Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06000462 |
| Other study ID # |
OmanMOH |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
December 2023 |
| Est. completion date |
December 2025 |
Study information
| Verified date |
September 2023 |
| Source |
Oman Ministry of Health |
| Contact |
Thuraiya Al Harthi, Masters |
| Phone |
00968 97272761 |
| Email |
thuraiya.alharthi[@]moh.gov.om |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The goal of this clinical trial is to examine the effectiveness of a drug named dapagliflozin
(tested drug) on weight loss in young adults aged between 18 and 40 years with obesity who
are not diagnosed with diabetes.
The main questions this study aims to answer are:
- How much weight in average can people loose with the use of tested drug compared to 2
other comparator drugs: metformin and placebo (non-medicated pill)?
- What is the effect of using tested drug on other parameters used to assess blood
pressure, cholesterol and sugar levels, and mental health?
- How frequent are the side effects from using the tested drug compared to the comparator
drugs? Participants will go through a 6-month program of physical activity and diet and
measure their weight progress. Those who do not achieve the target weight reduction will
be randomly assigned to any of the three drug groups, either testes drug group,
comparator 1 (metformin), or comparator 2 (placebo).
Description:
Background Obesity is a disease, generally defined as a body mass index (BMI) ≥ 30 kg/m2,1 is
a global issue that continues to grow at an alarming rate, imposing serious threat to
individuals, public health, and the economy. The prevalence of overweight and obesity has
tripled since 1975, with 1.6 billion overweight adults and 650 million obese adults,
according to World Health Organization report.2 In Oman, non-communicable diseases (NCDs)
represent a major burden on healthcare system at which 185.75 deaths per 100,000 population
are attributed to NCDs.3 Obesity is an independent risk factor for most NCDs, adding to
disease morbidity and mortality. According to a national survey conducted in 2017, the
prevalence of obesity and overweight were 30.7% and 66.1%, respectively, with higher
prevalence in females compared to males.4 The Look AHEAD trial revealed that losing 5% to 10%
of body weight through diet and exercise alone has been associated with reduced risk of
cardiovascular disease in obese and overweight adult patients.5 Whilst healthy lifestyle is
the mainstay for obesity management, there is a growing interest over pharmaceuticals that
support weight loss and prevent metabolic complications.
The US Food and Drug Administration (FDA) approved five drug therapies to treat obesity,
namely orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, liraglutide, and
recently saxenda,6 while the European Medicines Agency (EMA) supported three drug therapies,
orlistat, bupropion/naltrexone and liraglutide.7 Several anti-diabetic drugs have been
authorized for weight loss even for patients without diabetes.8 Sodium glucose cotransporter
2 inhibitors (SGLT2i) including empagliflozin, dapagliflozin and canagliflozin are classes of
hypoglycemic agents that have been studied in both human and animal models to measure their
glycemic and metabolic effect. These drugs reduce plasma glucose levels by inhibiting the
sodium glucose cotransporter 2, located in the proximal tubule of the kidney, leading to
increased urinary glucose excretion and a reduction in plasma glucose levels in patients with
type 2 diabetes mellitus (T2DM).8-11 This mechanism of action was found to lower the risk of
hypoglycemia, with additional benefits of weight loss, reductions in blood pressure,
cardiovascular (CVD), and chronic kidney disease risk (CKD). 8, 12, 13 The drugs are
prominent in most recent guidelines for the management on T2DM and are particularly
recommended when, in addition to glucose lowering, there is a compelling need to reduce body
weight.14 Weight reduction via behavior change and maintaining healthy lifestyle is the first
line and cost-effective treatment for obesity. According to the US Preventive Services Task
Force, all adults aged 18 years or above should be screened for obesity and intensive
behavior intervention to be given for weight loss,15 with at least one session per month for
at least three months.16 Body mass index (BMI) is a key indicator for weight assessment;
however waist circumference may be an acceptable alternative in people with central obesity
because BMI may not account for the cardiovascular risk of central adiposity.17
Dapagliflozin is a highly selective SGLT2i that blocks the reabsorption of 80% - 90% of the
glucose filtered by the glomerulus. It is an oral medication with three different dose
strengths; 2.5 mg, 5mg, 10 mg once daily, in addition to the combination formula with
metformin; dapagliflozin/ metformin, with strength of 2.5mg/1000mg, 5mg/500mg, 5mg/1000mg,
10mg/500mg, and 10mg/1000mg. Several RCTs have shown its effectiveness on glycaemic control,
weight loss, and blood pressure in patients with T2DM, in addition to the cardiovascular and
renal protection.24 A randomized placebo control trial (RCT) that enrolled 534 patients with
T2DM on preceding metformin treatment investigated the effectiveness of dapagliflozin 2·5 mg,
5 mg, and 10 mg per day dose versus placebo, over 24 weeks. There was a dose dependent
reduction in HbA1c in patients treated with dapagliflozin, with a reduction of 0·84% in
patients assigned to a maximum dose of 10 mg per day compared with a reduction of 0·3% in the
placebo group, at the end of study period. Mean HbA1c had decreased by -0·30% (95% CI -0·44
to -0·16) in the placebo group, compared with -0·67% (-0·81 to -0·53, p=0·0002) in the
dapagliflozin 2·5 mg group, -0·70% (-0·85 to -0·56, p<0·0001) in the dapagliflozin 5 mg
group, and -0·84% (-0·98 to -0·70, p<0·0001) in the dapagliflozin 10 mg group.25 The trial
also showed no apparent changes in fasting lipid profiles, apart from greater mean increases
in HDL cholesterol (1·8-4·4% vs 0·4%) and decreases in triglycerides (-2·4% to -6·2% vs 2·1%)
compared with placebo.25 Treatment with dapagliflozin was not superior to placebo in reducing
the risk of major adverse cardiovascular events but lowered the risk of hospitalization due
to heart failure or death from CVD (hazard ratio: 0.83; 95% CI, 0.73 to 0.95; P=0.005).26 In
patients with established chronic renal disease with an estimated glomerular filtration rate
(eGFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and/ or urinary
albumin-to-creatinine ratio of 200 to 5000) who received dapagliflozin 10 mg a day, showed a
significantly lower risk for sustained decline in the estimated eGFR of at least 50%,
end-stage kidney disease, or death from renal or cardiovascular causes than with placebo. The
hazard ratio for renal dysfunction or death from renal causes was 0.56 (95% CI, 0.45 to 0.68;
P<0.001) in dapagliflozin compared with placebo and a hazard ratio 0.71 (95% CI, 0.55 to
0.92; P=0.009) for death from cardiovascular causes or hospitalization for heart failure.27
In patients with mild to moderate chronic kidney disease of diabetes, no alterations in mean
renal function measures, including serum creatinine concentration, were reported.28 The most
common side effects of dapagliflozin were urinary and genital infection, 29 besides headache,
backpain, and diarrhea.30 An analysis of published data from 12 RCTs, included 3152 patients
who received dapagliflozin 2.5 mg, 5 mg, or 10 mg as monotherapy or add-on treatment, and
1393 placebo-treated patients, showed that the diagnosis of infection were reported in 3.6%,
5.7%, 4.3%, and 3.7%, respectively. However, most infections were treated and responded to
antimicrobial therapy. Discontinuations due to urinary tract infection were rare: 8 (0.3%)
dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient.30 Most studies were in
patients with diabetes who are at risk of asymptomatic bacteriuria and pyelonephritis in
combination with dysfunction of the urinary tract compared with people without diabetes, the
fact that further studies with longer observation period are required to confirm that
infection is related to the drug and not diabetes status.31 In fact, it has been found that
the frequency of serious adverse effects including urinary and genital fungal infection from
dapagliflozin were comparable to placebo in patients with T2DM.30 Dapagliflozin and obesity
management Obesity and T2DM are intrinsically linked with multiple shared pathology, besides
being associated with increased risk of multiple comorbidities.32 The weight loss observed
with SGLT2i is thought to be due to fluid loss, reduction in lean body mass, and thereafter
loss of calories via increased urinary glucose excretion. Dapagliflozin was found to improve
adipocyte function by lowering inflammatory markers, C-reactive protein and increasing
adiponectin besides lowering glycated hemoglobin and body weight, however evidence was
inconclusive due to small sample size.33 Animal based trials are still ongoing to provide
evidence of actual mechanism of weight loss with SGLT2i. Modest body of evidence have shown
the effectiveness of dapagliflozin in causing clinically significant reductions in body
weight.34 A double-blind placebo-controlled study of 182 patients with T2DM treated with
dapagliflozin 10mg a day versus placebo (added on metformin) over 102 weeks showed reductions
in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80
kg without increases in rate of hypoglycemia, in former drug compared with later placebo. In
addition to that, no significant changes from baseline in bone density or markers of bone
turnover, compared with placebo. The frequency of patients with at least one adverse event
(mainly urinary and genital infections) were comparable; 71.4% in the dapagliflozin and 69.2%
in placebo group by week 102. 35 Another RCT compared the metabolic effect of dapagliflozin
versus placebo on high density lipoprotein (HDL-C) over 16 weeks of treatment, showed reduced
HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and
lean mass, without evidence of improving HDL-cholesterol.36 Treatment with dapagliflozin 5
mg/day over 24 weeks showed a decrease in total body weight of 2.9kg (3.9%). Furthermore,
there was a decrease in serum alanine aminotransferase and γ-glutamyl transpeptidase levels
and a significant decrease in controlled attenuation parameter (CAP)- a measure of liver
stiffness and fibrosis from 314 ± 61 to 290 ± 73 decibel dibutyryl (dB)/m (P = 0.0424),
concluding that dapagliflozin might improve liver steatosis in patients with type 2 diabetes
and NAFLD. However, the possibility that a reduction in body weight or visceral adipose
tissue by dapagliflozin may be associated with a decrease of liver steatosis or fibrosis,
cannot be excluded.37 A small, prospective study of 26 patients with T2DM who received
dapagliflozin 5mg/day over 12 weeks showed a 23.8% loss of lean body mass but modest weight
loss of 2.5 Kg.36 A randomized double blind placebo control trial showed that empagliflozin
monotherapy at doses of 10 mg and 25 mg for ≥76 weeks was well tolerated and led to sustained
reductions in glycated hemoglobin (HbA1c) and weight compared with placebo.37 The
glucose-dependent mechanisms of action of SGLT2-i comes with low risk of hypoglycemia,
particularly when not used with sulphonylureas or insulin.38 Several studies have been
undertaken to evaluate and measure the effectiveness of SGLT-2i in managing obesity in
diabetic and non-diabetic patients, however evidence is inconclusive and necessitates further
high-quality trials to assess the long-term outcomes of this drug that is administered
orally, once daily dose, with expected low risk of severe adverse events.
The trial will evaluate the efficacy and safety of dapagliflozin compared to metformin and
placebo in weight loss management in young adults with obesity, who are not yet diagnosed
with diabetes.
Methods:
Study design:
All subjects will be prescribed a structured monitored and tailored program from the
beginning of the 24-week run-in period before randomization to drug therapy.
Patients who do not respond to the structured lifestyle program (not losing 5-10% of weight)
will be randomized to any of the three arms: placebo, metformin, or dapagliflozin.
After randomization, participants will go through 48-week double-blind, randomized,
parallel-group, placebo-controlled, trial. In the first 32 weeks, subjects will be randomized
1:1:1 to receive either dapagliflozin 10 mg or metformin 1000 mg or placebo. The
randomization will be stratified according to age and metabolic parameters. After 32 weeks
drugs will be discontinued and patients will be followed for another 16 weeks after end of
drug therapy "off-study-drug follow-up period" to assess effect maintenance and any evidence
of rebound, as well as to monitor post-treatment safety.
Trial interventions:
- Run- in period:
1. Behavioral weight management program alone:
Physical activity:
At baseline visit, the participants will be given a physical activity prescription
written by the family physician/ endocrinologist in obesity clinic to guide type and
frequency of exercises. Participants will be enrolled in a structured program for
physical activity in a fitness gym that is well-known of high fitness, health, and
safety standards throughout the study period - 24 (run-in) and 48 (post randomization)
weeks. A list of participant names will be given to a prespecified branch according to
patients' location preference. Each gym should nominate fitness instructors to monitor
the way workouts are done by the participants. A logbook approach will be used to ensure
adherence by patients and instructors, in which patients must submit to the care
provider every time they visit the clinic on their appointment. The logbook will include
information regarding date, time, type of exercise, duration of exercises, progress. In
case any participant missed more than one class, the instructor is expected to call for
a reminder and reschedule for the missing session. Type of exercises will include muscle
strengthening and aerobic exercises using machines. The participant is expected to
complete 75 to 150 minutes for muscle strengthening and 150 - 300 minutes for
cardio-based exercises per week, to achieve the World Health Organization recommendation
for physical activity, hence, at least 4 sessions of 30 minutes in each per week, might
be a target.
Nutrition counselling clinical nutritionist will be involved in providing proper dietary
and behavior modification counselling to all study participants and maintain schedule
follow ups later. Patients will be seen at baseline, 24 weeks, 48 weeks from baseline.
The nutritionists have been trained on motivational interview skills as part of their
professional development, hence motivation and encouragement care will be provided
during the dietary counselling sessions. The dietary plans will mainly focus on calorie
reduction rather than specific dietary composition of macronutrients to make it simple,
without overwhelming patients and ensure good adherence. A deficit of at least 500 kcal
per day can be achieved with intake of 1,200 to 1,500 kcal for women and 1,500 to 1,800
kcal for men. Although different diets with similar caloric intake can result in
comparable weight loss, a higher-quality diet of nutrient-dense foods (e.g., vegetables,
fruits, whole grains) that are rich in fiber, vitamins, and minerals will produce
greater results. Dieticians will follow the general guidance from Dietary Guidelines for
Americans 2015 - 2020 that reinforces the need for healthier food and beverage choices
by consuming nutrient-dense foods from all food groups and limiting intake of added
sugars, saturated fats, and sodium. In addition, intermittent fasting schedule will be
incorporated into the dietary regime.
Behavior modification counselling Motivational interview will be the main technique used
to encourage behavior change and adherence to healthy lifestyle including physical
activity and low-calorie diet. The technique includes 1. Asking permission to discuss
behavior change, 2. Showing empathy throughout discussion, 3. Using scale of motivation
and confidence, 4. Enquiring about the chosen scores, 5. Exploring barriers to change,
6. Exploring pros and cons of behavior change. 7. Listening to change talk "where the
patient takes the ownership to generate ideas and ways" and reinforce it. The
psychologists will provide comprehensive counselling at baseline and 12 weeks from
baseline, besides the scheduled counselling that will be given by dieticians throughout
the scheduled follow ups.
2. Pharmacotherapy
Recruitment of patients:
Recruitment will take place over a 6-month period in the primary care health centers by the
trial investigators. Patients fulfilling the inclusion criteria will be provided with a
participant information sheet about the study by the project officers and patients showing
interest will be given a consent sheet to confirm participation and adherence to study
conditions in written. Participants will be involved in 24 weeks (6 months) run in period to
provide them with a comparable behavior modification and healthy lifestyle program in their
health centers before randomization to ensure homogeneity and patient safety as drug of
interest is used off-label. Appointments will be given to all participants to attend the
obesity clinic for baseline measures and to receive care in polyclinics. Recruitment will be
monitored on a monthly basis and efforts to reduce loss to follow-up will be made.
Participants not attending their appointment will be called to consider rescheduling their
appointments.
Key randomization criteria:
- BMI corresponding to 30-35 kg/m2 for adults by international cut-off points (for
diagnosis of obesity).
- Compliance with run-in procedures and visit schedule (during the period between
screening and randomization) as judged by the investigator.
Randomization and allocation concealment After recruitment of eligible participants,
computerized number generator will be used to generate random identification of study arms
and patients, stratified according to age, gender, and metabolic parameters. The allocation
would be 1:1:1to each arm of the study group. An independent healthcare professional "most
probably a nurse" who is not part of the study team will lead the allocation concealment of
the randomized groups who will also be concealed from the study arms. The arms will be coded
A, B, C and only independent nurses will be aware of these codes that are saved and
registered electronically.
Ensure patient safety:
Any study participant is noticed to have side effects that warrants the clinician to know
with certainty, the medication he/she has been receiving will be identified through the
pharmacists who have the key to the codes and will be asked to reveal the medication given to
that patient. The treating physician will manage the patient with this knowledge. If several
patients show side effects and the code shows them to be in the same treatment arm, a
decision can then be made to discontinue that arm or stop the study (as per the severity or
risk of continuing the study) all these safety features can be built into the study.
Sample size:
To demonstrate a between groups difference of 5kg in body weight over 3 months from baseline,
that would be detected at a power of 80%, with significance level of 5%, and a standardized
difference of 0.700 gm (i.e., 0.394 of a standard deviation can be detected), the minimum
required sample size is 300 (75 in each arm). With an attrition rate of 20% and a recruitment
rate of 70% the required sample size is 500 (125 in each arm). However, due to patient safety
issue related to using a drug off-label, a sample size of 150 will be used in this study.
Data monitoring/ management Every two weeks, a research nurse will collect and process
electronic enrollment and randomization data, which will then be stored, reviewed, and shared
as anonymous files. Follow-up data will be obtained and updated quarterly, while real-time
monitoring will be conducted for deaths. Every six months, a batched process will be used to
assess and make decisions on adverse events in patients who have exceeded the 6-month
observation period. An independent statistician, who is not privy to the study's unblinded
data, will analyze and compile reports for the Drug safety team pharmacist every six months.
The study investigators will conduct annual audits of site data collection and procedures,
ensuring that no outcome or endpoint information is shared with clinical sites. Enrolment and
follow-up statistics will be accessible in a secure, password-protected section of the
trial's website.
Statistical analysis The intra group and intergroup differences in percentage of usual weight
change and mean weight and BMI will be calculated. It will generally be presented by
two-sided confidence intervals (CIs) with a confidence level of 95%. Superiority will be
claimed if the two-sided p-value is less than 5% and the treatment estimate favors
dapagliflozin arms. If the upper limit is below 0, superiority of dapagliflozin against
metformin and placebo can be concluded.
• Analysis of outcomes The full analysis set (FAS) will be used in the analysis of the
efficacy endpoints. For the safety endpoints, the safety analysis set (SAS) will be used.
FAS: includes all randomized subjects who have received at least one dose of trial product
and have any post-randomization data. The statistical evaluation of the FAS will follow the
intention-to-treat (ITT) principle and subjects will contribute to the evaluation "as
randomized".
SAS: includes all subjects exposed to at least one dose of trial product. Subjects in the SAS
will contribute to the evaluation "as treated".
Before data are locked for statistical analysis, a blinded review of all data will take
place. Any decision to exclude a subject or single observation from the statistical analysis
is the joint responsibility of principal investigator and co investigators. Exclusion of data
from analyses will be used restrictively and normally no data should be excluded from the
FAS. The subjects or observations to be excluded, and the reasons for their exclusion must be
documented and signed by those responsible before database lock. The subjects and
observations excluded from analysis sets, and the reason for this, will be described in the
clinical trial report Handling of missing values Missing data in the main analysis will be
handled by the following multiple imputation (MI) method. A pattern mixture model approach is
applied where withdrawn subjects or treatment discontinued subjects without a follow-up visit
are assumed to respond as if treated with placebo for the entire trial. Multiple copies (100
copies) of the full dataset will be generated by imputing missing values based on estimated
parameters for the placebo group.
