The Analysis of Fatigue on Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukaemia (TIRE)

January 30, 2024 updated by: Imperial College Healthcare NHS Trust

The goal of this clinical study is to gain essential insights into the relationship between Tyrosine kinase inhibitor (TKI) therapy and profound fatigue and abnormal sleep patterns using rest-activity monitoring (actigraphy) and peripheral blood biomarkers in patients with Chronic myeloid leukaemia in chronic phase. The main aims are to

  1. Determine the variance of subjective and objective sleep disturbance
  2. Determine the difference in serum biomarkers (activin B and L-carnitine)
  3. Determine how thes findings concord/discord between treatment and control groups.

Participants will asked to undergo 2 weeks of actigraphy monitoring and keep a sleep diary during this time. Blood and urine samples will be taken for analysis.

Researchers will compare two groups (patients with fatigue and those without) to assess the differences between groups.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

The therapeutic landscape of CML has evolved significantly, as a result of targeted TKI therapy, over the past 2 decades with patients now experiencing a near normal life expectancy due to achievement of deep molecular responses. As a consequence, the appropriate management of drug related adverse events to ensure minimal impact on quality of life has never been more vital. Fatigue and sleep disturbance are commonly described and whilst it is evident that there is a strong correlation between fatigue and TKI therapy, the mechanism which drives this remains unknown. In general, the prevalence of TKI induced fatigue and predicting factors is largely unexplored. This exploratory, pilot study aims to examine the rest-activity patterns, blood parameters and fatigue related serum biomarkers of CML patients affected by fatigue on TKI therapy, and aims to provide insight into the association between fatigue and sleep disturbance on treatment. The pilot study aims to recruit 25 patients with profound fatigue on TKI therapy, for a minimum of 6 months with an impact on their activities of daily living. Additionally, we will recruit 25 further patients (age, gender and TKI matched) as a control cohort, who also have a diagnosis of Chronic Phase CML with no symptoms of fatigue. Validated fatigue questionnaires will be used (Chalder fatigue scale and the Fisk fatigue impact scale), these are key diagnostic tools in Fatigue associated disorders. TKI- fatigue syndrome (TKI-FS) symptoms can emulate the clinical pattern of Chronic Fatigue Syndrome (CFS) and this project would delineate congruence between CFS and TKI-FS. The patient cohort will also undergo actigraphy, this will be used in this study as a validated objective sleep measure, this method uses sophisticated analysis of movement to infer sleep/wake patterns. Actigraphy is non-invasive and can be used for several weeks, alongside a daily sleep diary, allowing collection of naturalistic sleep data as a participant goes about their normal activities. In addition, serum biomarkers such as activin B is a member of the activin family of proteins, which belongs to the TGF-β superfamily of growth and differentiation factors; activin B has been shown to be a potential serum biomarker in fatigue related disorders. In addition, L-carnitine is a vital molecular component in many metabolic pathways, the majority of the total body carnitine is located within skeletal muscle. Impairments in L-carnitine synthesis, transport or metabolism can result in primary or secondary deficiencies, which ultimately results in muscle weakness and fatigue. Assessment of both of these serum biomarkers in both the fatigue and control cohort may shed insight on whether there are significant differences between those patients with TKI-FS and the control group.

The aim of the study is to use the above stated modalities in order to gain further insight into the association between fatigue and sleep disturbance in CML patients treated with TKI therapy, which can have a debilitating impact on patients.

Study Type

Observational

Enrollment (Actual)

50

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • London, United Kingdom, W12 0HS
        • Imperial NHS Healthcare Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

CML- Chronic phase patients in a single centre with significant fatigue on TKIs in group 1. In Group 2, CML chronic phase patients with no significant fatigue.

Description

Inclusion Criteria:

  1. Informed consent
  2. Diagnosis of CML on treatment with tyrosine kinase inhibitor.
  3. On stable TKI therapy for at least 6 months duration
  4. Confirmation of ongoing chronic phase
  5. Male or females aged: 18 - 70 years old
  6. On-going fatigue for more than 6 months with impairment in daily life activities/ or no fatigue as described in point 7.
  7. If recruited to fatigue group then subjects would require both a - Chalder score > or = 5 and a Modified Fatigue Impact scale score > or = 43
  8. If recruited to control group, then subjects would require both a Chalder score < or = 2 and a Modified Fatigue Impact Scale score <33

Exclusion Criteria:

  1. Not currently on treatment with a TKI inhibitor.
  2. Previous or active other neoplasm.
  3. Past medical history including diagnosed sleep disorder, depression and on current therapy, sleep apnoea, uncontrolled thyroid dysfunction and neurological disorder
  4. Active treatment with any of the following drug groups: anti cholinergic or anti muscarinic drugs, tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), Norepinephrine Dopamine Reuptake inhibitor (NDRI), Serotonin antagonist and reuptake inhibitor (SARI), Norepinephrine Antagonist serotonin antagonist (NASA), Monoamine oxidase inhibitors (MAO), regular sedating antihistamine use, regular opioid use, beta blockers, methyldopa, clonidine, benzodiazepines and zopiclone.
  5. Prior allogeneic SCT
  6. Have a history of alcohol or substance abuse

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Fatigue

Group 1: Fatigue present for more than 6 months with impairment in daily life activities.

Fatigue will be assessed using two validated fatigue questionnaires completed at the screening visit. The Chalder fatigue scale (CFQ) is an 11 item scale which assesses the severity of fatigue over the last 90 days and the Modified Fatigue Impact scale (MFIS), commonly used to determine the impact of fatigue on quality of life, assesses fatigue over the previous 30 days. Both scales are diagnostic tools in chronic disease associated fatigue. Scores on these scales will determine if patients are eligible. For this group a score > or = 5 for Chalder score and > or = 43 for the MFIS score.
Device: Motion watch
Actigraphy watch to be worn for 14 days
Non -Fatigue
Group 2: no significant symptoms of fatigue on TKI therapy. Fatigue will be assessed using two validated fatigue questionnaires completed at the screening visit. The Chalder fatigue scale (CFQ) is an 11 item scale which assesses the severity of fatigue over the last 90 days and the Modified Fatigue Impact scale (MFIS), commonly used to determine the impact of fatigue on quality of life, assesses fatigue over the previous 30 days. Both scales are diagnostic tools in chronic disease associated fatigue. Scores on these scales will determine if patients are eligible. For this group a score < or = 2 for Chalder score and < or = 33 for the MFIS score.
Device: Motion watch
Actigraphy watch to be worn for 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fatigue
Time Frame: 14 days
Assessed by validated questionnaires (Chalder and Modified Fatigue Impact scale), with scoring as described in eligibility criteria. Control group < or = 2 for Chalder score and < or = 33 for the MFIS score.For fatigue group a score > or = 5 for Chalder score and > or = 43 for the MFIS score.
14 days
Subjective sleep disturbance
Time Frame: 1 day
Assessed by Pittsburgh Sleep Quality Index (validated). Scores for each question range from 0 to 3, with higher scores indicating more acute sleep disturbances. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality.
1 day
Subjective sleep
Time Frame: 14 days
Assessed by sleep diary.
14 days
Percentage Sleep Efficiency
Time Frame: 14 days
Percentage Sleep efficiency assessed using actigraphy accelerometer that can reliably translate physical motion and exerted energy into a numeric representation measured in 30 or 60-second epochs allowing continuous data collection over weeks. Percentage sleep efficiency is assessed, defined as the ratio between the total sleep time, and the total time dedicated to sleep (both sleeping and awake eg attempting to fall asleep or back asleep), measured in hours and minutes.
14 days
Sleep fragmentation index
Time Frame: 14 days
Calculated by actigraphy using the total number of awakenings from deeper non-rapid eye movement to lighter sleep divided by the total sleep time in hours. Measured in hours and minutes.
14 days
Actigraphy variables
Time Frame: 14 days
total sleep time (assumed sleep) measured using muscle motion/movement by accelerator in actigraphy monitor, and using algorithms that transform the raw accelerometer data into counts.
14 days
Actual wake time (wake after sleep onset)
Time Frame: 14 days
Measured using accelerator in actigraphy monitor to assess objectively time to waking, measured in minutes and hours.
14 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum biomarker analysis
Time Frame: 1 day
Activin B peripheral blood analysis, measured in pg/ml
1 day
Serum biomarker analysis
Time Frame: 1 day
L-carnitine peripheral blood analysis, measured in umol/L
1 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Imperial College Healthcare NHS Trust

Investigators

  • Principal Investigator: Dragana Milojkovic, MbChB, PHD, Imperial NHS Healthcare Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 12, 2023

Primary Completion (Estimated)

May 12, 2025

Study Completion (Estimated)

May 12, 2026

Study Registration Dates

First Submitted

January 8, 2024

First Submitted That Met QC Criteria

January 30, 2024

First Posted (Estimated)

January 31, 2024

Study Record Updates

Last Update Posted (Estimated)

January 31, 2024

Last Update Submitted That Met QC Criteria

January 30, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 22HH7973

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

All data shared with coinvestigators will be anonymised.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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