GWMD1092 - GWP42003 : GWP42004 Together Plus Alone in Type II Diabetes

Jazz Pharmaceuticals62 enrolled

Overview

This 15-19 week study is being conducted by GW Pharma Ltd as a pilot study in order to determine the efficacy and safety of two cannabinoids: GWP42004 and GWP42003 alone, or in combination in patients with Type 2 diabetes. This is the first study to determine whether the study medications have a positive benefit for subjects on their cholesterol levels, body weight, liver fat content and other metabolic parameters compared with a placebo medication.

In this study there was a 1-5 week baseline period followed by a 13 week treatment period, and a one week follow-up. Eligible subjects entered the study at a screening visit (Visit 1) before returning for randomisation (Visit 2, Day 1). At the discretion of the investigator (based on individual subjects), Visit 1 could be split into two separate visits (Visits 1A and B) to allow a 21-day washout period of prohibited medications prior to blood sampling for eligibility. Further outpatient study visits (for assessment purposes) took place at the study site at the end of Week 4 of treatment (Visit 3, Day 29), and at the overall end of treatment at Week 13 (Visit 5, Day 92). A telephone assessment was also performed at Day 57 (Visit 4) and at Week 14 (Visit 6, Day 99) for safety follow-up purposes. During the 13 week randomised treatment phase, subjects received blinded, oral doses of their allocated randomised treatment twice daily. Treatment was self-administered on an outpatient basis, once in the morning and once in the evening for 13 weeks. Subjects were instructed to time study medication to 30 minutes before breakfast and evening meals. Physical and metabolic parameters were assessed before, during and after treatment to evaluate clinical response. Diabetic and dyslipidaemic medication usage (where applicable), and appetite 0-10 NRS data were collected daily during the treatment period, using the study diary.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Dyslipidemias Diabetes Mellitus, Type 2

Interventions

GWP42003DRUG

100 mg capsules, PO, BD, 91 days

GWP42003DRUG

5 mg capsules, PO, BD, 91 days

GWP42004DRUG

5 mg capsules, PO, BD, 91 days

Placebo

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Clinically diagnosed with Type 2 diabetes, with residual islet cell function; * Diet controlled or receiving oral anti-diabetic treatment (metformin or other biguanides and/or sulphonyl ureas) who have received a stable dose for at least 3 months prior to enrollment; * High Density Lipoprotein cholesterol ≤ 1.3mmol/L (females), ≤ 1.2mmol/L (males); * Glycosylated haemoglobin levels of ≤ 10%; * Triglycerides ≤ 10mmol/L; * Willing to maintain a stable dose of oral anti-diabetic and/or lipid-lowering agents/medications that may have an effect on plasma/serum glucose, insulin or lipid parameters for the duration of the study, where applicable; * No changes in diet or exercise for four weeks prior to and subject agrees to keep stable for the duration of the study (in the opinion of the investigator); Exclusion Criteria: * Subject is taking insulin (i.e. they are insulin-dependent); * Taking the following categories of medicines: fibrates, Thiazolidinediones, 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 at the discretion of the investigator); * 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 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. female condom or occlusive cap (diaphragm or cervical vault/caps) with spermicide) during the study and for three months thereafter; * 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 and for the duration of the study; * Received an unapproved Investigational Medicinal Product (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.

Locations (5)

Woolpit Health Centre

Bury Saint Edmonds, United Kingdom

Mount Farm Surgery

Bury Saint Edmonds, United Kingdom

University of Nottingham, Medical School at Derby, Royal Derby Hospital

Derby, United Kingdom

James Paget University Hospital

Gorleston-on-Sea, Norfolk, United Kingdom

Outcomes

Primary Outcomes

The Change From Baseline in Mean Serum High Density Lipoprotein Cholesterol Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum High Density Lipoprotein cholesterol. An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

Secondary Outcomes

The Change From Baseline in Mean High Density Lipoprotein Cholesterol Concentration by Ultracentrifugation After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of High Density Lipoprotein cholesterol by ultracentrifugation. An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Total Cholesterol Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum total cholesterol. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Total Cholesterol Concentration by Ultracentrifugation After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum total cholesterol by ultracentrifugation. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Low Density Lipoprotein Cholesterol Concentration After 91 Days (13 Weeks) of Treatment

Data from ClinicalTrials.gov

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0 mg capsules, QDS, PO, 91 days

MAC UK Neuroscience Ltd.

Manchester, United Kingdom

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum Low Density Lipoprotein cholesterol. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Low Density Lipoprotein Cholesterol Concentration by Ultracentrifugation After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of Low Density Lipoprotein cholesterol by ultracentrifugation. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum High Density Lipoprotein : Low Density Lipoprotein Cholesterol Ratio After 91 Days (13 Weeks) of Treatment

An increase from baseline (i.e. a positive value) to the end of treatment in the High Density Lipoprotein : Low Density Lipoprotein cholesterol ratio indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean High Density Lipoprotein : Low Density Lipoprotein Cholesterol Ratio by Ultracentrifugation After 91 Days (13 Weeks) of Treatment

An increase from baseline (i.e. a positive value) to the end of treatment in the High Density Lipoprotein : Low Density Lipoprotein cholesterol ratio indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Very Low Density Lipoprotein Cholesterol Concentration by Ultracentrifugation After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of Very Low Density Lipoprotein cholesterol by ultracentrifugation. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Triglyceride Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum triglyceride concentrations. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Triglyceride Concentration by Ultracentrifugation After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of triglyceride concentrations by ultracentrifugation. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Apolipoprotein A Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum Apolipoprotein A. An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Apolipoprotein B Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum Apolipoprotein B. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Apolipoprotein B : Apolipoprotein A Ratio After 91 Days (13 Weeks) of Treatment

A decrease from baseline to the end of treatment (i.e. a negative value) in the Apolipoprotein B : Apolipoprotein A ratio indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Serum Non-Esterified Fatty Acid Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of serum Non-Esterified Fatty Acid concentrations. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Fasting Glucose Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of fasting glucose concentrations. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Fructosamine Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of fructosamine concentrations. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Glycated Haemoglobin Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of glycated haemoglobin concentrations. At both time points, values were calculated as a percentage of total haemoglobin. A decrease from baseline to the end of treatment in base per cent values, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline to the End of 91 Days (13 Weeks) of Treatment in the Mean Serum Glucose Concentration Two Hours Post Glucose Challenge (Oral Glucose Tolerance Test [OGTT])

A two-hour OGTT was performed to investigate the rate of glucose metabolism or clearance from the blood with treatment. Blood samples were taken at -15 and 0 minutes prior to a glucose drink and at 30, 60, 90, 120 and 180 minutes post drink. The OGTT measured the change from baseline in serum glucose levels at two hours (120 minutes) compared to 0 minutes. The extent of the elevation in blood glucose levels following a glucose drink were compared between baseline and the end of treatment. A reduction in the elevation of serum glucose levels at the end of treatment (i.e. a negative value) indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline to the End of 91 Days (13 Weeks) of Treatment in the Mean Serum Insulin Concentration Two Hours Post Glucose Challenge (Oral Glucose Tolerance Test)

At baseline and the end of treatment, blood samples were taken at -15 and 0 minutes prior to a glucose drink and at 30, 60, 90, 120 and 180 minutes post drink. The OGTT measured the change from baseline in serum insulin levels at two hours (120 minutes) compared to 0 minutes. The extent of the elevation in blood glucose levels following a glucose drink were compared between baseline and the end of treatment. An increase in the elevation of serum insulin levels from baseline to the end of treatment (i.e. a positive value) indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Fasting Insulin Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of fasting insulin concentrations. An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean C-peptide Concentration After 91 Days (13 Weeks) of Treatment

At baseline and the end of treatment, an approximately 30 mL fasting blood sample was taken for measurement of C-peptide concentrations. An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Insulin Resistance Measured by Homeostasis Model Assessment 2 (HOMA2-IR) After 91 Days (13 Weeks) of Treatment

Changes from baseline to the end of treatment in mean insulin resistance were calculated by HOMA2-IR. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin resistance, which is the reciprocal of insulin sensitivity (%S)(100/%S) as a percentage of a normal reference population (normal young adults). A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Insulin Sensitivity Measured by Homeostasis Model Assessment 2 (HOMA2) After 91 Days (13 Weeks) of Treatment

Changes from baseline to the end of treatment in mean insulin sensitivity were calculated by HOMA2. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin sensitivity (%S) as a percentage of a normal reference population (normal young adults). An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Insulin B Cell Function Measured by Homeostasis Model Assessment 2 (HOMA2) After 91 Days (13 Weeks) of Treatment

Changes from baseline to the end of treatment in mean insulin B Cell Function were calculated by HOMA2. HOMA2-IR is a computer model that uses fasting plasma insulin and glucose concentrations to estimate beta cell function (%B) as a percentage of a normal reference population (normal young adults). An increase from baseline to the end of treatment, a positive value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Body Mass Index After 91 Days (13 Weeks) of Treatment

Body Mass Index was calculated at baseline and the end of treatment. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Waist-to-hip Ratio After 91 Days (13 Weeks) of Treatment

Subject's waist-to-hip ratios were calculated at baseline and the end of treatment. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Body Weight After 91 Days (13 Weeks) of Treatment

Subject's body weights were measured at baseline and the end of treatment. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Waist Measurement After 91 Days (13 Weeks) of Treatment

Subjects' waist measurements were taken at baseline and the end of treatment. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Hip Measurement After 91 Days (13 Weeks) of Treatment

Subjects' hip measurements were taken at baseline and the end of treatment. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Visceral Abdominal Fat After 91 Days (13 Weeks) of Treatment

Visceral Abdominal Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scans were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Subcutaneous Abdominal Fat After 91 Days (13 Weeks) of Treatment

Subcutaneous Abdominal Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scans were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Total Abdominal Fat After 91 Days (13 Weeks) of Treatment

Total Abdominal Fat was measured by magnetic resonance imaging, and the results of the scans were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Internal Non-Abdominal Fat After 91 Days (13 Weeks) of Treatment

Internal Non-Abdominal Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Subcutaneous Non-Abdominal Fat After 91 Days (13 Weeks) of Treatment

Subcutaneous Non-Abdominal Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Total Non-Abdominal Fat After 91 Days (13 Weeks) of Treatment

Total Non-Abdominal Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Total Internal Fat After 91 Days (13 Weeks) of Treatment

Total Internal Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Total Subcutaneous Fat After 91 Days (13 Weeks) of Treatment

Total Subcutaneous Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Total Fat After 91 Days (13 Weeks) of Treatment

Total Fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Abdominal Adiposity After 91 Days (13 Weeks) of Treatment

Abdominal Adiposity was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean % Liver Fat After 91 Days (13 Weeks) of Treatment

Percentage liver fat was measured by magnetic resonance imaging at baseline and the end of treatment, and the results of the scan were analysed blind by a single independent reviewer. A decrease from baseline to the end of treatment in base per cent values, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

The Change From Baseline in Mean Appetite 0-10 Numerical Rating Scale Score After 91 Days (13 Weeks) of Treatment

Subjects scored their appetite daily using an appetite 0-10 numerical rating scale score where 0 = no appetite (don't feel hungry) and 10 = maximum appetite (completely hungry all the time). The mean change from baseline to the end of treatment in scores were calculated. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Time frame: Baseline (Day 1) and End of treatment (Day 92)

Adverse Events as a Measure of Patient Safety

The incidence of treatment-emergent adverse events was recorded for the study duration, and the number of patients who experienced an adverse event is presented.

Time frame: Day 1 - Day 92

The Change From Baseline in Mean Beck Depression Inventory-II (BDI-II) Score at the End of 91 Days (13 Weeks) of Treatment

The BDI-II is a 21 question, multiple choice, self-reported inventory, and is one of the most widely used instruments for measuring the severity of depression. The 21 questions or items each had four possible responses. Each response was assigned a score ranging from zero to three, indicating the severity of the symptom, with a total possible score ranging from zero to 63. A score between zero and 13 indicates 'minimal depression'. A score between 14 and 19 indicates 'mild depression'. A score between 20 and 28 indicates 'moderate depression', and a score between 29 and 63 indicates 'severe depression'. As such, an increase from baseline to the end of treatment, a positive value, indicates a deterioration.

Time frame: Baseline (Day 1) and the End of Treatment (Day 92)