The Norwegian Drug Monitoring Study

Study Overview
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Brief Summary
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Infliximab and other TNF-inhibitors have revolutionised the treatment of several immunological inflammatory diseases. Still, more than half of the patients either do not respond sufficiently to infliximab therapy or loose efficacy over time. The large individual variation in the serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be main reasons for these treatment failures. An individualised treatment strategy based on systematic assessments of serum drug concentrations, therapeutic drug monitoring, has been proposed as a clinical tool to optimise efficacy of infliximab treatment. Therapeutic drug monitoring seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy still remain to be shown. The NOR-DRUM study is planned as a national, randomised controlled multicentre trial in two parts aiming to assess the effectiveness of therapeutic drug monitoring in order to achieve remission in patients with immunological inflammatory diseases starting infliximab treatment (part A) and in order to maintain disease control in patients on maintenance infliximab treatment (part B). The results of the NOR-DRUM study will hopefully contribute to an implementation of a personalised medicine approach to treatment with infliximab and other biological drugs.

Official Title
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A NORwegian Multicentre Randomised Controlled Trial Assessing the Effectiveness of Tailoring Infliximab Treatment by Therapeutic DRUg Monitoring - The NOR-DRUM Study

Conditions
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Rheumatoid Arthritis, Spondyloarthritis, Ankylosing Spondylitis, Crohn Disease, Ulcerative Colitis, Psoriasis, Psoriatic Arthritis

Intervention / Treatment
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* Other: Therapeutic drug monitoring
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NOR-DRUM A A clinical diagnosis of one of the following; rheumatoid arthritis, spondyloarthritis (including ankylosing spondylitis), psoriatic arthritis*, ulcerative colitis, Crohn's disease or chronic plaque psoriasis Male or non-pregnant female ≥18 and < 75 years of age at screening A clinical indication to start INX Subject not in remission according to diagnosis-specific disease activity scores Subject capable of understanding and signing an informed consent form Patients with psoriatic arthritis with predominantly axial manifestations should be included and assessed as spondyloarthritis NOR-DRUM B A clinical diagnosis of one of the following; rheumatoid arthritis, spondyloarthritis (including ankylosing spondylitis), psoriatic arthritis*, ulcerative colitis, Crohn's disease or chronic plaque psoriasis Male or non-pregnant female ≥18 and < 75 years of age at screening On maintenance therapy with infliximab for a minimum of 30 weeks and a maximum of 3 years A clinical indication for further infliximab treatment Subject capable of understanding and signing an informed consent form Patients with psoriatic arthritis and predominantly axial manifestations should be included and assessed as spondyloarthritis Exclusion Criteria: NOR-DRUM A Major co-morbidities, such as previous malignancies within the last 5 years, severe diabetes mellitus, severe infections (including HIV), uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4), severe respiratory diseases, demyelinating disease, significant chronic widespread pain syndrome, laboratory abnormalities or significant renal or hepatic disease and/or other diseases or conditions where treatment with infliximab is either found contra-indicated by the clinician or which make adherence to the protocol difficult A positive screening for TB and hepatitis Inadequate birth control, pregnancy or subject considering becoming pregnant during the study period Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol difficult Prior use of infliximab within the last 6 months NOR-DRUM B Major co-morbidities, such as previous malignancies within the last 5 years, severe diabetes mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4), severe respiratory diseases, demyelinating disease, significant chronic widespread pain syndrome, laboratory abnormalities or significant renal or hepatic disease and/or other diseases or conditions where treatment with infliximab is either found contra-indicated by the clinician or which make adherence to the protocol difficult Inadequate birth control, pregnancy or subject considering becoming pregnant during the study period Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol difficult

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic drug monitoring<br>Administration of infliximab according to a treatment strategy based on therapeutic drug monitoring and assessments of anti-drug antibodies | Other: Therapeutic drug monitoring<br>* Treatment algorithm based on assessments of serum drug levels and anti-drug antibodies<br>|
| Active Comparator: Standard care<br>Administration of infliximab according to standard clinical care, without knowledge of drug levels or status of anti-drug antibodies | Other: Standard care<br>* Treatment algorithm based on standard clinical assessments, without knowledge of serum drug levels and anti-drug antibodies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients in remission defined by disease specific composite scores Study part A | Definition of remission: DAS 28 score <2.6 in patients with RA and PsA, ASDAS score <1.3 in patients with SpA, Mayo score of ≤2 with no sub scores >1 in patients with UC, HBI score of ≤4 in CD and PASI score of ≤4 in patients with Ps. | 30 weeks | 
| Sustained disease control throughout the study period without disease worsening defined by disease specific composite scores Study part B | Definition of disease worsening: RA/PsA: Change DAS28 of ≥ 1.2 and min DAS 3.2 SpA: Increase in ASDAS of ≥1.1 and min ASDAS of 2.1 UC: Increase in Partial Mayo score of ≥ 3 and min score of ≥ 5 CD: Increase in HBI of ≥ 4 points and min score of 7 Ps: Increase in PASI of ≥ 3 points and min PASI score of 5 Or: Patient and investigator consensus on disease worsening | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sustained remission (Part A) | Remission at all following visit | Assessed at all time points up to 30 weeks | 
| Patient's and physician's global assessment of disease activity (Part A and B) | Visual analogue scale (VAS) 0 mm-100 mm (100 mm worst outcome) | 30 weeks (A) and 52 weeks (B) | 
| ESR (Part A and B) | 0-100 mmHg | 30 weeks (A) and 52 weeks (B) | 
| CRP (Part A and B) | mg/L | 30 weeks (A) and 52 weeks (B) | 
| Occurrence of anti-drug antibodies (Part A and B) | Defined as ADAb ≥15 µg/L | 30 weeks (A) and 52 weeks (B) | 
| Occurrence of drug discontinuation (Part A and B) | Infliximab discontinuation | 30 weeks (A) and 52 weeks (B) | 
| Cost effectiveness, QALY | Part A and B (Incremental Quality adjusted life years (QALYs) of the intervention arm and active comparator) | 30 weeks (A) and 52 weeks (B) | 
| Cost effectiveness, ICERs | Part A and B (Cost-effectiveness ratios (ICERs) of the intervention arm and active comparator) | 30 weeks (A) and 52 weeks (B) | 
| Health utility (EQ-5D) | EuroQol 5 (EQ-5D) dimensions The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state | 30 weeks (A) and 52 weeks (B) | 
| Quality of life (SF-36) | The SF-36 is a multi-purpose, short-form health survey with 36 questions. The SF-36 will be scored according to RAND 36-Item Health Survey 1.0 to form eight measures scores 0-100 (100 worst outcome): physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. | 30 weeks (A) and 52 weeks (B) | 
| Safety (adverse events frequency) | A and B | 30 weeks (A) and 52 weeks (B) | 
| Time to disease worsening | Part B | 52 weeks | 
| Proportion of patients in remission, diagnostic subgroups (overall in B) | RA/PsA: DAS28 remission, SDAI remission, ACR/EULAR remission, SpA: ASDAS inactive disease, UC: PMS, CD: HBI, Ps PASI | 30 weeks (A) and 52 weeks (B) | 
| Serum drug level | Trough level | Assessed at all time points up to 30 weeks | 
| Proportion of patients with improvement defined by disease specific composite scores (Part A) | Improvement in RA and PsA Improvement is defined as a decrease in DAS28 of ≥1.2 from baseline Improvement in SpA Improvement is defined as a decrease in ASDAS of ≥1.1 from baseline Improvement in UC Improvement in UC is defined as a decrease in the partial Mayo score of ≥ 3 points from baseline or a partial Mayo score of 0 Improvement in CD Improvement in CD is defined as a decrease in HBI of ≥ 4 points from baseline Improvement in Ps Improvement in Ps is defined as PASI 50 (A 50% decrease in the PASI obtained at baseline) Patient and investigators consensus on improvement | 14 weeks | 
| Time to remission (Part A) | Definition of remission: DAS 28 score <2.6 in patients with RA and PsA, ASDAS score <1.3 in patients with SpA, Mayo score of ≤2 with no sub scores >1 in patients with UC, HBI score of ≤4 in CD and PASI score of ≤4 in patients with Ps. | Assessed at all time points up to week 30 | 
| DAS28 (RA and PsA only) | The 28-joint Disease Activity Score (DAS28) includes the 28- tender joint counts (TJC28), 28-swollen joint counts (SJC28), Erythrocyte Sedimentation Rate (ESR) and Patient Global Assessment (PGA) on a VAS According to DAS28, the following cut-points are used: High disease activity: DAS28 > 5.1 Moderate disease activity: 5.1 ≥ DAS28>3.2 Low disease activity: 3.2 ≥ DAS28 ≥ 2.6 In remission: DAS28 < 2.6 | 30 weeks (A) and 52 weeks (B) | 
| Partial Mayo score | The Mayo score consists of four components (rectal bleeding, stool frequency, physician rating of disease activity, and mucosal appearance at endoscopy) rated from 0-3 that are summed to give a total score that ranges from 0-12. The non-invasive partial Mayo score (PMS) does not require an endoscopy, and thereby ranging from 0-9. Remission is defined as a partial Mayo score of ≤ 2 with no individual subscore >1 | 30 weeks (A) and 52 weeks (B) | 
| SDAI (RA and PsA only) | The Simplified Disease Activity Index (SDAI) includes TCJ28, SJC28, PGA, PhGA and CRP. In remission: SDAI ≤ 3.3. High values denotes worse outcomes. High values denotes worse outcomes. | 30 weeks (A) and 52 weeks (B) | 
| EULAR response (RA and PsA only) | Defined according to EULAR definition | 30 weeks (A) | 
| ACR/EULAR remission | TJC28 ≤ 1 SJC28 ≤ 1 CRP ≤ 10 (mg/l) PGA ≤ 14 | 30 weeks (A) | 
| ACR response | If a patient experiences a flare and treatment is escalated, the ACR response rates ACR20, ACR50, ACR70 and ACR90 as well as ACR remission rates will be calculated. An ACR20 response is defined if the following criteria are fulfilled: 20% improvement in RAI AND 20% improvement in swollen joint count 44 AND 20% improvement in at least 3 of 5 other core set items The other core set items consist of: Investigator global assessment of disease activity Patient global assessment of disease activity Patient pain Disability ESR/CRP | 30 weeks (A) | 
| DAPSA (PsA only) | Disease Activity index for PSoriatic Arthritis (DAPSA) is calculated as follows: TJC68 + SJC66 + CRP(mg/L)/10 + PGA(0-100)/10+VAS Pain(0-100)/10. High values denotes worse outcomes. | 30 weeks (A) and 52 weeks (B) | 
| BASDAI (SpA only) | The Bath Ankylosing Spondylitits Disease Activity Index (BASDAI) includes six questions pertaining to the five major symptoms of ankylosing spondylitis: fatigue (Q1), spinal pain (Q2), joint pain/swelling (Q3), areas of localized tenderness (Q4), morning stiffness duration (Q5) and morning stiffness severity (Q6). Each question is scored on an NRS (0-10). | 30 weeks (A) and 52 weeks (B) | 
| ASDAS | The Ankylosing Spondylitis Disease Activity Score (ASDAS) is computed based on patient reported outcomes (components of BASDAI) and the CRP. The ASDAS-CRP is calculated as follows: ASDAS-CRP=0.121*total back pain + 0.0110*patient global + 0.073*peripheral pain/swelling + 0.058*duration of morning stiffness + 0.579*ln(CRP+1 High values denotes worse outcomes | 30 weeks (A) and 52 weeks (B) | 
| Partial Mayo Score (UC only) | The Mayo score consists of four components (rectal bleeding, stool frequency, physician rating of disease activity, and mucosal appearance at endoscopy) rated from 0-3 that are summed to give a total score that ranges from 0-12. The non-invasive partial Mayo score (PMS) does not require an endoscopy, and thereby ranging from 0-9. Remission is defined as a partial Mayo score of ≤ 2 with no individual subscore >1 | 30 weeks (A) and 52 weeks (B) | 
| Harvey-Bradshaw Index (CD only) | The Harvey-Bradshaw index (HBI) consists of five domains, general well-being (0-4), abdominal pain (0-3), number of liquid soft stools per day, abdominal mass (0-3) and number of predefined complications. The scores of each sub-domain is summed up to compute the HBI. Remission is defined as a HBI score ≤ 4 points. | 30 weeks (A) and 52 weeks (B) | 
| Psoriasis Area and Severity Index (PASI) (Ps only) | A PASI 50/75 means a 50% /75% reduction in the PASI score. Complete clearance is defined as PASI=0, mild to moderate psoriasis is defined as PASI < 10, moderate to severe psoriasis between 10 and 20 and severe psoriasis above 20. Remission is defined as PASI <4 | 30 weeks (A) and 52 weeks (B) | 
| Modified Health Assessment Questionnaire | Each item of the Modified Health Assessment Questionnaire (MHAQ) is scored on a categorical 0-3 scale and the sum score is divided by 8 to form the MHAQ score 0.0 to 3.0 (3.0 worst outcome possible) | 30 weeks (A) and 52 weeks (B) | 
| Rheumatoid Arthritis Impact of Disease (RA only) | The Rheumatoid Arthritis Impact of Disease (RAID) score is calculated based on seven numerical rating scales (NRS) questions. Each NRS is assessed as a number between 0 and 10. The seven NRS correspond to pain, function, fatigue, sleep, emotional wellbeing, physical wellbeing and coping/self-efficacy. | 30 weeks (A) and 52 weeks (B) | 
| Psoriatic Arthritis Impact of Disease (PsAID) score | Psoriatic Arthritis Impact of Disease (PsAID) score is a questionnaire with 9 domains of health. The nine domains with relative weights are: pain (0.174), fatigue (0.131), skin (0.121), work and/or leisure activities (0.110), function (0.107), discomfort (0.098), sleep (0.089), coping (0.087) and anxiety (0.085), each rated on an NRS (0-10). The rates of each domain are weighted and summed to form a score in the range of 0-10 (10 worst outcome possible). The final RAID score is computed. The scale 0-10 where higher figures indicate worse status. | 30 weeks (A) and 52 weeks (B) | 
| Inflammatory Bowel Disease Questionnaire (IBDQ) | The Inflammatory Bowel Disease Questionnaire (IBDQ) is widely used tool to measure health-related quality of life in patients with inflammatory bowel diseases. The questionnaire consists of 32 questions scored in four domains: bowel symptoms, emotional health, systemic systems and social function. The total IBDQ score is the sum of all the question scores, ranging 32 to 224 (224 worst possible) | 30 weeks (A) and 52 weeks (B) | 
| Total drug consumption | mg/kg/ week | 30 weeks (A) and 52 weeks (B) | 
| Dermatology Life Quality Index (DLQI) | The Dermatology Life Quality Index (DLQI) consists of 10 questions concerning patients' perception of the impact of skin diseases on different aspects of their health-related quality of life over the last week. It has been validated for adult dermatology patients aged 16 years and older. The items of the DLQI encompass aspects of symptoms and feelings, daily activities, leisure, work or school, personal relationships and the side effects of treatment. Each question is scored on a 4-point Likert scale: Not at all/Not relevant=0, A little=1, A lot=2 and Very much=3. Scores of individual items (0-3) are added to yield a total score (0-30); higher scores mean greater impairment of patient's QoL. The DLQI will only be presented to patients with chronic plaque psoriasis. | 30 weeks (A) and 52 weeks (B) | 
| Calprotectin | Faecal calprotectin is an inflammatory marker for IBD. It is measured in mg/kg | 30 weeks (A) and 52 weeks (B) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TDM, infliximab, therapeutic drug monitoring, anti drug antibodies