Effect of Intensive Nutrition Training, Education, and Support Versus Standard Care in Reducing the Need for Insulin Therapy in Gestational Diabetes (INTENSE-GDM): A Randomised Controlled Trial
Phase: NA
Conditions: GDM, Gestational Diabetes, Nutritional and Metabolic Diseases, Nutrition Therapy, Medical Nutrition Therapy
Sponsor: Steno Diabetes Center Copenhagen

INTENSE-GDM, Protocol version 5.0 – 15.03.2024  
 
  
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
Effect of intensive nutrition training, education, and support versus 
standard care in reducing the need for insulin therapy in gestational 
diabetes (INTENSE-GDM): A randomised controlled trial 
 
 
Short title: The INTENSE-GDM Trial 
 
 
 
Trial site  
Steno Diabetes Center Copenhagen (SDCC) 
Borgmester Ib Juuls Vej 83, 2730 Herlev 
Denmark 
 
 
Version 4.0  
 
 
 
The study protocol has been prepared according to the National Ethics 
Committee’s guidelines for clinical trials 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
2 
 
1 Contact information on investigators and collaborators 
 
Principal investigator 
Head of Nutrition Bettina Ewers, MSc, PhD, The Clinic. Steno Diabetes Center Copenhagen, 
Borgmester Ib Juuls Vej, 2730 Herlev, Denmark. Phone: +45 30 91 29 97.  
E-mail: bettina.ewers@regionh.dk  
 
Co-investigators 
Professor and Chief Physician Elisabeth R Mathiesen, MD DMSc, Center for Pregnant Women with 
Diabetes, Department of Endocrinology, University of Copenhagen, Blegdamsvej 9, DK-2100 
Copenhagen, Denmark. E-mail: elisabeth.reinhardt.mathiesen@regionh.dk Phone: +45 35 45 83 58.                               
Researcher Martin Bæk Blond, MD, PhD, Clinical Research, Steno Diabetes Center Copenhagen, 
Borgmester Ib Juuls Vej 83 2730 Herlev, Denmark. Phone: +45 30 29 58 91.                                  E-
mail: martin.baek.blond@regionh.dk  
Associate professor and Chief Physician Louise Kelstrup, MD PhD, Department of Obstetrics, 
Herlev-Gentofte University Hospital, Borgmester Ib Juuls Vej 11, 2730 Herlev, Denmark.             
Phone: +45 38 68 26 51. E-mail: louise.kelstrup@regionh.dk  
 
Chief Physician Signe Foghsgaard, MD PhD, Department of Obstetrics, Herlev-Gentofte University 
Hospital, Borgmester Ib Juuls Vej 11, 2730 Herlev, Denmark. Phone: +45 38 68 89 02.                                        
E-mail: signe.foghsgaard.02@regionh.dk 
 
Professor and Chief Physician Thomas Bergholt, MD PhD, Department of Obstetrics, Herlev-
Gentofte University Hospital, Borgmester Ib Juuls Vej 11, 2730 Herlev, Denmark.  
E-mail: thomas.bergholt@regionh.dk 
 
Chief Physician Heidi Storgaard MD, PhD, The Clinic. Steno Diabetes Center Copenhagen, 
Borgmester Ib Juuls Vej 83, 2730 Herlev, Denmark. Phone: +45 21 58 98 17.                                                                   
E-mail: heidi.storgaard@regionh.dk 
  
Chief Physician Pernille Holmager, MD, PhD, Steno Diabetes Center Copenhagen, Borgmester Ib 
Juuls Vej 83, 2730 Herlev, Denmark. Phone: +45 40 41 29 98. E-mail: pernille.holmager@regionh.dk 
 
Clinical dietitian Marianne Juul Hansen, RD, Steno Diabetes Center Copenhagen, Borgmester Ib 
Juuls Vej 83, 2730 Herlev, Denmark. Phone: +45 23 81 93 38.                                                                           
Email: marianne.juhl.hansen@regionh.dk 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
3 
 
2 Table of contents 
 
1 
Contact information on investigators and collaborators ......................................... 2 
2 
Table of contents ........................................................................................ 3 
3 
Abbreviations and definitions of terms .............................................................. 5 
4 
Introduction .............................................................................................. 6 
4.1 
Background ........................................................................................ 6 
4.1.1 Prevalence and ethology ........................................................................... 6 
4.1.2 Dietary therapy ...................................................................................... 6 
4.1.3 Insulin therapy ....................................................................................... 7 
4.1.4 Nutrition recommendations ........................................................................ 8 
4.2 
Objective .......................................................................................... 9 
4.3 
Specific objectives ............................................................................... 9 
4.4 
Hypotheses ........................................................................................ 9 
4.5 
Study endpoints ................................................................................ 10 
4.5.1 Primary endpoint ...................................................................................10 
4.5.2 Secondary endpoints ...............................................................................10 
4.5.3 Descriptive/exploratory endpoints ..............................................................11 
4.5.4 Endpoints related to intervention and adherence .............................................11 
4.5.5 Endpoints related to hospital costs ..............................................................11 
5 
Investigational study design ......................................................................... 12 
5.1 
Study design ..................................................................................... 12 
5.2 
Randomisation .................................................................................. 12 
5.3 
Intervention ..................................................................................... 13 
5.3.1 Intensive dietary counselling .....................................................................13 
5.3.2 Standard dietary care (control) ..................................................................13 
5.3.3 General instructions ...............................................................................13 
5.3.4 Adherence ...........................................................................................14 
5.4 
Study visits ...................................................................................... 14 
5.4.1 Screening (V0) ......................................................................................14 
5.4.2 Baseline (V1) – both groups .......................................................................15 
5.4.3 Intervention – intensive dietary group (V2) .....................................................15 
5.4.4 Intervention – intensive dietary group (V3) .....................................................15 
5.4.5 Intervention – intensive dietary group (V4) .....................................................15 
5.4.6 Intervention – intensive dietary group (V5) .....................................................15 
5.4.7 Pre-delivery visit (V6) – both groups .............................................................15 
5.5 
Recruitment and informed consent ......................................................... 17 
6 
Participants ............................................................................................. 17 
6.1 
Inclusion criteria ............................................................................... 17 
6.2 
Exclusion criteria ............................................................................... 18 
6.3 
Criteria for withdrawal ........................................................................ 18 
7 
Examinations ........................................................................................... 19 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
4 
 
7.1 
Clinical examination ........................................................................... 19 
7.2 
Blood samples ................................................................................... 20 
7.3 
Electronic medical record data .............................................................. 20 
7.4 
Socioeconomic baseline data ................................................................ 21 
8 
Sample size determination........................................................................... 22 
9 
Data management ..................................................................................... 22 
9.1 
Data handling ................................................................................... 22 
9.2 
Data reporting and protection ............................................................... 23 
9.3 
Source data identification and verification ............................................... 23 
9.4 
Data reporting and protection ............................................................... 23 
9.5 
Protocol changes ............................................................................... 23 
10 Publication .............................................................................................. 23 
11 Study timeframe ....................................................................................... 24 
12 Financing ................................................................................................ 24 
12.1 
Conflicts of interest ............................................................................ 24 
13 Compensation of participants ....................................................................... 24 
14 Ethics and regulations ................................................................................ 24 
14.1 
Independent ethics committee and regulatory authority .............................. 24 
14.2 
Ethical considerations ......................................................................... 25 
14.3 
Risks related to participation ................................................................ 25 
15 Insurance ................................................................................................ 25 
16 References .............................................................................................. 25 
 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
5 
 
3 Abbreviations and definitions of terms 
BMI 
Body Mass Index 
Clinically relevant differences 
Definitions of clinically relevant differences for all hypothesis-related 
outcomes will be reported in a statistical analyses plan (SAP). The 
SAP will be written and uploaded to clinicaltrials.gov before the 
statistical analyses will be conducted. 
DDQOL 
Diabetes Diet-related Quality of Life 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
EMR 
Electronic Medical Record 
GA 
Gestational age 
GDM 
Gestational Diabetes Mellitus 
HbA1c 
Glycosylated haemoglobin A1c 
HCCQ 
Health Care Climate Questionnaire 
Jaundice 
Neonatal jaundice or neonatal hyperbilirubinemia is defined as 
elevated total serum bilirubin (TSB) (>68-137 µmol/l) and clinically 
manifests as yellowish discoloration of the skin, sclera, and mucous 
membrane.  
LGA 
Large for gestational age 
Macrosomia 
Macrosomia or foetal overgrowth is defined as birth weight >4,500 g 
Neonatal hypoglycaemia 
Neonatal hypoglycaemia is defined as plasma glucose level < 2.5 
mmol/l after the first 2 postnatal hours. 
NICU 
Neonatal Intensive Care Unit 
Non-white ethnic minority background  Non-white ethnic minority groups are defined as groups belonging to 
minority populations of non-European origin characterised by their 
non-white 
status. 
These 
include 
Asian 
(Indian, 
Pakistani, 
Bangladeshi, Chinese, any other Asian background), Caribbean, 
Black, African, Middle East, Hispanic/Latino, and any mixed or 
multiple ethnic background (1).  
OGTT 
Oral Glucose Tolerance Test. 
PCDS 
Perceived Competence in Diabetes Scale 
PPAQ 
Pregnancy Physical Activity Questionnaire 
Preeclampsia 
Preeclampsia is defined as new-onset gestationel hypertension (with 
a blood pressure ≥140/90 mmHg after 20 weeks of gestation in 
combination with proteinuria (≥0.3 g protein in 24-hour urine 
specimen or (≥0.1 g protein in a midstream urine spot), pulmonary 
oedema and/or specific symptoms of significant end-organ 
dysfunctions (e.g., headache, nausea, vomiting).  
Preterm birth 
Preterm birth is defined as GA less than 37 completed weeks    
SD 
Standard deviation 
SGA 
Small for gestational age 
SOP 
Standard operational procedure 
Telemedicine 
Telemedicine consultations are defined as tele- or video consultation 
V 
Visit 
White ethnic background 
White origin is defined as people with European ancestral origins who 
identify, or are identified, as white (also called European, or in terms 
of racial classifications, the group known as Caucasian). The term 
derives from the concept of race but is used as an indicator of 
ethnicity(1). 
WHO-5 
The WHO-Five Wellbeing Index (WHO-5) to assess wellbeing  
 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
6 
 
4 Introduction 
4.1 Background 
 
4.1.1 Prevalence and ethology  
The prevalence of gestational diabetes (GDM) is increasing in parallel with the global epidemic of 
obesity, both worldwide and in Denmark. GDM now affects around 6% of all pregnancies in Denmark 
(2), and 14% of pregnancies worldwide (standardised estimation) ranging from 8% in North America 
and Europe, 10% in South and Central America, 14% in Africa, 21% in South-East Asia to 28% in 
Middle East and North Africa (3). Higher risks of GDM have been reported in immigrants from Non-
Western countries living in Denmark , reflecting ethnic differences in the prevalence of GDM (4). 
 
GDM is defined as glucose intolerance with onset or first recognition during pregnancy (5). The disease 
is characterized by hyperglycaemia and a marked insulin resistance secondary to placental hormonal 
release (6). Risk factors for developing GDM in pregnancy include obesity, excessive gestational weight 
gain, previous GDM, glucosuria, family history of diabetes, ethnicity, and hypertension (6). 
Hyperglycaemia is associated with serious short- and long-term complications for mother and child 
including delivering large-for-gestational-age (LGA) babies, macrosomia (birth weight >4,500 g), 
preterm birth, caesarean section, preeclampsia, birth injury (e.g., shoulder dystocia), respiratory distress 
syndrome, neonatal hypoglycaemia, jaundice, and increased admission to neonatal intensive care unit 
(NICU) (7). Finally, hyperglycaemia during pregnancy also increases the long-term risk of obesity, type 
2-diabetes (T2D), and cardiovascular disease both in the mother and the offspring later in life (6). 
4.1.2 Dietary therapy  
First-line treatment in GDM after diagnosis is dietary therapy including a systematic and detailed dietary 
assessment to identify relevant areas for adjusting the diet and overall lifestyle (e.g., increasing physical 
activity). The overall goals with dietary therapy are 1) To provide adequate calories and micro- and 
macronutrients to meet the needs of pregnancy consistent with maintaining normoglycaemia, 1) To 
improve glycaemic control; and 3) To secure appropriate gestational weight gain and avoid excessive 
weekly gestational weight gain (6, 8). In addition to dietary therapy, women are trained in self-
monitoring blood glucose (SMBG) to assess if glycaemic targets are met. The American Diabetes 
Association (ADA) recommends continuous dietary adjustments based on the women's regularly 
measured blood glucose, appetite, weight-gain patterns, changes in dietary preferences, exercise 
patterns, and overall life situation (e.g., work and leisure time versus maternity leave changes affecting 
diet and physical activity) (6).  
 
Most pregnant women are screened and diagnosed with GDM between 24-28 weeks of gestation. This 
leaves a very short window for dietary intervention to improve blood glucose control and limit body 
weight gain during pregnancy. Currently, no evidence exists for specific recommendations concerning 
the optimal frequency, intensity, or duration of visits with a dietitian for improving maternal, foetal, or 
neonatal outcomes (6, 9). National clinical guidelines for treatment of GDM recommends up to three 
visits with a dietitian depending on the time of diagnosis (10). However, in the latest national clinical 
guidelines under review this has been changed to only one visit (11). Real-world data show that women 
with GDM are only seen once by a dietitian during pregnancy at Danish hospitals (unpublished data). 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
7 
 
In some international clinics, dietitians review women with GDM again prior to starting insulin (the 
second-line treatment in GDM) to see whether any dietary modifications can be made so that insulin 
therapy may be averted (12). ADA also recommends telehealth visits including feedback systems for 
women with GDM to improve outcome compared with standard in person care based on high 
evidence(6, 13).  
 
Kurtzhals et al. found that women with GDM with a lower weekly gestational weight gain from time of 
diagnosis and throughout dietary therapy, reflecting higher dietary adherence, was associated with 
improved maternal and neonatal outcomes including lower late-pregnancy HbA1c and healthier foetal 
growth (14). Based on clinical experiences most women with GDM are highly motivated for behavioural 
changes to protect the health of their unborn child (14). But with only one visit with a dietitian after 
diagnosis, the women are left much on their own to assess when, where, and how to adjust their diet 
most appropriately to meet targets for glycaemic control and body weight management while securing 
sufficient intake of micro- and macronutrients. In semi-structured interviews with 20 women with GDM 
of different ethnicity conducted in the Department of Obstetrics, Herlev Hospital, Autumn 2022, most 
of the women experienced being left much on their own after diagnosis and missed having more 
intensive dietary support (unpublished data).  
4.1.3 Insulin therapy 
In most cases dietary improvements are sufficient to achieve glycaemic goals but in some cases insulin 
therapy is needed (6, 10). The need for initiating insulin therapy is assessed by the obstetrician at regular 
visits based on the woman’s pre- and postprandial blood glucose, and ultrasonographic evaluation of 
foetal growth/abdominal circumference (10). The exact proportion of women with GDM requiring 
insulin therapy is not well-described due to lack of valid register-based data (incorrect use of diagnosis 
codes, and supply of insulin directly from the hospitals). One Danish cohort study found that the 
proportion of women with GDM requiring insulin therapy to be 27% during the reported period 2004 – 
2016 (15). Another Danish cohort study reported that 32% of women with GDM were treated with 
insulin during the reported period 2011 – 2017 (14). No changes in diagnostic criteria for GDM have 
been made in Denmark during the reported periods. Based on data from Herlev Hospital, we found that 
30% of women with GDM had been treated with insulin in 2019 – 2022 (unpublished data).  
 
Several studies have tried to identify patient characteristics and predict failure of dietary therapy and 
need for insulin therapy (12, 14, 16-18). Factors include higher pre-pregnancy body mass index (BMI); 
BMI at diagnosis; previous GDM; higher haemoglobin A1c (HbA1c) at diagnosis and in late pregnancy; 
higher 2-hour glucose level on an oral glucose tolerance test (OGTT); lower gestational age (GA) at 
diagnosis; and higher weekly weight gain during pregnancy. The percentages starting insulin therapy 
also vary significantly according to ethnicity as shown in a retrospective review of five ethnic groups 
(South-East Asian, South Asian, Middle Eastern, Anglo-European and Pacific Islander) (19). 
 
Insulin therapy can improve glycaemic control and has been shown to be effective in reducing the rate 
of macrosomia in GDM (20). But use of insulin during pregnancy is also associated with several clinical 
implications (e.g., increased risk of maternal hypoglycaemia) (6, 14, 21), increased hospital costs 
(endocrinologist visits, extra visits to other health care professionals, additional ultrasonographic 
examinations depending on the time of insulin initiation), and medical costs (insulin) (22) as well as 
higher costs in relation to delivery (e.g., induction of labor, pre-term delivery) (14) , and neonatal care 
(increased risk of neonatal hypoglycaemia) (23, 24). Finally, the personal burden associated with insulin 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
8 
 
use (e.g., extra worries, additional SMBG measurements, and insulin injections every day) also affects 
women with GDM (25). Only one smaller case-control study has looked at quality of life (QoL) in GDM 
and found no differences between the diet-treated vs. insulin-treated group (26). 
4.1.4 Nutrition recommendations  
There is no clear consensus on an ideal dietary composition in GDM. A Cochrane review from 2014 
examined the evidence for different dietary approaches and ended up concluding that all the studies for 
comparisons of maternal and infant health outcomes were too small for reliable conclusions about which 
type of dietary recommendations are most suitable for women with GDM (27). In a systematic review 
and meta-analysis for maternal glucose control and neonatal outcomes in GDM, it was found that 
modified dietary interventions (including low glycaemic index diets; low- versus high-carbohydrate 
diets; fibre-enriched diet; Dietary Approaches to Stop Hypertension (DASH)-diet; moderate energy 
restriction diet; high monounsaturated/polyunsaturated fatty acids diets; soy protein diets; personalised 
diet; ethnic meal plan diet) were associated with lower infant birth weight and less macrosomia. These 
associations were found despite a high heterogeneity between studies indicating that several methods 
can be used, and that dietary education and support should be individualised (28).  
 
Since carbohydrate is the main energy-contributing nutrient in our diet with the highest impact on 
postprandial blood glucose levels (and a significant impact on the total energy balance), awareness 
concerning the intake of carbohydrate-rich food sources constitutes an important aspect of dietary 
therapy in GDM. Carbohydrates make up approx. 45% of total daily energy intake (E%) in the traditional 
Danish diet (29) which is in the lower end of the range of recommended intake in GDM (46-60 E%) (8). 
Institute for Medicine (IOM) and ADA recommends a minimum of 175 g of carbohydrates daily (≈35% 
of 8,400 kJ/2,000 kcal per day) for normal pregnant women and for women with GDM to ensure 
appropriate glucose for normal foetal growth and cerebral development and function (6). However, the 
amount, type and distribution of carbohydrate intake varies greatly between different ethnic and cultural 
groups with the highest carbohydrate intake (>60 E%) in traditional South-Asian, East-Asian, and 
African diets (30).  
 
The total amount of carbohydrates consumed in a meal is a major predictor of the postprandial glucose 
response. However, both the quantity and quality (i.e., intake of dietary fibre, added sugar and glycaemic 
index) of carbohydrates influence blood glucose levels (6, 8). Thus, monitoring the dietary intake of 
carbohydrates continuously is important to control postprandial glucose fluctuations. This may lead to 
clinical benefits such as a reduction in the need for insulin, limit gestational weight gain, and potentially 
reduce foetal overgrowth, neonatal hypoglycaemia, and admission to NICU. 
 
Health literacy especially among women from non-White ethnic minority groups are highly variable, 
and this may have a significant impact on GDM management including adherence to dietary therapy 
(31). Furthermore, migrants in Western society may also face huge challenges in managing their GDM 
due to language barriers. For example, some studies have shown that women living in English-speaking 
countries predominantly speaking other languages than English, have lower rates of dietary 
understanding compared with their English-speaking counterparts. This may also affect dietary 
adherence (32). Thus dietary recommendations must be culturally sensitive (4) and not based on Western 
ideas of what ideal meals should include to support dietary adherence and glycaemic control.  
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
9 
 
In summary, the most optimal way to deliver dietary therapy to women with GDM is not known. The 
possibility that intensive dietary therapy may reduce the need for initiating insulin treatment without 
increasing hospital service costs for these women in comparison with women receiving standard dietary 
care needs to be explored.  
 
4.2 Objective 
The overall objective is to investigate the effectiveness and hospital service costs of implementing an 
intervention with intensive dietary counselling and support during pregnancy in women with GDM.  
 
4.3 Specific objectives 
The overall objective is to investigate differences in clinical, cost-related, and patient-reported outcomes 
between women with GDM randomised to either intensive dietary therapy or standard dietary care. 
The specific objectives are: 
1. To investigate the effect of intensive dietary therapy on the likelihood of remaining treated with 
diet only vs. needing insulin therapy based on a hypothesis hierarchy (main objective) 
2. To investigate the effects on maternal outcomes: changes in gestational weight gain; glycaemic 
control (HbA1c); gestational age at insulin initiation and prescribed insulin dose  
3. To investigate the effects on neonatal outcomes: changes in birth weight; birth weight standard 
deviation score; neonatal hypoglycaemia; and admission to NICU 
4. To describe changes in other pregnancy outcomes: number of cases of preeclampsia; preterm 
birth; mode of birth (caesarean section); jaundice; and macrosomia 
5. To describe changes in patient-reported outcomes: treatment satisfaction; well-being; diet-
related quality of life; autonomy support; and health competencies  
6. To describe changes in dietary intake and physical activity  
7. To describe if the intervention was conducted as planned, including number and type of visits 
8. To describe hospital service costs related to the intensive dietary intervention compared with 
standard care in a cost-analysis. 
 
4.4 Hypotheses 
1. Hypothesis hierarchy for the primary outcome (objective 1): 
The type I error will be controlled in the strong sense using the following hierarchical (fixed 
sequence A-C) testing procedure. This is based on priority ordering of the hypotheses and 
testing them in this order until an insignificant result appears: 
A. We hypothesise that intensive dietary therapy is superior to standard dietary care (control 
group) in reducing the need for initiating insulin therapy in all women with GDM. 
Superiority will be claimed if the difference between the two groups is equal to, or surpass, 
the minimal important difference (defined as 50% reduction in need for initiating insulin 
therapy in the intervention group compared with the control group) in favour of the intensive 
treated group, and if the P-value is < 0.05.  
B. We hypothesise that intensive dietary therapy is superior to standard dietary care (control 
group) in reducing the need for insulin therapy in women with a white ethnic background 
with GDM. Superiority will be claimed if the difference between the two groups is equal 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
10 
 
to, or surpass, the minimal important difference (defined as 50% reduction in need for 
initiating insulin therapy in the intervention group compared with the control group) in 
favour of the intensive treated group, and if the P-value is < 0.05.  
C. We hypothesise that intensive dietary therapy is superior to standard dietary care (control 
group) in reducing the need for initiating insulin therapy in women with GDM with a non-
white ethnic minority background. Superiority will be claimed if the difference between the 
two groups is equal to, or surpass, the minimal important difference (defined as 50% 
reduction in need for insulin therapy in the intervention group compared with the control 
group) in favour of the intensive treated group, and if the P-value is < 0.05.  
2. Hypotheses for secondary outcomes (objective 2 and 3): 
• 
We hypothesise that an intensive dietary intervention in comparison with standard dietary 
care will induce:  
o a clinically relevant limitation in gestational weight gain  
o a clinically relevant improvement in HbA1c 
o a clinically relevant delay in insulin therapy initiation  
o a clinically relevant limited maximal insulin dose (units per kg body weight)  
o a clinically relevant reduction in birth weight at delivery at term 
o a clinically relevant reduction in birth weight SD at delivery  
o a clinically relevant reduction in neonatal hypoglycaemia 
o a clinically relevant reduction in new-borns admitted to NICU 
3. Objectives 4-7 are regarded descriptive  
4. Hypothesis for hospital care costs related to the intensive dietary intervention (objective 8): 
• 
We hypothesise that an intensive dietary intervention in comparison with standard dietary 
care will have a positive effect on the net hospital costs, or at least be cost neutral (non-
inferiority) if insulin therapy can be prevented for some of the women. The reason being 
that insulin therapy is associated with more cost intensive GDM treatment during 
pregnancy, higher expenses for inducement of labour, and higher cost of adverse events for 
mother and child as caesarean section and NICU stay, and length of hospital stay.  The cost 
will be estimated from referral with GDM to discharge of mother and offspring.  
 
 
4.5 Study endpoints 
4.5.1 Primary endpoint 
The primary endpoint is the percentage of women with GDM treated with insulin therapy in the 
intervention group and the control group at delivery. 
4.5.2 Secondary endpoints 
Secondary endpoints include the following measures: 
• 
Maternal endpoints 
o Changes in body weight (kg) from referral to delivery 
o Changes in HbA1c (mmol/mol) from referral to delivery 
o Time to insulin treatment onset (days) from study inclusion until prescription or 
delivery if insulin therapy is not initiated   

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
11 
 
o Mean prescribed initial and maximal insulin dose (units/kg body weight) 
• 
Neonatal endpoints 
o Percentage of LGA new-borns  
o Percentage of new-borns small for gestational age (SGA) 
o Percentage of new-borns with macrosomia (birth weight >4,500 g) 
o Percentage of new-borns with neonatal hypoglycaemia (see definition in section 3)   
o Percentage of new-borns admitted to NICU 
4.5.3 Descriptive/exploratory endpoints 
Descriptive/exploratory endpoints include changes in the following study inclusion until delivery: 
• 
Maternal endpoints 
o Percentage of cases of preeclampsia (see definition in section 3) 
o Percentage of cases of preterm births (see definition in section 3)    
o Percentage of cases of acute caesarean sections 
o Percentage of cases of planned caesarean sections 
• 
Neonatal endpoints 
o Number of cases of neonatal jaundice (see definition in section 3)  
• 
Questionnaires  
o Diabetes Diet-related Quality of Life (DDQOL) 
o Well-being (WHO-5)  
o Health Care Climate Questionnaire (HCCQ) 
o Perceived Competence in Diabetes Scale (PCDS) 
o Diabetes Treatment Satisfaction Questionnaire (DTSQ) 
o Pregnancy Physical Activity Questionnaire (PPAQ) 
4.5.4 Endpoints related to intervention and adherence  
• 
Adherence to intervention (number of no shows for planned visits) 
• 
Number and types of visits (face-to-face, video and telephone)  
• 
Changes in dietary intake with focus on carbohydrate intakes (total intake and meals) 
• 
Adverse events 
4.5.5 Endpoints related to hospital costs 
Hospital costs will be analysed for the two study groups (intensive dietary therapy vs. standard care) 
including costs from referral with GDM to discharge after delivery divided into the categories:  
• 
Outpatient contacts and costs related to the treatment of GDM 
• 
Delivery costs 
• 
Inpatient costs after delivery for mother and offspring separately, including NICU costs 
• 
Total net costs  
 
 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
12 
 
5 Investigational study design  
5.1 Study design 
The INTENSE-GDM trial is a randomised controlled parallel group open-label effectiveness trial 
aiming to include 214 women with GDM (Figure 1). Participants will attend one consultation with a 
dietitian in the standard care group and up to 5 consultations with a dietitian in the intensive dietary 
counselling group. Both groups will receive one end-of-intervention telephone call. Each study visit is 
described in detail in section 5.4. 
 
Study visits 
V0: Screening  
V1: Baseline visit including one dietary consultation max 2 days after screening (both groups) 
V2: Follow-up 1 with the dietitian max 2-3 days after V1 (only in the intensive group) 
V3: Follow-up 2 with the dietitian a week after V2 (only in the intensive group) 
V4: Follow-up 3 with the dietitian only if needed (only in the intensive group) 
V5: Follow-up 4 with the dietitian only if needed (only in the intensive group) 
V6: Telephone visit 2 weeks before delivery (both groups) 
 
 
Figure 1 Study design. Depending on GA at GDM diagnosis and time of delivery the intervention 
duration will be 5 – 20 weeks. Min. two follow-up consultations are provided in the intensive group. 
 
5.2 Randomisation 
Participants eligible for inclusion in the study according to the screening will have their baseline 
measurements collected followed by a randomisation at V1. Participants will be randomised to either an 
intensive dietary counselling group or a usual dietary care group (control group) in a 1:1 ratio. 
Randomisation will be performed by the research dietitian using the randomisation module in the 
software program REDCap. The randomisation list will be made by a researcher/statistician not involved 
in the trial, who will be the only person to access the randomisation list during the trial. Should this 
person be unable to continue this function, a new person not involved in the trial will be appointed to 
store and access the sequence. 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
13 
 
 
5.3 Intervention 
5.3.1 Intensive dietary counselling  
Women randomised to the intensive dietary intervention group will receive one initial dietary 
counselling consultation, and two mandatory follow-up consultations with a dietitian. In addition, 
participants in this group will be offered 1-2 follow-up consultations if needed (see figure 1).   
 
Intervention 
• 
1 x 60 min initial dietary counselling (in-person) 
• 
2 x 30 min follow-up dietary consultations (phone/video/in-person according to preference) 
• 
1-2 x 15-30 min follow-up dietary consultations if needed (phone/video) 
 
The initial dietary counselling includes setting personal dietary goals for behavioural change according 
to individual challenges with the diet, patient preferences and the overall goal for weight and glycaemic 
control. Women will be educated in basic carbohydrate counselling. This includes identifying 
carbohydrates, learning how to count carbohydrates e.g., by calculating the carbohydrate content from 
food labels, carbohydrate food tables, or apps for smartphones and use of a personalised carbohydrate 
plan with guiding suggestions for daily intake of carbohydrates at meals based on the personal dietary 
history. An app from the Danish Diabetes Association (Diabetes og Kulhydrattælling®. The Danish 
Diabetes Association’s app, Pragma soft A/S, available in Google Play® and App Store® 12/2014, Free) 
will be introduced to support calculation of carbohydrates if the patient is able to understand and use 
this app. In addition, attention concerning carbohydrate quality (dietary fibre intake, and glycaemic 
index principles) and overall calorie intake will be introduced.  
 
Follow-up consultations will include feedback on postprandial plasma glucose measurements and foods 
eaten, and adjustments of dietary plan until delivery. 
 
5.3.2 Standard dietary care (control) 
Women randomised to the standard dietary care group will receive one dietary counselling consultation 
according to the initial dietary counselling described in section 5.3.1 without any follow-up 
consultations with a dietitian. Participants are encouraged to follow their dietary plan until delivery. 
 
• 
1 x 60 min dietary counselling (in-person) 
 
5.3.3 General instructions 
All study participants will be encouraged to obtain and maintain a moderate-intensity aerobic activity 
level such as brisk walking during their pregnancy and achieving the best possible sleep. Additionally, 
all study participants will be instructed to follow their usual care at the Department of Obstetrics at 
Herlev Hospital and at SDCC if referred to an endocrinologist eventually. The medical doctors at the 
Department of Obstetrics will assess the need for initiating insulin therapy and referral to an 
endocrinologist.  

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
14 
 
5.3.4 Adherence 
Dietary adherence will be measured by the dietitian using the dietary history method for data collection. 
A dietary history is a structured interview methods consisting of questions about habitual dietary intake 
of foods from core food groups, in this study with particular focus on collecting data on carbohydrate 
sources and estimation of carbohydrate portions sizes (in grams) distributed throughout the day before 
and after the intervention. Dietary data will be collected at V1 and V6.  
 
5.4 Study visits  
The following section describes all visits included in the study. An overview of the data collection 
procedures is presented in table 1. The visits will be conducted by the research dietitians including the 
principal investigator. Examinations are described in section 7. Windows are allowed for all study visits 
during the study period. However, we aim to carry out the initial dietary counselling within the first 
week after referral to Herlev Hospital for both groups, and the first follow-up consultation within the 
first 2-3 days after the initial dietary counselling in the intensive dietary intervention group. An outline 
of the protocol is detailed in Figure 2. 
 
Figure 2 INTENSE-GDM protocol summary 
GA, gestational age; GDM, gestational diabetes; HbA1c, haemoglobin A1c; OGTT, oral glucose tolerance test. 
5.4.1 Screening (V0) 
The screening visit (V0) will take place in quiet surroundings at SDCC. After information about the 
study, and signing of an informed consent, information on medical history (medication, previous and 
current diseases) will be collected, and in- and exclusion criteria will be assessed by a research dietitian. 
If the patient fulfils all inclusion criteria and none of the exclusion criteria, the patient will be included 
in the study. If the patient needs additional time to consider, a new date for a screening visit will be 
scheduled. If the patient is not eligible for study inclusion the cause of screening failure will be recorded. 
Patients eligible for inclusion will be registered with an ID code. 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
15 
 
5.4.2 Baseline (V1) – both groups 
At the baseline visit (V1) participants will meet with a research dietitian in the clinic at SDCC. The 
following procedures and assessments will be performed: A clinical examination with measurement of 
body weight and height; HbA1c after diagnosis will be collected from the patient’s medical record; and 
information about family history and ethnic origin will be collected.  
 
A diet history interview will be performed as part of the dietary counselling focusing on carbohydrate 
intake before and after diagnosis. The dietitian assesses the diet, and a balanced dietary plan will be 
prescribed with emphasis on appropriate nutritional intake and distribution especially of carbohydrates, 
and low glycaemic index diet. Dietary recommendations will be culturally adapted and tailored to the 
individual. 
 
Randomisation will be performed before the participant is sent home to plan follow-up consultations for 
women randomised to the intensive dietary group. Questionnaires will be sent electronically through 
REDCap after the visit. 
5.4.3 Intervention – intensive dietary group (V2)  
V2 is a mandatory follow-up visit with the dietitian either in person or remote as telemedicine based on 
the participant’s preference. The visit will take place ±2-3 days after the initial dietary counselling (V1). 
Focus will be on dietary adherence, carbohydrate distribution and amounts of carbohydrates eaten at 
each meal in relation to 7-point SMBG measurements in this dietary consultation. 
5.4.4 Intervention – intensive dietary group (V3)  
V3 is a mandatory follow-up visit with the dietitian either in person or remote as telemedicine based on 
the participant’s preference. The visit will take place ±7 days after V2. Focus will be on dietary 
adherence, in relation to 7-point SMBG measurements. Evaluation of the need for a dietary follow-up 
visit.  
5.4.5 Intervention – intensive dietary group (V4)  
Optional follow-up telemedicine consultation with the dietitian. The visit can take place up to 3 weeks 
before delivery. 
5.4.6 Intervention – intensive dietary group (V5)  
Optional follow-up telemedicine consultation with the dietitian. The visit can take place up to 3 weeks 
before delivery. 
5.4.7 Pre-delivery visit (V6) – both groups 
A telephone visit will be carried out 1-2 weeks before the planned delivery with both groups. A diet 
history interview will be performed focusing on the carbohydrate intake during the intervention period. 
Obstetric history, changes in medication, HbA1c, body weight and 7-point SMGB measurements 
registered in the participant’s medical record will be recorded in REDCap. Questionnaires will be sent 
electronically through REDCap after the telephone visit. 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
16 
 
Table 1. Data collection procedures in the INTENSE-GDM Trial 
Variable 
Measurement 
Participant 
Screening  
Baseline  Pre-delivery 
Post-delivery 
 
 
    
V0 
V1 
V6 
No visit 
Ethnicity and 
socio-economic, 
status  
Self-constructed questions  
W 
 
• 
 
 
 
Medical history 
EMR 
W 
• 
 
• 
 
 
 
Dietary history 
Personal interview 
W 
 
• 
 
• 
 
 
Alcohol, sleep, 
and smoking 
Self-constructed questions  
W 
 
• 
 
• 
 
 
Obstetric history 
EMR 
W 
 
• 
 
• 
 
• 
 
Medication 
EMR 
W 
 
• 
 
• 
 
 
Glycose control 
HbA1c 
W 
 
• 
 
• 
 
 
 
7-point SMGB 
W 
 
• 
 
• 
 
 
 
Neonatal hypoglycaemia 
N 
 
 
 
• 
 
 
Admission to NICU  
W, N 
 
 
 
• 
 
Anthropometry 
Height, BW, BMI 
W 
 
• 
 
• 
 
 
 
Delivery weight (EMR) 
N 
 
 
 
• 
 
 
LGA (EMR) 
N 
 
 
 
• 
 
 
SGA (EMR) 
N 
 
 
 
• 
 
 
Macrosomia (EMR) 
N 
 
 
 
• 
 
Delivery 
complications 
Preterm birth (EMR) 
Preeclampsia (EMR) 
Caesarean section (EMR) 
Jaundice (EMR) 
 
W 
W 
W 
N 
 
 
 
• 
 
• 
 
 
 
 
 
• 
 
 
 
 
 
• 
 
Well-being 
The WHO-Five Wellbeing 
Index (WHO-5)(33) 
W 
 
• 
 
• 
 
 
Diet-Related 
Quality of Life 
Diabetes Diet-Related 
Quality of Life (DDRQOL) 
(34) 
W 
 
• 
 
• 
 
 
Autonomy 
support 
Health Care Climate 
Questionnaire (HCCQ) (35) 
W 
 
• 
 
• 
 
 
Perceived 
competences 
 
Perceived Competence in 
Diabetes Scale (PCDS) (35) 
W 
 
• 
 
• 
 
 
Treatment 
satisfaction 
Diabetes Treatment 
Satisfaction Questionnaire 
(DTSQ) (36, 37) 
W 
 
• 
 
• 
 
 
Physical activity 
 
Pregnancy Physical Activity 
Questionnaire (PPAQ) (38) 
W 
 
• 
 
• 
 
 
Adherence  
EMR data  
W 
 
 
 
• 
 
Hospital costs 
EMR and registry data 
W, N 
 
 
 
• 
 
Safety  
Adverse events 
W 
 
 
• 
 
• 
 
BMI, Body Mass Index; BW, Body weight; EMR, Electronic Medical Record; HbA1, Haemoglobin A1c; W, Woman with 
GDM; N, neonate delivered by women with GDM in the study; NICU, neonatal intensive care unit. 
 
 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
17 
 
5.5 Recruitment and informed consent 
We plan to recruit at 214 women with GDM from the Department of Obstetrics at Herlev-Gentofte 
Hospital. Written informed consent will be obtained either in paper format or digitally using REDCap 
prior to entry into the study.   
Participants will be recruited when they are newly diagnosed with GDM and referred to the Department 
of Obstetrics at Herlev Hospital for GDM management. A written participant information in Danish and 
English will be sent together with the brochure “Forsøgspersoners rettigheder i et 
sundhedsvidenskabeligt forskningsprojekt” through E-Boks together with the invitation to the initial 
consultation with a dietitian (standard procedure). The right to bring a relative is mentioned in the written 
information. Women are encouraged to bring their partner. There will be allocated plenty of time for the 
oral study information at the first appointment with one of the research dietitians (who also perform the 
routine dietitian visits with all women with GDM). The research dietitian will start by asking the woman 
if she has read the participant information and if she is still interested in oral information about the 
clinical trial. If she has read the information and is still interested, the research dietitian will provide an 
oral information (either in Danish or English or together with an interpreter) including information about 
study objectives, significance, content, and requirements including risks implications and principles for 
randomisation with allocation to one of two groups. In particular, the woman will be informed about: 1) 
the possibility of withdrawing from the study at any time without giving any reason; 2) how personal 
health-related data will be collected and used and processed in accordance with the data protection 
legislation in the study; and 3) that all personal and health-related data will be anonymised.  
The woman will be given time to discuss any questions and will be offered a minimum of 24 hours to 
consider before signing the informed consent. If the woman decides to participate in the study right 
away, the women, and the research dietitian will sign the written informed consent (in Danish or 
English), and the research dietitian will perform a screening (V0) to assess if the woman is eligible for 
inclusion in the study. Women eligible for study inclusion will subsequently be offered an initial dietary 
counselling, performance of baseline measurements, and randomisation (in the mentioned order) (V1) 
by the research dietitian. Alternatively, the patient will be booked for a visit (V1) within 48 hours after 
the screening visit. If the woman needs more time to decide if she wants to participate in the study, or 
has not read the participant information, the research dietitian will schedule for a new meeting after 24 
hours.  
 
6 Participants  
6.1 Inclusion criteria  
• 
Newly diagnosed women with GDM referred to Department of Obstetrics Herlev Hospital  
• 
Women diagnosed with GDM based on a 2-hour OGTT plasma glucose value ≥ 9.0 mmol/l 
• 
Women diagnosed with GDM based on at least 2 plasma glucose measurements above targets 
(either pre-prandial ≥6.0 mmol/l, or 2-hours postprandial ≥8.0 mmol/l)  
• 
GA at GDM diagnosis ≤ 34 
• 
Women with an estimated probability of ≥20% for initiating insulin treatment during 
pregnancy. The estimated probability is based on a logistic regression model developed at 
SDCC and includes the following variables: prepregnancy BMI, GA at GDM diagnosis, and 
HbA1c at GDM diagnosis. In cases where HbA1c has not been measured during the initial 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
18 
 
visit with the dietitian (screening visit), prepregnancy BMI and GA at the time of diagnosis 
will be used to estimate the probability of initiating insulin therapy.  
• 
Provided voluntary written informed parental consent in Danish or English or after translation 
by an interpreter for non-Danish and non-English speaking parents 
 
6.2 Exclusion criteria  
• 
Bariatric surgery 
• 
Other intercurrent illness (e.g., cancer, ulcerative colitis) as judged by the medical experts 
• 
Uncontrolled medical issues, as judged by the investigators  
• 
Concomitant participation in other clinical trials that could interfere with the INTENSE-GDM 
trial as evaluated by the investigators  
• 
Unable to understand the informed consent and procedures regardless of the language spoken 
 
6.3 Criteria for withdrawal 
One or more of these criteria will result in withdrawal of the participant from the study: 
• 
A participant withdraws the informed consent  
• 
A participant’s general condition contraindicates continuing the study as judged by the 
investigators or medical experts 
• 
Other reasons determined by the investigator 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
19 
 
7 Examinations 
All patients found eligible for inclusion in the study will be invited to a first study visit (V1) for 
collection of baseline measurements according to study specific SOPs. Subsequently, all participants 
will be randomised to one of the two study groups. All examinations will be performed in the outpatient 
diabetes clinic at SDCC. Study visits and examinations are described in detail in table 2 below, in the 
current section and section 5.4. 
Table 2: Schematic overview of study visits 
Visit 
V0 
V1 
V6 
Patient-related information 
 
 
 
Informed consent 
X 
 
 
Assessment of in- and exclusion criteria  
X 
 
 
Medical history  
X 
 
 
Dietary history 
 
X 
X 
Medication use 
 
X 
X 
Randomisation 
X 
 
 
Clinical efficacy outcomes 
 
 
 
Insulin use 
 
 
X 
Insulin dose (IE per kg body weight) 
 
 
X 
Time to insulin (days) from study allocation until prescription 
 
 
X 
Diet history interview 
 
X 
X 
HbA1c 
 
X 
X 
Body weight and height (height only at V1) 
 
X 
X 
7-point SMGB 
 
X 
X 
Questionnaires 
 
 
 
Socio-economic and ethnic characteristics  
 
X 
 
Well-being (WHO-5)  
 
X 
X 
Diabetes Diet-Related Quality of Life (DDRQOL) 
 
X 
X 
Health Care Climate Questionnaire (HCCQ) 
 
X 
X 
Perceived Competence in Diabetes Scale (PCDS) 
 
X 
X 
Diabetes Treatment Satisfaction Questionnaire (DTSQ) 
 
X 
X 
Pregnancy Physical Activity Questionnaire (PPAQ) 
 
X 
X 
Abbreviations: SMBG, Self-Monitored Blood Glucose; V0, Screening, V1, data collected at baseline; V6, data collected pre-delivery. 
 
7.1 Clinical examination  
Body weight and height will be measured to the nearest 0.1 kg and 0.1 cm, respectively with calculation 
of BMI (kg/m2) at the baseline visit (V1). Body weight will be measured with the participant wearing 
light indoor clothes and no shoes after emptying the bladder. Height is measured using a wall-mounted 
stadiometer with the participants not wearing shoes and with the heels, buttocks and upper part of the 
back remaining in contact with the wall/back of the stadiometer. Body weight at V6 will be recorded 
based on data from the patients’ medical records. GA at the time of the registered body weight 
measurement in EMR will be recorded.  
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
20 
 
7.2 Blood samples  
HbA1c will be measured in a non-fasting condition. The routine HbA1c measurement performed shortly 
after referral to Department of Obstetrics at Herlev Hospital will be recorded at V1, and HbA1c 
measured closest to delivery (GA recorded) will be recorded at V6. Laboratory analyses of blood 
samples will be performed in the laboratory at Herlev-Gentofte Hospital by skilled laboratory 
technicians. 
 
7.3 Electronic medical record data 
The written consent provides the trial investigators, the sponsor, the sponsor's representatives, and 
regulatory authorities direct access to obtain information from the patient's medical records, including 
electronic records, with the purpose of reviewing information regarding the participant's health 
condition. This access is necessary for conducting the research project and for regulatory oversight, 
including self-regulation, quality control, and monitoring, which they are obligated to perform. 
According to planned and described procedures, the research dietitians will access the participant's 
medical record to collect information relevant to the study as described under screening (assessment of 
in- and exclusion criteria), collection of medical history, concomitant medications, and clinical 
outcomes from referral until discharge after delivery. The purpose of obtaining information from the 
medical records is to assess whether the women is eligible for inclusion, to describe the study population, 
and report study outcomes related to pregnancy and child delivery.  
The following data from the mother’s and infant medical records and The National Patient Register 
will be collected (see Table 1 for details about data sources): 
 
Background data 
Age  
GA at GDM diagnosis and referral to the Department of Obstetrics  
Method for diagnosing GDM (OGTT or 3-days SMBG monitoring) 
OGTT value, mmol/l at diagnosis 
Number of pregnancies, n 
Multiple pregnancy 
Previous GDM 
Prepregnancy BMI, kg/m2 
Hypertensive disorders of pregnancy 
Pregestational hypertension 
Pregestational dyslipidaemia 
Diet-affecting diseases e.g., gastroparesis, kidney disease, coeliac disease  
 
Prenatal care data 
Number and types of visits in each study group from referral to discharge after delivery:  
o Type and number of visits with a dietitian (initial 60 min visit, 15-30 min follow-up 
visits, face-to-face, telephone or video) 
o Number of visits with a midwife  
o Number of visits with a nurse (individually) 
o Number of visits with a nurse (in a group) 
o Number of visits with an endocrinologist  
Number of telephone contacts with an endocrinologist 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
21 
 
Number of visits with an obstetrician  
Number of visits for ultrasonographic examination 
Number of visits including an interpreter (face-to-face, telephone or video)  
Body weight, kg at diagnosis and until delivery 
HbA1c, mmol/mol measured at diagnosis and until delivery 
Insulin-treated 
Time to insulin (days): 
- from study allocation until insulin prescription  
- from maternal GA 
Prescribed insulin, type, and dose (units/kg body weight) 
Prescribed antihypertensive medication, type, and dose 
Hospital admissions before delivery due to GDM 
Registered blood glucose measurements 
Preeclampsia 
 
Labor data 
Induction of labour (yes vs no) and what weeks of gestation 
Preterm birth (defined as <37 weeks of gestation) 
Mode of delivery (vaginal delivery or caesarean section) 
 
Post-natal care 
Neonatal gestational age at birth 
Neonatal delivery weight, gram 
LGA 
SGA 
Macrosomia 
Jaundice 
Hospital days after delivery 
Neonatal hypoglycaemia  
Admission and number of days in NICU  
Stillbirth/neonatal death 
 
 
7.4 Socioeconomic baseline data 
The following self-administered questions on baseline demographics for background information will 
be sent out electronically after V1: 
• 
Educational level 
• 
Main occupation 
• 
Civil status 
• 
Household composition 
 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
22 
 
 
8 Sample size determination 
A 50% difference in the incidence of insulin therapy between the two study groups during the study 
period was defined as the minimally important difference for the primary outcome. The sample size 
estimation was based on a logistic regression model (outcome = group) and the following assumptions: 
An allocation ratio of 1:1; alpha = 0.05; 0.8 power, an incidence of insulin therapy of 30% in the usual 
care group and 15% in the intervention group in need of insulin therapy. The expected incidence in the 
standard care group is based on register data from Herlev Hospital in the period 2019-2022 showing that 
approximately 30% of the women with GDM referred to the hospital had been prescribed insulin. Since 
we are only investigating women with GDM with an estimated risk of insulin therapy above 20% based 
on our inclusion criteria), our analysis shows that it will result in an incidence of 50%. Thus, we aim to 
include 214 women (see table 3 for sample size estimations), but if fewer women are included, we will 
only test the main hypothesis for all participants whereas subgroup-analysis testing based on ethnicity 
(white_nonwhite) will be exploratory. 
 
 
 
Table 3: Sample size estimations 
N Total 
Power All 
Power Subgroups 
107 
0.80 
0.51 
150 
0.92 
0.65 
175 
0.95 
0.72 
200 
0.97 
0.78 
214 
0.98 
0.80 
 
 
8.1 Study feasibility 
Register data show that 200-300 women are diagnosed with GDM and treated in the Department of 
Obstetrics at Herlev Hospital yearly based on the current OGTT cut off value of ≥ 9,0 mmol/l for GDM 
in pregnancy (10). A high proportion of these women are expected to meet the criteria for study 
inclusion. Thus, it is realistic to expect that the study can recruit and include up to 214 women with 
GDM during the planned study recruitment period of approximately 1.5 years from October 2023 to 
December 2025.   
 
 
9 Data management 
9.1 Data handling  
The study will comply with the Danish Data Protection Agency and the General Data Protection 
Regulation. All health-related matters and sensitive personal data will be handled in accordance with 
the Danish “Act on Processing of Personal Data”. Adequate blinding of all personal data during data 
processing and publication will be ensured. Data will be stored in coded form for 10 years after last 
participant has attended the last visit after which it will be fully anonymised.  

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
23 
 
All data will be entered directly into electronic case report forms (CRFs) using the software system 
REDCap licensed by the Capital Region in Denmark. Errors and corrections are logged as provided by 
the REDCap interface. It is possible to transport validated data from REDCap to e.g., a statistical 
program (e.g., SAS) for further statistical analysis. When data have been entered, reviewed, and verified 
the data will be frozen to prevent editing. 
 
9.2 Data reporting and protection 
Before initiating the study, acceptance from the Danish Data Protection Agency will be secured. All 
health-related matters and sensitive personal data will be handled in accordance with the Danish “Act 
on Processing of Personal Data”. All health-related matters and sensitive personal data (blood test result 
etc.) will be depersonalized. All participants will be given a study number referring to their personal 
information, which will be stored securely and separately. Adequate blinding of all personal data during 
data processing and publication will be ensured. Data will be stored in coded form in 10 years after last 
participant has attended the last visit, where after the data will be fully anonymised. 
 
9.3 Source data identification and verification 
All study-related information will be recorded, handled, and stored in a way that allows accurate 
reporting, interpretation, and verification. All questionnaire data will be collected electronically using 
the software system REDCap according to local standards for research projects in the capital region of 
Denmark. In addition, source data will be registered in REDCap on an ongoing basis and at the end of 
study. Data is stored in coded form for 10 years from last participant last visit. Hereafter, data will be 
fully anonymised.  
 
 
9.4 Data reporting and protection  
All information on study participants is protected according to the General Data Protection Regulation 
and the Danish Data Protection Agency (“Databeskyttelsesloven” and “Datatilsynet”), and the law of 
health and it will not be possible to identify any participant. None of the study-related blood samples or 
data will be stored or analysed in countries outside Denmark. 
 
9.5 Protocol changes 
Substantial amendments to this protocol may be implemented only after a favourable opinion of the 
Ethics Committee of the Capital Region, Copenhagen has been obtained. Amendments to the protocol 
are regarded as substantial if they have a significant impact on the safety, physical health, and mental 
integrity of the participants. If an event occurs related to the conduct of the study which may affect the 
safety of the participants, the study investigators may take appropriate measures to protect the 
participants against immediate hazards. The investigator will inform Ethics Committee of the Capital 
Region, Copenhagen of the new events and the measures taken as soon as possible.  
 
10 Publication  
Positive, negative, or inconclusive study results will be published by the investigators in international 
peer-reviewed journals. the study results. Positive, negative, or inconclusive study results will be 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
24 
 
published by the investigators in international peer-reviewed scientific journals. Principal investigator 
Bettina Ewers will be first and corresponding author. All co-authors must comply with the international 
committee of medical journal editors (ICMJE) guidelines. The author order depends on the different 
authors’ contributions to the study. Co‐authorship also requires that all co‐authors have approved the 
final manuscript and confirmed that they wish to be co‐authors. 
 
11 Study timeframe 
The active study period will begin with recruitment of participants from October 2023 and expected to 
be finalised by December 2025. 
 
12 Financing  
The study is initiated by the principal investigator Bettina Ewers and co-investigators at SDCC and 
Herlev-Gentofte Hospital. In 2022, Bettina Ewers received funding from the Novo Nordisk Foundation 
as part of the non-standard initiatives (“Supplerende behandlingsinitiativer”) primarily to cover salary 
for research dietitians, postdoc, and administration at SDCC (DKK 1.8 mill) to conduct the study. The 
funding is administered through the Management, Secretariat and Research Administration at SDCC. 
The sponsor and investigators have no economic interest in the results of the study. If external funding 
is obtained, the Ethics Committee of the Capital Region, Copenhagen will be notified.  
 
12.1 Conflicts of interest 
SDCC is a hospital in the Capital Region of Denmark providing health services for individuals with 
diabetes for the public health care system. The trial is funded by the Novo Nordisk Foundation through 
unrestricted grants. Thus, the Novo Nordisk Foundation has no economic interests in the study. The 
Novo Nordisk Foundation will not have influence on 1) The study design; 2) The collection, analysis, 
and interpretation of data; 3) The writing of the study report, or any publication; and 4) The decision to 
submit the paper for publication. The investigators employed at SDCC will not benefit economically 
from conducting the study.  
 
13 Compensation of participants 
The study covers interpreter expenses. Travelling expenses related to study visits will not be reimbursed. 
Participants will not receive financial compensation for participating in the study. 
 
14 Ethics and regulations 
14.1 Independent ethics committee and regulatory authority 
The study protocol will be submitted for approval by the Ethics Committee of the Capital Region, 
Copenhagen and the study will be registered for approval of data storage at the Danish Data Protection 
Agency. After obtaining approvals from all authorities the study will be registered at clinical trials.gov 
and before study commencement. 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
25 
 
  
14.2 Ethical considerations 
The study will be conducted in accordance with the ethical principles in the Declaration of Helsinki and 
to the regulations for Good Clinical Practice (GCP) to the extent that this is relevant for a non-
pharmacological study. The study will deliver important new insights on the effects of an intensive 
dietary intervention for reducing insulin needs during pregnancy as well as improving other relevant 
clinical maternal and neonatal outcomes in women with GDM. Additionally, this study will provide a 
cost-benefit analyses to assess if implementing more intensive dietary support in a clinic is cost neutral 
or even cost saving. To our knowledge this has not previously been done in our study population. The 
findings from the study may also have direct patient-related implications for future national guidelines. 
Thus, there is great need for studies investigating the effectiveness of a more intensive dietary regime 
for management of GDM.  
The study has no obvious ethical concerns for the participants, and only minor potential risks in relation 
to participation (described in the next section) which are compensated by the expectable advances of 
conducting the study. The anticipated benefits for the participants are high including improved 
glycaemic control for both mother and child reducing the risk of pregnancy complications. 
 
14.3 Risks related to participation 
Overall, limited risks are expected with the current study. Obstetricians will assess the need for initiating 
insulin therapy according to standard procedure based on current national guidelines for management 
of GDM. Only a minor disadvantage associated with delayed onset of dietary guidance can be expected 
when women with newly diagnosed GDM are referred to a dietitian due to time needed for informed 
consent and screening in the study. Rapid education and support to improve dietary habits and thereby 
glycaemic control are crucial components after diagnosis. However, the standard procedure at the 
Department of Obstetrics at Herlev Hospital has been up to one week of waiting time until deliverance 
of dietary support. It is regarded as realistic to be able to match this procedure or and even improve time 
until dietary support in the study despite time used on informed consent and screening procedures.  
 
15 Insurance  
The patients are covered by the Patient Insurance Act according to the Danish Act on the Right to 
Complain (Lov om klage- og erstatningsadgang inden for sundhedsvæsenet, lov nr. 1113 07/11/2011). 
and Receive Compensation within the Health Service.  
 
16 References 
1. Bhopal R. Glossary of terms relating to ethnicity and race: for reflection and debate. J Epidemiol 
Community Health. 2004;58(6):441-5. 
2. Scheuer CM, Andersen MH, Mathiesen ER, Ringholm L, Muller CL, Truong JM, et al. Regional 
divergence and time trends in the prevalence of gestational diabetes mellitus: a national Danish cohort 
study. Acta Diabetol. 2023;60(3):379-86. 
3. Wang H, Li N, Chivese T, Werfalli M, Sun H, Yuen L, et al. IDF Diabetes Atlas: Estimation of Global 
and Regional Gestational Diabetes Mellitus Prevalence for 2021 by International Association of 
Diabetes in Pregnancy Study Group's Criteria. Diabetes Res Clin Pract. 2022;183:109050. 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
26 
 
4. Yuen L, Wong VW. Gestational diabetes mellitus: Challenges for different ethnic groups. World J 
Diabetes. 2015;6(8):1024-32. 
5. Metzger BE, Coustan DR. Summary and recommendations of the Fourth International Workshop-
Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care. 1998;21 
Suppl 2:B161-7. 
6. American Diabetes Association Professional Practice C. 15. Management of Diabetes in Pregnancy: 
Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S232-S43. 
7. Group HSCR, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia 
and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002. 
8. Rasmussen L, Poulsen CW, Kampmann U, Smedegaard SB, Ovesen PG, Fuglsang J. Diet and Healthy 
Lifestyle in the Management of Gestational Diabetes Mellitus. Nutrients. 2020;12(10). 
9. Duarte-Gardea MO, Gonzales-Pacheco DM, Reader DM, Thomas AM, Wang SR, Gregory RP, et al. 
Academy of Nutrition and Dietetics Gestational Diabetes Evidence-Based Nutrition Practice Guideline. 
J Acad Nutr Diet. 2018;118(9):1719-42. 
10. Ovesen P, Damm P, Renault K, Holm AM, Wolff C, Knold B, et al. Sandbjerg 2007 – Guideline. 
Behandling af gestationel diabetes mellitus. Dansk Selskab for Obstetrik og Gynækologi (DSOG). 2007. 
11. Gestationel diabetes mellitus (GDM) – behandling, obstetrisk kontrol og post partum opfølgning 
samt standarder for OGTT og screening af bariatrisk opererede. Afventer godkendelse i DES, 
DSAM/PLO, DSKB samt SST Guideline. Dansk Selskab for Obstetrik og Gynækologi; 2023. 
12. Wong VW, Jalaludin B. Gestational diabetes mellitus: who requires insulin therapy? Aust N Z J 
Obstet Gynaecol. 2011;51(5):432-6. 
13. Xie W, Dai P, Qin Y, Wu M, Yang B, Yu X. Effectiveness of telemedicine for pregnant women 
with gestational diabetes mellitus: an updated meta-analysis of 32 randomized controlled trials with trial 
sequential analysis. BMC Pregnancy Childbirth. 2020;20(1):198. 
14. Kurtzhals LL, Norgaard SK, Secher AL, Nichum VL, Ronneby H, Tabor A, et al. The impact of 
restricted gestational weight gain by dietary intervention on fetal growth in women with gestational 
diabetes mellitus. Diabetologia. 2018;61(12):2528-38. 
15. Ovesen PG, Fuglsang J, Andersen MB, Wolff C, Petersen OB, David McIntyre H. Temporal Trends 
in Gestational Diabetes Prevalence, Treatment, and Outcomes at Aarhus University Hospital, Skejby, 
between 2004 and 2016. J Diabetes Res. 2018;2018:5937059. 
16. Eleftheriades M, Chatzakis C, Papachatzopoulou E, Papadopoulos V, Lambrinoudaki I, Dinas K, et 
al. Prediction of insulin treatment in women with gestational diabetes mellitus. Nutr Diabetes. 
2021;11(1):30. 
17. Barnes RA, Wong T, Ross GP, Jalaludin BB, Wong VW, Smart CE, et al. A novel validated model 
for the prediction of insulin therapy initiation and adverse perinatal outcomes in women with gestational 
diabetes mellitus. Diabetologia. 2016;59(11):2331-8. 
18. Zhang Y, Shao J, Li F, Xu X. Factors in Gestational Diabetes Mellitus Predicting the Needs for 
Insulin Therapy. Int J Endocrinol. 2016;2016:4858976. 
19. Wong VW. Gestational diabetes mellitus in five ethnic groups: a comparison of their clinical 
characteristics. Diabet Med. 2012;29(3):366-71. 
20. Coustan DR, Imarah J. Prophylactic insulin treatment of gestational diabetes reduces the incidence 
of macrosomia, operative delivery, and birth trauma. Am J Obstet Gynecol. 1984;150(7):836-42. 
21. Sun T, Meng F, Zang S, Li Y, Zhang R, Yu Z, et al. The effects of insulin therapy on maternal blood 
pressure and weight in women with gestational diabetes mellitus. BMC Pregnancy Childbirth. 
2021;21(1):657. 
22. Kolu P, Raitanen J, Rissanen P, Luoto R. Health care costs associated with gestational diabetes 
mellitus among high-risk women--results from a randomised trial. BMC Pregnancy Childbirth. 
2012;12:71. 
23. Ye W, Luo C, Huang J, Li C, Liu Z, Liu F. Gestational diabetes mellitus and adverse pregnancy 
outcomes: systematic review and meta-analysis. BMJ. 2022;377:e067946. 
24. Subiabre M, Silva L, Toledo F, Paublo M, Lopez MA, Boric MP, et al. Insulin therapy and its 
consequences for the mother, foetus, and newborn in gestational diabetes mellitus. Biochim Biophys 
Acta Mol Basis Dis. 2018;1864(9 Pt B):2949-56. 

INTENSE-GDM, Protocol version 5.0 – 15.03.2024 
27 
 
25. Gray FG, Hsu C, Kiel L, Dublin S. “It’s a Very Big Burden on Me”: Women’s Experiences Using 
Insulin for Gestational Diabetes. Matern Child Health J. 2017;21:1678-86. 
26. Pantzartzis KA, Manolopoulos PP, Paschou SA, Kazakos K, Kotsa K, Goulis DG. Gestational 
diabetes mellitus and quality of life during the third trimester of pregnancy. Qual Life Res. 
2019;28(5):1349-54. 
27. Han S, Crowther CA, Middleton P, Heatley E. Different types of dietary advice for women with 
gestational diabetes mellitus. Cochrane Database Syst Rev. 2013(3):CD009275. 
28. Yamamoto JM, Kellett JE, Balsells M, Garcia-Patterson A, Hadar E, Sola I, et al. Gestational 
Diabetes Mellitus and Diet: A Systematic Review and Meta-analysis of Randomized Controlled Trials 
Examining the Impact of Modified Dietary Interventions on Maternal Glucose Control and Neonatal 
Birth Weight. Diabetes Care. 2018;41(7):1346-61. 
29. Ewers B, Trolle E, Jacobsen SS, Vististen D, Almdal TP, Vilsboll T, et al. Dietary habits and 
adherence to dietary recommendations in patients with type 1 and type 2 diabetes compared with the 
general population in Denmark. Nutrition. 2019;61:49-55. 
30. Pariona A. Countries That Rely The Most On Carbs: World Facts, Worldatlas; 2019 [Available from 
https://www.worldatlas.com/articles/countries-with-the-highest-carbohydrate-intakes-relative-to-
energy-intake.html 
31. Ali HI, Jarrar AH, El Sadig M, K BY. Diet and carbohydrate food knowledge of multi-ethnic women: 
a comparative analysis of pregnant women with and without Gestational Diabetes Mellitus. PLoS One. 
2013;8(9):e73486. 
32. Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, et al. Summary and 
recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. 
Diabetes Care. 2007;30 Suppl 2:S251-60. 
33. Topp CW, Ostergaard SD, Sondergaard S, Bech P. The WHO-5 Well-Being Index: a systematic 
review of the literature. Psychother Psychosom. 2015;84(3):167-76. 
34. Sato E, Suzukamo Y, Miyashita M, Kazuma K. Development of a diabetes diet-related quality-of-
life scale. Diabetes Care. 2004;27(6):1271-5. 
35. Williams GC, McGregor HA, Zeldman A, Freedman ZR, Deci EL. Testing a self-determination 
theory process model for promoting glycemic control through diabetes self-management. Health 
Psychol. 2004;23(1):58-66. 
36. Bradley C, Lewis KS. Measures of psychological well-being and treatment satisfaction developed 
from the responses of people with tablet-treated diabetes. Diabet Med. 1990;7(5):445-51. 
37. Bradley C. The Diabetes Treatment Satisfaction Questionnaire: DTSQ.  Handbook of Psychology 
and Diabetes: a guide to psychological measurement in diabetes research and practice Chur, 
Switzerland: Harwood Academic Publishers.; 1994. 
38. Kroner FH, Knudsen SP, Roland CB, Alomairah SA, Molsted S. Validity and reliability of the 
Danish version of the pregnancy physical activity questionnaire to assess levels of physical activity 
during pregnancy. J Matern Fetal Neonatal Med. 2022;35(23):4566-72.