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.
Combination product containing CBD and HCQ UniGel™ technology by ProCaps®. IHL-675A consists of a solid, film coated HCQ tablet that is contained within a CBD oil solution gel cap. Each IHL-675A gel cap contains 75 mg of CBD and 100 mg HCQ.
Formulated using UniGel™ technology by ProCaps®. The CBD soft gel capsules contain 75 mg CBD oil solution. These capsules look identical to the IHL-675A UniGel™ capsules, to aid double-blinding
Formulated using UniGel™ technology by ProCaps®. The soft gel capsules each contain a 100 mg HCQ tablet. These capsules look identical to the IHL-675A UniGel™ capsules to aid double-blinding.
Paratus Clinical (Woden Dermatology)
Phillip, Australian Capital Territory, Australia
Genesis Research Services
Broadmeadow, New South Wales, Australia
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
Change in pain and function
Routine Assessment of Patient Index Data 3 (RAPID-3) questionnaire to assess pain and function in arthritis patients. RAPID-3 is a pooled index of the 3 patient-reported American College of Rheumatology RA Core Data Set measures: function, pain, and patient global estimate of status. Each of the 3 individual measures is scored 0 to 10, for a total of 30. Disease severity may be classified on the basis of RAPID3 scores: \>12 = high; 6.1-12 = moderate; 3.1-6 = low; \< or =3 = remission
Time frame: 24 weeks
Safety and tolerability - Incidence of the use of concomitant medications for pain management
Incidence of the use of concomitant pain medications for the treatment of arthritis related pain. Subjects will report the use of rescue pain medication for pain associated with arthritis using an electronic patient reported outcome (ePRO) on their personal device.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - Vital signs - Temperature
Change from baseline in body temperature (°C)
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - Vital signs - Pulse Rate
Change from baseline in pulse rate (BPM)
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - Vital signs - Respiratory Rate
Change from baseline in respiratory rate (RPM)
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - Vital signs - Blood Pressure
Change from baseline in systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) to report change in blood pressure
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
20
Formulated using UniGel™ technology by ProCaps®. The soft gel capsules contain the inactive ingredients of the IHL-675A capsules and no active ingredients. These capsules look identical to the IHL-675A UniGel™ capsules to aid double-blinding.
Novatrials
Kotara, New South Wales, Australia
Emeritus Research
Sydney, New South Wales, Australia
Coast Joint Care
Maroochydore, Queensland, Australia
AusTrials Westside (Taringa)
Taringa, Queensland, Australia
AusTrials Wellers Hill
Wellers Hill, Queensland, Australia
Emeritus Research Melbourne
Camberwell, Victoria, Australia
Captain Sterling Medical Centre
Nedlands, Western Australia, Australia
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - 12-lead ECG
Change from baseline in 12-lead ECG results: PR interval, QRS, QTcF
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - Adverse Events
Assess the number of treatment emergent adverse events (TEAEs) and serious treatment emergent adverse events associated with the dosing of IHL-675A in comparison to the active comparators (CBD and HCQ), and placebo.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Safety and tolerability - OCT Eye Exam
Changes from baseline in retinopathy as assessed by Optical Coherence Tomography (OCT) eye exam
Time frame: 24 weeks
Safety and tolerability - The Columbia Suicide Severity Rating Scale (C-SSRS)
Change from baseline in suicidality assessed by The Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS is an instrument that measures suicidal ideation and behaviour. The ideation subscale evaluates severity on a 5-point scale, ranging from "wish to be dead" to "active suicidal ideation with specific plan and intent." The behaviour subscale assesses various categories of suicidal behaviour. Higher scores on the C-SSRS represent more severe levels of suicidal ideation or behaviour. Lower scores, therefore, indicate a better outcome as it represents lower levels of suicidal ideation or behaviour.
Time frame: 24 weeks
Change in pain - Routine Assessment of Patient Index Data 3 (RAPID-3)
Change in pain from baseline. Assessed by change in Routine Assessment of Patient Index Data 3 (RAPID-3) score relative to baseline. RAPID-3 is a composite score that measures physical function, pain, and patient global assessment on a scale from 0 to 30, with higher scores indicating worse outcomes (i.e., more pain and disability). A decrease in the RAPID-3 score from baseline represents an improvement.
Time frame: 4, 8, 12, 16 and 20 weeks
Change in fatigue - Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)
Change in fatigue from baseline. Assessed by change in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) score. FACIT-F is a 40-item measure that assesses self-reported fatigue and its impact upon daily activities and function on a scale from 0 to 160. Higher scores indicate better outcomes (i.e., less fatigue). An increase in the FACIT-F score from baseline represents an improvement.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in quality of life - Health Assessment Questionnaire - Disability Index (HAQ-DI)
Change in quality of life from baseline. Assessed by change in Health Assessment Questionnaire - Disability Index (HAQ-DI) score. The HAQ-DI assesses a patient's level of functional ability on a scale from 0 to 3. Higher scores indicate worse outcomes (i.e., greater disability). A decrease in the HAQ-DI score from baseline represents an improvement.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in disease activity - ACR20
Change in disease activity from baseline. Assessed by change in American College of Rheumatology-20 (ACR20) response rate. The ACR response is scored as a percentage improvement, comparing disease activity at two discrete time points (usually baseline and post-baseline comparison). ACR20 is ≥ 20% improvement
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in disease activity - JC66/68
Change in disease activity from baseline. Assessed by change in joint swelling/tenderness count 66/68 (JC66/68). The 66/68 Joint Count evaluates 66 joints for swelling and 68 joints for tenderness and pain with movement. Note that the hip joints can be evaluated for tenderness only-not for swelling. The total score is composed of points that are based on the presence of pain and/or swelling in a joint
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in disease activity - CDAI-RA
Change in disease activity from baseline. Assessed by change in clinical disease activity index for rheumatoid arthritis (CDAI-RA) score. CDAI is based on the simple summation of the count of swollen/tender joint count of 28 joints along with patient and physician global assessment on VAS (0-10 cm) Scale for estimating disease activity. The CDAI has range from 0 to 76.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in inflammatory serology - C-Reactive Protein (CRP)
Change in CRP levels from baseline. Assessed by the change in blood C-reactive protein (CRP) levels relative to baseline. CRP is a systemic marker of inflammation. The measurement is reported in milligrams per litre (mg/L). Higher levels of CRP typically indicate a higher level of systemic inflammation, so a decrease in CRP levels from baseline would generally indicate an improvement.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in inflammatory serology - Erythrocyte sedimentation rate (ESR)
Change in ESR levels from baseline. This outcome is assessed by the change in blood erythrocyte sedimentation rate (ESR) levels relative to baseline. ESR is a systemic marker of inflammation. The measurement is reported in millimetres per hour (mm/hr). Higher ESR levels typically indicate a higher level of systemic inflammation, so a decrease in ESR levels from baseline would generally indicate an improvement.
Time frame: 4, 8, 12, 16, 20 and 24 weeks
Change in tiredness
Change in tiredness from baseline. Assessed by an electronic patient reported outcome (ePRO). Subjects will be prompted daily to answer a set of 5 questions that will ask the patient about their pain, joint stiffness duration and severity, and tiredness, and to record the use of any concomitant medication for pain associated with arthritis.
Time frame: 24 weeks
Change in pain (daily)
Change in pain from baseline. Assessed by an electronic patient reported outcome (ePRO). Subjects will be prompted daily to answer a set of 5 questions that will ask the patient about their pain, joint stiffness duration and severity, and tiredness, and to record the use of any concomitant medication for pain associated with arthritis.
Time frame: 24 weeks
Change in joint stiffness duration
Change in joint stiffness duration from baseline. Assessed by an electronic patient reported outcome (ePRO). Subjects will be prompted daily to answer a set of 5 questions that will ask the patient about their pain, joint stiffness duration and severity, and tiredness, and to record the use of any concomitant medication for pain associated with arthritis.
Time frame: 24 weeks
Change in joint stiffness severity
Change in joint stiffness severity from baseline. Assessed by an electronic patient reported outcome (ePRO). Subjects will be prompted daily to answer a set of 5 questions that will ask the patient about their pain, joint stiffness duration and severity, and tiredness, and to record the use of any concomitant medication for pain associated with arthritis.
Time frame: 24 weeks
Effect of IHL-675A on cytokines
Change in cytokines IL-1β, IL-6, TNF levels compared to pre-dose levels.
Time frame: 12 and 24 weeks