 259118 0
HREC/10/Alfred/22 SSA/10/SVHM/33
Ethics committee name [5] 259119 0
Alfred Health
Ethics committee address [5] 259119 0
PO Box 315
Prahan VIC 3181
Ethics committee country [5] 259119 0
Australia
Date submitted for ethics approval [5] 259119 0
21/06/2010
Approval date [5] 259119 0
07/09/2010
Ethics approval number [5] 259119 0
HREC/10/Alfred/22
Ethics committee name [6] 259120 0
Barwon Health
Ethics committee address [6] 259120 0
45-95 Ballarat Rd
North Geelong VIC 3215
Ethics committee country [6] 259120 0
Australia
Date submitted for ethics approval [6] 259120 0
29/06/2010
Approval date [6] 259120 0
07/10/2010
Ethics approval number [6] 259120 0
HREC/10/Alfred/22 AU/5/C12709
Ethics committee name [7] 259121 0
Hunter New England Area Health Service
Ethics committee address [7] 259121 0
Hunter Region Mail Centre
Warabrook NSW 2217
Ethics committee country [7] 259121 0
Australia
Date submitted for ethics approval [7] 259121 0
30/06/2010
Approval date [7] 259121 0
01/09/2010
Ethics approval number [7] 259121 0
HREC/10/HNE/167 SSA/10/HNE/288
Ethics committee name [8] 259122 0
Calvary Health Care
Ethics committee address [8] 259122 0
91-111 Rocky Point Road
Kogarah NSW 2217
Ethics committee country [8] 259122 0
Australia
Date submitted for ethics approval [8] 259122 0
07/07/2010
Approval date [8] 259122 0
14/02/2011
Ethics approval number [8] 259122 0
HREC/10/HNE/167 2011.02.02
Ethics committee name [9] 259123 0
Braeside Hospital
Ethics committee address [9] 259123 0
Locked Bag 82
Wetherill Park NSW 2164
Ethics committee country [9] 259123 0
Australia
Date submitted for ethics approval [9] 259123 0
07/07/2010
Approval date [9] 259123 0
02/12/2010
Ethics approval number [9] 259123 0
HREC/10/HNE/167 SSA/10/HOPE/13
Ethics committee name [10] 289366 0
St Vincent's Health and Aged Care HREC
Ethics committee address [10] 289366 0
48 Montpelier Road
Bowen Hills QLD 4004
Ethics committee country [10] 289366 0
Australia
Date submitted for ethics approval [10] 289366 0
14/10/2011
Approval date [10] 289366 0
05/03/2012
Ethics approval number [10] 289366 0
HREC #11/14
Ethics committee name [11] 289367 0
St Vincent's Hospital (Sydney) HREC
Ethics committee address [11] 289367 0
Level 6, deLacy Building
St Vincent's Hospital
390 Victoria St
Darlinghurst NSW 2010
Ethics committee country [11] 289367 0
Australia
Date submitted for ethics approval [11] 289367 0
28/05/2013
Approval date [11] 289367 0
Ethics approval number [11] 289367 0
Ethics committee name [12] 289368 0
The Melbourne Health Human Research Ethics Committee
Ethics committee address [12] 289368 0
Level 6, Central Building
The Royal Melbourne Hospital
300 Gratten Street
Parkville VIC 3050
Ethics committee country [12] 289368 0
Australia
Date submitted for ethics approval [12] 289368 0
28/05/2013
Approval date [12] 289368 0
Ethics approval number [12] 289368 0

Summary
Brief summary
Nausea in advanced cancer is a multifaceted problem. Recent systematic reviews have concluded that aetiology based guidelines may be effective in reducing nausea, but no rigorously controlled studies have been undertaken to trial this approach. Moreover, evidence to support the implementation of guidelines in practice is limited and contradictory, and a number of barriers to the implementation of the guidelines have been identified.

This is a randomised open label study to compare the effectiveness of aetiology based antiemetic guideline therapy (targeted) versus haloperidol (single agent therapy) in improving the management of nausea not related to anticancer therapy in patients with advanced cancer. The hypothesis is that for advanced cancer patients with nausea not related to treatment, there is no difference in response to targeted aetiology-based antiemetic guideline treatment compared to using haloperidol alone, after 72 hours of treatment. Response to treatment is defined as a minimum two point improvement from baseline and end score <3 on an 11 point (0-10) numeric rating scale for average nausea for the previous 24 hours, measured 72 hours after the first study antiemetic administered
Participants will be randomised into one of two study arms. In Arm 1, guideline driven antiemetic therapy is given orally or parenterally (subcutaneous or intravenous) according to the presumed cause of nausea using freely available PBS listed antiemetics in a 3 step dose escalation schedule. In Arm 2, Haloperidol is administered in a 3 step dose escalation schedule from 1mg/24 hours to 3mg/24hours orally or parenterally (subcutaneously). The active comparator is standard guideline treatment.
Trial website
Trial related presentations / publications
1. Hardy J, O'Shea A, Gilbert C, Norris R. Is levomepromazine stable over time? Palliat Medicine, 2010, 25 (3) 284-285.
2. Yates, P, (2012) Management of nausea. In O’Connor, M., Lee, S. & Aranda, S. Palliative Nursing: A Guide to Practice (3rd Ed). Ausmed: Melbourne.
3. J Hardy. “Symptom management in end-of-life care”. 2011 RBWH Health Care Symposium, Brisbane, 13th October 2011.
4. Yates, P. “A randomised controlled trial of aetiology based guidelines for the management of nausea in advanced cancer: a work in progress”. 11th Annual Palliative Care Research Conference, Royal Brisbane and Women’s Hospital, 27th April 2012.
5. Hardy, J. & Yates, P. “A two-stage trial of antiemetic therapy in patients with cancer and nausea not related to anticancer therapy”. Palliative Care Clinical Studies Collaborative (PaCCSC) 3rd Research Forum, Sydney, 15th March 2012.
6. J Hardy, P Yates, P Martin, J Phillip, P Hudson, H Kerman, D Currow. “Targeted versus single agent antiemetic therapy in patients with cancer and nausea not related to anticancer therapy” The Australian and New Zealand Society of Palliative Medicine Inc. Conference. Queenstown, New Zealand, 4th – 7th September 2012.
Public notes

Contacts
Principal investigator
Name 30706 0
Prof Patsy Yates
Address 30706 0
Queensland University of Technology School of Nursing Victoria Park Road Kelvin Grove QLD 4059
Country 30706 0
Australia
Phone 30706 0
+61 7 3138 3835
Fax 30706 0
Email 30706 0
p.yates@qut.edu.au
Contact person for public queries
Name 13953 0
Prof Professor Patsy Yates
Address 13953 0
Queensland University of Technology
School of Nursing and Midwifery
Victoria Park Road
Kelvin Grove QLD 4059
Country 13953 0
Australia
Phone 13953 0
+ 61 7 3138 3835
Fax 13953 0
Email 13953 0
p.yates@qut.edu.au
Contact person for scientific queries
Name 4881 0
Prof Professor Patsy Yates
Address 4881 0
Queensland University of Technology
School of Nursing and Midwifery
Victoria Park Road
Kelvin Grove QLD 4059
Country 4881 0
Australia
Phone 4881 0
+ 61 7 3138 3835
Fax 4881 0
Email 4881 0
p.yates@qut.edu.au

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No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
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Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseHaloperidol for the treatment of nausea and vomiting in palliative care patients.2015https://dx.doi.org/10.1002/14651858.CD006271.pub3
N.B. These documents automatically identified may not have been verified by the study sponsor.