Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03633279 |
| Other study ID # |
SIMM 2018 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
June 22, 2018 |
| Est. completion date |
October 2023 |
Study information
| Verified date |
September 2023 |
| Source |
Dayanand Medical College and Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Sarcopenia is defined as loss of skeletal muscle mass. In cirrhosis, due to impaired urea
genesis and decreased hepatic ammonia disposal, the skeletal muscle functions as a metabolic
partner for the liver. The proportion of patients with sarcopenia is higher in those with
alcoholic liver cirrhosis (80%) compared to cirrhosis due to other etiologies (31%-71%).
Sarcopenia is prevalent in > 50% patients with Child C cirrhosis. Sarcopenia increases the
risk for severe infections in patients with cirrhosis. Adequate amino acid supply is needed
for appropriate antibody and cytokine responses, that is impaired when skeletal muscle mass.
The sepsis-related mortality rates in patients with and without sarcopenia are 22% and 8%,
respectively (P = 0.02). In patients with liver cirrhosis is protein-calorie malnutrition,
leading to severe consequences to the general state and clinical evolution of the patient.
Description:
Globally, the mortality after any infection in cirrhosis patients is very high. The
cumulative mortality in patients with infections was 43.5% (11,987 patients) where as the
mortality rate without infection was 13.6% (2317 patients). Over the years, variceal bleeding
causing death in cirrhosis has declined substantially but there has been no improvement in
infection causing mortality over several decades. It adversely affects clinical outcomes
including survival, quality of life, development of other complications.
Radiological image analysis is currently used to diagnose sarcopenia in cirrhosis. The
European Working Group on Sarcopenia in Older People and Wilson D et al, recommend using the
presence of both low muscle mass and low muscle function (strength or performance) for the
diagnosis of sarcopenia.
Cirrhosis is believed to be a state of anabolic resistance and standard replacement of
nutrients are generally ineffective.
Patients with cirrhosis frequently show protein and energy deficiency. Protein deficiency
leads to hypoalbuminemia, inducing ascites and edema, whereas energy deficiency decreases fat
and muscle mass and causes muscle weakness, decreasing the quality of life of patients with
cirrhosis. Moreover, in patients with advanced chronic liver disease, Branched Chain Amino
acids concentrations are low, whereas the concentrations of aromatic amino acids such as
phenylalanine and tyrosine are high, conditions that may be closely associated with hepatic
encephalopathy and the prognosis of these patients. The survival rate of patients with
sarcopenia liver cirrhosis has been found to be significantly lower than that of
non-sarcopenia cirrhotic patients. Long-term Branched Chain Amino acids supplementation
significantly raises the survival rate in sarcopenia liver cirrhosis but not in
non-sarcopenia liver cirrhosis showed that sarcopenia was associated with mortality in
patients undergoing Live Donor Liver Transplantation, and perioperative nutritional therapy
significantly improved overall survival in patients with sarcopenia.
It has been reported that the longer the duration on a waiting list for liver
transplantation, the more sarcopenia the patient has become, even though their Model for
End-stage Liver Disease scores stay the same. Patients in an advanced state of sarcopenia are
confronted by their vulnerability to infection, and ultimately their imminent death. Patients
with sarcopenia tended to have postoperative complications, especially infectious
complications. Studies differ on the effect of of Sarcopenia on post transplant mortality.
Montano-Loza et al reported that patients with "extreme" sarcopenia exhibited significantly
worse prognosis. Nevertheless, patients with severe sarcopenia must have worse prognoses
because of the vulnerability to infectious problems.
The main immunosuppressants used in liver transplant recipients are calcineurin inhibitors.
Although liver transplant recipients usually gain weight after transplantation, that gain is
mainly caused by the accumulation of fat, while skeletal muscle mass rather decreases. The
state of sarcopenia rather worsen after liver transplantation. reported that sarcopenia
continued to be a risk factor for mortality even in patients who managed to survive their
early post transplant periods. Because sarcopenia continues, or rather worsens in some
recipients, after liver transplantation, their vulnerability to infections, frailty syndrome
in general, caused by sarcopenia should be seriously cautioned in addition to the problems
relating to immunosuppressants.
With regard to nutritional intervention for sarcopenia, Branched Chain Amino acids
supplementation is vital because Branched Chain Amino acids are an essential amino acid
substrate for protein synthesis and energy generation in skeletal muscles. Branched Chain
Amino acids are a group of three essential amino acids comprising valine, leucine and
isoleucine; these account for 35% of the essential amino acids in skeletal muscle proteins.
In patients with liver cirrhosis, Branched Chain Amino acids is not only a substrate of
protein synthesis and ammonia detoxification, but is also a source of energy for the skeletal
muscles.
Therefore, the consumption of Branched Chain Amino acids by skeletal muscle is accelerated in
Liver Cirrhosis, leading to muscle protein breakdown, and resulting in sarcopenia As an
effect on cirrhotic patients, Branched Chain Amino acids supplementation has been
demonstrated to improve Protein Energy Malnutrition, raise serum albumin levels, and
subsequently improve quality of life and prognosis The possible effect of Branched Chain
Amino acids on sarcopenia is that leucine primarily activates the mammalian target of
rapamycin signaling pathway involved in muscle protein synthesis, and additionally stimulates
the pancreatic β cells to release insulin, which has an anabolic effect in skeletal muscle.
The present study demonstrated that Branched Chain Amino acids supplementation significantly
improves the prognosis of sarcopenia liver cirrhosis, but its direct effect on sarcopenia
itself remains unknown.
Several clinical trials have suggested that Branched Chain Amino acids supplementation
improves the prognosis of cirrhotic patients. For example, a multicenter randomized trial
from Italy showed that oral Branched Chain Amino acids supplementation in patients with
advanced cirrhosis prevented progressive hepatic failure and improved surrogate markers and
perceived health status.
The standard of care for nutrition in patients with liver cirrhosis are as follows -
Nutritional recommendations target the optimal supply of adequate substrates related to
requirements linked to energy, protein, carbohydrates, lipids, vitamins and minerals.
Based on these basic observations, patients with advanced chronic liver disease have been
treated clinically with Branched Chain Amino acids-rich medicines, with positive effects.
Branched Chain Amino acids will complement frequent feeding with late evening snacks in
reversing muscle loss in cirrhosis. The diet combined with resistance exercises shall
increase skeletal muscle mass.
Clinical and laboratory Assessment Complete medical record regarding the cirrhosis, its
aetiology, complications and co-morbidities will be noted. Liver Function test, Renal
function test, Prothrombin time/international normalized ratio will be recorded. The severity
of cirrhosis will be assessed using the Child- Pugh score and the Model of End Stage Liver
Disease score.
Testing- Assessment of sarcopenia
Patients will participate in the following 4 procedures to measure sarcopenia:
1. L3 Skeletal Muscle Index Skeletal muscle area derived from a single slice CT has become
more easily reproducible, and reduces the radiation exposure required to only 2.6
millisieverts. Measuring cross-sectional muscle area at either the level of the third
(L3) or fourth (L4) lumbar vertebrae has been shown to correlate well with total body
muscle mass (r = 0.71). When adjusted for patient height to take stature into account it
is referred to as skeletal muscle index. Skeletal muscle index will be calculated from
Slice-O-matic software, version 5 (Tomovision), Montreal, QC, Canada). Skeletal muscle
index has been shown to be of higher accuracy in the diagnosis of sarcopenia in
cirrhosis than anthropometry or dual-energy x-ray absorptiometry (DEXA) scanning and is
now the most commonly employed method in studies investigating sarcopenia in cirrhosis.
Diagnostic criteria have been extrapolated from Western cirrhosis populations. Multiple
studies in cirrhosis, which have employed this definition, have produced clinically
meaningful results and it is increasingly accepted as the most appropriate definition of
sarcopenia when using cross-sectional imaging.
2. Muscle strength:It is assessed by grip strength and measured using a Jamar dynamometer.
The summary of measures are as follow.
Posture Subject seated Arm position Shoulders adducted and neutrally rotated, elbow
flexed at 90°, forearm in neutral Wrist position Wrist between 0 and 30° of dorsiflexion
3. The participant will be allowed to perform one test trial. After this, three trials
followed and the best score was used for analysis. Handgrip strength will be expressed
in kilogram's (Kg). Three trials for each hand will be carried out and the highest value
for diagnosing sarcopenia.
3. Muscle Performance [Gait Speed Test (4-metre)]:
The test can be performed with any patient able to walk 4 meters using the instructions
below:
1. Instruct the patient to walk at their normal pace. Patients may use an assistive device,
if needed.
2. Ask the patient to walk down a hallway through a 1-metre zone for acceleration, a
central 4-metre "testing" zone, and a 1-metre zone for deceleration (the patient should
not start to slow down before the 4-metre mark).
3. Start the timer with the first footfall after the 0-metre line of the testing zone
4. Stop the timer with the first footfall after the 4-metre line of the testing zone
SCORING: Gait speed of longer than 5 seconds to walk 4 meters (<0.8 m/s) suggests an
increased risk of poor muscle performance.
4. Muscle Performance-The chair stand test is a physical performance test used to assess
lower-extremity function. A 5 repetition test is a measure of strength; a 10 repetition test
is a measure of strength and endurance. Equipment/Set Up Use a standard chair with arms and
with a seat height of approximately 17 inches for all assessments, regardless of the height
of the subject. Place the back of the chair against a wall to prevent movement during the
test. Procedure Instruct and demonstrate the following protocol before asking the subject to
perform the test:
- Sit as far back as possible in the chair seat. Keep feet firmly planted on the floor
approximately hip width apart and the back of lower legs away from the chair. Keep knees
bent at a 90-degree angle with arms crossed over the chest. (An individual of average or
taller height will be able to sit with their upper back against the back of the chair.
Individuals of shorter than average height will not be able to touch the chair back
while maintaining proper position and are not required to touch the chair back during
testing).
- Stand up one time and sit down, returning completely to the correct starting position.
- Indicate that any chair stands done with improper technique, e.g. not standing all the
way up, not sitting all the way back, lifting feet off the floor, etc. will not be
counted.
- Allow the participant the opportunity to try one chair stand to be sure when they stand
up the back of their legs are not touching the chair.
- Instruct the subject that the timed assessment will begin on the command, "Ready, Set,
Go" and that they are to stand up and sit back down 5 times as quickly and safely as
possible. At the command "Ready, Set, Go" the tester begins timing by starting the
stopwatch.
- Count each chair stand out loud when the subject is in the standing position. Provide
continuous verbal encouragement during the test.
- At the tenth repetition click the stopwatch off while participant is in the standing
position.
- Conduct two trials, separated by three minutes. If subjects are unable to stand up one
time without assistance than they can use their hands to assist them in rising and
returning to the seated position while following all other procedures as described
above. Make sure to note that hands were used when recording the assessment data.
Normative value of Sarcopenia indices and association of Sarcopenia indices and mortality in
child C cirrhosis patients will be also calculated.
Follow up Three months after randomization, data will be collected on the 4 objective indices
of sarcopenia, as outlined above.In addition, event free survival, number of
hospitalisations, combined liver events (variceal bleeds, ascites , Hepato-renal syndrome,
Overt Hepatic encephalopathy, Septic complications - Pneumonias, Urinary Tract Infection,
spontaneous bacterial peritonitis, skin infections and septic shock) and Quality of Life
(assessed using SF 36 questionnaire) will also be recorded.
Monitoring for Adverse Events:
Branched Chain Amino acids did not increase the risk of serious adverse events, but was
associated with nausea and diarrhoea. Any adverse event will be recorded specifying the time
of onset, the duration, the severity and the relationship to the test medication.
Sample size: The primary objective is to show the superiority of Branched Chain Amino acids
(experimental arm) versus placebo to improve both the muscle mass and muscle strength
(co-primary endpoint) after 3 month of treatment in patients with sarcopeniacirrhosis (Child
C) treated with standard nutrition and exercises. The co-primary endpoint is the 3-month
change in CT Skeletal muscle index and Hand Grip Strength (i.e difference between the
baseline and 3 month values). The study success will be only declared if both primary
endpoints are statistically significant in favor of the experimental arm at two-sided
significant level of 0.05. The sample size will determined as the maximum value of the sample
sizes separately calculated for each endpoint with a 90% power for each comparison
(considering independence between the two primary outcome as conservative approach) in order
to guarantee a power of 0.80 to show the treatment efficacy on both primary outcomes. As
analyzing the changes or values at 3 months are equivalent since the primary analysis will be
adjusted for baseline values,Investigator determined the sample size using the 3-month values
for each primary endpoints obtained in a study carried out in our center. In control arm,
Investigator expect a mean CT Skeletal muscle index of 45.4±5.9 at 3-months and Mean Hand
Grip Strength of 33.7+9. Compared to placebo Investigator expect that Branched Chain Amino
acids will be associated with an increasing in 10% in mean value of CT Skeletal muscle index
(i.e. an absolute mean difference of 4.5) and with an increasing in 20% in mean value of Hand
Grip Strength (i.e. an absolute mean difference of 6.7). With a two-sided test (alpha=5%,
power=90%), 38 patients per arm will be required to detect the effect size on CT Skeletal
muscle index (assuming a standard deviation of 5.9) and 45 per arm to detect the effect size
on Hand Grip Strength (assuming a standard deviation of 9.6). Thus, a total of 90 patients
will be required. To account for an anticipated attrition rate of 20%, a total of 114
patients will be included and randomized.
Statistical Analysis Plan Statistical analyses will be independently performed by the
Biostatistics Department of University of Lille under the responsibility of Professor Alain
Duhamel. Data will be analyzed using the SAS software (SAS Institute Inc, Cary, NC, USA) and
all statistical tests will be performed with a 2-tailed alpha risk of 0.05. A detailed
statistical analysis plan will be written and finalized prior to the database lock.
All analyses will be performed for all randomized patients based on their original group of
randomization, regardless of the treatment they actually received, study eligibility, or
compliance post randomization, according to the intention-to-treat principle. Nis planned
Baseline characteristics will be described for each arm. Quantitative variables will be
expressed as mean (standard deviation), median (interquartile range) and range. Qualitative
variables will be expressed as frequencies and percentages. Normality of distribution will be
assessed graphically and using the Shapiro-Wilk test.
Co-Primary outcome The change in CT Skeletal muscle index and Hand Grip Strength from
baseline to 3 months will be estimated and compared between the 2 arms using the constrained
longitudinal data analysis model that was proposed by Liang and Zeger. The constrained
longitudinal data analysis model will be used for its potential advantages compared to a
conventional longitudinal analysis of covariance (ANCOVA) model. In the constrained
longitudinal data analysis, both the baseline and post baseline values are modeled as
dependent variables using a linear mixed model (an unstructured covariance pattern model),
and the true baseline means are constrained to be the same for the 2 treatment arms. Hence,
the constrained longitudinal data analysis provides an adjustment for observed baseline
differences in estimating treatment effects, using all available baseline and post-baseline
values. The mean between-group difference (with a 95% confidence interval(CI)) in the 3-month
change in CT Skeletal muscle index and Hand Grip Strength (BCAA vs. placebo) will be
estimated as an effect size with the time-by-group interaction. If normality of the model
residuals is not satisfied, nonparametric analysis will be used; absolute changes between
baseline and 3-month visits will be calculated and compared between the 2 arms using a
non-parametric analysis of covariance that is adjusted for baseline values. The efficacy of
Branched chain amino acids will be declared only if the comparison in both primary outcome is
significant at p<0.05 (two-sided test).
Missing values in CT Skeletal muscle index and Hand Grip Strength measures will be handled
with a multiple imputation procedure. Missing data will be imputed under the missing at
random assumption (whatever the reason for missing data) by using regression switching
approach (a chained equation with m=20 imputations), with the predictive mean matching method
for continuous variables, and logistic regression models (binary, ordinal or polynomial) for
categorical variables. The imputation procedure will be performed using main baseline
characteristics and allocated arm. Treatment effect estimates that are obtained from multiple
imputed data sets will be combined using Rubin's rules. Sensitivity analyses will be
conducted on the observed data (case-complete analysis) and in per-protocol population. The
per-protocol population will include all randomised patients who remain eligible for the
study and will be 80% compliant to the allocated treatment. Any patients who will withdraw
from the trial or treatment or who will not receive the allocated treatment will be excluded
for per-protocol population.
Secondary outcomes The same strategy employed to analyze the co-primary outcome will be used
to compare the 3-month change in muscle performance (Measured by change in Chair Stand and
Gait Velocity) and the 3-month change in SF 36 - patient-reported outcome.
3-month event-free survival will be estimated using Kaplan-Meier method treating death or
complications of cirrhosis as a combined events. The treatment effect will be estimated by
calculating Hazard ratio (HR) and its 95% CI by using a Cox proportional hazards regression
model including centers as random effect (frailty model). The proportional hazards assumption
will be assessed by plotting the scaled Schoenfeld residuals of treatment effect against the
rank of survival time.
Adverse events will be analyzed using descriptive analysis.
