Clinical trial NCT06233890: The Analysis of Fatigue on Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukaemia
Official title: The Analysis of Fatigue on Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukaemia
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Chronic Myeloid Leukemia
Chronic Myeloid Leukemia, Chronic Phase
Fatigue
Sleep Disturbance
Keywords: Tyrosine kinase inhibitor
chronic myeloid leukaemia
sleep disturbance
fatigue
Activin B
L-carnitine
Lead sponsor: Imperial College Healthcare NHS Trust
Sponsor class: OTHER
First posted: 2024-01-31
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Fatigue
timeFrame: 14 days
measure: Subjective sleep disturbance
timeFrame: 1 day
measure: Subjective sleep
timeFrame: 14 days
measure: Percentage Sleep Efficiency
timeFrame: 14 days
measure: Sleep fragmentation index
timeFrame: 14 days
measure: Actigraphy variables
timeFrame: 14 days
measure: Actual wake time (wake after sleep onset)
timeFrame: 14 days
Secondary outcomes:
measure: Serum biomarker analysis
timeFrame: 1 day
measure: Serum biomarker analysis
timeFrame: 1 day
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Imperial NHS Healthcare Trust
Study officials:
affiliation: Imperial NHS Healthcare Trust
name: Dragana Milojkovic, MbChB, PHD
role: PRINCIPAL_INVESTIGATOR
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