Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06446908 |
| Other study ID # |
2024-A06PHYSACTIV |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2024 |
| Est. completion date |
March 31, 2027 |
Study information
| Verified date |
May 2024 |
| Source |
Hopital Montfort |
| Contact |
Celine Fresne, MD |
| Phone |
6137464621 |
| Email |
celinefresne[@]montfort.on.ca |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Steatosis is the building of fat in the liver. Steatotic liver disease (SLD) regroups MASLD
(metabolic dysfunction-associated steatotic liver disease) and MASH (metabolic
dysfunction-associated steatohepatitis) i.e. MASLD with inflammation. An estimated 30% of the
population worldwide has MASLD and 5% of Canadians have MASH. MASH is a leading cause of
liver transplantation in Canada. There is no cure for SLD, and the treatment relies on diet,
weight loss, and physical activity (PA).
Is a counselling intervention to help patients progressively engage in more PA a feasible and
acceptable approach? Objectives. This proposal has three primary objectives: 1) To assess the
feasibility of our PA counselling intervention (to be delivered online) with SLD patients; 2)
To evaluate the acceptability of our intervention; 3) To evaluate the feasibility of the
study methods/procedures.
Methodology. This study is an open-label, mono-centred, single-case experimental design with
multiple base levels. The study will comprise 3 phases, alternating periods of observation
(A) and 1 period of counselling (B) with an A1-B-A2 design.
PA will be assessed continuously using an accelerometer for 7 to 14 days per (A) phase.
During phase (B), participants will receive the intervention, i.e. 6 x 45-minute, real-time,
face-to-face, virtual sessions with a PA counsellor.
Based on past studies, our sample size will be 12 participants. They will be recruited
through the hepatology clinic at Hôpital Montfort.
The primary outcomes of the project are to evaluate the feasibility and acceptability of the
trial and intervention. The secondary outcomes are Daily PA time and biological/imaging data
evolution
Description:
Background and rationale: This pilot trial aims to evaluate the feasibility and acceptability
of a counselling intervention on physical activity in patients with liver steatosis (primary
aim) and changes in molecular outcomes (exploratory aim).
Liver steatosis is the build-up of fat in the form of lipid droplets inside hepatocytes
(liver cells). Although it is a form of energy storage, it is considered pathological when
more than 5% of hepatocytes demonstrate fat infiltration on a liver biopsy or imaging
(ultrasound, magnetic resonance, or computed tomography). Until recently, liver steatosis was
described as two entities with a clinicopathological continuum: non-alcoholic fatty liver
disease (NAFLD) and non-alcoholic steatohepatitis (NASH) i.e. NAFLD with inflammation.
NAFLD/NASH is strongly associated with features of the metabolic syndrome: type 2 diabetes
mellitus (DM), hyperlipidemia, and obesity. Insulin resistance is considered one of the first
steps to developing fatty liver infiltration. Indeed, 70% to 80% of patients with diabetes
have NASH. A recent change in nomenclature now accounts for the link with cardiometabolic
criteria. NAFLD is now MASLD (metabolic dysfunction-associated steatotic liver disease) i.e.
steatosis and at least 1 cardiometabolic factor and NASH is MASH (metabolic
dysfunction-associated steatohepatitis) i.e. MASLD with inflammation, regrouped as steatotic
liver disease (SLD).
SLD is a silent disease: patients have no symptoms, are not routinely screened for the
disease, and SLD is often revealed through complications of cirrhosis, at a late stage for
intervention. Inflammation is confirmed when liver function tests alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) are elevated. It is recommended to assess the
level of associated fibrosis through non-invasive tests such as elastography that evaluates
liver stiffness that increases with fibrosis, or algorithms such as Fibrosis-4 (FIB-4) that
combines age, ALT, AST, and platelets count to identify fibrosis in patients over 35 years
old. The SLD burden is expected to increase. An estimated 30% of the population worldwide has
MASLD and 5% of Canadians have MASH (2). A Canadian study concluded that the number of people
with post-MASH decompensated cirrhosis will double by 2030 and cases of liver cancer will
increase by 80 % (2). MASH is a leading cause of liver transplantation in Canada (2). Despite
extensive research with currently over 1350 active clinical trials (clinicaltrials.gov,
accessed 19/09/2023), there is no cure for SLD, and the treatment relies on diet, weight
loss, and physical activity (PA). The current North American guidelines state that patients
with NAFLD should be strongly encouraged to engage in PA to the extent possible.
The effects of PA on SLD have been studied extensively. A systematic review (3) showed
personalized PA improved the quality of life for cirrhotic patients without significant side
effects and may reduce the 90-day readmission rates for transplant patients at the end of the
program. Henri et al. showed US NAFLD adults who engaged in vigorous PA have a lower risk of
death from cancer and all causes than NAFLD adults who do not engage in any PA; benefits
persisted for low PA and any PA versus no PA (4). Similarly, a US study showed PA is
inversely associated with NALFD and associated with better survival for NALFD patients (5).
PA is also successful in preventing DM, which is now included in the MASH definition (6).
Moreover, meta-analyses have concluded that PA contributes to decreasing levels of various
biological markers of SLD (7), (8) and inflammatory markers (9), thus reducing intra-hepatic
fat (10), (11), (12), (13). PA is thus efficacious in reducing inflammation and fibrosis in
patients with SLD. However, key knowledge gaps remain including (1) scarce data on the impact
of sustained PA in MASH patients, especially post-participation in studies, (2) lack of
consistency in terms of eligibility criteria that are often too narrow and exclude patients
seen in practice, (3) heterogeneous PA parameters (e.g., dosage, type, duration), and (4)
variability of biological data collected. It is thus difficult to precisely define through
meta-analyses and/or systematic reviews the optimal program to help support PA or its
duration. Another critical gap is what is the influence of interventions that aim to have
patients initiate and maintain PA on their own. This is important because in reality, it is
not possible (or sustainable) to offer patients supervised PA sessions in the amount that is
commensurate with current PA guidelines, considering patients have their own barriers to PA
and the lack of support to help them initiate and maintain PA in everyday life. Indeed, from
discussions with patients during clinical evaluation with Dr. Fresne, some barriers are lack
of time, insufficient knowledge, fear of injury, and lack of financial resources. In the
literature, perceived lack of resources and education, physical discomfort or limitations or
pain, lack of space, and time constraints have been identified as barriers for PA (13),(14),
(15).
We believe individualized support and guidance to help patients progressively engage in more
PA is a better results-oriented sustainable approach than delivering supervised PA training
sessions and propose a personalized counselling intervention to engage patients with SLD in
PA.
Additionally, whether having patients initiate and maintain PA in everyday life by providing
them with support can contribute to reducing inflammation and/or fibrosis in the liver
remains to be described. It is known that sarcopenia (loss of skeletal muscle mass and
strength) is associated with cirrhosis/liver fibrosis and DM, suggesting communication
between the liver and muscles. During PA, the muscle secretes small peptides called myokines
that act on the skeletal muscle, but also on distant organs, to improve their function,
including decreasing inflammation and liver lipid content, such as interleukin 6 (IL-6),
IL-15, irisin (16). PA also modifies the secretion of hepatokines, peptides secreted by
hepatocytes. It is therefore possible that levels of these proteins will be modified in our
population if they can initiate and maintain PA during their participation in PA counselling
compared to their baseline PA level. These proteins could therefore serve as biomarkers to
determine the efficacy of the PA counselling in improving SLD and reducing inflammation.
Significance and Innovation:
Engaging SLD patients in PA is crucial and a matter of public health. The number of SLD
patients will increase in the next 10 years and there is currently no medication to treat the
condition nor prevent the evolution towards cirrhosis with the associated risk of liver
transplant and cancer. PA has proven its efficacy in SLD. However, physicians may not know
how to help their patients to practice PA as a treatment and SLD patients face barriers to PA
that need better characterization. We believe our innovative PA intervention using
personalized counselling could help patients to overcome their barriers to PA. To our
knowledge, this would be the first study that would provide patients keys to successfully
engage in PA and empower SLD patients with PA through counselling. We believe participants in
our study will be more likely to maintain long-term PA and the project will help us
understand the barriers and facilitators to PA behavior change faced by SLD patients. If this
feasibility project proves successful, we will develop a larger trial to assess the long-term
engagement of SLD patients in PA and study the effects of PA on the interaction between
liver, fat, and muscle in SLD patients.
Population and recruitment: Based on past SCED studies, our sample size will be 12
participants. They will be recruited through the hepatology clinic at Hôpital Montfort.
Intervention: The intervention is informed by the Telehealth Bariatric Behavioral
Intervention (TELE-BariACTIV) study led by Drs Baillot and Brunet (18). The TELE-BariACTIV
has been developed to increase PA for patients awaiting bariatric surgery. It is based on the
principles of the BariACTIV trials (19),(20) that demonstrated a 6-week period of
personalized face-to-face counselling before surgery centered on behavioral strategies such
as goal-setting and self-monitoring significantly increased pre-surgery moderate-to-vigourous
PA. TELE-BariACTIV was designed to reinforce theory-based content and participant's
perspective, and include telehealth to increase reach. It was successfully tested (article in
preparation) using a SCED. The purpose of the intervention is to increase autonomy,
motivation, and self-confidence so participants can autonomously engage in PA. The content of
the TELE-BariACTIV counselling is meant to be adapted to reflect participants' conditions,
and we will do so by working with a patient-partner. The intervention aims to increase
motivation (via satisfaction of basic psychological needs) and self-efficacy, critical
determinants of PA behavior change.
Data collection: We will collect sociodemographic data such as age, sex, gender, language,
level of education, profession, and income. PA will be measured daily throughout the trial
via an accelerometer (7-14 days in each (A) phase) mailed to the participants. They will be
instructed to wear the accelerometer continuously, except during water-based activities, and
to maintain a log of wear times with waking and bed times. Accelerometer data will be
extracted and downloaded (10-second epochs) using the appropriate software and will be
cleaned in accordance with the logbooks provided by the participants.
Qualitative data: We will collect data on (1) participants' opinions of the trial
(assessments, timing, etc.) and intervention via with a semi-structured interview at the end
of their participation, (2) onacceptability with a 7-item questionnaire developed and
validated by the research team, and (3) on PA counsellor notes for each intervention session,
for examples, duration, topics discussed, accomplishment of session objectives, participants'
reactions to the content, next steps with the participants, and reflections as a PA
counsellor (e.g., problems arising during the sessions, overall experience delivering the
session, suggestion for intervention or personal improvements, and session deviations).
Quantitative data: We will collect/measure pre and post intervention data for : liver
function tests (ALT, AST, Gamma Glutamyl Transferase, Alkaline Phosphatase, bilirubin,
albumin), total/High Density Lipoprotein/Low Density Lipoprotein cholesterol levels,
triglycerides levels, fasting glucose and insulin, HbA1c, fasting free fatty acids, Body Mass
Index, waist circumference, IL-6, TNF-α, CReactive Protein, and leptin, and calculate
composite scores such as FIB-4. We will also evaluate liver fibrosis with a liver
elastography before screening and at the end of participation. Myokines and hepatokines will
be measured using available kits.
Data analysis:
Quantitative data: Descriptive statistics will be computed for baseline sociodemographic,
clinical, biological, feasibility, and acceptability data derived from the numerical
responses and close-ended questions. All statistical analyses will be carried out using R and
the appropriate packages. A Tau-U test for each participant and for the group will be
performed to compare daily PA based on accelerometer data between phases A1 and B, as well as
A1 and A2. Individual effect sizes will be aggregated in a meta-analysis to obtain a
group-based effect size. A sensitivity analysis will also be performed with a randomization
test.
Qualitative data: The content of the interviews and the PA counselors' notes completed after
the sessions will be analyzed by two team members using content analysis after verbatim
transcription, using the NVivo software.
Based on data from the TELE-bariACTIV study, our project will be deemed successful if the
refusal rate is ≤25%, the retention rate after phase B (PA intervention) is ≥75%, the
intervention attendance rate is ≥75%, and the intervention attrition rate ≤25%. The main
objectives of our project are feasibility and acceptability: at this point, the evolution or
lack of evolution of biological or imaging markers before and after participation will not be
considered for the success of the project. It will, however, help define which markers should
be used for a large-scale trial.
