| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis (RA)
and Ankylosing Spondylitis (AS) |
|
| E.1.1.1 | Medical condition in easily understood language |
RA and AS are autoimmune diseases. In RA the immune system attacks the membranes lining the joints, typically initially in small joints.
AS affects the joints of the spine and the pelvic girdle. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002556 |
| E.1.2 | Term | Ankylosing spondylitis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
RA and AS are systemic autoimmune diseases characterized by chronic, systemic inflammatory conditions, primarily of the musculoskeletal system. Pain and fatigue are typical symptoms and their treatment is a clinical challenge. The present study aims to clarify the potential of medical cannabis as a complement to the existing treatment in RA and AS.
More precisely, the study aims to clarify in RA and AS patients, whether the “add-on” treatment with CBD (placebo controlled) or the combination of CBD and THC (open label) results in a significantly improved pain situation as assessed by the number of patients achieving an improvement of pain visual analogue scores (VAS) with a reduction of Δ VAS > 20. |
|
| E.2.2 | Secondary objectives of the trial |
A significantly improved pain situation as assessed by the number of AS patients that achieve a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 40 and / or improvement in BASDAI with Δ > 20 after 12 and/ or 24 weeks of treatment with CBD or 12 weeks of treatment with CBD followed 12 weeks of treatment with the combination of CBD and THC in an open follow-up.
A significantly improved life situation as assessed by the number of patients that achieve a Global VAS < 50 and / or an improvement in Global-VAS with Δ VAS> 20 after 12 and/ or 24 weeks of treatment with CBD or 12 weeks of treatment with CBD followed by 12 weeks of treatment with a combination of CBD and THC in an open follow-up study.
The effect of the intervention on the patients attention and concentration is investigated using cognitive tests (Trail Making Test (TMT) and Digit Symbol Substitution Test (DSST)). Additionally, sleep quality is evaluated with the Pitssburgh Sleep Quality Index. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are patients diagnosed with seropositive RA, more specifically inflammatory well-treated patients, characterized by absence of arthritis at 40 counts and normal C-reactive protein (CRP) or with diagnosis AS in accordance with the modified New York criteria, i.e. based on physiotherapy and / or non-steroidal anti-inflammatory drugs (NSAIDs) and / or bDMARD inflammatory well-treated patients, characterized by absence of axial and peripheral arthritis as well as clinically detectable entesitis, as assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS < 2.1) and where normally CRP is documented.
Participant with the above mentioned diagnoses and relevant clinical status quo, followed regularly at one of the four departments are invited to participate in the study. Furthermore:
a. Receiving treatment on an outpatient basis
b. Diagnosed for at least 2 years
c. seropositive (anti CCP and/ or IgM RF) RA, radiology (MRI and/ or conventional X-ray) verified AS
d. RA: a stable inflammatory treatment situation achieved by ongoing cDMARD and / or bDMARD, 40 joint count without joint swelling
e. AS: a stable inflammatory treatment situation achieved by ongoing physiotherapy, NSAID, cDMARD and / or bDMARD: ASDAS < 2.1 for at least 4 weeks
f. Ongoing or earlier attempt of treatment with Paracetamol or NSAIDs with the outcome of parameters as mentioned in item e. or f.
g. Pain relief treatment unchanged at least 4 weeks before trial start
h. Minimum Pain VAS 50
|
|
| E.4 | Principal exclusion criteria |
a. Age < 18 years
b. Pregnancy or desiring pregnancy, ongoing breastfeeding
c. CRP > 10 mg/L
d. Swollen Joints
e. Comorbidities, more specific competitive rheumatologic disorders such as systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma or polymyositis, chronic pain condition based on a further etiology (e.g. fibromyalgia)
f. Severe competing cardiovascular, pneumological, neurological, endocrinological, gastro-enterological, urogenital or nephrological disorder
g. Major surgery performed <8 weeks before randomization or planned major surgical interventions
h. Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are commonly treated with oral or parenteral corticosteroids.
i. Verified cancer
j. Known actual or previous alcohol or drug abuse
k. Ongoing treatment with opiods and / or cannabis products and / or neuroleptics, or treatment terminated less than 4 weeks before trial start
l. Known hypersensitivity to the study compounds
m. Suspected or known schizophrenia or other psychotic illness in the family history or other significant psychiatric disorder in addition to depression associated with underlying condition
n. Epilepsy or recurrent seizures
o. Use of strong CYP3A4 inducers, e.g. rifampicin, carbamazepine, phenytoin, phenobarbital and perforate St. Johns wort.
p. severe hepatic/ renal impairment
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The study investigates the effect of CBD, more specific whether the add-on treatment with CBD results in a significantly improved pain situation as assessed by the number of patients achieving an improvement of pain-VAS with a reduction of Δ VAS> 20. Assessment takes place after 12 and 24 weeks of active treatment with CBD.
B. If the patient does not experience an acceptable effect of the CBD treatment in the assessment after 12 weeks (as defined by study protocol, i.e. pain VAS reduction > 20), the randomization is terminated and the treatment proceeds by a combination of CBD and THC.
THC 2.5 mg daily in week 13 and 14, increasing to 5 mg (2.5 mg x 2 daily) in the following two weeks. If no effect has occurred after week 16, the dose increases in the beginning of the 17th week to the maximum of 7.5 mg THC (2.5 mg x 3 daily) in the 3rd week
2. Thus, the study investigates the effect of the combination of CBD and THC, more specific whether the add-on treatment with CBD for 12 weeks followed by the combined treatment of CBD and THC for another 12 weeks results in a significantly improved pain situation as assessed by the number of patients achieving an improvement of pain-VAS with a reduction of Δ VAS> 20. Assessment takes place after 12 and 24 weeks of active treatment with CBD and after 12 weeks of active treatment with CBD followed by another 12 weeks combined treament with CBD and THC.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
During this study period, the participants are invited to four visits at one of the participating centers. At baseline and after 12 and 24 weeks( ± 7 days) respectively, the key data i.e. the pain VAS scores are determined and registered in the Danish nationwide quality registry DANBIO.
Briefly the data are obtained at consultation visit 1 (baseline), a consultation visit at week 12 ± 7 days, another consultation visit at week 24 ± 7 days.
Furthermore a follow up consultation visit will take place at week 36 ± 7 days and define this endpoint 12 weeks after the active treatment is terminated.
|
|
| E.5.2 | Secondary end point(s) |
Secondary outcomes
1) Outcomes: Clinical measurements, i.e. in RA the Disease Activity Score 28-joints (DAS28-CRP), Health Assessment Questionnaire (HAQ) and in the case of AS the Ankylosing spondylitis disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis (BAS)-scores for disease activity (BASDAI), function (BASFI) and measures (BASMI) are registered . Patient Reported Outcome Measures (PROMs) more specific, visual analogue scales (VAS) for fatigue, patient’s global; the Quality of Life (QoL) - and pain- scores SF-36 and PainDETECT are obtained.
Furthermore, the effect of intervention on attention and concentration is investigated using the following cognitive test: Trail Making Test (TMT) and Digit Symbol Substitution Test (DSST). Additionally, sleep quality is evaluated with the Pitssburgh Sleep Quality Index and the expected effect for treatment is measured with Credibility/expectancy Questionnare Devilly and semistructured course interviews.
Thus, the study investigates the effect of CBD, more specific whether the add-on treatment with CBD results in a significantly improved fatigue situation and as well more holistic qulaity of life situation as assessed by the number of patients achieving an improvement of fatigue-VAS with a reduction of Δ VAS> 20 and an improvement of global-VAS with a reduction of Δ VAS> 20.
Assessment takes place after 12 and 24 weeks of active treatment with CBD.
Furthermore, the study investigates the effect of the combination of CBD and THC, more specific whether the add-on treatment with CBD for 12 weeks followed by the combined treatment of CBD and THC for another 12 weeks results in a significantly improved fatigue situation and as well more holistic qulaity of life situation as assessed by the number of patients achieving an improvement of fatigue-VAS with a reduction of Δ VAS> 20 and an improvement of global-VAS with a reduction of Δ VAS> 20.
2) Exposures, i.e. current treatments with DMARDs and/or analgesics including dosing schedule and treatment onset.
3) Patient demographics, e.g. diagnosis, age and gender, height, weight and Body Mass index (BMI)
4) Comorbidities, e.g. cardiovascular disease, diabetes and hypertension
5) Life-style (blood pressure, exercise habits and smoking status)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At baseline and after 12 and 24 weeks( ± 7 days) respectively, the data are registered.
Furthermore, the effect of intervention on attention and concentration is investigated using the following cognitive test: Trail Making Test (TMT) and Digit Symbol Substitution Test (DSST). Additionally, sleep quality is evaluated with the Pitssburgh Sleep Quality Index and the expected effect for treatment is measured with Credibility/expectancy Questionnare Devilly and semistructured course interviews take place at timepoints baseline and after 12 and 24 weeks.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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