Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03864783 |
| Other study ID # |
H-18045227 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 5, 2019 |
| Est. completion date |
December 16, 2020 |
Study information
| Verified date |
June 2020 |
| Source |
Steno Diabetes Center Copenhagen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The majority of obese have non-alcoholic fatty liver disease (NALFD). Currently, no
pharmacological agents are licenced for the prevention or treatment of NAFLD, and weight
loss, notoriously difficult to obtain (and specially to maintain), remains the only treatment
option. Interestingly, curcumin, a phenolic compound extracted from the turmeric root, has
from in vitro and animal studies shown promising effects in preventing and treating NAFLD,
and the sparse available human data point in the same direction; but solid human data are
missing. This study will delineate the effects of curcumin when treating NAFLD in humans.
The primary aim of this study is to investigate the effect of 6 weeks of curcumin on liver
fat content (assessed by magnetic resonance spectroscopy (MRS)) in obese subject with NAFLD.
Additionally, a range of secondary endpoints have been chosen in order to delineate the role
of NAFLD in the newly discovered liver-alpha cell axis governing circulating levels of the
glucose-mobilising pancreatic alpha cell hormone glucagon and, thus, to elucidate the link
between liver fat content and the risk of developing reduced glucose tolerance and type 2
diabetes (T2D). Also, the anti-inflammatory effect of curcumin will be elucidated, as
inflammatory markers will be measured before and after intervention. Furthermore, the effect
of curcumin will be measured by measuring the following parameters before and after
intervention: Transient elastography, anthropometric measurements, body weight, appetite,
food-consumption, calory balance, resting energy expenditure, gut microbiota, bioimpedance
measures, visceral- and subcutaneous fat, glucose tolerance, lipids, blood pressure, pulse,
liver parameters (blood-tests) and adipokines. During the oral glucose tolerance test before
and after intervention, incretin hormones, glucagon, amino acids, insulin, c-peptide and urea
will be measured.
Description:
The prevalence of obesity is increasing worldwide. Obesity and its associated complications
represent an enormous burden for obese individuals, their families, healthcare systems and
societies. Non-alcoholic fatty liver disease (NAFLD) has emerged as a frequent and serious
complication of obesity. Steatosis, the benign and potentially reversible form of NAFLD, may
progress to a more severe form, non-alcoholic steatohepatitis (NASH), which can result in
fibrosis and ultimately liver cirrhosis, and rarely hepatocellular carcinoma. The majority of
obese have NAFLD. Currently, no pharmacological agents are licenced for the prevention or
treatment of NAFLD, and weight loss, notoriously difficult to obtain (and specially to
maintain), remains the only treatment option. Interestingly, curcumin, a phenolic compound
extracted from the turmeric root, has from in vitro and animal studies shown promising
effects in preventing and treating NAFLD, and the sparse available human data point in the
same direction; but solid human data are missing. This study seeks to investigate the effects
of curcumin on treating NAFLD in humans by looking at the effects of ingestion of curcumin
for 6 weeks in obese subject with NAFLD on lipid, glucose and protein metabolism.
In this randomised, double-blinded, placebo-controlled trial, eligible participants will
undergo baseline assessments before being randomised to receive two capsules of placebo twice
daily or two capsules of curcumin (corresponding to 200 mg) twice daily for 6 weeks. In the
end of the 6-week intervention periods, end-of-trial assessments (similar to baseline
assessments) will be performed.
Information meeting:
Prior to any protocol-related procedures, an information meeting at Center for Clinical
Metabolic Research, Gentofte Hospital, will be arranged, and subjects will be informed of the
possibility of bringing a person of own choice to the visit. During this meeting, a member of
the research group will explain the purpose, procedures and possible risks of the study in
undisturbed and confidential surroundings. The subject will be informed that if extra time to
evaluate participation is needed, a minimum of 24 hours from oral information is given until
the consent and sign the informed consent form should be given is acceptable. After obtaining
the informed consent, time of screening is planned. The subject will be informed that it is
possible to withdraw the written consent at any time prior to or during the study.
Screening visit:
If a person agrees to participate in the study following the information meeting, and oral
and written informed consent has been obtained, a screening visit will be planned. The
subject will be instructed in a 10 hour overnight fast before screening (including medicine,
but water may be consumed until 2 hours before screening). After this fast the subject will
meet in the department in the morning. Height and body weight will be measured, medication
and medical history will be recorded, blood will be sampled for assessment of plasma/serum
concentrations of thyroid-stimulating hormone, creatinine, electrolytes, aspartate
aminotransferase (ASAT), alanine aminotransferase (ALAT), lactate dehydrogenase, alkaline
phosphatase, albumin, bilirubin, gamma-glutamyltransferase, viral hepatitis markers, platelet
count, ferritin and haemoglobin, and albumin-creatinine ratio in the urine will be measured.
A Fibro Scan will be performed. A physical examination will be made including evaluation of
blood pressure and pulse rate. Alcohol habits will be evaluated based on The Alcohol Use
Disorder Identification Test (AUDIT) questionnaire76,77 and quantification of the weekly
amount of alcohol. A magnetic resonance (MR) safety checklist will be completed and a MR
information sheet will be given. If all inclusion criteria and none of the exclusion criteria
are met, dates for baseline assessments and randomisation visit will be planned within 6
weeks from the screening visit. The subject will be instructed in not to consume
curcumin-containing food on a daily basis from screening until end of trial.
Baseline assessments and randomisation visit:
Included subjects will undergo an MRS, which will be scheduled as close as possible to the
start of intervention. The subject will meet at the Department of Radiology at Herlev
Hospital and be placed in a horizontal position during the scan. During the MRS, a
spectroscopy of the liver will be assessed, and an estimation of visceral adipose tissue and
subcutaneous adipose tissue will be done. The subject will be placed in a horizontal position
during the scan (duration: approximately 30 minutes).
Food and physical activity diary and standardised food intake period: Before start of
intervention and during the week before end-of-trial visit, each subject will fill out a
three days food and physical activity dairy. The food and physical activity diary will be
registered manually by participants, using a questionnaire. The two last days before test
days, the participants are requested to have a standardized food intake high in
carbohydrates, to get the most valid oral glucose tolerance test (OGTT) response, and the
subject will be thoroughly instructed in this.
During the last week before randomisation, the subject is kindly asked to collect a stool
sample for the determination of gut bacteria count and subtype. The participant will receive
sample kits consisting of cooler bag, freezer packs and stool sample tubes. Stool samples
will be collected by the participant at home: Prior to defecation a disposable collector will
be placed in the toilet from where stool will be transferred to a tube that immediately is
transferred to a transport container and placed at -20°C in the patient's freezer. Prior to
transport to Gentofte Hospital, the transport container is transferred to the cooler bag and
at arrival at Gentofte Hospital the transport container (with the sample tube) is immediately
stored in at -80°C for later analysis. This entails DNA extraction, library preparation,
MiSeq 16S rRNA sequencing and microbiota analysis (relative abundance, alpha/beta diversity,
link to phenotype of interest).
On the randomisation visit, the subject will meet in the laboratory around 8 a.m. after 10
hours of fast (including medication) and refrainment from tobacco or nicotine supplements
use. The subject is allowed to drink water until 8 hours before meeting in department.
Furthermore, the subject will be requested to avoid heavy alcohol intake and strenuous
exercise two days prior to the visit and instructed to use non-strenuous methods of
transportation to the research facility. The following procedures will be conducted:
1. A fasting urine sample will be collected, and the participant is kindly asked to empty
the bladder completely. Urine volume will be measured.
2. Measurement of bioimpedance.
3. Fasting blood samples will be collected (genetic markers for NASH, biomarkers of NASH
and fibrosis, fibroblast growths factors, triglycerides, cholesterols, liver parameters,
haemoglobin A1c, inflammatory markers, adipokines, haemoglobin, creatinine) amounting 22
ml.
4. FibroScan: The subject will be lying in a supine position for approximately 10 minutes
during which a probe using shear-waves and ultrasound is applied in the right side of
the body below the ribs
5. Measurement of blood pressure, pulse rate, body weight and hip and waist circumference
6. One cannula will be inserted in the cubital vein for collection of blood samples; the
forearm from which blood samples are drawn will be wrapped in a heating blanket (42°C)
throughout the experiment (for arterialisation of venous blood)
7. Blood samples will be collected according to Table 1 below (total amino acids, gut
hormones, glucose, glucagon, insulin, c-peptide, urea, free fatty acids)
8. At time 0 min, the subject will ingest 75 g of water-free glucose dissolved in 300 ml
water over a period of 5 minutes
9. At time 0, 30, 60, 90, 120, 150, 180, 210 and 240 min, hunger, satiety, fullness and
prospective food consumption will be measured by visual analogue scales (VASs). (see
enclosure 5 "VAS").
10. During the last hour (~180min - ~240 min), resting energy expenditure (REE) will be
measured in a supine position by indirect calorimetry to determine oxygen consumption
(V02) and carbon dioxide production (VC02). A flow-through canopy gas analyser will be
used.
11. At time ~240 min the subject will be asked to provide a new urine sample for measurement
of urea concentration. The participant is kindly asked to empty the bladder completely.
Urine volume will be measured.
12. At time 250 min, the subject will ingest a standardised ad libitum meal consisting of
minced meat, pasta, corn, carrots, peppers, cream, salt and pepper (50 energy (E) %
carbohydrate, 37 E% fat, 13 E% protein); the subject will be instructed to eat as much
as possible until feeling comfortable satiated; the meal should be consumed within a
maximum of 30 minutes and by the end of the meal, time spent eating, weight of the meal
and the total amount of energy consumed will be noted. Additionally, the participants
rated the appearance, smell, taste, off-taste, and overall impression of the ad libitum
meal on VAS scores during the ad libitum meal. 10 minutes after termination of the meal
consumption, the last questionnaire regarding hunger, satiety, fullness and prospective
food consumption will be measured by visual analogue scales.
The interventional period:
The intervention will start soon after randomization visit and first MRS. During the entire
intervention period, each subject will fill out a dairy to keep track of any new concomitant
medication, compliance and possible adverse events. Each subject will take either two
capsules of Meriva® or two placebo capsules each morning and each evening for 42 days (±3
days) with a small glass of water, preferably in relation to a meal. Should the subject
forget/miss to take a dose, it can be ingested until 6 hours before the next planned dose. If
the subject forgets/misses a dose, and the next planned dose is within the next 6 hours, the
dose should be passed, and the subject must note the incident in the diary. The subject is
kindly asked to keep the alcohol and smoking habits they might have had before screening and,
thus, not to consume more than 21 units of alcohol per week. Furthermore, it is not allowed
to consume more than 5 units in one night or to consume curcumin-containing food on a daily
basis until end of trial. Mid-way through the intervention period, the subject will receive a
phone call from the investigator or other delegated site staff, checking on adverse events,
concomitant medication and compliance, and to answer any questions from the subject.
In the last week of intervention, participants are once more requested to fill out
questionnaires regarding food intake and physical activity. Starting two days prior to
end-of-trial visit, the subject must once more follow two days of standardized food intake.
End-of-trial assessments and visit:
The end-of-trial visit will be scheduled 42±3 days after start of intervention. Within one
week prior to the end-of-trial visit, stool sample collection will be scheduled and performed
as described above under "Baseline assessments and randomisation visit" and MRS in assessed
as close to end-of-trial visit as possible. Procedures during the end-of-trial visit are
similar to the ones described above under "Baseline assessments and randomisation visit".
Also, during this day, to check for any effect of curcumin intervention, physical examination
will be performed by a physician from the research team and additional blood samples
(identical with the samples at the screening visit, except viral hepatitis markers) will be
collected (which adds another 5 ml blood samples compared to randomisation visit) and
albumin-creatinine ratio in the urine will be measured.
