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The Norwegian Drug Monitoring Study (NOR-DRUM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03074656
Recruitment Status : Active, not recruiting
First Posted : March 9, 2017
Last Update Posted : February 10, 2020
Sponsor:
Collaborators:
Oslo University Hospital
University Hospital, Akershus
Information provided by (Responsible Party):
Espen A. Haavardsholm, MD PhD, Diakonhjemmet Hospital

Tracking Information
First Submitted Date  ICMJE February 10, 2017
First Posted Date  ICMJE March 9, 2017
Last Update Posted Date February 10, 2020
Actual Study Start Date  ICMJE March 1, 2017
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • Proportion of patients in remission defined by disease specific composite scores Study part A [ Time Frame: 30 weeks ]
    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.
  • Sustained disease control throughout the study period without disease worsening defined by disease specific composite scores Study part B [ Time Frame: 52 weeks ]
    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
Original Primary Outcome Measures  ICMJE
 (submitted: March 3, 2017)
  • Proportion of patients in remission defined by disease specific composite scores [ Time Frame: 30 weeks ]
    Study part A
  • Sustained disease control throughout the study period without disease worsening defined by disease specific composite scores [ Time Frame: 52 weeks ]
    Study part B
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • Time to sustained remission (Part A) [ Time Frame: Assessed at all time points up to 30 weeks ]
    Remission at all following visit
  • Patient's and physician's global assessment of disease activity (Part A and B) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Visual analogue scale (VAS) 0 mm-100 mm (100 mm worst outcome)
  • ESR (Part A and B) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    0-100 mmHg
  • CRP (Part A and B) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    mg/L
  • Occurrence of anti-drug antibodies (Part A and B) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Defined as ADAb ≥15 µg/L
  • Occurrence of drug discontinuation (Part A and B) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Infliximab discontinuation
  • Cost effectiveness, QALY [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B (Incremental Quality adjusted life years (QALYs) of the intervention arm and active comparator)
  • Cost effectiveness, ICERs [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B (Cost-effectiveness ratios (ICERs) of the intervention arm and active comparator)
  • Health utility (EQ-5D) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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
  • Quality of life (SF-36) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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.
  • Safety (adverse events frequency) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    A and B
  • Time to disease worsening [ Time Frame: 52 weeks ]
    Part B
  • Proportion of patients in remission, diagnostic subgroups [ Time Frame: 30 weeks (A) ]
    RA/PsA: DAS28 remission, SDAI remission, ACR/EULAR remission, SpA: ASDAS inactive disease, UC: PMS, CD: HBI, Ps PASI
  • Serum drug level [ Time Frame: Assessed at all time points up to 30 weeks ]
    Trough level
  • Proportion of patients with improvement defined by disease specific composite scores (Part A) [ Time Frame: 14 weeks ]
    • 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
  • Time to remission (Part A) [ Time Frame: Assessed at all time points up to week 30 ]
    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.
  • DAS28 (RA and PsA only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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
  • Partial Mayo score [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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
  • SDAI (RA and PsA only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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.
  • EULAR response (RA and PsA only) [ Time Frame: 30 weeks (A) ]
    Defined according to EULAR definition
  • ACR/EULAR remission [ Time Frame: 30 weeks (A) ]
    • TJC28 ≤ 1
    • SJC28 ≤ 1
    • CRP ≤ 10 (mg/l)
    • PGA ≤ 14
  • ACR response [ Time Frame: 30 weeks (A) ]
    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
  • DAPSA (PsA only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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.
  • BASDAI (SpA only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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).
  • ASDAS [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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
  • Partial Mayo Score (UC only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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
  • Harvey-Bradshaw Index (CD only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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.
  • Psoriasis Area and Severity Index (PASI) (Ps only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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
  • Modified Health Assessment Questionnaire [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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)
  • Rheumatoid Arthritis Impact of Disease (RA only) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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.
  • Psoriatic Arthritis Impact of Disease (PsAID) score [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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.
  • Inflammatory Bowel Disease Questionnaire (IBDQ) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    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)
  • Total drug consumption [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    mg/kg/ week
Original Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2017)
  • Time to sustained remission [ Time Frame: 30 weeks ]
    Part A
  • Patient's and physician's global assessment of disease activity [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Change in ESR [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Change in CRP [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Occurrence of anti-drug antibodies [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Reason for drug discontinuation [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Occurrence of drug discontinuation [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Cost effectiveness [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B (Incremental QALYs of the intervention arm and active comparator)
  • Cost effectiveness [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B (Cost-effectiveness ratios (ICERs) of the intervention arm and active comparator)
  • Health utility (EQ-5D) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Quality of life (SF-36) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    Part A and B
  • Safety (adverse events frequency) [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    A and B
  • Efficacy assessed by composite disease activity scores [ Time Frame: 30 weeks (A) and 52 weeks (B) ]
    A and B
  • Time to disease worsening [ Time Frame: 52 weeks ]
    Part B
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Norwegian Drug Monitoring Study
Official Title  ICMJE A NORwegian Multicentre Randomised Controlled Trial Assessing the Effectiveness of Tailoring Infliximab Treatment by Therapeutic DRUg Monitoring - The NOR-DRUM Study
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Rheumatoid Arthritis
  • Spondyloarthritis
  • Ankylosing Spondylitis
  • Crohn Disease
  • Ulcerative Colitis
  • Psoriasis
  • Psoriatic Arthritis
Intervention  ICMJE
  • Other: Therapeutic drug monitoring
    Treatment algorithm based on assessments of serum drug levels and anti-drug antibodies
  • Other: Standard care
    Treatment algorithm based on standard clinical assessments, without knowledge of serum drug levels and anti-drug antibodies
Study Arms  ICMJE
  • Experimental: Therapeutic drug monitoring
    Administration of infliximab according to a treatment strategy based on therapeutic drug monitoring and assessments of anti-drug antibodies
    Intervention: Other: Therapeutic drug monitoring
  • Active Comparator: Standard care
    Administration of infliximab according to standard clinical care, without knowledge of drug levels or status of anti-drug antibodies
    Intervention: Other: Standard care
Publications * Syversen SW, Goll GL, Jørgensen KK, Olsen IC, Sandanger Ø, Gehin JE, Warren DJ, Sexton J, Mørk C, Jahnsen J, Kvien TK, Bolstad N, Haavardsholm EA. Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study). Trials. 2020 Jan 6;21(1):13. doi: 10.1186/s13063-019-3734-4.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 7, 2020)
611
Original Estimated Enrollment  ICMJE
 (submitted: March 3, 2017)
600
Estimated Study Completion Date  ICMJE January 1, 2022
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

NOR-DRUM A

  1. 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
  2. Male or non-pregnant female
  3. ≥18 and < 75 years of age at screening
  4. A clinical indication to start INX
  5. Subject not in remission according to diagnosis-specific disease activity scores
  6. 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

  1. 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
  2. Male or non-pregnant female
  3. ≥18 and < 75 years of age at screening
  4. On maintenance therapy with infliximab for a minimum of 30 weeks and a maximum of 3 years
  5. A clinical indication for further infliximab treatment
  6. 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

  1. 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
  2. A positive screening for TB and hepatitis
  3. Inadequate birth control, pregnancy or subject considering becoming pregnant during the study period
  4. Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol difficult
  5. Prior use of infliximab within the last 6 months

NOR-DRUM B

  1. 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
  2. Inadequate birth control, pregnancy or subject considering becoming pregnant during the study period
  3. Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol difficult
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03074656
Other Study ID Numbers  ICMJE DIA2016-1
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Espen A. Haavardsholm, MD PhD, Diakonhjemmet Hospital
Study Sponsor  ICMJE Diakonhjemmet Hospital
Collaborators  ICMJE
  • Oslo University Hospital
  • University Hospital, Akershus
Investigators  ICMJE
Principal Investigator: Espen A Haavardsholm, MD, PhD Diakonhjemmet Hospital
Study Director: Tore K Kvien, MD, PhD Diakonhjemmet Hospital
PRS Account Diakonhjemmet Hospital
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP