Clinical trial NCT03074656: The Norwegian Drug Monitoring Study
Official title: A NORwegian Multicentre Randomised Controlled Trial Assessing the Effectiveness of Tailoring Infliximab Treatment by Therapeutic DRUg Monitoring - The NOR-DRUM Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Rheumatoid Arthritis
Spondyloarthritis
Ankylosing Spondylitis
Crohn Disease
Ulcerative Colitis
Psoriasis
Psoriatic Arthritis
Keywords: infliximab
therapeutic drug monitoring
anti drug antibodies
TDM
Lead sponsor: Diakonhjemmet Hospital
Sponsor class: OTHER
Collaborators: name: Oslo University Hospital
name: University Hospital, Akershus
First posted: 2017-03-09
Enrollment: 611
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Proportion of patients in remission defined by disease specific composite scores Study part A
timeFrame: 30 weeks
measure: Sustained disease control throughout the study period without disease worsening defined by disease specific composite scores Study part B
timeFrame: 52 weeks
Secondary outcomes:
measure: Time to sustained remission (Part A)
timeFrame: Assessed at all time points up to 30 weeks
measure: Patient's and physician's global assessment of disease activity (Part A and B)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: ESR (Part A and B)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: CRP (Part A and B)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Occurrence of anti-drug antibodies (Part A and B)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Occurrence of drug discontinuation (Part A and B)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Cost effectiveness, QALY
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Cost effectiveness, ICERs
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Health utility (EQ-5D)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Quality of life (SF-36)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Safety (adverse events frequency)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Time to disease worsening
timeFrame: 52 weeks
measure: Proportion of patients in remission, diagnostic subgroups (overall in B)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Serum drug level
timeFrame: Assessed at all time points up to 30 weeks
measure: Proportion of patients with improvement defined by disease specific composite scores (Part A)
timeFrame: 14 weeks
measure: Time to remission (Part A)
timeFrame: Assessed at all time points up to week 30
measure: DAS28 (RA and PsA only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Partial Mayo score
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: SDAI (RA and PsA only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: EULAR response (RA and PsA only)
timeFrame: 30 weeks (A)
measure: ACR/EULAR remission
timeFrame: 30 weeks (A)
measure: ACR response
timeFrame: 30 weeks (A)
measure: DAPSA (PsA only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: BASDAI (SpA only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: ASDAS
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Partial Mayo Score (UC only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Harvey-Bradshaw Index (CD only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Psoriasis Area and Severity Index (PASI) (Ps only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Modified Health Assessment Questionnaire
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Rheumatoid Arthritis Impact of Disease (RA only)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Psoriatic Arthritis Impact of Disease (PsAID) score
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Inflammatory Bowel Disease Questionnaire (IBDQ)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Total drug consumption
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Dermatology Life Quality Index (DLQI)
timeFrame: 30 weeks (A) and 52 weeks (B)
measure: Calprotectin
timeFrame: 30 weeks (A) and 52 weeks (B)
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Akershus University Hospital
state: Lørenskog
city: Arendal
country: Norway
facility: Sørlandet Sykehus, Arendal
city: Bergen
country: Norway
facility: Haukeland, HELSE BERGEN HF,
city: Bodø
country: Norway
facility: Bodø, NORDLANDSSYKEHUSET
city: Drammen
country: Norway
facility: Drammen, VESTRE VIKEN HF
city: Elverum
country: Norway
facility: Elverum, SYKEHUSET INNLANDET HF
city: Førde
country: Norway
facility: Helse Førde Hf
city: Hamar
country: Norway
facility: Hamar, SYKEHUSET INNLANDET HF
city: Haugesund
country: Norway
facility: HAUGESUND SANITETSFORENING revmatismesykehus
city: Haugesund
country: Norway
facility: Haugesund Sjukehus
city: Kristiansand
country: Norway
facility: SØRLANDET SYKEHUS HF Kristiansand
city: Lillehammer
country: Norway
facility: REVMATISMESYKEHUSET AS, Lillehammer
city: Moss
country: Norway
facility: Sykehuset Østfold Moss
city: Oslo
country: Norway
facility: Rikshospitalet
city: Oslo
country: Norway
facility: Diakonhjemmet Sykehus
city: Skien
country: Norway
facility: Betanien Hospital
city: Stavanger
country: Norway
facility: Stavanger Universitetssjukehus
city: Tromsø
country: Norway
facility: Tromsø, UNIVERSITETSSYKEHUSET NORD-NORGE HF
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Tønsberg
country: Norway
facility: Sykehuset Vestfold, Tønsberg
city: Ålesund
country: Norway
facility: Ålesund, HELSE MØRE OG ROMSDAL HF
Study officials:
affiliation: Diakonhjemmet Hospital
name: Espen A Haavardsholm, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Diakonhjemmet Hospital
name: Tore K Kvien, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Syversen SW, Jorgensen KK, Goll GL, Brun MK, Sandanger O, Bjorlykke KH, Sexton J, Olsen IC, Gehin JE, Warren DJ, Klaasen RA, Noraberg G, Bruun TJ, Dotterud CK, Ljosa MKA, Haugen AJ, Njalla RJ, Zettel C, Ystrom CM, Bragnes YH, Skorpe S, Thune T, Seeberg KA, Michelsen B, Blomgren IM, Strand EK, Mielnik P, Torp R, Mork C, Kvien TK, Jahnsen J, Bolstad N, Haavardsholm EA. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA. 2021 Dec 21;326(23):2375-2384. doi: 10.1001/jama.2021.21316.
citation: Syversen SW, Goll GL, Jorgensen KK, Sandanger O, Sexton J, Olsen IC, Gehin JE, Warren DJ, Brun MK, Klaasen RA, Karlsen LN, Noraberg G, Zettel C, Ljosa MKA, Haugen AJ, Njalla RJ, Bruun TJ, Seeberg KA, Michelsen B, Strand EK, Skorpe S, Blomgren IM, Bragnes YH, Dotterud CK, Thune T, Ystrom CM, Torp R, Mielnik P, Mork C, Kvien TK, Jahnsen J, Bolstad N, Haavardsholm EA. Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA. 2021 May 4;325(17):1744-1754. doi: 10.1001/jama.2021.4172.
citation: Syversen SW, Goll GL, Jorgensen KK, Olsen IC, Sandanger O, Gehin JE, Warren DJ, Sexton J, Mork 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.