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Trial registered on ANZCTR


Registration number
ACTRN12610000482066
Ethics application status
Approved
Date submitted
3/06/2010
Date registered
11/06/2010
Date last updated
12/03/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
The effectiveness of alternative antiemetic therapies 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 2: A randomised controlled double blind study of levomepromazine versus placebo with rescue antiemetics (best supportive care) in patients with refractory nausea
Secondary ID [1] 251932 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 257506 0
Condition category
Condition code
Cancer 257666 257666 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multi-centre randomised controlled double-blind trial evaluating the effectiveness of one agent unlicensed for this indication versus placebo with best supportive care (BSC) rescue in both arms, in improving the management of refractory nausea in patients with advanced cancer.
The interventions will be administered in a 3-step escalated dosing schedule over 72 hours. Treatment period is 3x24 hour periods. The daily dosing schedule is fixed. All syringes will be identical and prepared by the pharmacists according to the randomisation schedule. Treatment allocation will not be disclosed to study staff, treating clinicians or investigators. The last dose must be given at least 6 hours prior to each response assessment. All doses will be administered subcutaneously or intravenously.
The mode of administration will be determined by the clinician based on patient characteristics. BSC rescue therapy will be available in both arms over the 72 hours. BSC is defined as any Pharmaceutical Benefits Scheme (PBS) approved antiemetic or combination of PBS approved antiemetics at any dose or route thought appropriate by the investigator, given “as required” (prn) for nausea control. Each patient will have access to laxatives according to the practice of the treating clinician.

Arm1 Levomepromazine (methotrimeprazine, Nozinan Registered Trademark (R)). 3.125mg-9.375mg per 24 hours delivered subcutaneously or intravenously in multiples of 3.125mg/2ml. Treatment period: 3 X 24 hours. Day 1= single dose at 0 hours (3.125mg) Day 2 (after 24 hours) = twice daily (6.25mg/24hours) Day 3 (after 48 hours) = 3 times per day (9.375mg/24 hours). Patients will be followed up for a maximum of 4 weeks after the primary endpoint for ongoing nausea control and safety.
Intervention code [1] 256601 0
Treatment: Drugs
Comparator / control treatment
Arm 2 Normal saline 2ml - 6ml will be administered in multiples of 2ml subcutaneously or intravenously with BSC rescue as required. Treatment period = 3 X 24 hours. Day 1= single dose at 0 hours (2ml), Day 2 (after 24 hours) = twice daily (4ml/24 hours), Day 3 (after 48 hours) = 3 times per day (6ml/24 hours).
Control group
Placebo

Outcomes
Primary outcome [1] 258574 0
Response to treatment at 72 hours. Response is defined as at least a two point improvement in average nausea score from baseline and an end score less than 3, measured on an 11-point numerical rating scale (NRS) where 0=No nausea and 10 = Worst possible nausea in the previous 24 hours.
Timepoint [1] 258574 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] 264437 0
Best nausea score over the preceding 24 hours, using an 11-point (0-10) NRS.
Timepoint [1] 264437 0
Baseline, 24, 48 and 72 hours after first study antiemetic administered.
Secondary outcome [2] 264438 0
Worst nausea score over the preceding 24 hours, using an 11-point (0-10) NRS.
Timepoint [2] 264438 0
Baseline, 24, 48 and 72 hours after first study antiemetic administered.
Secondary outcome [3] 264439 0
The number of patients with nausea who were not eligible for study 1 who proceeded directly to study 2, who in study 1 received appropriate antiemetics at sufficient dose (equivalent to step 3 in the antiemetic guidelines) and reported refractory nausea (defined as an average nausea score greater than or equal to 3).
Timepoint [3] 264439 0
At recruitment
Secondary outcome [4] 264440 0
Number of patients with refractory nausea who proceeded to study 2 following completion of study 1. 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 [4] 264440 0
At recruitment
Secondary outcome [5] 264441 0
Number of rescue doses delivered, obtained from medical records of drug and dose recorded by treating nurse.
Timepoint [5] 264441 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 [6] 264442 0
Toxicity identifed by the National Cancer Institute Advers Events Criteria (V4.0)
Timepoint [6] 264442 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 [7] 264443 0
Number of episodes of vomiting in a 20 minute window, defined as 'expulsion of stomach contents through mouth', not necessarily witnessed by clinical staff and determined from nurse-held records of patient self-reported episodes.
Timepoint [7] 264443 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).

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); have refractory nausea despite adequate treatment (as defined below); are able to comply with all trial requirements; are able to provide fully informed consent.

Refractory nausea is defined as: 1. nausea rated as greater than or equal to 3/10 on a NRS for average nausea after completion of study 1; or 2. nausea rated as greater than or equal to 3/10 at baseline despite the use of: appropriate antiemetics at sufficient dose (step 3) as specified in the study 1 targeted guideline category or haloperidol 3mg/24hrs or promethazine 25mg po tds (25mg sc 24 hrly) or metoclopramide 60mg/24hrs or domperidone 20mg qid or cyclizine 100mg/24hrs (75mg/24hrs in the elderly) or ondansetron 8mg/day or 3. nausea rated as greater than or equal to 3/10 at baseline if appropriate antiemetics, or any of those listed above, have not been tolerated because of side-effects.
If patients have been on antiemetic combinations, at least one of the agents must have been given at doses as specified above.
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) - within 5 days of anticancer therapy; have nausea for which a specific antiemetic is indicated and randomisation to study medications or placebo 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 the study or are likely to undergo a procedure or intervention with the potential to affect nausea during the 3 day study period; have received levomepromazine within the last 3 days; if on corticosteroids, the dose has changed within 48 hours prior to study; have a definite contraindication to levomepromazine (e.g. severe hepatic impairment (LFTs > 5 x upper limit of normal (this applies to AST, ALT or bilirubin but not to ALP or GGT measurements)), symptomatic postural hypotension); have had a previous adverse reaction to the study medication; are pregnant or breastfeeding; have participated in a trial of a new clinical entity within the last 28 days

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.

The central registry will supply the schedule tables to the dispensing pharmacy for allocation. Following changes to the protocol, the randomisation schedules supplied to sites will continue to be used. However, when an allocation to the ondansetron arm is drawn, this will be put aside and a new allocation selected until one of the included arms (levomepromazine or placebo) is drawn. The pharmacy manual reflects the Protocol changes and revised randomisation allocation.

Pharmacy will be contacted whenever a person is to commence study 2 to warn them of a potential participant. The randomisation request will take the form of the prescription of the study medicines. The site clinical trials pharmacist will prepare the study drugs for the patient according to the allocation determined in the supplied schedule (as per the revised allocation method), and label the intervention providing the details as described above. The allocation will be recorded on the schedule along with the date of allocation, the signature of the pharmacist preparing the syringe and the patient ID number. Participant randomisation will be registered with the coordinating site. PaCCSC has a Standard Operating Procedure for Randomisation, this procedure is to be followed. In summary, the procedure outlines that on randomisation of a patient, the site pharmacy is to fax a notification to the coordinating site. This notice will be monitored alongside the patient eligibility as entered onto the on-line data base from the eligibility CRF. The allocation will be recorded on the schedule along with the date of allocation, the signature of the pharmacist preparing the syringe and the patient ID number.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation schedules have been developed for each site using random number tables, generated at an independent centre (central registry). Originally, treatment for each patient was allocated according to a block randomisation schedule held by the central registry in a 1:1:1 ratio. Block randomisation within centre will ensure even allocation to each code in each site.
Removal of one arm of the study has necessitated a revision to the allocation process, as described in the previous section, effectively producing a 1:1 ratio. Any new schedules generated by the central registry for additional sites will be in a 1:1 ratio.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analyses will be done on an intention-to-treat basis. Descriptive statistics and frequency distributions will be generated from the patient’s demographic and clinical characteristics. The null hypothesis will be tested initially, using chi-square tests of differences in response rates between treatments. The success of randomisation will be considered; a preliminary analysis of differences between treatment groups will be carried out using chi-square tests to ensure comparability of covariates and factors, including centres. With respect to these baseline variables, any statistically significant differences will be controlled for in the main analyses, using logistic regression to fit the binary outcome of response to treatment, although based on data from our previous study we anticipate that the associated centre effect is negligible with respect to individuals’ nausea trajectories (the primary outcomes).

Regression modelling of the incidence of refractive nausea and of nausea scores over time, and the impact of the intervention on these trends, will be undertaken implementing a generalised estimating equations approach to (i) adjust for confounding variables including centres, and (ii) to ensure that individuals with missing data over time may be included as far as their data permit. An independent working correlations matrix will be assumed initially (and conservatively), although it is plausible that an exchangeable correlations matrix will be appropriate in this context, and produce models of better fit, which will be established. Multiple linear regression models will be fitted to the continuously-scaled nausea score variable and binary logistic regression models for the dichotomous outcome of refractory nausea. The primary outcomes of interest are based on a priori hypotheses, with each endpoint being considered separately in the analysis. Results will be expressed as prevalence rates, adjusted mean changes or adjusted odds ratios, with associated 95% confidence intervals.

Allowing for 50% attrition, it is anticipated that 272 participants, (136 per treatment arm), will be randomized to achieve a sample size of 68 participants per arm. It is expected some patients will follow on from Study 1, but the majority will be de novo patients. This sample size is adequate to detect a statistically significant difference in response rates between study arms with 85% power, assuming a simple random sampling scheme and a Type 1 error of 5% (two-tailed). The sample size is also sufficient for adjusted multivariable analyses.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
15/06/2010
Actual
15/02/2011
Date of last participant enrolment
Anticipated
30/06/2014
Actual
31/01/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
272
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 1077 0
St Vincent's Hospital Brisbane - Kangaroo Point
Recruitment hospital [2] 1078 0
Sacred Heart Hospice - Darlinghurst
Recruitment hospital [3] 1079 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 2967 0
4101
Recruitment postcode(s) [2] 2968 0
5041
Recruitment postcode(s) [3] 2969 0
3002
Recruitment postcode(s) [4] 2970 0
3181
Recruitment postcode(s) [5] 2971 0
3065
Recruitment postcode(s) [6] 2972 0
3215
Recruitment postcode(s) [7] 2973 0
2164
Recruitment postcode(s) [8] 2974 0
2310
Recruitment postcode(s) [9] 2975 0
2217
Recruitment postcode(s) [10] 6936 0
4169 - Kangaroo Point
Recruitment postcode(s) [11] 6937 0
2010 - Darlinghurst
Recruitment postcode(s) [12] 6938 0
3050 - Royal Melbourne Hospital

Funding & Sponsors
Funding source category [1] 257098 0
Government body
Name [1] 257098 0
National Health and Medical Reserach Council (NHMRC)
Country [1] 257098 0
Australia
Primary sponsor type
Individual
Name
Professor Patsy Yates
Address
Queensland University of Technology
School of Nursing adn Midwifery
Victoria Park Rd
Kelvin Grove QLD 4059
Country
Australia
Secondary sponsor category [1] 256358 0
Other Collaborative groups
Name [1] 256358 0
Palliative Care Clinical Studies Collaborative
Address [1] 256358 0
Flinders University
700 Goodwood Rd
Daw Park SA 5041
Country [1] 256358 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259131 0
Mater Adult Hospital
Ethics committee address [1] 259131 0
Raymond Terrace
South Brisbane QLD 4101
Ethics committee country [1] 259131 0
Australia
Date submitted for ethics approval [1] 259131 0
14/04/2010
Approval date [1] 259131 0
14/07/2010
Ethics approval number [1] 259131 0
1518A
Ethics committee name [2] 259136 0
Southern Adelaide Palliative Services
Ethics committee address [2] 259136 0
700 Goodwood Road
Daw Park SA 5041
Ethics committee country [2] 259136 0
Australia
Date submitted for ethics approval [2] 259136 0
11/10/2010
Approval date [2] 259136 0
08/02/2011
Ethics approval number [2] 259136 0
SAFUHREC 371.1
Ethics committee name [3] 259137 0
Peter MacCallum Cancer Centre
Ethics committee address [3] 259137 0
St Andrew's Place
East Melbourne VIC 3002
Ethics committee country [3] 259137 0
Australia
Date submitted for ethics approval [3] 259137 0
09/07/2010
Approval date [3] 259137 0
03/02/2011
Ethics approval number [3] 259137 0
HREC/10/Alfred/23 SSA/10/PMCC/20
Ethics committee name [4] 259138 0
St Vncent's Hospital
Ethics committee address [4] 259138 0
PO Box 2900
Fitzroy VIC 3065
Ethics committee country [4] 259138 0
Australia
Date submitted for ethics approval [4] 259138 0
01/07/2010
Approval date [4] 259138 0
02/03/2011
Ethics approval number [4] 259138 0
HREC/10/Alfred/23 123/10
Ethics committee name [5] 259139 0
Alfred Health
Ethics committee address [5] 259139 0
PO Box 315
Prahan VIC 3181
Ethics committee country [5] 259139 0
Australia
Date submitted for ethics approval [5] 259139 0
26/07/2010
Approval date [5] 259139 0
07/09/2010
Ethics approval number [5] 259139 0
HREC/10/Alfred/23 AU/5/B12703
Ethics committee name [6] 259140 0
Barwon Health
Ethics committee address [6] 259140 0
45-95 Ballarat Road
North Geelong VIC 3215
Ethics committee country [6] 259140 0
Australia
Date submitted for ethics approval [6] 259140 0
19/08/2010
Approval date [6] 259140 0
28/09/2010
Ethics approval number [6] 259140 0
HREC/10/Alfred/23 10/58
Ethics committee name [7] 259141 0
Hunter New England Area Health Service
Ethics committee address [7] 259141 0
Hunter Region Mail Centre
Warabrook NSW 2217
Ethics committee country [7] 259141 0
Australia
Date submitted for ethics approval [7] 259141 0
30/06/2010
Approval date [7] 259141 0
Ethics approval number [7] 259141 0
Ethics committee name [8] 259142 0
Calvary Health Centre
Ethics committee address [8] 259142 0
91-111 Rocky Point Road
Kogarah NSW 2217
Ethics committee country [8] 259142 0
Australia
Date submitted for ethics approval [8] 259142 0
07/07/2010
Approval date [8] 259142 0
Ethics approval number [8] 259142 0
Ethics committee name [9] 259143 0
Braeside Hospital
Ethics committee address [9] 259143 0
Locked Bag 82
Wetherill Park NSW 2164
Ethics committee country [9] 259143 0
Australia
Date submitted for ethics approval [9] 259143 0
07/07/2010
Approval date [9] 259143 0
Ethics approval number [9] 259143 0
Ethics committee name [10] 289369 0
St Vincent's Health and Aged Care HREC
Ethics committee address [10] 289369 0
48 Montpelier Road
Bowen Hills QLD 4004
Ethics committee country [10] 289369 0
Australia
Date submitted for ethics approval [10] 289369 0
26/09/2011
Approval date [10] 289369 0
16/02/2012
Ethics approval number [10] 289369 0
HREC#11/15
Ethics committee name [11] 289370 0
St Vincent's Hospital (Sydney) HREC
Ethics committee address [11] 289370 0
Level 6, deLacy Building
St Vincent's Hospital
390 Victoria St
Darlinghurst NSW 2010
Ethics committee country [11] 289370 0
Australia
Date submitted for ethics approval [11] 289370 0
28/05/2013
Approval date [11] 289370 0
Ethics approval number [11] 289370 0
Ethics committee name [12] 289371 0
Royal Melbourne Hospital
Ethics committee address [12] 289371 0
Level 6, Central Building
The Royal Melbourne Hospital
300 Gratten Street
Parkville VIC 3050
Ethics committee country [12] 289371 0
Australia
Date submitted for ethics approval [12] 289371 0
28/05/2013
Approval date [12] 289371 0
Ethics approval number [12] 289371 0

Summary
Brief summary
In some cases, nausea remains refractory to treatment despite multiple lines of treatment, often in combination. This is a randomised controlled double-blind trial evaluating the effectiveness of one drug (levomepromazine) against placebo with rescue antiemetics (BSC) in both arms in patients with nausea that has been demonstrated to be refractory to standard guideline driven targeted antiemetic therapy or single agent therapy with haloperidol. This test drug has not yet been rigorously evaluated in this setting and does not yet have a registered indication for use in palliative care. The hypothesis to be tested is that for cancer patients with nausea not related to anticancer treatment, there is no difference in response at 72 hours to levomepromazine versus a placebo with rescue antiemetics. 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 in the previous 24 hours, measured 72 hours after 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 Skerman, 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 31251 0
Prof Janet Hardy
Address 31251 0
Mater Health Services
Raymond Terrace
South Brisbane QLD 4101
Country 31251 0
Australia
Phone 31251 0
+61 07 3163 2775
Fax 31251 0
Email 31251 0
[email protected]
Contact person for public queries
Name 14498 0
Professor Patsy Yates
Address 14498 0
Queensland University of Technology
School of Nursing and Midwifery
Victoria Park Road
Kelvin Grove QLD 4059
Country 14498 0
Australia
Phone 14498 0
+61 7 3138 3835
Fax 14498 0
Email 14498 0
[email protected]
Contact person for scientific queries
Name 5426 0
Professor Patsy Yates
Address 5426 0
Queensland University of Technology
School of Nursing and Midwifery
Victoria Park Road
Kelvin Grove QLD 4059
Country 5426 0
Australia
Phone 5426 0
+61 7 3138 3835
Fax 5426 0
Email 5426 0
[email protected]

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