Recruitment challenges

The goal of this randomised, double-blind, placebo-controlled Phase II clinical trial is to assess the safety and effect of of IHL-675A in rheumatoid arthritis patients on pain, and function according to RAPID-3.

128 volunteers will be enrolled and randomised to one of four treatments (32 subjects per treatment). Each treatment will be self-administered twice daily for 24 weeks.

The four treatments are:

• Treatment 1 - IHL-675A
• Treatment 2 - CBD
• Treatment 3 - HCQ
• Treatment 4 - Placebo

This is a Phase II, double-blind, randomised, placebo-controlled clinical trial to assess the safety and effect of IHL-675A (a combination of cannabidiol (CBD) and hydroxychloroquine (HCQ)) on pain and function using the RAPID-3 patient reported outcome (PRO) in patients with Rheumatoid Arthritis. This study will compare IHL-675A to the component drugs, CBD and HCQ, as well as a placebo. The study will aim to enrol a total of 128 subjects across the 4 treatment groups (32 per group).

The study will also assess structural changes in joint damage in an MRI sub-study using the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS).

During the 28-day screening period, subjects will provide information on their demographics, medical history, history of inflammatory conditions and weight/body mass index (BMI). A physical exam, vital signs, and 12-lead ECG will be conducted. Urine and blood samples will be collected for urinalysis, to assess for pregnancy, the presence of illicit drugs and to detect any clinically significant outcomes that would exclude subjects from being eligible for the clinical trial and to measure erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. A series of questionnaires will be conducted to assess eligibility and mental health status.

These questionnaires will be:

• RAPID-3
• JC 66/68
• Health Assessment Questionnaire-Disability Index (HAQ-DI)
• Columbia-Suicide Severity Rating Scale (C-SSRS) Subjects will also undergo an optical coherence tomography (OCT) eye examination to rule out retinopathy.

Subjects who have consented to the MRI sub-study will also undergo an MRI during screening.

Once the participant is deemed eligible to be enrolled in the study, the baseline visit will be performed and the participant will be randomised into one of the four treatment groups:

• Treatment 1 - IHL-675A (150 mg CBD, 200 mg HCQ: two soft gel capsules each containing 75 mg CBD and 100 mg HCQ twice per day for a total daily dose of 300 mg CBD and 400 mg HCQ)
• Treatment 2 - CBD (150 mg: two capsules each containing 75 mg CBD twice per day for a total daily dose of 300 mg CBD)
• Treatment 3 - HCQ (200 mg: two capsules each containing 100 mg HCQ twice per day for a total daily dose of 400 mg HCQ)
• Treatment 4 - Placebo (two capsules twice per day).

Subjects will visit the clinic on Day 1 and undergo baseline assessments, including:

• RAPID-3
• JC 66/68
• ACR20
• CDAI-RA
• FACIT-F
• HAQ-DI
• AE
• Concomitant medication review
• Weight/BMI
• Physical exam
• Vitals
• ECG
• Safety blood collection

Subjects will then be supplied with their first 28-day supply of their allocated treatment and will be set up with and instructed on the use of an electronic patient reported outcome (ePRO) either web based or using an app on the subject's personal device. The ePRO will be used daily by the subject to record pain, joint stiffness, tiredness, and use of other pain medication for the control of pain associated with arthritis.

Every 4 weeks, subjects will return to the clinical to undergo the same assessments and to receive the next 28-day supply of their allocated treatment. At 24 weeks, subjects will take their final dose prior to their return to the clinical for the final time (and will not receive another supply of the treatment) where they will undergo the same assessments as well as a final OCT eye exam, and subjects in the MRI sub-study will undergo a final MRI.

Inclusion Criteria:

Subjects will be included in the study if they satisfy all the following criteria:

1. Must have given written informed consent, before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects

2. Has been diagnosed with RA and on stable treatment for RA for at least 3 months prior to the screening visit

3. Subject has a RAPID-3 score of >4.5 at screening

4. Male or female, aged 18 or older inclusive at the screening visit

5. Body mass index (BMI) of 18 to 32 kg/m2, inclusive, at screening

6. Has at least two swollen or tender joints on the JC 66/68 at screening

7. Subject is otherwise medically healthy (in the opinion of the investigator), as determined by pre-study medical history and without clinically significant abnormalities including:

   1. Physical examination at screening without any additional clinically relevant findings apart from those consistent with RA in the opinion of the investigator.
   2. Systolic blood pressure at screening in the range of 90 to 160 mmHg and diastolic blood pressure in the range of 50 to 95 mmHg after 5 minutes in supine or semi-supine position.
   3. Pulse rate at screening in the range of 45 to 100 beats/minute after 5 minutes rest in supine or semi-supine position.
   4. Body temperature (tympanic) at screening between 35.5°C and 37.5°C.
   5. Electrocardiogram (ECG) at screening without clinically significant abnormal findings including QT interval corrected for Fredericia (QTcF) ≤470msec for females and ≤450msec for males.

8. Physically well, in the opinion of the investigator, with no severe psychiatric, cardiac, renal, endocrine, gastrointestinal, bleeding, thyroid, cholesterol, or hypertension disorders

9. Male subjects must:

   1. Agree not to donate sperm from the time of signing consent until at least 340 days (t1/2 *5 +90 days) after the last dose of study drug
   2. If engaging in sexual intercourse with a female partner who could become pregnant, must agree to use adequate contraception (defined as use of a condom plus a highly effective method of contraception (Appendix 10) from the time of signing consent until at least 340 days after the last dose of study drug).
   3. If engaging in sexual intercourse with a female partner who is not of childbearing potential or a same-sex partner, must agree to use a condom from the time of signing consent until at least 340 days after the last dose of study drug.

10. Female subjects must be of non-childbearing potential i.e., surgically sterilised (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before screening) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause and a follicle-stimulating hormone (FSH) level consistent with postmenopausal status, per local laboratory guidelines), or, if of childbearing potential (Women who have been surgically sterilised through tubal ligation are permitted to participate, if they agree to use an additional barrier method of contraception from one month prior to the first dose of study drug, until at least 280 days (t1/2 * 5 +30 days) after the last dose of study drug.):

    1. Must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to administration of the first dose of study drug. Note: subjects must also have a negative urine pregnancy test at each clinic visit.
    2. Must agree not to donate ova or attempt to become pregnant from the time of signing consent until at least 280 days after the last dose of study drug.
    3. If not exclusively in a same-sex relationship, must agree to use adequate contraception (which is defined as use of a condom by the male partner combined with use of a highly effective method of contraception (Appendix 10) from one month prior the first dose of study drug until at least 280 days after the last dose of study drug).

11. Able to avoid strenuous exercise from 72 hours prior to each visit to the clinical unit

12. Fluent in written and spoken English

13. Willing and able to comply with all study required tasks, including the completion of questionnaires, and to adhere to the study schedule and restrictions, as instructed by the protocol.

Exclusion Criteria:

Subjects will be excluded from the study if there is evidence of any of the following at screening.

Subjects will be excluded from the study if there is evidence of any of the following at screening.

1. Known hypersensitivity to any of the study drug ingredients (cannabis products, sesame oil, hydroxychloroquine or chloroquine)
2. History of any clinically significant (in the opinion of the investigator) disorder within the last 3 months including cardiovascular (cardiac disease or arrythmias), haematologic, pulmonary, hepatic, renal, or gastrointestinal (such as cholecystitis, Gilbert's syndrome) disorders, or connective tissue, uncontrolled endocrine/metabolic, oncologic (within the last 5 years), neurologic, or any disorder within the last 3 months that may prevent the successful completion of the study or influence the absorption, distribution, metabolism, excretion or action of the study drug (in the opinion of the investigator). Note: a history of fully resolved childhood asthma is not exclusionary; a history of cholecystectomy is not exclusionary
3. Family history of QT issues
4. Currently taking or have taken hydroxychloroquine, chloroquine or any drugs containing HCQ or chloroquine within 3 months of screening
5. Taking more than 10 mg prednisone per day
6. Pregnant, lactating, planning to become pregnant
7. Known substance abuse or medical, psychological, or social conditions or significant psychiatric illness (defined as hospitalisation), suicidal ideation, or suicidal attempts that, in the opinion of the investigator, may interfere with the subjects inclusion in the clinical study or evaluation of the clinical study results
8. Regular consumption of >10 standard alcoholic drinks/week where 1 standard drink is 10 g of pure alcohol and is equivalent to 285 mL beer [4.9% Alc/Vol], 100 mL wine [12% Alc/Vol], 30 mL spirit [40% Alc/Vol])
9. Positive urine illicit drug test at screening
10. C-SSRS score ≥4 OR reported suicidal behaviour within the past 3 months
11. Hepatic or renal impairment or disease defined as aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) >1.5 x upper limit of normal (ULN), estimated glomerular filtration rate (eGFR) <60 at screening
12. Subject has retinopathy or history thereof (as determined by the OCT eye examination at screening)
13. A positive test result for active human immunodeficiency virus (HIV-1 or HIV-2), hepatitis B antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit.
14. History of gastrointestinal disorders which may impact absorption, distribution, metabolism and/or excretion of the IP (such as cholecystitis, cholecystectomy, Gilbert's syndrome)
15. Participation in another clinical trial of an investigational drug within 30 Days or 5 half-lives of the investigational drug (whichever is longer) prior to screening
16. Any other condition or prior therapy that in the opinion of the Investigator (or delegate) would make the subject unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements.

MRI Sub-Study Inclusion Criteria:

Subjects may also participate in the MRI Sub-Study based on the below inclusion criteria.

1. Must have given written informed consent to participate in the MRI sub-study
2. Able and willing to undergo an MRI
3. Have at least 1 swollen and/or tender joint in left or right wrist or hand
4. Have a RAMRIS synovitis score of at least 1

Double-blind