E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Frailty and the preceding 'pre-frail' state in patients with type 2 Diabetes Mellitus. |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 aim of this study is to investigate the effects of exercise training in individuals prescribed dapagliflozin for the management of type 2 diabetes on physical function, compared to diet-induced weight loss or dapagliflozin alone. |
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E.2.2 | Secondary objectives of the trial |
Major secondary objectives are to examine the effects of dapagliflozin-plus-exercise or dapagliflozin alone on markers of cardiac function, factors underpinning physical function and other markers of cardiometabolic health. |
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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 |
The two optional sub-studies are as follows:
(i) Skeletal muscle biopsy sub-study: 10 participants in each of the DAPA+EX, DAPA and DIET-CON groups will undergo a further two optional visits, one during Baseline Assessments (Visit 1x) and one during Week 24 Assessments (Visit 3x). Each of these visits will contain a skeletal muscle biopsy and an additional blood test. Muscle biopsies will be analysed for key signalling proteins related to a number of biochmecial pathways in the body.
(ii) MRI sub-study: 20 individuals in the DAPA group only will also undergo an additional optional MRI assessment (Visit 2x). MRI imaging will used to measure cardiac outcomes only. |
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E.3 | Principal inclusion criteria |
(i) Men and women (ii) Age 40 to 75 years, inclusive (iii) Diagnosed T2DM, treated by lifestyle management alone or in combination with mono- or combination therapy with oral glucose-lowering pharmacological therapies (with exception of pre-defined exclusion criteria; see below) (iv) HbA1c 6.5 to 10% (47 to 86 mmol/mol), inclusive (v) Historical evidence of functional limitation or frailty defined as at least one of : a. Impaired physical function or frailty; SPPB score 1 to 10 (inclusive) recorded within the preceding 5 years b. A coding of mild-to-moderate frailty based on the Electronic Frailty Index (eFI) within primary care c. V02peak ≤ 18 ml/kg recorded within the preceding 5 years d. SARC-F questionnaire score of 4 or more (vi) BMI ≥ 25 kg/m2 (≥ 22.5 kg/m2 if of Ssouth Asian ethnicity) (vii) Weight stable; < 3kg weight change in preceding 3 months (viii) Treatment stable; no significant change to glucose-lowering regimen in the preceding 3 months, as determined by a study investigator (ix) Able and willing to give informed consent (x) Able to understand spoken English (xi) Able to take part in structured exercise training (in the opinion of the Investigator).
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E.4 | Principal exclusion criteria |
(i) Individuals with type 1, gestational or monogenic diabetes mellitus (ii) eGFR < 60 ml.min-1 per 1.73m2 or as per licencing at the point of prescription (iii) Individuals with familial renal glycosuria (iv) Documented or self-reported cirrhosis (v) Patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption (vi) Individual with recurrent balanitis, vaginal or urinary tract infections (vii) Current or planned pregnancy, or breast feeding (viii) Females of childbearing age, unwilling to use adequate contraceptive methods during the study period (ix) Currently on SLGT2i, GLP-1RA, basal-bolus or premixed insulin therapies (x) Contra-indications to exercise or SGLT2i therapy (xi) Current participation in another research study with investigational medical product (xii) Scoring 0 on the SPPB, or otherwise unable to complete the test due to severe functional limitations (xiii) Active malignancy; at discretion of study clinician (xiv) Serious illness with life-expectancy < 1 year or other significant illness which, in the opinion of a study clinician, precludes involvement (xv) Individuals with history of chronic pancreatitis (xvi) Individuals with Latent Autoimmune Diabetes in Adults (LADA) (xvii) Patients with a history of excessive alcohol consumption (xviii) Patients on a severely calorie restricted diet (i.e. <800 calories per day)
Additional exclusion criteria for MRI scanning visits (this does not impact on the participant’s enrolment in the study) (i) Individuals with absolute contra-indication to MRI that, in the opinion of a study clinician, precludes an MRI scan will not be invited to attend the MRI visits, but will engage in all other aspects of the study.
Additional exclusion criteria for individuals wishing to undertake skeletal muscle biopsy sub-study (this does not impact on the participant’s enrolment in the main study) (i) Individuals taking any medication that, in the opinion of a study clinician, preclude involvement in the muscle biopsy sub-study (including blood thinning medications). (ii) Individuals with any concurrent disease/condition that, in the opinion of a study clinician, precludes involvement in the muscle biopsy sub-study (including those with low platelet counts and those with blood borne infections). (iii) Individuals with a documented or self-reported history of local anaesthetic sensitivity.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the difference in the change in physical function between groups (measured using the modified physical performance test; mPPT) at 24 weeks. All other comparisons and outcomes will be considered secondary. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The change in physical function between groups will be measured at 24 weeks. |
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E.5.2 | Secondary end point(s) |
Difference between groups at 24 weeks in relative aerobic capacity, lean body mass and circumferential peak early-diastolic strain rate (all powered), other indices of physical activity/fitness and body composition, other indices of cardiac structure and function, HbA1c, cardiovascular risk factors, systemic inflammation, skeletal muscle metabolic signalling pathways (protein balance, insulin signalling, inflammatory), mental wellbeing and quality of life (all exploratory).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The difference between groups will be measured at 24 weeks, as per the primary end point. The time-course of change will also be assessed at 12 weeks. |
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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.6.13.1 | Other scope of the trial description |
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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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Exercise (in combination with IMP) and diet (control) |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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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The end of trial is the date of the final statistical analysis for primary or secondary outcomes. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 31 |