Effect of Fibre Supplements on Gestational Diabetes
Effect of Fibre Supplements on Gestational Diabetes
The primary aim of this study is to evaluate the effect of a soluble fibre supplement in the
 development of gestational diabetes in women at high-risk. The secondary aim will to evaluate
 the effect of the soluble fibre supplement on glycaemic control in high-risk women who
 develop gestational diabetes in early pregnancy.

 DESIGN We plan to conduct a randomised open label controlled study to evaluate the effect of
 the consumption of soluble fibre, from early to mid-pregnancy, on the incidence of
 gestational diabetes, insulin sensitivity, insulin secretion and metabolic control in GDM
 diagnosed participants.

 POPULATION We will be studying women with diagnosis of gestational diabetes in previous
 pregnancies, (considered as high-risk) aged >18 years.

 TREATMENT Participants in the treatment arms will be 5 gr of Guar gum fibre supplement with
 meals three times a day (total daily 15 g). Participants in the placebo arms will be taking 5
 gr of Cellulose three times a day (total daily dose 15 g).

 DURATION Participants will be involved for 12 weeks.

 In women with early gestational diabetes (diagnosed at first assessment):

 Primary outcome: Glycaemic control assessed the need of insulin treatment Secondary outcomes:
 In women requiring insulin treatment: days-to-insulin and total daily insulin dose.
Aim: To evaluate the effect of a soluble fibre supplement in glucose metabolism in pregnant
 women at high risk of developing gestational diabetes.

 Study methodology: 12 week randomised, placebo-controlled, single-blinded study.

 Intervention: Women will first be categorised according to their glycaemic status into two
 groups: GDM and glucose tolerant women. Afterwards, each group will be randomised into two
 groups and given either

 1. Fibre supplement (Guar gum)

 2. Placebo (Cellulose) The participants will take the dietary supplement three times a day
 for 12 weeks. They will receive regular antenatal control according to NICE guidelines
 recommendations. Compliance will be addressed by weekly phone calls.

 Number of volunteers: The number of participants will be arbitrarily define as no data of
 this type of intervention exists in this cohort. 40 participants will be recruited. Previous
 studies, outside pregnancy, have observed metabolic effects in samples of 15-40 subjects.

 Recruitment: Women will be recruited in the antenatal clinic at Queen Charlotte and Chelsea's
 Hospital. An information sheet will be provided to eligible women in the first antenatal
 visit to explain the purposes of the study. Women who decide to take part will be asked to
 sign a consent form.

 Randomisation: Initially women will be categorised according to glycaemic status in two
 cohorts: Glucose tolerant and Early gestational diabetes (GDM) cohort. Each of the two
 cohorts will then be independently randomised to either intervention or standard care using
 the sealed envelope website. Guar gum (intervention) and cellulose (placebo) will be provided
 in identical packed sachets.

 PRIMARY OUTCOME MEASURES

 -  Glucose values at 0 and 120 minutes during an OGTT performed at 28 weeks in the glucose
 tolerant group.

 -  Glycaemic control assessed by need of insulin treatment, days to insulin treatment and
 total insulin dose.

 SECONDARY OUTCOME MEASURES

 Assessing insulin sensitivity and insulin secretion at 28 weeks of pregnancy in the glucose
 tolerant cohort of women through validated indices using glucose and insulin (or C-peptide)
 values derived from the OGTT.

 • Insulin sensitivity will be assessed using the Matsuda formula

 • Insulin secretion will be assessed by second-void fasting UCPCR. In the gestational
 diabetes cohort, where a second OGTT will not be performed, parameters of insulin resistance
 (HOMA_IR index) and secretion could be assessed using urinary C-peptide obtained from a
 fasting second-void urine sample at 28 weeks gestation, although these measurements have not
 been validated in pregnancy.

 6. ASSESSMENT AND FOLLOW UP Women will be assess by the researchers at four different visits.
 At the first antenatal visit, the general care team will mentioned the study, if the patient
 consents, she will then be approached by the researchers to explain the study protocol. At
 the second visit, when the OGTT is performed, women who decided to take part in the study
 will sign the consent from. At the next antenatal visit where results from the OGTT are
 explained, women included will be randomised. The last research visit will take place at 28
 weeks gestation. Additionally, they will be contacted weekly, by telephone to assess
 compliance and confirm willingness to participate in the study. All participating women will
 continue to attend routine follow up by the Obstetrics team at the antenatal clinic. Women
 diagnosed with GDM in early pregnancy will continue their routine care under the Obstetric
 team at Queen Charlotte's Hospital. We will be collecting information regarding treatment
 from the notes taken at this follow-up visits.

 1. st visit (≤16 weeks gestation) Women with a previous history of GDM will be considered
 at high risk of recurrence and will be referred to the antenatal clinic before 16 weeks
 of pregnancy. At this first visit, the direct care team will inform them about the study
 and ask them if they are willing to speak with a member of the research team. If they
 agree, a research team member will explain the protocol and invite them to participate
 in the study. An information sheet will be provided and women will have time to consider
 if they are willing to participate and inform the research team at their next antenatal
 visit.

 2. nd visit Women who decide to participate will inform the research team when they attend
 their second antenatal visit, when an OGTT is to be performed. In this visit, women
 willing to participate will be asked to sign a consent form.

 As part of the standard pregnancy care, these women will be booked for GDM early
 screening. The following investigations will be performed as part of their usual NHS
 care:

 -  Blood tests: full blood count, renal function. GAD antibodies can be requested in
 women in whom type 1 diabetes is suspected.

 -  Urine sample to test for proteinuria, glycosuria, leucocytes and nitrates.

 -  Women willing to participate in the study will be additionally requested to provide
 a second urine sample after the 120 min during the OGTT. When bloods are taken will
 also request HbA1c as part of the study's investigations.

 -  An OGTT to test for early GDM will be performed as part of routine care. During the
 OGTT blood samples are taken at 0 and 120 minutes. Additionally to glucose, which
 is normally measure during the OGTT, for study purposes we will request serum
 C-peptide at these time points.

 Baseline insulin sensitivity and insulin secretion will be estimated through validated
 indices using serum glucose, insulin (or C-peptide) and urinary C-peptide.

 After the participants have agreed to take part in the study and consent has been
 signed, data regarding anthropometrics, demographics and medical history will be
 collected. This information will be obtained by reviewing the participant's medical
 notes.

 Anthropometric measurements will be recorded at the first antenatal routine visit,
 including: pre-pregnancy weight, weight at first visit and height. BMI will be
 calculated with this data.

 Demographics, personal and medical history will be extracted from medical records,
 including: maternal age, ethnicity, education, smoking during pregnancy, medical history
 (hypertension, PCOS, other relevant condition), obstetric history (parity, stillbirth,
 macrosomia, pre-eclampsia).

 3. rd visit (Randomisation)

 After obtaining the results from the OGTT, women will be categorised by their glycaemic
 status and divided into two independent cohorts:

 -  Women diagnosed with gestational diabetes (according to NICE guidelines 2015
 diagnostic criteria): early GDM cohort

 -  Women with normal glucose tolerance or impaired glucose tolerance but not
 fulfilling GDM criteria: Glucose tolerant cohort.

 Women from each cohort will be randomised into two groups after the results of the OGTT
 are obtained:

 -  Intervention group: Guar gum fibre supplement

 -  Placebo group: Cellulose supplement Women will the fibre supplement 3 times a day
 (with each main meal) until the 28th week of pregnancy when they will be
 re-evaluated.

 4. rd visit (28th weeks gestation)

 Glycaemic status will be assessed at 28 weeks gestation in the two cohorts of women
 participating in the study:

 -  Women from the Glucose tolerant cohort will undergo a second OGTT. Blood and urine
 samples will be collected at 0 and 120 minutes. Glycaemic status will then be
 assessed with the endpoint being the diagnosis of GDM (yes/no). Insulin sensitivity
 and insulin secretion will be estimated using the same parameters as in the first
 visit. As part of the study, women will be weight to calculate BMI and gestational
 weight gain at 28 weeks gestation. The research team will have their last face to
 face visit with the participant to discontinue the intervention and answer any
 potential questions about the study.

 -  In women in the Early GDM cohort, glycaemic control will be assessed by the need of
 insulin treatment (yes/no) and in those requiring insulin the days-to-treatment
 (insulin) and total insulin dose will be recorded. Data will be obtained by
 reviewing medical records. As part of the study, women will be weight to calculate
 BMI and gestational weight gain at 28 weeks gestation. The research team will have
 their last face to face visit with the participant to discontinue the intervention
 and answer any potential questions about the study.

 PROCEDURES Women will be advised to fast for 10 hours the night before the oral glucose
 tolerance test. They will also be advised no to restrict carbohydrate ingestion the
 three days prior to the OGTT. At the antenatal clinic, blood samples will be collected
 at baseline (0 min) and at 120 min after the administration of an oral load of 75 g of
 glucose.

 In the baseline sample other parameters will also be determined. Creatinine and HbA1c
 will measure in all participants and GAD antibodies will be requested in women in whom
 type 1 diabetes is suspected.

 Serum insulin and C-peptide will be collected at 0 and 120 min during the OGTT. Women
 will be advised to void their first urine before attending the antenatal clinic.
 Second-void fasting urine sample will be collected at 0 min during the OGTT. A second
 urine sample will be collected at 120 min. Urinary C-peptide will measure in these
 samples will be transfer to boric acid containers, the alliquoted into 1 ml cryotubes
 ans stored at -80 ºC until analysis. Serum creatinine will be collected at baseline (0
 min) and measure in the central lab. The urinary C-peptide creatinine ratio (UCPCR) will
 be calculated using these data.

 ASSESSMENTS

 (i) Gestational diabetes Gestational diabetes will be diagnosed if fasting plasma
 glucose >5.6 mmol/L and/or 120 min plasma glucose >7.8 mmol/L after the glucose load
 administered in the OGTT. Women with fasting plasma glucose <5.6 mmol/L and 120 min
 plasma glucose <7.8 mmol/L will be classified as "Glucose tolerant".

 (ii) Insulin sensitivity Insulin sensitivity will be assessed using the Matsuda index as
 originally described (18) (Equation 1) and using two modified Matsuda equations in which
 insulin is substitute by either serum or urinary C-peptide (21,22) (Equations 2 and 3).

 Equation 1. ISOGTT= 10,000 / √ {[FPG x fasting insulin] x [mean glucose x mean insulin
 during OGTT]} Equation 2. ISOGTTC-pep=500,000/√{[FPGxFsC-pep] x [mean glucose x mean
 sC-pep during the OGTT]} Equation 3. ISOGTT-UCPCR=500,000/√{[FPG×FUCPCR pmol/mmol] x
 [mean glucose x mean UCPCR during the OGTT]}

 (iii) Insulin secretion Insulin secretion will be estimated by the UCPCR obtained using
 the fasting second-void urine sample, as it is strongly correlated with serum insulin,
 serum C-peptide (19) and 24-h urinary C-peptide (20).

 Insulin response will be estimated using the UCPCR calculated with 120 min post-OGTT
 urine sample, as it is strongly correlated with the C-peptide and insulin area under the
 curve (19).

 (iv) Need of insulin treatment, Days to insulin treatment and Total insulin dose Medical
 records of women in the Early GDM cohort will be review in order to determine the need
 of insulin treatment (yes/no) at 28 weeks gestation. In women requiring insulin
 treatment at any time during follow up, days-to-insulin treatment, calculated from
 randomisation day to the day insulin treatment is prescribed, and total insulin dose,
 calculated as the total dose of insulin international units (IU) divided by weight in Kg
 (insulin UI/Kg), will be recorded

 PRE-RANDOMISATION EVALUATIONS Women will be evaluated by the mid-wife at the first visit
 in the antenatal clinic. An OGTT will be book to test for early GDM in women with
 previous GDM considered at high risk of recurrence. Personal and medical history will be
 recorded. When women attend for the OGTT, blood and urine samples will be collected at 0
 and 120 minutes.

 WITHDRAWAL CRITERIA Participants will be free to withdraw at any time and are not
 required to give a reason.

 ADVERSE EVENTS Adverse Event (AE): Any untoward medical occurrence in a patient or
 clinical study subject.

 Serious Adverse Event (SAE): Any untoward and unexpected medical occurrence that:
 results in death, is life- threatening, requires hospitalisation, results in persistent
 or significant disability or incapacity or a congenital abnormality or birth defect

 Medical judgement should be exercised in deciding whether an AE is serious in other
 situations. Important AEs that are not immediately life threatening or do not result in
 death or hospitalisation but may jeopardise the subject or may require intervention to
 prevent one of the other outcomes listed in the definition above, should also be
 considered serious.

 REPORTING PROCEDURES All adverse events should be reported. Depending on the nature of
 the event the reporting procedures below should be followed. Any questions concerning
 adverse event reporting should be directed to the Chief Investigator in the first
 instance.

 Non serious AEs All such events, whether expected or not, should be recorded.

 Serious AEs An SAE form should be completed and faxed to the Chief Investigator within
 24 hours. However, relapse, death and hospitalisations for elective treatment of a
 pre-existing condition do not need reporting as SAEs. All SAEs should be reported to the
 sponsor.

 All SAEs should be reported to the Bromley Research Ethics Committee where in the
 opinion of the Chief Investigator the event was:

 'Related', i.e. resulted from the administration of any of the research procedures; and
 'Unexpected', i.e. an event that is not listed in the protocol as an expected
 occurrence.

 Reports of related and unexpected SAEs should be submitted within 15 days of the Chief
 Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.

 Local investigators should report any SAEs as required by their Local Research Ethics
 Committee and/ or Research and Development Office.

 STATISTICS AND DATA ANALYSIS Data handling and analysis will be carried out by SPSS
 version 20.0 version. No power calculation to decide sample size will be used. The
 number of participants has been arbitrarily defined, as it is a pilot study. We aim to
 recruit 40 women.

 Before randomisation, women will be categorised according to their glycaemic status in
 two cohorts: Glucose tolerant and GDM. Each of these two cohorts will be randomly
 allocated into the intervention (soluble fibre supplement) and control (placebo) group.
 Randomisation will be by sealed envelopes. Participants but not researchers will be
 blinded as to the type of intervention prescribed.

 Differences between group en each cohort will be assessed using Student t test or
 Mann-Whitney U test for numeric variables depending on distribution; X2 will be used for
 categorical variables.

 In the Glucose tolerant women cohort:

 For the primary outcome, GDM (yes/no), logistic regression analysis will be performed.

 For the secondary outcomes, insulin sensitivity and insulin secretion, linear regression
 analysis will be performed.

 In the early GDM cohort:

 For the primary outcome, need for insulin treatment (yes/no), logistic regression
 analysis will be performed. Additionally days-to-treatment analysis will be performed
 for those participants starting insulin therapy during follow up.
Inclusion Criteria:

 -  Women with a history of GDM in previous pregnancies

 -  Age ≥ 18 years

 -  Singleton pregnancy

 -  ≤ 16 weeks gestation

 Exclusion Criteria:• Women unable or unwilling to give consent

 -  Pre-gestational diabetes or use of anti-diabetic medication in the first visit

 -  Significant chronic medical conditions (cardiovascular, liver or kidney disease)

 -  Women participating in other medical trial

 -  Women who have undergone bariatric surgery

 -  Women with milk allergy/intolerance

 -  Women unable to speak/understand English