Research Title: A Randomised Control Trial comparing graded exercise therapy or cognitive behaviour therapy (non pharmacological) with methylphenidate (pharmacological) for severe fatigue in patients with advanced cancer.
Background and Introduction
Cancer is the leading cause of mortality worldwide with 8.2 million deaths in year 2013 (1). It accounts for more than a quarter (28%) of deaths in the UK(2017). Every year there are around 363,000 new cancer cases in the UK(2014-2016).
Studies have shown that one of the most common,distressing,debilitating(2,3,4) and exhausting symptoms associated with advanced cancer and its treatment is fatigue that limits one's ability to enjoy life and perform activities(2,5,6), less likely to be improved by rest.Both physiological and psychological factors contribute to its development.There could be different ways to define fatigue but cancer related fatigue (CRF) is most commonly used to describe severe fatigue particularly common in patients with advanced cancer on palliative treatment with reports of upto 78% of such patients being affected (7,8).The National Comprehensive Cancer Network (NCCN) defines CRF as "a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning" (9).There are many factors associated with fatigue like anemia, cancer, cancer treatments, and depression. Because of so many factors, it can be difficult for a doctor to know the exact source of a patient's fatigue.
So far, there is no recommendation for the specific pharmacological treatment of CRF(10) but a lot of non-pharmacological interventions are used against CRF and many trials, systematic reviews and meta-analyses have been published(11).The Oncology Nursing Society 'Putting Evidence into Practice' tool on CRF proposed exercise and physical activity as a first-line intervention for CRF (12).However, Graded Exercise therapy(GET) and Cognitive behaviour therapy(CBT) have given promising results and have helped to reduce CRF.But, it is still unclear which of these anti-CRF interventions provides the better treatment results, as there is no systematic review comparing the effects of different non-pharmaceutical interventions on CRF with pharmacological treatments. Therefore this research proposal is prepared to compare the clinical effectiveness of GET and CBT with Methylphenidate for the treatment of CRF in patients with advanced cancer,in order to improve CRF with specific treatment guidelines.
To access and determine better management options for cancer related fatigue by comparing Graded exercise therapy and CBT with Methylphenidate( a psychostimulant) to help cope with the symptoms of fatigue ,hence improving and maintaining their quality of life and to compare the adverse effects of the patients receiving GET,CBT and methylphenidate.
Are graded exercise therapy or cognitive behavior therapy better management options than methylphenidate for the treatment of cancer related fatigue in patients with advanced cancer?
Methodology Study Design
A non blinded multicentered randomised control trial will be conducted to evaluate the effectiveness of GET and CBT compared to methylphenidate for cancer related fatigue in patients with advanced cancer.
This is a multicentre three-armed randomised controlled trial (RCT) for Cancer related fatigue (CRF) in patients with advanced incurable cancer who are on palliative treatment. Participants will be randomised to assess the clinical effectiveness of GET, CBT, and methylphenidate for CRF.The GET group will participate in a supervised exercise programme and the CBT group will receive CBT intervention for 12 weeks.Study participants will remain on treatment with methylphenidate for 12 weeks.The dose will be titrated on weekly basis either by a face to face or telephonic consultation with the members of the study team, and tapered during the last week and stopped at the end of 12 week.After that, the participants will be dealt according to their circumstances and the patients who wish a continued treatment,will be recorded.The assessment of primary and secondary outcomes will be done at baseline,14 weeks (post-intervention) and at 18 and 26 weeks post-randomisation (follow-up assessments)
During weeks 10 and 11,the dose of methylphenidate will not be changed at whatever dose level was reached during week 9, unless participants report does-limiting adverse events at their weekly telephone consultations with the study nurse or member of the study team.
Outcomes at 14 weeks (primary endpoint) of either treatment arm will be compared to the participants taking methylphenidate.In addition, outcomes at 18 and 26 weeks (follow-up assessments) of either treatment arm will be compared to those of UC participants. It is planned that this study will take place at 10 different palliative care services. It is planned that during the internal pilot phase,at least four sites will be involved. A comprehensive screening log will be maintained at each participating site.
A clinical staff member will perform the initial screening and will broadly identify the patients fulfilling the inclusion and exclusion criteria.The potentially eligible participants will have a fatigue score of >3/10(moderate-severe), will be given Patient Information Sheet (PIS) and a member of the research team will send an invitation to meet the participant of study.Then, they will be formally screened to check whether they fulfil the inclusion or exclusion criteria.
Selection of Participants
- Age 18 years or above
- Advanced cancer of all tumor types
- Patient is willing and able to give informed consent for participation
- Receiving palliative treatment for advanced cancer
- Cancer treatment plan based on expected survival of more than 6 months according to their oncologists.
- Severely fatigued( CIS fatigue score of >35)
- Expected prognosis is 2-12 months according to the oncologists
- Allow notification of participation to their GP
- Under the care of specialist palliative team
- Contraindication to physical exercise
- Severe cognitive problems
- Symptomatic brain metastasis
- Females of childbearing age and males must use an effective method of contraception from the time consent is signed until 6 weeks after treatment is stopped and inform if pregnancy occurs
- Females of childbearing age should have a negative pregnancy test within 7 days before being registered for trial treatment and should not be breastfeeding
- Allergic to methylphenidate
- History of pheochromocytoma , glaucoma,thyrotoxicosis, severe depression, anorexia disorders,psychotic symptoms,suicidal tendencies and schizophrenia
- Known history of severe uncontrolled Type 1 bipolar disorder
- Know pre existing cardiovascular and cerebrovascular disorders
- Current or previous psychostimulant used in the last month
- White blood count >30 × 109 /L,Platelets <50 × 103 /μL,Severe anaemia (Haemoglobin < 80g/L)
- Participating in another research study
- Currently taking clonidine, warfarin, monoamine oxidase inhibitors or modafinil
- Not able to swallow tablets/capsules
- Any other significant disease which, according to the Investigator, may put the participant at risk or affect his ability to take part in the investigation
The primary outcome is fatigue severity measured by subscale fatigue severity (8 items, 7-point Likert scale) of the Checklist Individual Strength (CIS-fatigue)(18),score range is 8 to 56 and a score >35 shows severe fatigue.The fatigue subscale of the Functional Assessment of Chronic Illness Therapy (FACIT-F) questionnaire (13) measures the cancer related fatigue.It consists of the QOL questionnaires for the management of chronic illnesses and consists of 13 items targeting fatigue. This CRF specific tool is perhaps the most important and reliable primary outcome measure and is also used in previous studies(14)The score are between 0-52 and higher the scores ,the higher the fatigue would be.
Fatigue will also be assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, version 3.0) which is developed for use in clinical trials in cancer patients(15).
The QLQ-C15-PAL(16) is recommended in patients with advanced, incurable, and symptomatic cancer who have a median life expectancy of a few months, higher scores represent a higher level of symptoms.Appetite will be measured by using the anorexia item on the EORTC QLQ-C15-PAL EQ-5D-5L is a standardised instrument used in cost-effectiveness analyses of health outcomes. Activities of daily living will be measured by EQ-5D-5L. Satisfaction of advanced cancer patients will be measured on a weekly basis using the Global benefit score (GBS). Adverse events or reactions will be documented on the case report form and graded as mild, moderate or severe.
The level of physical activity will be assessed with actigraphy. The mean daily physical activity score can be calculated as a measure of physical activity.
The seven-item self-efficacy scale (SES) will be used to measure the amount of experienced control over fatigue(17). Higher scores show more sense of control.
A data analysis will be performed by a statistician to compare the effectiveness of both the GET and CBT compared with methylphenidate for CRF, an ANCOVA will be helpful at 14 weeks(post intervention) with CIS fatigue score as covariate,a dependant measure anf a fixed factor(19). An important problem faced by the palliative care researchers is missing data.Data will be analysed primarily on complete case basis. The p-level is adjusted to 0.025 to account for the two primary analyses, i.e., GET versus methylphenidate and CBT versus methylphenidate.An additional sensitivity analysis will be done, when the statisticians find statistically significant differences in comparing GET and CBT with methylphenidate, accounting for all randomised participants of the study to explore the impact of missing data. Several methods are available and will depend on the actual circumstances of missing data.Hence,it is important to record the causes of missing data and careful undertakings should be used.
ANCOVA will also be helpful for the secondary outcomes, where p-level of 0.05 will be used , where the baseline score on the dependent measure will be used as a covariate.
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