A Study of GWP42004 as Add on to Metformin in the Treatment of Participants With Type 2 Diabetes

A study to compare the change in glycaemic control in participants with Type 2 diabetes when treated with GWP42004 or placebo as add-on therapy to metformin over a period of 12 weeks. The safety and tolerability of GWP42004 compared with placebo will also be assessed.

This 14 week (one week baseline, 12 week treatment period and one week follow-up), multicentre, randomised, double blind, placebo controlled, parallel group study will evaluate the efficacy, safety and tolerability of 2, 5 and 15 mg of GWP42004 as add on to metformin compared with placebo in participants with Type 2 diabetes.

Eligible participants will enter the study at a screening visit (Visit 1, Day -7) where the following information will be obtained for each participant:

1. Informed consent
2. Demographics
3. Medical history
4. Concomitant medications
5. Electrocardiogram (ECG)
6. Physical examination
7. Vital signs
8. Body weight
9. Height
10. Body Mass Index (BMI)
11. Beck Depression Inventory-II (BDI-II)
12. Safety blood test (biochemistry and haematology)
13. Efficacy blood test (HbA1c)
14. Urinalysis (including drugs of abuse screen)
15. Pregnancy test (if appropriate)

Once all inclusion and exclusion criteria have been reviewed, participants will be commence a seven day baseline period. The day before Visit 2, participants will perform blood glucose tests and record the results, along with the associated time of assessment, in the study diary. Participants will then fast overnight.

Participants will return to the clinic at Visit 2 (Day 1) and following review of all inclusion and exclusion criteria, the following information will be obtained for each participant:

1. Body weight
2. BMI
3. Physical examination
4. Vital signs
5. Safety blood test (biochemistry and haematology)
6. GWP42004 exposure blood test (plasma levels)
7. Efficacy blood test (HbA1c, fasting plasma glucose, serum fructosamine, fasting plasma insulin, HOMA2-IR, pro-insulin, C-peptide, HOMA2-%B, total cholesterol, HDL-cholesterol, serum triglycerides, C-reactive protein)
8. Urinalysis
9. Concomitant medications
10. Adverse events (AEs)
11. BDI-II
12. Columbia-Suicide Severity Rating Scale (C-SSRS)
13. Diabetes Treatment Satisfaction Questionnaire (DTSQs)
14. Overall health Visual Analogue Scale (VAS)
15. Cannabis withdrawal scale assessment (UK only).

Participants will then be randomised to receive either GWP42004 (2, 5 or 15 mg bid) or placebo to be taken adjunctive to their currently prescribed medication. The first dose will be administered and a Oral Glucose Tolerance Test (OGTT) performed.

A third (Visit 3, Day 29) and fourth (Visit 4, Day 57) visit will take place mid-treatment. The day before these visits, participants will perform blood glucose tests and record the results, along with the associated time of assessment, in the study diary. Participants will then fast overnight. The following information will be obtained for each participant at Visits 3 and 4:

1. Body weight
2. BMI
3. Physical examination
4. Vital signs
5. Safety blood test (biochemistry and haematology)
6. Efficacy blood test (HbA1c, fasting plasma glucose, fasting plasma insulin, HOMA2-IR, HOMA2-%B)
7. Urinalysis
8. Concomitant medications
9. AEs
10. BDI-II
11. C-SSRS
12. DTSQs
13. Overall health VAS

A cannabis withdrawal scale assessment will be made by telephone (UK only) between Visits 4 and 5.

A further visit will take place at the end of treatment (Visit 5, Day 85). Two days before this visit, a cannabis withdrawal scale assessment will be made by telephone (UK only). The day before Visit 5, participants will perform blood glucose tests and record the results, along with the associated time of assessment, in the study diary. Participants will then fast overnight. The following information will be obtained for each participant at Visit 5:

the following information will be obtained for each participant:

1. Body weight
2. BMI
3. Physical examination
4. ECG
5. Vital signs
6. Safety blood test (biochemistry and haematology)
7. GWP42004 exposure blood test (plasma levels)
8. Efficacy blood test (HbA1c, fasting plasma glucose, serum fructosamine, fasting plasma insulin, HOMA2-IR, pro-insulin, C-peptide, HOMA2-%B, total cholesterol, HDL-cholesterol, serum triglycerides, C-reactive protein)
9. Urinalysis (including drugs of abuse screen)
10. Pregnancy test (if appropriate)
11. Concomitant medications
12. Adverse events (AEs)
13. BDI-II
14. OGTT
15. C-SSRS
16. DTSQs
17. Overall health VAS

One, three and seven days following Visit 5 (Days 86, 89 and 92, respectively), further cannabis withdrawal scale assessments will be made by telephone (UK only). A final review of AEs and concomitant medications will be made by telephone to all participants on Day 92.

Eligibility Criteria:
Inclusion Criteria:

* Participant is willing and able to give informed consent for participation in the study (see Section 15.2).
* 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 enrolment (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).
* Participant is able (in the investigators opinion) and willing to comply with all study requirements.
* Participant is willing for his or her name to be notified to the responsible authorities for participation in this study, as applicable in individual countries.
* Participant is willing to allow his or her primary care practitioner and consultant, if appropriate, to be notified of participation in the study.

Exclusion Criteria:

* Participant is taking or has taken insulin at any point in the last year (does not include short term use (\<10 days) to treat acute events).
* Participant is taking or has taken anti-diabetic treatment (other than metformin) in the three months prior to screening.
* Any concomitant medications which, in the opinion of the investigator, could affect the primary endpoint should remain stable or not be prescribed in the one month prior to Visit 1 or during the study period.
* Any known of suspected history of:
* Alcohol or substance abuse.
* Epilepsy or recurrent seizures.
* Participants receiving treatment with antidepressants or under observation for depression.
* BDI-II item 9 score of 1, 2 or 3.
* Participant who has significant history of suicidal ideation or self-harm.
* Recent (within three months of screening) blood loss (including blood donation).
* Haemolytic anaemia.
* Genetic abnormality in haemoglobin molecule (e.g. sickle cell anaemia).
* Clinically significant cardiac, renal or hepatic impairment in the opinion of the investigator.
* Has significantly impaired renal function as evidenced by a creatinine clearance lower than 40 mL/min at Visit 1.
* Has significantly impaired hepatic function at Visit 1 (alanine aminotransferase (ALT) levels \>5x upper limit of normal (ULN) or total bilirubin (TBL) levels \> 2x ULN). If the ALT or aspartate aminotransferase (AST) levels are \>3x ULN and the TBL levels \>2x ULN (or International Normalised Ratio (INR) \>1.5), then this participant should not enter the study.
* Any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMPs.
* Female participants of child bearing potential and male participants whose partner is of child bearing potential, unless willing to ensure that they or their partner use effective double barrier contraception.
* Female participant who is pregnant, lactating or planning pregnancy during the course of the study and for three months thereafter.
* Participants who have received an Investigational Medicinal Product (IMP) within the 12 weeks prior to the screening visit.
* Any other significant disease or disorder which, in the opinion of the investigator, may either put the participant at risk because of participation in the study, may influence the result of the study, or the participant's ability to participate in the study.
* Following a physical examination, the participant has any abnormalities that, in the opinion of the investigator would prevent the participant from safe participation in the study.
* Unwilling to abstain from donation of blood during the study.
* Participants who have previously undergone bariatric surgery.
* Travel outside the country of residence planned during the study, unless the participant has prior permission from the embassy of the destination country.
* Participants previously randomised into this study.
* The patient is currently using or has used cannabis or cannabinoid based medications within 30 days of study entry and is unwilling to abstain for the duration of the study.