| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Dyslipidaemia in subjects with type 2 diabetes who have failed to achieve satisfactory lipid control with existing therapies. |
|
| E.1.1.1 | Medical condition in easily understood language |
| High blood cholesterol and triglycerides in persons with type 2 diabetes |
|
| 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 | LLT |
| E.1.2 | Classification code | 10058110 |
| E.1.2 | Term | Dyslipidemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| 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 |
| To evaluate the efficacy of a 1:1 and 20:1 ratio of GW42003: GW42004 plus GW42003 and GW42004 alone compared with placebo in the treatment of dyslipidaemia in subjects with Type 2 diabetes. This will be evaluated primarily by assessing the impact of treatment on high density lipoprotein (HDL) cholesterol. Secondary measures of the primary objective are Total Cholesterol, low density lipoprotein (LDL) Cholesterol, HDL / LDL ratio, serum triglycerides, apolipoprotein markers (Apo A & Apo B and determination of Apo A/Apo B ratio). |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of a 1:1 and 20:1 ratio of GW42003 : GW42004 plus GW42003 and GW42004 alone compared with placebo on:
• Lipid parameters;
• Glucose control;
• Insulin sensitivity;
• Body weight & body mass index;
• Adipose tissue distribution;
• Appetite 11 point numerical rating scale (0-10 NRS).
To assess the safety and tolerability of a 1:1 and, 20:1 ratio of GW42003 : GW42004 plus GW42003 and GW42004 alone compared with placebo on:
• adverse events (AE)
• vital signs
• Beck Depression Inventory (BDI)
• Electrocardiogram (ECG)
• laboratory findings
• physical examination |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study subjects must fulfil ALL of the following criteria:
- Subject is aged 18 years or above;
- Clinically diagnosed with Type 2 diabetes, with residual islet cell function;
- Diet controlled Type 2 diabetes or receiving oral metformin (or other biguanides) and/or sulphonylurea as anti-diabetic treatment who have received a stable dose for at least three months prior to enrolment (Visit 1);
- HDL cholesterol ≤ 1.3 mmol/L (females), ≤ 1.2 mmol/L (males);
- Haemoglobin A1c level of ≤ 10%;
- Triglycerides ≤ 10 mmol/L;
- Willing to maintain a stable dose of oral anti-diabetic and lipid-lowering agents/medications that may have an effect on plasma/serum glucose, insulin or lipid parameters for the duration of the study, if appropriate;
- No changes in diet or exercise for four weeks prior to and for the duration of the study (in the opinion of the investigator);
- Capable of complying with the study requirements and completing the study (in the opinion of the investigator);
- Willing and able to give informed consent for participation in the study;
- Willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable;
- Willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study. |
|
| E.4 | Principal exclusion criteria |
The subject may not enter the study if ANY of the following apply:
- Subject is taking insulin (i.e. they are insulin-dependent);
- Taking the following categories of medicines: fibrates, TZDs, therapeutic Omega-3 fatty acids; alpha-glucosidase inhibitors and unwilling abstain for the duration of the study;
- Currently using or has used recreational cannabis, medicinal cannabis, cannabinoid medications (including Sativex®), or synthetic cannabinoid based medications (within 30 days prior to study entry and unwilling to abstain for the duration for the study;
- Any known or suspected history of:
- alcohol or substance abuse
- epilepsy or recurrent seizures;
- Any known or suspected history of depression sufficient to require treatment with antidepressants or disrupt ordinary life (excluding episodes of reactive depression at the discretion of the investigator);
- BDI Score ≥ 15;
- Subject who has significant history of anxiety, suicidal ideation or self-harm;
- Clinically significant cardiac, renal or hepatic impairment in the opinion of the investigator;
- Genetic dyslipidaemic condition in the opinion of the investigator;
- Currently taking a lipid lowering agent and a stable dose has not been maintained for at least four weeks prior to randomisation (Visit 2);
- Female subject, who is pregnant, lactating or planning pregnancy during the course of the study and for three months from date of last dose;
- Female subjects of child bearing potential unless willing to use two forms of contraception, one of which must be barrier contraception (e.g. female condom or occlusive cap (diaphragm or cervical vault/caps) with spermicide) during the study and for three months thereafter;
- Male subjects whose partner is of child bearing potential, unless willing to use an appropriate barrier method of contraception (condom and spermicide) in addition to having their female partner use another form of barrier contraception (e.g. occlusive cap (diaphragm or cervical vault/caps) with spermicide) during the study and for 3 months thereafter (however a male condom should not be used in conjunction with the female condom);
- Body weight >150kg;
- Travel outside the country of residence planned during the study;
- Currently receiving a prohibited medication and unwilling to stop at the screening visit (Visit 1) and for the duration of the study
- Received an unapproved IMP within the 30 days before the screening visit;
- In the opinion of the investigator, is not considered to be suitable for the study;
- Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP(s);
- Any other significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, may influence the result of the study, or the subject’s ability to participate in the study;
- Has a postural drop of ≥20 mmHg in systolic blood pressure at Visit 1;
- Any abnormalities identified during the physical exam at Visit 1 that in the opinion of the investigator, would prevent the subject from safe participation in the study;
- Unwilling to abstain from donation of blood during the study;
- Previously randomised into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline in serum HDL, cholesterol concentration after 91 days (13 weeks) of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
To evaluate the efficacy of a 1:1 and 20:1 ratio of
GW42003 : GW42004 plus GW42003 and GW42004 alone compared with placebo on:
Lipid parameters
• Change from baseline in serum Total Cholesterol to the end of treatment;
• Change from baseline in serum LDL Cholesterol to the end of treatment;
• Change from baseline in serum HDL / LDL Cholesterol ratio to the end of treatment;
• Change from baseline in serum Triglycerides to the end of treatment;
• Change from baseline in serum apolipoprotein markers (Apo A & Apo B) and lipid subfractions using ultracentrifugation to the end of treatment;
• Change from baseline in Apo A/Apo B ratio to the end of treatment;
• Change from baseline in non-esterified (“free”) fatty acids to the end of treatment;
• Change in lipid subfractions measured by ultracentrifugation to the end of treatment;
• Proportion of subjects showing a response (defined as an increase of 10% or more in HDL cholesterol from baseline to the primary endpoint);
Glucose Control
• Change from baseline in glucose control parameters (fasting plasma glucose, glucose tolerance, serum fructosamine, HbA1c (whole blood)) to the end of treatment;
Insulin Sensitivity
• Change from baseline in insulin sensitivity parameters (fasting serum insulin levels, insulin sensitivity) (Homeostasis Model Assessment (HOMA) insulin response to an Oral Glucose Tolerance Test (OGTT)) to the end of treatment.
• Change from baseline in islet cell function (c-peptide levels) to the end of treatment.
Body Weight and Fat Loss
• Change from baseline in body weight parameters (BMI, waist-to-hip ratio, neck circumference, skin fold thickness, body weight, waist circumference, visceral adiposity) to the end of treatment;
• Proportions of subjects showing a response (defined as a loss of 5% or 10% or more in body weight from baseline to end of treatment);
• Change from baseline in adipose tissue distribution (liver triglycerides and visceral adiposity as measured by MRI/MRS Scan) to the end of treatment.
Appetite Assessment
• Change from baseline in mean 0-10 NRS appetite score to end of treatment.
Safety Endpoints:
To assess the safety and tolerability of a 1:1 and 20:1 ratio of GW42003 : GW42004 plus GW42003 and GW42004 alone compared with placebo on.
• AEs
• vital signs
• BDI
• ECG
• laboratory findings
• physical examination |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 91 (End of 13 weeks)
A safety follow up will be performed on day 99 (Week 14) |
|
| 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 | No |
| 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 | 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) | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 5 |
| 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 | 5 |
| 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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