| 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 | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012601 |
| E.1.2 | Term | 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 primary objective of the Part A trial is to assess the amount of meal-time (prandial) insulin dose reduction that will avoid hypoglycaemic episodes (low blood sugar levels) when taken alongside a GLP-1 receptor agonist called lixisenatide at a dose of 10µg/day.
The primary objective of the Part B trial is to determine whether adding lixisenatide to basal bolus insulin (combination of long acting insulin once a day called basal with short acting insulin with meals, called bolus) significantly improves glycaemic (blood sugar) control during the 3 hour post prandial period (i.e. following a meal) compared to basal bolus insulin and a 'dummy' or placebo injection.
The primary objective of the sub-study is to determine if prediction of imminent hypoglycaemia from continuous glucose monitoring data can be enhanced by using data fusion techniques to combine variations in physiological measurements related to early counter-regulatory responses.
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| E.2.2 | Secondary objectives of the trial |
There are no secondary objectives for the Part A trial.
The secondary objective of the Part B trial is to determine
1) If there is an overall improvement in glycaemic control (blood sugar levels) over 24 hours when lixisenatide is added to insulin
2) If there is an improvement in post prandial (i.e. after a meal) glycaemic status, to determine whether
• this is only in participants with residual β cell function,
• this is associated with C-peptide / insulin response to hyperglycaemia (low blood sugar episodes)
• this is associated with change in glucagon and counter-regulatory hormone response to hyperglycaemia (low blood sugar episodes).
3) To assess if adding lixisenatide to insulin delays decline in cognitive function with hypoglycaemia
There are no secondary objectives for the sub-study. |
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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 |
Title: Non-invasive ancillary physiologic parameter monitoring sub-study
Date and Version: As this sub-study will take place at the same time as the Part B study, the date and version are the same as those of the clinical trial protocol in this submission.
The primary objective of the sub-study is: To determine if prediction of imminent hypoglycaemia from continuous glucose monitoring data can be enhanced by using data fusion techniques to combine variations in physiological measurements related to early counter-regulatory responses.
There are no secondary objectives of the sub-study. |
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| E.3 | Principal inclusion criteria |
The following inclusion criteria apply to both Part A and B studies:
The patient may enter the study if ALL the following criteria apply:
• Has provided written informed consent
• Type 1 diabetes
• Diabetes duration for at least 12 months
• Insulin treatment since the diagnosis of diabetes
• Age 18-65 years (upper age limit specified for clinical safety as there is limited experience of using lixisenatide beyond 65 years)
• Basal-Bolus insulin regimen
• HbA1c between 7.0% and 9.0% (inclusive)
• Stable insulin dose (within 20%) over 3 months prior to recruitment. Patients on low doses of insulin, who have had a change of insulin dose by >20% over the preceding 3 months maybe included at the discretion of the Principal Investigator.
• BMI < 27 kg/m2
For the C-peptide positive group:
• Random or fasting C-peptide ≥ 0.1 nmol/l
• If clinically indicated, screen negative for mutations in HNF1A, HNF4A or GCK genes (indicative of MODY, maturity onset diabetes of the young)
For the C-Peptide negative group:
• Random or fasting C-peptide <0.02 nmol/l with accompanying glucose >4 mmol/l
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| E.4 | Principal exclusion criteria |
The following inclusion criteria apply to both Part A and B studies:
The patient may not enter the study if ANY of the following apply:
• Type 2 diabetes
• Maturity Onset Diabetes of the Young (MODY)
• Pregnancy or women of childbearing age without adequate contraception
• Women who are breast-feeding
• Major psychiatric disease including diagnosed eating disorders, history of drug or alcohol abuse
• Renal impairment (eGFR ≤ 50 ml/min)
• Abnormal liver function tests (> 1.5 x upper limit of the normal range)
• Have high blood pressure (>180 mmHg systolic or >100 mmHg diastolic)
• Known ischaemic heart disease or heart failure
• History of stroke
• Patient has received any investigational drug within 30 days prior to screening
• Oral steroid treatment 30 days prior to randomisation
• Known malignancy or any other condition or circumstance, which, in the opinion of the investigator, would affect the patient’s ability to participate in the protocol
• Non-English speakers will be excluded due to the nature and complexity of the hypoglycaemic clamp methodology
• Known allergy to the drugs or any of the components
• Severe hypoglycaemia requiring 3rd party intervention on more than one occasion in the preceding 12 months
• Felt to be unsuitable to participate in the trial in the opinion of the Principal Investigator
• Currently taking domperidone, metoclopramide or warfarin
The following criterion applies to Part B study only:
• (For Part B study), took part in the lixisenatide prandial dose finding Part A study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure for the Part A study is as follows:
The percentage reduction in prandial insulin that, when co-prescribed with lixisenatide (10µg/d), will maintain blood glucose levels within 6-9mmol/l, without any instance of blood glucose level dropping below 4mmol/l.
The primary outcome measure for the Part B study is as follows:
The change in the percentage of Continuous Glucose Monitoring (CGM) readings between 4 and 10 mmol/l (inclusive) during the 3 hour post-prandial period, before and after treatment with lixisenatide compared to matching placebo.
The primary outcome measure for the sub-study is as follows:
To develop an algorithm using integrated vital sign monitoring that could be used to improve sensitivity and specificity of hypoglycaemia prediction in patients with type 1 diabetes in the future.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline results taken at the randomisation visit will be compared to those results obtained following the two study interventions. |
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| E.5.2 | Secondary end point(s) |
There are no secondary end points for the Part A study.
The secondary end points for the Part B study are as follows:
1) Difference in area under the curve for glucose during a mixed meal test with and without lixisenatide
2) Change in the percentage of CGM readings above 10 mmol/l (hyperglycaemia) and below 3mmol/l (hypoglycaemia, classified in section 13.6) during the 24-hour period before and after treatment with lixisenatide.
3) Change in counter regulatory hormones during the hypoglycaemic clamp with and without lixisenatide.
4) Comparison in CGM outcomes (defined above) between C-peptide positive and C-peptide negative participants with and without lixisenatide.
5) Comparison in the rate of decline of cognitive function with hypoglycaemia between participants with or without lixisenatide.
6) Differences in C-peptide/insulin response during the meal tolerance test between C-peptide positive and C-peptide negative participants with lixisenatide.
7) Differences in counter regulatory response in the hypoglycaemic clamp between C-peptide positive and C-peptide negative participants with lixisenatide.
8) Differences in insulin dose requirement between lixisenatide and placebo groups
9) Differences in bode weight between lixisenatide and placebo groups.
There are no secondary end points for the Part B sub-study.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline results taken at the randomisation visit will be compared to those results obtained following the two study interventions. |
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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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| Date of electronic Case Report Form (eCRF) close (database lock). This date will extend beyond the date of LVLS to ensure adequate time to transport, analyse and report the results of the Glucagon-Like Peptide-1 (GLP-1), Glucose-dependant Insulinotropic Peptide (GIP) and glucagon research samples analysed by Professor Jens Holst's laboratory, Copenhagen, Denmark. |
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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 | 9 |
| E.8.9.1 | In the Member State concerned days | 4 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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