Mitochondrial dysfUnction: a Key Player in Doxorubicin-induced Skeletal and Cardiac muscLE Damage

B-cell Lymphoma Clinical Trial

— MUSCLE  

Official title:

Mitochondrial dysfUnction: a Key Player in Doxorubicin-induced Skeletal and Cardiac muscLE Damage

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05731375
• Other study ID #: NL83538.041
• Status: Not yet recruiting
• Start date: April 2024
• Est. completion date: December 2025

Study information

• Verified date: February 2023
• Source: UMC Utrecht
• Contact: David Binyam, MD
• Phone: +31648564688
• Email: d.binyam-2[@]umcutrecht.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this observational study is to demonstrate the ability of using non-invasive Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) to monitor changes of in-vivo markers of mitochondrial function in skeletal and cardiac muscles in muscles in large B- or T-cell lymphoma patients during treatment with (R-)CHOP. The main question it aims to answer is:

• Can 31P-MRS be used to monitor changes of in vivo markers of mitochondrial function in skeletal and cardiac muscles in large B- or T-cell lymphoma patients during treatment with (R-)CHOP?

To be able to answer this main question, participants will undergo 31P-MRS imaging of the calf muscles and of the heart 3 times during the study period.

Description:

Rationale: Patients with large B-cell lymphoma or T-cell lymphoma are often treated with (R-)CHOP chemotherapy with the intent to cure the disease, but this treatment can also lead to serious toxicities, which may last for many years. (R-)CHOP contains doxorubicin, which has detrimental effects on skeletal and cardiac muscles. Loss of skeletal muscle mass is associated with treatment modifications (i.e., dose delay/reduction/discontinuation), increased levels of fatigue, decreased quality of life (QoL) and shorter survival. Cardiomyopathy might lead to chronic heart failure in the long-term, which negatively affects prognosis as well. Preclinical studies investigating underlying mechanisms of these detrimental effects suggest that mitochondrial dysfunction plays a key role. However, human data is lacking due to the need of invasive repeated muscle biopsies. Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS) is an innovative, non-invasive technique, which enables repeated measures of skeletal and cardiac muscle mitochondrial energy metabolism.

Hypothesis:

In this study the investigators hypothesize that patients with large B-cell lymphoma or T-cell lymphoma treated with (R-)CHOP will show decreased mitochondrial function in skeletal and cardiac muscle tissue following chemotherapy treatment.

Objective:

To demonstrate the ability of using non-invasive 31P-MRS to monitor changes of in vivo markers of mitochondrial function in skeletal and cardiac muscles (i.e., skeletal muscle PCr recovery rate constant and cardiac PCr/ATP ratio) in patients with large B-cell lymphoma or T-cell lymphoma during treatment with (R-)CHOP. Furthermore, the investigators will assess the feasibility of undergoing the study measurements for patients with large B-cell lymphoma or T-cell lymphoma during intensive (R-)CHOP treatment and explore the association between changes in in vivo measured mitochondrial function in skeletal and cardiac muscle tissue and changes in muscle mass, physical fitness, muscle strength, physical activity levels measured by Fitbit, chemotherapy completion rate and patient-reported outcomes, including physical activity, fatigue and quality of life.

Study design: Cohort study.

Study population: Patients with large B-cell lymphoma or T-cell lymphoma scheduled for 6 full-dose cycles of 1st line immunochemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone with or without rituximab ((reversed) (R-)CHOP).

Main study parameters/endpoints:

The main study parameters are differences in skeletal muscle PCr recovery rate constant and cardiac PCr/ATP ratio. These parameters will be compared within-patients before, halfway during and after completion of chemotherapy treatment.

Nature and extent of the burden and risks associated with participation and benefit:

Included patients will visit the UMC Utrecht 3 times (i.e., before, halfway during and after completion of chemotherapy treatment). During these visits, participants will undergo 31P-MRS imaging of the calf muscles and of the heart at 7 Tesla. During the calf muscle scan, patients will be asked to perform a mild exercise challenge (i.e., dynamic plantar flexions). 7T 31P-MRS is a safe and reliable technique for subjects without contra-indications for undergoing MRI. Possible side-effects are limited to short-term vertigo and nausea. In addition, anthropometrics will be measured and small tests to evaluate muscle strength and physical performance will be performed. Participants will be asked to complete questionnaires regarding physical activity, quality of life and fatigue. Finally, patients will be asked to wear a Fitbit, provided by the study team, to objectively assess their levels of physical activity.

Subjects will not experience direct benefits by participating in this study. By the end of the study, the investigators will demonstrate the ability to non-invasively monitor skeletal and cardiac muscle mitochondrial damage using 31P-MRS, which is a pre-requisite to assess the efficacy of (non-)pharmacological interventions.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 12
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• Age = 18 years

• Patients with large B-cell lymphoma or T-cell lymphoma scheduled for 6 full-dose cycles of 1st line immunochemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone with or without rituximab ((reversed) (R-)CHOP).

• WHO-performance score 0-2.

• Patients with sufficient Dutch writing and reading skills.

• Written informed consent.

Exclusion Criteria:

• Contra-indications for 7T MR scanning, including patients with a non-MRI compatible pacemaker, cochlear implant or neurostimulator; patients with non-MR compatible metallic implants in their eye, spine, thorax or abdomen; patients with a non-MR compatible aneurysm clip in their brain; patients with claustrophobia, and/or severe obesity.

• Any circumstances that would impede adherence to study requirements or ability to give informed consent.

• Medical disorders affecting mitochondrial function; e.g., spinal muscular atrophy.

• (Other) relevant medical disorders; e.g., comorbidities affecting exercise tolerance.

• Being under examination for non-diagnosed disease at the time of investigation.

Related Conditions & MeSH terms

• B-cell Lymphoma
• Cardiomyopathies
• Chemotherapeutic Toxicity
• Doxorubicin Induced Cardiomyopathy
• Lymphoma
• T-cell Lymphoma

Intervention

Diagnostic Test:
• 31-MRS at 7 Tesla (T)
31-MRS imaging at 7T to evaluate mitochondrial function in skeletal and cardiac muscles.

Locations

Country	Name	City	State
Netherlands	Diakonessenhuis	Utrecht
Netherlands	UMC Utrecht	Utrecht

Sponsors (2)

Lead Sponsor	Collaborator
UMC Utrecht	Julius Clinical

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in weight (kg)	As measured by investigator during study visit.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Other	Height (cm)	As measured by investigator during study visit.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Primary	Changes in skeletal and cardiac muscle mitochondrial function	Assessed through 31P-MRS imaging. Parameters include: PCr recovery rate (in seconds); PCr/ATP ratio	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Adherence rates to the study protocol	Measured as: recruitment/retention rates; completion of study measurements within timeframes	Baseline to 18 weeks.
Secondary	Changes in physical fitness (Maximum short exercise capacity (Watt))	Assessed through Steep Ramp test	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in hand grip strength (kg)	Assessed through Hand Grip Strength Test	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in leg strength (kg)	Assessed through hypothetical 1-repetition max leg press	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in skeletal muscle area in cm2	Assessed through routine CT-scans	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in subjective physical activity levels (min/week moderate-to-vigorous physical activity)	Physical activity levels will be assessed subjectively using the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH)	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in objective physical activity levels (min/week moderate-to-vigorous physical activity)	Participants are provided with a Fitbit Inspire HR and are asked to wear these as much as possible during the whole study period. The Fitbit continuously registers the heart rate. Based on this, physical activity levels will be calculated.	Throughout the whole study, but of particular interest are the 9th week after baseline and 18th week post-baseline
Secondary	Changes in health-related Quality of Life	Measured using the core EORTC Quality of life questionnaire (QLQ-C30). The results of the questionnaire can be used to calculate a summary score, global health status, functional subscales and symptom subscales. For the summary score, global health status and functional subscales, a higher score is a better outcome, whilst for the symptom subscales, a lower score is a better outcome. All scores range from 0 to 100.; Global health status; Summary score; Functional scales: Physical functioning; Role functioning; Emotional functioning; Cognitive functioning; Social functioning; Symptom scales: Fatigue; Nausea and vomiting; Pain; Dyspnoea; Insomnia; Appetite loss; Constipation; Diarrhoea; Financial difficulties	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in lymphoma specific symptoms	Measured using the add-on of the abovementioned EORTC QLQ-C30, which is specifically developed for non-Hodgkin lymphoma patients (EORTC QLQ-NHL-HG29). A higher score depicts worse outcomes. All scores range from 0 to 100.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in fatigue	The EORTC provides several questionnaires to asses the quality of life of cancer patients. To assess fatigue the EORTC developed a specific fatigue questionnaire (QLQ-FA12). This questionnaire can be used to assess different dimensions of fatigue. A lower score depicts a better outcome. All scores range from 0 to 100.; Fatigue dimensions: Physical fatigue; Emotional fatigue; Cognitive fatigue	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in skeletal muscle end-exercise pH	Assessed through 31P-MRS imaging.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)
Secondary	Changes in skeletal muscle delta PCr during recovery after exercise in mM	Assessed through 31P-MRS imaging.	Baseline, halfway (R-)CHOP treatment (+/- 9 weeks), after (R-)CHOP treatment (+/- 18 weeks)