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

Active, not recruiting

• Conditions: Chronic Myeloid Leukemia, Chronic Phase; Fatigue; Chronic Myeloid Leukemia; Sleep Disturbance
• Interventions: Device: Motion watch

• Registration Number: NCT06233890
• Lead Sponsor: Imperial College Healthcare NHS Trust

Brief Summary

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.

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 Timeline

• Study Start: 2023-05-12
• Status Verified: 2024-01
• Study First Submitted: 2024-01-08
• Study First Submitted QC: 2024-01-30
• Last Update Submitted: 2024-01-30
• Study First Posted: 2024-01-31
• Last Update Posted: 2024-01-31
• Primary Completion: 2025-05-12
• Study Completion: 2026-05-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 50

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

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Non -Fatigue	Motion watch	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.
Fatigue	Motion watch	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.

Primary Outcome Measures

Name	Time	Method
Actual wake time (wake after sleep onset)	14 days	Measured using accelerator in actigraphy monitor to assess objectively time to waking, measured in minutes and hours.
Subjective sleep disturbance	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.
Subjective sleep	14 days	Assessed by sleep diary.
Percentage Sleep Efficiency	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.
Fatigue	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.
Sleep fragmentation index	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.
Actigraphy variables	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.

Secondary Outcome Measures

Name	Time	Method
Serum biomarker analysis	1 day	L-carnitine peripheral blood analysis, measured in umol/L

Trial Locations

Locations (1)

Imperial NHS Healthcare Trust; 🇬🇧 London, United Kingdom