Clinical Research

Dr Hiba Jebeile, PhD MNutDiet BMedSci/BBus

NHMRC Emerging Leadership Fellow, Research Dietitian, Children’s Hospital Westmead
Clinical School, University of Sydney

Eve House, BSc MNutDiet

PhD Candidate, Research Dietitian, University of Sydney, Children’s Hospital Westmead
Clinical School
Sydney School of Public Health, The University of Sydney
 Workshop Overview

1. Overview of adolescent obesity

2. Summary of obesity treatment approaches and research

conducted at Children’s Hospital at Westmead examining
dietary interventions for adolescents with obesity

3. Clinical trial planning activity in small groups

4. Discussion of clinical trial design

 Appropriate language
• People should not be defined by their conditions
• Many terms are stigmatising
• Person-first language mostly acceptable

Obese person Person with obesity

Diabetics People with diabetes

People with
Depressed people
depression
Adolescent obesity research at CHW

Obesity
Research
Clinic
▪Evidence based practice: developing a
“wardrobe” of dietary options

▪Clinical decision making: severity,

background, preferences etc
 Defining obesity

https://www.worldobesity.org/data/cut-points-
https://pro.healthykids.nsw.gov.au/assess/ used/newchildcutoffs/
 Australian children (7 to 15 y)
Overweight, obesity, morbid obesity
IOTF criteria
30

1.8 1.9
7.4%
25 1.8 7.4%
0.7
4.9
5.7% 6.1
20 5.6
4.5% 20.2% Morbid
4.8 BMI ≥ 35 @18y
18.3%
15
0.2 15.7% 17.2% Obesity

1.5%10
1.4
Overwt
10.0%
10.2 16.6 18.1 19.3 20.6
5

0
1985 1995 2007 2012 2014
Xu et al J Paediatr Child Health 2018
1985 Health & Fitness Survey; 1995 National Nutritional Survey; 2007 National Children's Nutrition & PA Survey; 2012/2014 Australian Health Survey
 Australian children (7 to 15 y)
Overweight, obesity, morbid obesity
IOTF criteria
30
1 in 4 children and adolescents
1.8 1.9
has
overweight or obesity
25 7.4%
1.8 7.4%
0.7
4.9
5.7% 6.1
20 5.6 Morbid
>260,000 have obesity
4.5% 20.2%
4.8 BMI ≥ 35 @18y
18.3%
15
0.2 15.7% 17.2% Obese

1.5%10 >60,000
1.4 have severe obesity
Overwt
10.0%
10.2 16.6 18.1 19.3 20.6
5

0
1985 1995 2007 2012 2014

1985 Health & Fitness Survey; 1995 National Nutritional Survey; 2007 National Children's Nutrition & PA Survey; 2012/2014 Australian Health Survey
Steinbeck et al. 2018,
Nat Rev Endocrinol
Defining effective management
▪ Reduction in weight outcomes (BMIz)

▪ Changed weight gain trajectory

▪ Improvement in obesity associated

complications

▪ Changed markers of future complications

Steinbeck, K. S., et al. (2018). "Treatment of adolescent obesity." Nature Reviews Endocrinology.
 Standard care
Healthy eating - dietary
guidelines Traffic Light diet
▪ 45 to 65% carbohydrate Energy controlled approach
▪
▪
< 35% fat
~15% protein ▪ low-energy eaten freely

Energy restricted intervention ▪ moderate-energy eaten occasionally

trials
▪ daily calorie deficit of 300-500
calories/day
▪ high-energy eaten rarely

▪ 30% < reported energy

▪ 15% < estimated energy
▪ micronutrient adequacy can be
challenging & careful selection of
foods is required Steinbeck, K. S., et al. (2018). "Treatment of adolescent
obesity." Nature Reviews Endocrinology.
Researching novel diets for adolescents

Increased protein High CHO ▪ Evidence based practice:

developing a “wardrobe” of
options
Weight loss

▪ Individual variation in
response

▪ Long-term weight loss is

difficult to achieve

▪ Clinical decision making:

BMI %95 centile change at 12 months
Garnett J Clin Endo Met 2013 severity, background,
preferences etc.
 RESIST Results
Early weight loss: indicative of longer term wt loss
More likely to drop out at 12
10 Less likely to lose weight during months OR 2.8 [95%CI: 1.3 to
12 month intervention OR 3.2 5.9], P=0.016
[95%CI: 1.5 to 7.0], P=0.018
5
Percentage change in BMI95

-5
52% maintained/ had
-10 further weight loss

Gained weight
-15
Lost 0 to 4.99%
62% maintained/ had Lost 5 to 9.99%
-20 further weight loss Lost ≥ 10%
0 3 6 9 12 15 18 21 24
Month
Intensive dietary interventions
Possible adjunctive therapy to behavioural weight
management for some individuals

Intermittent
Very Low
Energy
Energy diets
restriction (IER)
 Very Low Energy Diets (VLED)
▪ Strict diet aiming for < 800calories/day (3350kJ) typically <50g
carbohydrate
▪ Effective rapid short-term weight loss – long term outcomes
unclear
Why VLED in adolescents??
▪ Potential greater initial weight loss
▪ kick-start weight reduction
▪ Potential to reverse type 2 diabetes (adults)
▪ The diet, although strict, may be an alternative to
pharmacological therapies/surgical interventions
▪ Increasing interest in bariatric surgery for adolescents
 What is a VLED?
• 3-4 nutrient complete meal replacement
products per day
• Family meal (150g protein source +
vegetables)
• 2 L water
Intermittent energy
restriction (IER)
 An effective alternative in adults
IER as effective as continuous energy restriction for
weight loss in adults
(Varady 2011, Seimon et. al. 2015, Headland et. al. 2016, David et. al. 2016)

▪No previous studies in adolescents

▪ Adolescents asking about the 5:2 diet in clinic
▪Will having ‘days off’ suit an adolescent lifestyle?
▪Continuous energy restriction/daily dieting - difficult to
adhere to as never able to eat freely
 Study aims
Aim
To determine the feasibility and effectiveness of an
intermittent energy restricted diet in adolescents with obesity.

Primary outcome
Change in BMI at 26 weeks (z-score and BMI %95centile)

Secondary outcomes
• Cardiometabolic risk factors: blood pressure, fasting blood
glucose, insulin, liver function and lipids
• Eating behaviours and quality of life
• Diet acceptability
 Study design
• VLED (600-700 calories per day) 3 days per week – food
provided
Phase 1:
weeks 0-8
• Normal healthy eating 4 days per week

• VLED (600-700 calories per day) 3 days per week –

provide own food
Phase 1:
weeks 9-12
• Normal healthy eating 4 days per week

• Participants choose
1. 3 VLED days + 4 healthy eating days OR
Phase 2: 2. 2 VLED days + 5 healthy eating days OR
weeks 13- 3. 1 VLED days + 6 healthy eating days OR
26 4. 7 healthy eating days
 Change in BMI
BMI %95centile at 12 weeks BMI %95centile at 26 weeks

Weight loss

Weight loss
Mean change -5.4% (2.2), p<0.0001 Mean change -5.0% (9.3), p=0.02
Improved cardiovascular profile

• Reduced central adiposity

• Reduced triglycerides
• Reversed damage to blood vessels
• Reduced emotional eating
• Increased quality of life
 easy to follow…
didn’t eat into my
social life because

Diet acceptability
only 3 days were
strict…
… you could
change fast days
• Retention 70% to suit when you
were going out…
• Choice at 12 weeks …learning which
foods I should be
– 3 VLED days/week (n=11) eating and giving
more routine to my
– 2 VLED days/week (n=10) eating habits….

– 5 VLED days per fortnight (n=1)

-4 -3 -2 -1 0 +1 +2 +3 +4
Most unpleasant n=19, mean [SD] +1.9 [2.1] Most pleasant

-4 -3 -2 -1 0 +1 +2 +3 +4
Most difficult n=19, +2.1[1.2] Most easy
 Conclusion
• Intermittent energy restriction in adolescents
with obesity is:
– an acceptable dietary intervention
– an effective weight management
intervention
 Summary

What we know Unknown

▪‘Standard care’ dietary ▪Is one diet superior?
approaches lead to weight ▪Are VLED and IER diets
loss and improved effective in large samples?
cardiometabolic risk. ▪Does targeted early
▪VLED and IER are viable weight loss lead to better
alternatives. long term outcomes?
▪Early weight loss
improved long term
outcomes.
 Workshop

• You will be investigators on a new 12-

month trial
• Aim of the study:
– To determine if intermittent energy restriction
results in better weight loss after 52 weeks,
compared to a conventional approach (reduced
calorie plan), in adolescents with obesity.
• Aim of the study:
– To determine if intermittent energy restriction results
in better weight loss after 52 weeks, compared to a
conventional approach (reduced calorie plan), in
adolescents with obesity.

• Participants: Inclusion/ exclusion criteria, sample,

recruitment strategies, randomisation
• Intervention design: Intervention vs. control group,
duration of intervention, frequency of visits, monitoring
adherence, retention strategies and support
• Outcomes: what to measure, frequency, considerations,
data management

All groups: ethical considerations

 Participants
• Inclusion/ exclusion criteria?
• Sample?
• Recruitment strategies?
• Randomisation?
Fast Track protocol
 Eat (BASE),
Monash
University
Inclusion Criteria
• Adolescents aged 13–17 years (inclusive)
• Obesity (defined as equivalent to adult BMI 30–45 kg/m2)
• At least one obesity-related co-morbidity
Exclusion Criteria
• Secondary obesity
• Significant intellectual disability as documented by the referring doctor
• Significant medical or psychiatric illness
• Previous diagnosis of Type 2 Diabetes
• Currently undergoing treatment for a clinical eating disorder
• Pregnancy, or planning to become pregnant within the next 18 months
• Taking medications that have an effect on weight (excluding metformin)
• Adolescent or parent with poor level of spoken English
• Current enrolment in a weight loss program

Depression screening
Eating disorder screening
Clinical assessment
 Recruitment strategies

• Hospital clinics – endocrinology, weight

management services, nutrition and
dietetics, other
• GPs – information packs
• Self-referral – social media, posters,
website, flyers
ren’s Hospital at Westmead, 3 University of Illinois , 4Monash Children’s
robe University, 7Monash University

Recruitment
Recruitment
124
The Children’s
Hospital at
186 Westmead
adolescents
with obesity 62
(12-17years) Be Active Sleep
Eat (BASE),
Monash
University
usion Criteria
Adolescents aged 13–17 years (inclusive)
Obesity (defined as equivalent to adult BMI 30–45 kg/m2)
 Randomisation
• Computer-generated randomisation
(1:1) from NHMRC Clinical Trials Centre
• Stratified by:
– intervention site
– age (13–14 years; 15–17 years)
– sex
– body mass index
• Forced allocation
 Intervention design
• Intervention vs. control group
– Diet
– Physical activity?
• Duration of intervention?
• Frequency of visits?
• Monitoring adherence?
• Retention strategies and support?
 Study design
Phase 1: Jumpstart, Very Low Energy Diet (VLED)

• 4 Optifast® meal replacements per day OR

• 3 Optifast® meal replacements plus 1 meal consisting of 100-
150g lean, cooked meat and carbohydrate free vegetables
• ~800kcal/day, less than 40% energy from carbohydrate
(~60g/day), 40-55% of energy as protein and less than 20%
energy as fat
 Study design
Phase 2: Intensive Intervention

Modified Alternate
Intermittent energyDay Fasting (4:3
restriction (4:3 plan)
plan)
• 33 VLED
fastingdays
dayseach
eachweek,
week, consuming
consuming ~25% of daily energy
energy
requirements
requirements
• Standard
Standard healthy diet 4 days
days per
per week
weekwith
withno
noenergy
energyrestriction
restriction
•• Meal
Meal plans
plans provided to maximise
provided to maximise nutritional
nutritionaladequacy
adequacy

Standard hypocaloric diet (active control)

• High in fibre, moderate carbohydrate and increased energy from
protein. Meal plans provided
• Prescriptive energy levels: 6000-7000kJ (1430-1670kcal) for 13-
14 years and 7000-8000kJ (1670-1900kcal) for 15-17 years
 Study design
Phase 3: Step-down diet intervention
• Participants in both arms continue with the prescribed
intervention
• Ongoing dietary review with the study dietitian
• If goal weight is achieved, participants are transitioned off the
prescribed intervention onto healthy eating guidelines
 Frequency of visits
Start of Weeks 1-3 Week 4 Weeks 5-15 Week Weeks 17-51 Week
study 16 52
✓ ✓ ✓
Dietitian review ✓ Weekly ✓ Three review ✓ Three review ✓
visits appointments appointments
✓ ✓
Dietitian support SMS, email, SMS, email,
phone phone

Adjustments due to COVID-19

 Monitoring adherence

• Weight change
• Ketones (weeks 1-4)
• Diet review/ diet history
• ASA-24 (24 hour diet recall)

• Challenges…
Retention strategies/ support

• Regular contact with dietitian between

visits
• Automated SMS messages
• Facebook groups (now ceased)
• Fitbit (week 16)
• Parking/ petrol vouchers
• Provide Optifast
 Outcomes

• What to measure?
• Frequency of measurements?
• Considerations?
• Data management?
 Start of Weeks 1-3 Week 4 Weeks 5-15 Week Weeks 17-51 Week
study 16 52
✓ ✓ ✓
Dietitian review ✓ Weekly ✓ Three review ✓ Three review ✓
visits appointments appointments
✓ ✓
Dietitian support SMS, email, SMS, email,
phone phone
Height, weight,
waist ✓ ✓ ✓ ✓
circumference, BIA
✓ ✓
Blood Ketone test
✓ ✓ MADF MADF
(finger prick)
only only
Blood glucose test
✓
(finger prick)
DEXA scan ✓ ✓ ✓
Fasting blood test ✓ ✓ ✓
Blood pressure ✓ ✓ ✓ ✓
Medical review ✓
✓ ✓
Questionnaires ✓ ✓ Diet recall ✓ Diet recall ✓
only only
Length of Visit 3.5 hours 30 mins 1.5 hours 30 mins 3 hours 30 mins 3 hours
 Questionnaires
• Australian Child and Adolescent Eating Survey (ACAES)
• Eating Disorder Examination Questionnaire (EDE-Q)
• Body Appreciation Scale
• Weight Bias Internalisation scale
• Binge Eating Scale
• Rosenberg Self-Esteem Scale
• Centre for Epidemiologic Studies Depression Scale Revised
(CESDR-10)
• Depression, Anxiety and Stress Scales (DASS)
• Quality of Life using Impact of Weight on Quality of Life – Kids
• Dutch Eating Behaviour Questionnaire (DEBQ)
• Godin Leisure-time Questionnaire
• Pittsburgh Sleep Quality Index
 Considerations

• Participant burden
• Cost
• Access and availability
 Data management

• REDCap
– Secure
– Online

• Data storage
 Research timeline
COVID-19

February
June 2013 2016 October Approx. End early
2016 end 2021 2023
• SHAKE IT •NHMRC
pilot study • Fast Track • Fast Track • Follow-up to
Project funding 2024
commenced completion
Grant received
application

February 2023
2015 2015 February
2017 • Data
2018
•IER pilot • RCT grant • Prepare Fast cleaning
study preparatio • See first Fast
Track protocol
Track • Analysis
commence n and ethics
participant • Papers
d