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Trial registered on ANZCTR


Registration number
ACTRN12617001211358
Ethics application status
Approved
Date submitted
7/08/2017
Date registered
18/08/2017
Date last updated
20/12/2018
Date data sharing statement initially provided
20/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A sequential multiple assignment randomised trial (SMART) of nursing interventions to reduce pain associated with chemotherapy induced peripheral neuropathy (CIPN Study)
Scientific title
A sequential multiple assignment randomised trial (SMART) of nursing interventions including standard treatment, heat treatment, self-massage treatment and heat and self-massage treatment combined to reduce pain associated with chemotherapy induced peripheral neuropathy (CIPN Study)
Secondary ID [1] 292589 0
APP1129532
Universal Trial Number (UTN)
Trial acronym
CIPN Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chemotherapy induced peripheral neuropathy 304259 0
Cancer 304260 0
Condition category
Condition code
Cancer 303609 303609 0 0
Any cancer
Neurological 303655 303655 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment Group A - Heat Treatment - usual treatment to manage symptoms and heat treatment. The participant will continue to have the same treatment they would have had if they were not in the trial and will be asked to put their hands and or feet on a heat pad for 20 minutes a day (can be tailored according to patient tolerance to a minimum duration of 10minutes), 4 times a week, for 4 or 8 weeks. An easy to use heat pad will be provided and the participant will be shown how to use the equipment by an experienced study nurse, who will contact them via video call.
Treatment Group B - Massage Treatment - usual treatment to manage symptoms and massage treatment. The participant will continue to have the same treatment they would have had if they were not in the trial and will be asked to massage their hands and or feet using a massage ball for 5 minutes a day, 4 times a week, for 4 weeks. The participant will be provided with a small massage ball (approximately 10cm diameter) with raised finger-like protrusions to aid the massage and an experienced study nurse will show the participant how to use the ball via video call.
Treatment Group C - Heat and Massage Treatment - usual treatment to manage symptoms, heat treatment and massage treatment. This treatment is for 4 weeks and includes usual treatment plus both heat treatment and massage treatment as outlined under Treatment A and B above.
The intervention education for all treatment arms may be done face to face by the study nurse if the participant is recruited within a clinic setting.
Participants will be allocated to usual care or Treatment A for the first 4 weeks of the study.
At the end of week 4, research staff will contact the participant via phone call to determine whether they have had a response to treatment.
If the participant in the usual treatment group has not had a response to usual treatment at the end of 4 weeks, they will be re-allocated to either Treatment A or B for weeks 5 to 8.
If the participant in the Treatment A group has not had a response to Treatment A at the end of 4 weeks, they will be re-allocated to Treatment B or C for weeks 5 to 8.
If the participant has had a response to usual treatment or Treatment A in the first 4 weeks they will remain on the same treatment for weeks 5 to 8.
Fidelity of the intervention will be assessed using the framework for behavioural interventions recommended by National Institutes of Health (NIH, US).
Intervention Fidelity Strategies
Study Design Study design procedures have been designed to ensure that the study can adequately test its hypotheses in relation to underlying theory and clinical practices.
Training Providers Standardized provider training includes procedures to ensure that interventionists have been satisfactorily trained to deliver the intervention to study participants. This will involve:
o Provision of a study manual to all staff which includes:
o Generic study related information: standard operating procedures, study overview, reporting/documentation guidelines, communication flowchart, rationale for the study treatment, treatment side effects
o Intervener specific information: Job description, intervention protocol, related literature, quality assurance and monitoring
o Training program including didactic presentations, performance assessment and role play
o Manualised intervention protocol
Delivery of Treatment: Treatment procedures will be monitored to improve delivery of intervention and comparison of conditions, and ensure that treatment is delivered as intended, through:
o Bi monthly teleconferences
o Quality assurance monitoring – first five sessions observed by trial manager (trainer), and self and trainer assessment completed using a checklist; if performance is satisfactory at this point one session per month will be recorded and self and trainer assessment completed with feedback provided on performance.
o Omissions and/or protocol deviations with interveners reviewed on an individual basis.
o Intervention checklist completed at the end of each intervention to allow protocol deviation tracking across interveners and conditions.
o Minimising contamination between conditions by training interveners to address participant questions about randomisation and their assigned condition using non-biased explanations
Treatment receipt focuses on the participant and includes procedures to assure that the treatment was both received and understood. This will be achieved by:
o Ensuring participants understand the information provided in intervention, by checking through use of active questions and behavioural observations
Enactment of Treatment Skills Enactment of treatment skills includes processes to monitor and improve participant ability to perform treatment-related behavioural skills and cognitive strategies in relevant real-life settings as intended. This will be achieved by:
o ensuring participants are able to demonstrate use of treatments through observing at least one practice session and recording observations in Intervention checklist at the end of each session
o checking in with participants 3 times in the first week of commencing the first intervention, then weekly until the end of the trial period

Intervention Adherence - participants will be asked to complete diaries to record intervention sessions and standard care treatments.
Intervention code [1] 298797 0
Treatment: Devices
Intervention code [2] 298798 0
Treatment: Other
Comparator / control treatment
Usual Treatment (Standard Care) includes the treatment that the participant is currently taking to manage their symptoms of chemotherapy induced peripheral neuropathy. This may include treatment prescribed by a health professional or self initiated management.
Control group
Active

Outcomes
Primary outcome [1] 302964 0
The proportion of patients with sensory symptoms, measured by the EORTC CIPN20, who respond to treatment
Timepoint [1] 302964 0
Measured at 4 weeks (end of Stage 1)
Secondary outcome [1] 337583 0
Pain as measured by the Pain Qualities Assessment Scale (PQAS).
Timepoint [1] 337583 0
Measured at 0, 4 and 8 weeks; and Month 3 and 6
Secondary outcome [2] 337585 0
Functional ability as measured by the Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS).
Timepoint [2] 337585 0
Measured at 0, 4 and 8 weeks; and Month 3 and 6
Secondary outcome [3] 337586 0
Depression as measured by the Center for Epidemiologic Studies Depression Scale (CES-D).
Timepoint [3] 337586 0
measured at 0, 4 and 8 weeks
Secondary outcome [4] 337589 0
Cost-effectiveness of the primary and adaptive CIPN interventions relative to standard care. This outcome will be assessed using patient diaries of health resource use, Department of Health Services administrative data and the EQ-5D-5L survey.
Timepoint [4] 337589 0
measured at 0, 4 and 8 weeks; and Months 3 and 6
Secondary outcome [5] 337882 0
Anxiety measured by Spielberger State Anxiety Inventory
Timepoint [5] 337882 0
Measured at 0, 4 and 8 weeks
Secondary outcome [6] 337884 0
The proportion of responders with sensory symptoms measured by the EORTC QLQ CIPN20
Timepoint [6] 337884 0
Measured at Week 8, Month 3 and 6
Secondary outcome [7] 337885 0
The proportion of responders with autonomic symptoms measured by the EORTC QLQ CIPN20
Timepoint [7] 337885 0
Measured at Week 4 and 8, and Month 3 and 6
Secondary outcome [8] 337886 0
The proportion of responders with motor symptoms measured by the EORTC QLQ CIPN20
Timepoint [8] 337886 0
Measured at Week 4 and 8; and Month 3 and 6
Secondary outcome [9] 346604 0
Pain interference as measured by Brief Pain Inventory Pain Interference question 9
Timepoint [9] 346604 0
measured at 0, 4 and 8 weeks; and Months 3 and 6
Secondary outcome [10] 346605 0
Quality of Life as measured by EORTC QLQ-C30
Timepoint [10] 346605 0
measured at 0, 4 and 8 Weeks and Months 3 and 6.
Secondary outcome [11] 346606 0
Quality of life as measured by the EQ-5D
Timepoint [11] 346606 0
measured at 0, 4 and 8 weeks; and Months 3 and 6.

Eligibility
Key inclusion criteria
Greater than or equal to 18 years of age
• Able to read, write, and understand English
• Internet access is not essential but participant must be willing and able to see a health care professional and or send photo/s via email or phone in relation to any adverse events
• Capacity to give informed consent
• Have an Australian-modified KPS score of greater than or equal to 60
• Are within greater than or equal to 3 months to less than or equal to 3 years of completing a course of CTX known to cause peripheral neuropathy such as those containing taxane or platinum-based agents for the treatment of cancer
• Meet study definition of CIPN:
a) Changes in sensation and/or pain in their feet and/or hands of greater than or equal to 3 month duration following the completion of CTX; and
b) A current rating of greater than or equal to 3 on a 0 to 10 numerical rating scale (NRS) on any one of the following sensations from the PQAS (i.e., numb, tender, shooting, sensitive, electrical, tingling radiating, throbbing, cramping, itchy, unpleasant)
• Able to comply with all study requirements
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The presence of any of the following criteria will constitute cause for the exclusion of the participant:
• Any prior history of conditions associated with neuropathy, including diabetes mellitus; peripheral vascular disease; history of chronic vitamin B12 deficiency; unstable/severe thyroid dysfunction (confirmed by treating medical practitioner); HIV neuropathy; current cervical or lumbar pain with radiculopathy, or another painful condition that is difficult for them to distinguish from CIPN; or a history of hereditary sensory or autonomic neuropathy; and/or a hereditary mitochondrial disorder. These exclusion criteria will minimise a number of confounding factors that could influence analysis of the study data.
• Any condition or treatment for which heat or massage therapy may be contraindicated, including increased risk of haemorrhage, impaired cognitive ability, impaired skin integrity, known malignant hypertension, pacemaker and pregnancy.

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)
Allocation is concealed using a central randomization system accessed via computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be determined using a computer-generated sequence of numbers for each site to randomly allocate patients to a specific treatment. Randomisation schedules will be developed for each site using random number tables, generated at a central registry. Treatment for each patient will be allocated according to a block randomisation schedule held by the central registry. Block randomisation within the centre will ensure even allocation to each code in each site, and sites will not be informed of the block size due to the lack of blinding.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The study is a smart or adaptive design whereby the participants will initially be randomized to usual treatment or treatment A. If the participant does not respond to their original randomized treatment, they will be re-randomized to another treatment.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Assuming the required minimum difference in proportions between the two groups is 20%, to achieve 80% power for a one-sided test and 95% level of confidence, the required minimum sample size at Stage 2 is 55 per non-responder group. As the intervention is undertaken by individuals at home, and study outcomes relate to each individual’s health behaviours, we have estimated a minimal intra-cluster correlation (ICC) of 0.01. The proportion of non-responders to the initial interventions is not known, so we estimate 70% non-response to heat therapy. Allowing 30% for attrition at 6 months, 10% for confounders, and an effect size of 1.2, working backwards from the required sample size of 55 per non-responder group at Stage 2, the estimated minimum total sample size for randomisation is 612 (306 per group).
Outcomes will be assessed on a priori hypotheses, with each endpoint being considered separately in the analysis.
Objective 1. The primary outcome variable Y is ‘response to treatment’ (yes/no) at 4 weeks. Response is defined as greater than or equal to 20% reduction from baseline as assessed by the EORTC CIPN20 sensory scale. Response indicates improvement in each variable being assessed (e.g., sensory symptoms).
Primary hypothesis, H1: The impact of the initial intervention in Stage 1 will be assessed in both an unadjusted and adjusted logistic regression analysis of the response to treatment at 4 weeks (Y), comparing Intervention A (heat therapy) and standard treatment groups, and adjusting for covariates such as adherence, time since treatment, site, and baseline variables correlated with Y. Odds ratios and 95% confidence intervals will be reported.

Secondary hypotheses, H2 and H3: Similarly, unadjusted and adjusted logistic regression analyses, adjusting for covariates will be conducted to assess the impact of the adaptive interventions at Stage 2, to determine: (1) for non-responders to initial Standard Care, the impact of the alternative interventions (A and B); and (2) for non-responders to initial Intervention A, the impact of the alternative interventions (B and C).

Additional secondary hypotheses, H4 and H5: Similar to the above analyses at Stage 1 and Stage 2, logistic regression analyses will be conducted, but the outcome variables in each analysis will be the proportion of responders with: (1) CIPN motor symptoms; and (2) autonomic symptoms; (3) high levels of depression; (4) high levels of anxiety; and (5) low quality of life.

For outcome variables other than Anxiety and Depression measures (STAI and CES-D), the overall change over time (0, 4 and 8 weeks, 3 and 6 months) between intervention groups and (time*group) interaction effects will be examined, with adjustment for covariates using GLMMs. For the outcome variables measuring Anxiety and Depression, the overall change over time (0, 4 and 8 weeks) between intervention groups and (time*group) interaction effects will be examined, with adjustment for covariates using GLMMs. If there are missing data, analyses are based on the assumption that data are missing at random. GLMMs will allow the inclusion of all available data, including those participants who do not complete all assessments.
Evaluation of the first-stage interventions requires pooling Y from the adaptive subgroups 1 to 3 and comparing the resulting average to the pooled Y from subgroups 4 to 6, This analysis over 8 weeks assesses the difference between the Stage 1 interventions (Standard care vs heat therapy), averaging over the Stage 2 intervention options. There will be no imputation for missing data.
Objective 2. To identify the best performing adaptive intervention embedded within the SMART design, we will order the embedded interventions in terms of the largest average reduction in CIPN to the smallest reduction.
Objective 3. Determinants of CIPN will be assessed using GLMMs for separate analyses of each of the subscales and the total CIPN scale and potential predictors such as time since treatment and demographic variables.
Objective 4. Economic evaluation: The primary measure for the economic evaluation for each trial arm will be the cost (healthcare provider perspective) per Quality Adjusted Life Year (QALY), derived from participants’ EQ-5D-5L assessments and estimated using an area under the curve approach. Incremental cost-effectiveness ratios (ICERs) will be used to estimate the comparative cost-effectiveness of the respective intervention approaches consistent with the trial arm comparisons outlined above. Healthcare resource utilisation will be collected for the duration of the trial using the health resource questionnaire and directly from the Australian Department of Human Services (Medicare and Pharmaceutical Benefits Schemes databases). This evaluation will include both labour and non-labour resource utilisation from each trial arm, which may include usual care, hospitalisations, community-based health services, and other healthcare-associated resource use (e.g. G.P. visits, medicines captured through MBS and PBS). Resource utilisation will be costed at market rates. Detailed pathway analysis will specify all resource consuming intervention and usual care healthcare activities for each trial arm path. The primary trial-based time-horizon for the economic evaluation will correspond with the final re-assessment. Due to the potential for uncertainty and non-normal distribution for the primary-trial based analysis, 95% confidence intervals (for costs and QALY estimates) and a 95% confidence ellipse (for incremental cost effectiveness ratio estimate) will be derived from bootstrap resampling (2000 replications of original sample size). However, if between group differences in health-related QoL remain at 6 months, QALYs will be probabilistically modelled (using discrete event simulations) under an assumption that between group differences in health-related QoL will diminish over time until a complete convergence is observed (probabilities and distributions for QALY modelling will be based on best evidence from the trial and prior longitudinal investigations of survivorship, cancer recurrence and QoL among comparable cancer populations). Cost effectiveness acceptability curves for varying threshold values of cost effectiveness will be prepared. An assessment of the sensitivity of the results obtained to variation in measured resource use, effectiveness, time-horizon, discounting, and unit costs will be undertaken where indicated using appropriate sensitivity analyses. This trial based economic evaluation with additional (and cost-efficient) modelling of QALYs will provide health service decision makers with clear probabilistic cost-effectiveness data necessary for informed resource allocation decision making. The economic evaluation will be conducted and reported according to the Consolidated Health Economic Evaluation Reporting Standards statement and supervised by CIF McPhail.
Objective 5. Genetic analyses: For each polymorphism, four genetic models (i.e., multiplicative, additive, dominant, recessive) will be tested, adjusting for differences in ethnicity, population stratification, and data-driven covariates (e.g., age). Null SNPs will be employed to assess and adjust for population stratification using principal components analysis. Logistic regression will be employed to test for differences in genotype frequency between patients with and without poorer CIPN outcomes, while adjusting for other covariates (e.g., age, diagnosis).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 8690 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 8691 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 8692 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 8693 0
Holy Spirit Northside - Chermside
Recruitment postcode(s) [1] 16803 0
4029 - Herston
Recruitment postcode(s) [2] 16804 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 16805 0
4032 - Chermside

Funding & Sponsors
Funding source category [1] 297165 0
Government body
Name [1] 297165 0
National Health and Medical Research Council
Address [1] 297165 0
Research Committee Secretariat NHMRC GPO Box 1421 Canberra ACT 2601
Country [1] 297165 0
Australia
Primary sponsor type
University
Name
Queensland University of Technology
Address
Victoria Park Rd, Kelvin Grove QLD 4059
Country
Australia
Secondary sponsor category [1] 296184 0
None
Name [1] 296184 0
Address [1] 296184 0
Country [1] 296184 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298333 0
Royal Brisbane & Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 298333 0
Level 7, Block 7, Butterfield Street, Herston, Qld,4029
Ethics committee country [1] 298333 0
Australia
Date submitted for ethics approval [1] 298333 0
29/05/2017
Approval date [1] 298333 0
27/07/2017
Ethics approval number [1] 298333 0
HREC/17/QRBW/300
Ethics committee name [2] 298338 0
QUT Human Reserach Ethics Committee - Administrative Review
Ethics committee address [2] 298338 0
Office of Research Ethics and Integrity Level 4 88 Musk Avenue, QUT Kelvin Grove Campus, Kelvin Grove, Qld, 4059
Ethics committee country [2] 298338 0
Australia
Date submitted for ethics approval [2] 298338 0
28/07/2017
Approval date [2] 298338 0
03/08/2017
Ethics approval number [2] 298338 0
1700000710
Ethics committee name [3] 298357 0
St. Vincent's Health and Aged Care Human Research Ethics Committee (SVHAC HREC)
Ethics committee address [3] 298357 0
St Vincent's Health & Aged Care Human Research Ethics Committee
PO Box 555
Spring Hill QLD 4000
Ethics committee country [3] 298357 0
Australia
Date submitted for ethics approval [3] 298357 0
28/08/2017
Approval date [3] 298357 0
10/04/2018
Ethics approval number [3] 298357 0
Ethics committee name [4] 302239 0
QUT Human Reserach Ethics Committe - Full committee Review
Ethics committee address [4] 302239 0
Office of Research Ethics and Integrity Level 4, 88 Musk Avenue, QUT Kelvin Grove Campus, Kelvin Grove, Qld, 4059
Ethics committee country [4] 302239 0
Australia
Date submitted for ethics approval [4] 302239 0
03/09/2018
Approval date [4] 302239 0
01/11/2018
Ethics approval number [4] 302239 0
1800000971

Summary
Brief summary
The purpose of the proposed study is to evaluate effectiveness and cost effectiveness of heat therapy and/or massage in addition to standard care in people with chemotherapy induced peripheral neuropathy.

Who is it for?
You may be eligible to join this study if you aged 18 years or over and meet study definition of chemotherapy induced peripheral neuropathy.

Study details
Patients will be assigned on a 'chance' basis, (like flipping a coin) to receive standard care or an intervention of standard care and heat therapy treatment for four weeks. If after four weeks the intervention decreases CIN nervous system symptoms then the intervention will continue for another 4 weeks. If symptoms do not improve, then the patient will be assigned on a chance basis to receive an alternative intervention of standard care and heat therapy, standard care and massage or standard care, heat therapy and massage. The second intervention will then be received for four weeks.
Chemotherapy induced peripheral neuropathy has become a significant health issue which can cause treatment delays and affect functional abilities and quality of life. There are currently no pharmacological interventions that effectively prevent or manage CIN.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76750 0
Prof Patsy Yates
Address 76750 0
Head, School of Nursing,
Queensland University of Technology,
Victoria Park Rd,
Kelvin Grove, QLD, 4059
Country 76750 0
Australia
Phone 76750 0
+617 3138 3835
Fax 76750 0
+617 3138 3814
Email 76750 0
p.yates@qut.edu.au
Contact person for public queries
Name 76751 0
Prof Patsy Yates
Address 76751 0
Head, School of Nursing,
Queensland University of Technology,
Victoria Park Rd,
Kelvin Grove, QLD, 4059
Country 76751 0
Australia
Phone 76751 0
+617 3138 3835
Fax 76751 0
+617 3138 3814
Email 76751 0
p.yates@qut.edu.au
Contact person for scientific queries
Name 76752 0
Prof Patsy Yates
Address 76752 0
Head, School of Nursing,
Queensland University of Technology,
Victoria Park Rd,
Kelvin Grove, QLD, 4059
Country 76752 0
Australia
Phone 76752 0
+617 3138 3835
Fax 76752 0
+617 3138 3814
Email 76752 0
p.yates@qut.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not planned at this stage
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable