A randomised, double blind, placebo controlled, parallel group, dose ranging study of GWP42004 as add on to metformin in the treatment of participants with Type 2 diabetes.

INTERVENTION: Product Name: Delta‐9‐Tetrahydrocannabivarin Product Code: GWP42004 Pharmaceutical Form: Capsule, hard INN or Proposed INN: N/A CAS Number: 28172‐17‐0 Current Sponsor code: GWP42004 Other descriptive name: TETRAHYDROCANNABIVARIN 9 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 2‐ INN or Proposed INN: N/A CAS Number: 28172‐17‐0 Current Sponsor code: GWP42004 Other descriptive name: TETRAHYDROCANNABIVARIN 9 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 5‐ INN or Proposed INN: N/A CAS Number: 28172‐17‐0 Current Sponsor code: GWP42004 Other descriptive name: TETRAHYDROCANNABIVARIN 9 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 15‐ Pharmaceutical form of the placebo: Capsule, hard Route of administration of the placebo: Oral use CONDITION: Therapeutic area: Diseases [C] ‐ Hormonal diseases [C19] Type 2 diabetes ; MedDRA version: 17.1 Level: PT Classification code 10067585 Term: Type 2 diabetes mellitus System Organ Class: 10027433 ‐ Metabolism and nutrition disorders PRIMARY OUTCOME: Main Objective: To evaluate the efficacy of 2, 5 and 15 mg twice daily of GWP42004 compared with placebo by assessing the impact of treatment on glycaemic control in the treatment of participants with Type 2 diabetes. Primary end point(s): To evaluate the efficacy of 2, 5 and 15 mg twice daily of GWP42004 compared with placebo by assessing the change from baseline in glycosylated haemoglobin A 1c (HbA1c). Secondary Objective: To evaluate the efficacy of 2, 5 and 15 mg twice daily of GWP42004 compared with placebo on:; • Other measures of glycaemic control; • Measures of insulin sensitivity; • Measures of beta cell function; • Body weight; • Body Mass Index (BMI); • Lipid parameters; • A marker of inflammation; • Cardiovascular parameters; • Health economics; ; To assess the safety and tolerability of GWP42004 compared with placebo on:; • Adverse Events (AEs); • Vital signs; • Depression (Beck Depression Inventory‐II [BDI‐II]); • Suicidal tendencies (Columbia‐Suicide Severity Rating Scale [C‐SSRS]); • Electrocardiogram (ECG); • Clinical pathology (haematology and clinical chemistry); • Physical examination; • Blood glucose safety (Self‐Monitoring of Blood Glucose [SMBG]); • Cannabis withdrawal (Cannabis Withdrawal Scale [CWS]) (UK based participants only); ; To assess evidence of absorption of GWP42004. Timepoint(s) of evaluation of this end point: Assessed at: Visit 1 (Day ‐7); Visit 2 (Day 1); Visit 3 (Day 29), Visit 4 (Day 57) and Visit 5 (Day 85) SECONDARY OUTCOME: Secondary end point(s): To evaluate the efficacy of 2, 5 and 15 mg of GWP42004 twice daily compared with placebo on: ; • Glycaemic Control: ; o Fasting plasma glucose levels ; o Glucose response to an Oral Glucose Tolerance Test (OGTT) ; o Serum fructosamine levels ; o Number of participants with HbA1c levels <7% (53 mmol/mol) following treatment ; ; Insulin related parameters: ; o Fasting plasma insulin levels ; o Insulin resistance (by Homeostatic Model Assessment 2 for Insulin Resistance) ; o Insulin response to OGTT ; o Pro‐insulin ; o C‐peptide ; o Beta cell function (by Homeostatic Model Assessment 2 for beta cell protection) ; • BMI ; • Lipid parameters: ; o Total cholesterol levels ; o High Density Lipoprotein‐cholesterol levels ; o Serum triglyceride levels ; • A marker of inflammation: ; o High sensitivity C‐Reactive Protein levels ; • Cardiovascular parameters: ; o Blood pressure ; • Health economics: ; o Diabetes Treatment Satisfaction Questionnaire (status version) (DTSQs) ; o Overall health Visual Analogue Scale (VAS) ; ; To assess the safety and tolerability of GWP42004 compared with placebo on: ; • AEs ; • Vital signs ; • BDI‐II ; • C‐SSRS ; • ECG ; • Laboratory findings ; • Physical examination ; • Blood glucose safety (SMBG) ; o Rates of hypoglycaemia ; • CWS (UK‐based participants only) ; ; Evidence of absorption of GWP42004: ; • Pre‐ and post‐dose plasma levels of GWP42004 and metabolites Timepoint(s) of evaluation of this end point: Efficacy ; Fasting plasma glucose ‐ V2, 3, 4 & 5 ; Glucose response to OGTT ‐ V2 & 5 ; Serum fructosamine ‐ V2 & 5 ; Participants with HbA1c <7% ‐ V3, 4 & 5 ; Fasting plasma insulin ‐ V2, 3, 4 & 5 ; Insulin resistance ‐ V2, 3, 4 & 5 ; Insulin response to OGTT ‐ V2 & 5 ; Pro‐insulin ‐ V2 & 5 ; C‐peptide ‐ V2 & 5 ; B‐cell function ‐ V2, 3, 4 & 5 ; BMI ‐ V2, 3, 4 & 5 ; Total cholesterol ‐ V2 & 5 ; HDL‐cholesterol ‐ V2 & 5 ; Serum triglyceride ‐ V2 & 5 ; CRP‐ V2 & 5 ; Blood pressure ‐ V2, 3, 4 & 5 ; DTSQ ‐ V2, 3, 4 & 5 ; Health VAS ‐ V2, 3, 4 & 5 ; Safety‐ V1, 2, 3, 4 & 5 except where indicated ; A Es ; Vital signs ; BDI‐II ; C‐SSRS ‐ V2, 3, 4 & 5 ; ECG ‐ V1 & 5 ; Labs ; Physical exam ; Rates of hypoglycaemia ; CWS (UK) ‐ V2, 2 days before V5 & 1, 3 and ; 7 days after V5 ; Absorption ; Plasma GWP42004 & metabolites ‐ V2 & 5 INCLUSION CRITERIA: • Male or female participants aged 18 years or above • Clinically diagnosed with Type 2 diabetes • Participants receiving oral metformin (= 1000 mg per day) as anti‐diabetic treatment who have received a stable dose for at least three months prior to screening (Visit 1) and willing to maintain a stable dose for the duration of the trial • HbA1c level of >7% ‐ =9 % (53 ‐ 74.9 mmol/mol) • BMI of>25 ‐ <40 (>23 ‐ <40 for Asian populations) • No changes in diet or exercise for three months prior to study entry and participant agrees to keep stable for the duration of the study • Capable of complying with the study requirements and completing the study (in the opinion of the investigator) • Willing and able to give written informed consent • Willing and able to comply with all study requirements • Willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable • Willing to