| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
| E.1.2 | System Organ Class | 100000004861 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to achieve the double composite endpoint of a reduction in HbA1c (≥ 0.3%) and weight loss (≥1kg) 3-4 weeks post-Ramadan. |
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| E.2.2 | Secondary objectives of the trial |
The main secondary outcome is a triple composite endpoint of a reduction or maintenance of HbA1c, reduction in weight (≥ 1kg) and no hypoglycaemic events between baseline and 3-4 weeks post-Ramadan.
Further secondary outcomes are listed below. These outcomes will be measured at each time point described in A13 below and a comparison calculated between treatment groups.
1. Mean change in HbA1c level
2. Mean change in fructosamine
3. Mean change in body weight
4. Mean change in systolic blood pressure
5. Mean change in diastolic blood pressure
6. Mean changes in total cholesterol
7. Mean changes in HDL cholesterol
8. Mean change LDL cholesterol
9. Mean change in triglycerides
10. Mean change in treatment satisfaction (DTSQ)
11. Mean change in IPAQ score (self-reported activity levels)
12. Mean change in light, moderate, and vigorous intensity physical activity as determined by GENEActiv
13. Mean change in total volume of movement as determined by GENEActiv
14. Me |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are two sub-studies associated with this application. The sub-studies aim to recruit 15-20 participants and will recruit from the Leicester site only. The sub-studies are optional and will be explained in the PIS and Informed Consent Form and will be discussed with the participant at the baseline visit prior to obtaining informed consent.
Sub-study 1 – Flash Glucose Monitoring (FGM)
We will collect 14 consecutive days of FGM data at baseline, and at 12 month follow-up (e.g., measuring FGM data for 2 x 7 consecutive days). We will also collect an additional 14 days’ worth of FGM data for those within this sub-group that agree to wear the FGM device during Ramadan (e.g., measuring FGM data for 4 x 7 consecutive days). FGM is a minimally invasive technique used for monitoring interstitial blood glucose levels. The FGM sensor measures glucose levels at this site continuously for up to 14 consecutive days with a glucose range of 1.1 – 27.8mmol/L. The sensor automatically measures glucose levels every minute and stores readings at 15 minute intervals for 8 hours.
To aid interpretation of the data the following definitions will apply:
(1) ≤3.1mmol/L (referred to as 'FGM3.1'), and
(2) ≤2.2mmol/L (referred to as 'FGM2.2')
Therefore, the following glycaemic ranges will be used:
(1) Hypoglycaemia = ≤3.1mmol/l,
(2) Normoglycaemia = >3.1 to 9.9mmol/l (inclusive), and
(3) Hyperglycaemia = ≥10mmol/L
Hyperglycaemic events will be termed ‘FGM high glucose event’ and defined as readings ≥10mmol/L.
The time points used to calculate the change within a treatment group will be between:
(1) Baseline and 3-4 weeks post-Ramadan
(2) Baseline and during Ramadan
In addition we will calculate the ‘difference’ between treatment groups for the data collected during Ramadan.
The following outcomes will be determined using the definitions and thresholds for each of the time points described above:
(1) Change in proportion of time spent in each glycaemic range calculated between treatment groups
(2) Incidence of FGM3.1 and FGM2.2 events
(3) Change in the frequency of FGM3.1 and FGM2.2 events
(4) Change in Mean Average Glucose Excursion (MAGE)
Sub-study 2 - Objective measures of Physical Activity
We will objectively measure physical activity levels before, There is limited evidence on the changes in levels of
physical activity for people who observe Ramadan. It is widely believed that levels of physical activity are reduced due to fear of feeling too weak. However, recent evidence suggests either no change or only a reduction in approximately a third of participants observed. Therefore, we will objectively measure physical activity levels before, during and after Ramadan, in addition to using the validated self-reported international physical activity questionnaire (IPAQ). We aim to quantify any changes to habitual levels of sitting, walking and physical activity energy expenditure as described below:
Physical activity and sedentary behaviour will be measured using a GeneACTIV device. which has been found to be a valid and reliable objective measure of physical activity and sedentary behaviour in adults. The GENEActiv wrist worn accelerometer is a lightweight device, resembling a sports watch and can be worn 24 hours a day, and participants will be asked to wear the device for 8 consecutive days. Using published thresholds we will calculate mean change in light, moderate and vigorous intensity PA and mean change in total volume of movement. |
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| E.3 | Principal inclusion criteria |
1. Able, in the opinion of the Investigator, and willing to give informed consent
2. Age ≥ 25 years old
3. Established T2DM (≥ 3 months) on stable dose monotherapy (metformin only for ≥ 8 weeks prior to enrolment) OR stable dose dual therapy (metformin plus either repaglinide, a sulphonylurea or pioglitazone for ≥ 8 weeks prior to enrolment)
4. HbA1c between 7 – 10.5% (53 - 91mmol/mol) if on monotherapy OR between 6.5 - 9.5% (48 – 80mmol/mol) if on dual therapy at the screening visit
5. Individuals intending to fast for a minimum of 10 consecutive days during the holy month of Ramadan
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| E.4 | Principal exclusion criteria |
1. Unable, in the opinion of the Investigator, and unable to provide informed consent
2. Aged ≤ 25 years old
3. Established T2DM (≤ 3 months) on medication for fewer than 8 weeks prior to enrolment
4. HbA1c ≤7 and ≥10.5% (if on monotherapy) and ≤6.5 and ≥9.5% (if on dual therapy)
5. Individuals not intending to fast for a minimum of 10 consecutive days during the holy month of Ramadan
6. Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods. The latter includes avoiding sex, hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (e.g., condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization, consistent with local regulations regarding use of birth control methods for subjects participating in clinical trials, for the duration of their participation in the study, or not heterosexually active. Furthermore, subjects who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study. Women of childbearing potential must have a negative urine pregnancy test at baseline.
7. Suffer from terminal illness
8. Have renal disease that requires immunosuppressive therapy, dialysis or transplant
9. Have nephrotic syndrome or inflammatory renal disease
10. Have an estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2 at screening
11. Have serum creatinine levels >132.6μmol/L for men or >123.8μmol/L for women
12. Impaired liver function (ALAT ≥ 2.5 times upper limit of normal)
13. Known Hepatitis B antigen or Hepatitis C antibody positive
14. Clinically significant active cardiovascular disease (including history of myocardial infarction, unstable angina, previous revascularization procedure or cerebrovascular accident) within the past 6 months before screening
15. Have uncontrolled hypertension (defined as systolic blood pressure ≥180mm/Hg and diastolic ≥100mm/Hg in the supine position after >5minutes rest with confirmed compliance to antihypertensive medication)
16. Heart failure (NYHA class III and IV) at the discretion of the investigator
17. Previous history of recurrent major hypoglycaemia as judged by the study clinician
18. Known or suspected allergy to the study product
19. Receipt of any investigational drug within four weeks prior to this study
20. Has had previous treatment with a GLP-1 receptor agonist, DPP-IV inhibitor, insulin, or another SGLT2 inhibitor within 12 weeks of screening
21. Have severe and enduring mental health problems
22. Are not primarily responsible for their own care
23. Are receiving insulin therapy
24. Type 1 diabetes
25. Any contraindication to sulphonylureas, repaglinide and/or pioglitazone
26. Have severe irritable bowel disorder
27. Have hereditary glucose-galactose malabsorption
28. Have primary renal glycosuria
29. Patients who have participated in another study of an investigational medicinal product in the last 3 months
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to achieve the double composite endpoint of a reduction in HbA1c (≥ 0.3%) and weight loss (≥1kg) 3-4 weeks post-Ramadan. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Between baseline and 3-4 weeks post Ramadan. |
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| E.5.2 | Secondary end point(s) |
The main secondary outcome is a triple composite endpoint of a reduction and/or maintenance of HbA1c, reduction in body weight and no hypoglycaemic events between baseline and 3-4 weeks post-Ramadan.
Further secondary outcomes are listed below. These outcomes will be measured at each time-point and a comparison calculated between treatment groups;
(1) Mean change HbA1c level
(2) Mean change in fructosamine
(3) Mean change in body weight
(4) Mean change in systolic blood pressure
(5) Mean change in diastolic blood pressure
(6) Mean changes in total cholesterol, LDLc, HDLc, and Triglycerides
(7) Mean change in treatment satisfaction (DTSQ)
(8) Mean change in IPAQ score (self-reported activity levels)
(9) Mean change in light, moderate, and vigorous intensity physical activity as determined by the GENEActiv
(10) Mean change in total volume of movement as determined by the GENEActiv
(12) Mean change in frequency of self-measured hypoglycaemic events recorded in glucose diaries and severe hypoglycaemic events
(13) Median (IQR) number of self-measured hypoglycaemic episodes per patient
(14) Median (IQR) number of severe hypoglycaemic episodes per patient
(15) Incidence rate of self-measured hypoglycaemia per person year (incidence rate ratio (IRR)
16) Incident rate of severe hypoglycaemia per person year (incidence rate ratio (IRR))
Double composite end-points
(1) Double composite endpoint of weight loss and no severe hypoglycaemic events (2) Double composite endpoint of no weight-gain and a reduction in number of self-measured hypoglycaemic events +/- symptoms
(3) Double composite endpoint of improved HbA1c and no severe hypoglycaemic events
(4) Double composite endpoint of improved HbA1c and reduction in number of self-measured hypoglycaemic events
(5) Double composite endpoint of no weight gain and improved HbA1c
(6) Double composite endpoint of no weight gain and no severe hypoglycaemic events
(7) Double composite endpoint of no weight gain and no self-measured hypoglycaemic events |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) Pre-Ramadan vs. 3-4 weeks post-Ramadan
(2) Baseline vs. 12 weeks post-Ramadan
(3) Baseline vs. 12 months post-baseline
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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