Overview of study design
The NOR-DRUM study is a randomised, controlled, parallel-group, open, comparative, multi-centre, national, superiority, phase IV study with two separate parts (NOR-DRUM A and NOR-DRUM B) comparing TDM of INX treatment to standard INX treatment. The study design is outlined in Figure 1. Schedule of enrolment, interventions and assessments are given in Figure 2 (NOR-DRUM A) and Figure 3 (NOR-DRUM B). The Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) checklist detailing the items in this clinical trial protocol is provided as Additional file 1.
Study setting and population
All Norwegian hospitals treating patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), ulcerative colitis (UC), Crohn’s disease (CD) or psoriasis (Ps) are invited to participate. The study is conducted at 21 study centres distributed across all four Norwegian health regions. After initiation of the sites, potential study participants (patients who are either starting INX or who have been treated with INX for minimum 30 weeks or maximum 3 years) are informed about the study by their treating physician. To maintain a high rate of enrolment, the study lead and the clinical coordinators (one rheumatologist, one gastroenterologist and one dermatologist) are in frequent contact with the local PIs and study nurses, holding national investigators meetings and are frequently sending out newsletters. After giving informed consent, patients are screened and if eligible included in the study by study personnel. Inclusion- and exclusion criteria are shown in Table 1. Recruitment of patients is taking place in a competitive manner until 400 patients have been included in NOR-DRUM A and 450 patients have been included in NOR-DRUM BAs the study visits are carried out according to the patient’s INX treatment schedule we expect a high retention rate in the NOR-DRUM trial. If a patient is missing for scheduled INX infusion, the study nurse will contact the patient and ensure that a new appointment for infusion/study visit is scheduled.
Table 1 Eligibility criteria
Inclusion criteria
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NOR-DRUM A
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All of the following conditions must apply to the prospective patient at screening;
1. A clinical diagnosis of one of the following; RA, SpA, PsA*, UC, CD or Ps
2. Male or non-pregnant female
3. ≥18 and < 75 years of age at screening
4. A clinical indication to start INX
5. Patient not in remission according to diagnosis-specific disease activity scores
6. Patient capable of understanding and signing an informed consent form
*PsA with predominantly axial manifestations should be included and assessed as SpA
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NOR-DRUM B
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All of the following conditions must apply to the prospective patient at screening;
1. A clinical diagnosis of one of the following; RA, SpA, PsA*, UC, CD or Ps
2. Male or non-pregnant female
3. ≥18 and < 75 years of age at screening
4. On maintenance therapy with INX for a minimum of 30 weeks and a maximum of 3 years
5. A clinical indication for further INX treatment
6. Patient capable of understanding and signing an informed consent form
*PsA with predominantly axial manifestations should be included and assessed as SpA
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Exclusion Criteria
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NOR-DRUM A
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A patient will be excluded from the study if they meet any of the following criteria:
1. Major co-morbidities, such as previous malignancies within the last 5 years, severe diabetes mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease, severe respiratory diseases, demyelinating disease, significant chronic widespread pain syndrome, laboratory abnormalities/significant renal or hepatic disease and/or other diseases or conditions where treatment with INX is either found contra-indicated by the clinician or which make adherence to the protocol difficult
2. A positive screening for tuberculosis or viral hepatitis
3. Inadequate birth control, pregnancy or patient 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 INX within the last 6 months
6. For patients with UC and CD: functional colostomy or ileostomy or extensive colonic resection with less than 25 cm of the colon left in situ
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NOR-DRUM B
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A patient will be excluded from the study if they meet any of the following criteria:
1. Major co-morbidities, such as previous malignancies within the last 5 years, severe diabetes mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease, severe respiratory diseases, demyelinating disease, significant chronic widespread pain syndrome, laboratory abnormalities/significant renal or hepatic disease and/or other diseases or conditions where treatment with INX is either found contra-indicated by the clinician or which make adherence to the protocol difficult
2. Inadequate birth control, pregnancy or patient 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
4. For patients with UC and CD: functional colostomy or ileostomy. Extensive colonic resection with less than 25 cm of the colon left in situ.
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Abbreviations: CD: Crohn’s disease; INX: Infliximab; Ps: Psoriasis; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; SpA: Spondyloarthritis; UC: Ulcerative colitis
Randomisation procedures and allocation
Eligible patients are assigned a unique patient identification number. In NOR-DRUM A, patients are allocated in a 1:1 ratio between intervention and control, using a computer randomisation procedure stratifying by diagnosis (RA, SpA, PsA, UC, CD, Ps). The randomisation is blocked within each stratum. In NOR-DRUM B, patients are allocated in a 1:1 ratio between intervention and control, using a computer randomisation procedure stratifying by diagnosis (RA, SpA, PsA, UC, CD, Ps) and 1) by study arm (intervention or control) if the patient originates from NOR-DRUM A or 2) by prior or no prior TDM in the clinic (defined as one or more assessments of serum drug level during the last 3 infusions) if the patient originates from NOR-DRUM B. The randomisation is blocked within each stratum. The computer-generated randomised allocation sequence is imported into the electronic Case Report Form (eCRF) system and made available to site personnel. The allocation is not available until the patient has signed the informed consent form, deemed eligible to participate and entered in the eCRF. Authorised personnel will only know the allocation of included patients, but not for future patients. Details of block size and allocation sequence generation are kept unavailable to those who enrol patients or assign treatment.
Intervention
In both study parts (A and B) patients are randomised to either:
- Administration of INX according to a treatment strategy based on TDM and assessments of ADAb (intervention group)
- Administration of INX according to standard clinical care, without knowledge of drug levels or ADAb status (control group)
The treatment strategy in the intervention group is outlined in Figure 4 and 5. At each visit/infusion, serum levels of INX (s-INX) and ADAb are assessed, and in the intervention group the levels are reported back to the investigators who will adjust the dose or infusion interval according to the strategy (Figure 4 and 5). During the first infusions (up to and including week 14), the dose is adjusted by decreasing the infusion interval (Figure 4). After week 14, the INX dose or interval can be increased or decreased to reach the target range of 3-8 µg/ml (Figure 5).
The randomised treatment strategy is continued for the whole study period (38 (+/-4) weeks in NOR-DRUM A and 52 (+/-4) weeks in NOR-DRUM B) with study visits at each scheduled INX infusion. After 38 weeks in NOR-DRUM A, patients who are still on INX are included and re-randomised in NOR-DRUM B. Patients who for any reason (lack of efficacy, side effects or other) are switched to another treatment during the study, will still be followed with study visits according to the intentional infusion intervals and remain in the allocated group. Immunosuppressive concomitant treatments initiated before inclusion in the study are continued. To improve compliance to the strategy in the intervention group, an interactive eCRF with guidelines for INX dosing based on INX levels have been developed (Viedoc 4™, Uppsala, Sweden).
In NOR-DRUM A, improvement is assessed after 3 months (Week 14 visit), for which a separate algorithm is used (Figure 4). Improvement is defined as: RA and PsA: a decrease in Disease Activity Score using 28 joints (DAS 28-SR) of ≥1.2 from baseline; SpA: a decrease in Ankylosing Spondylitis Disease Activity-C-reactive protein Score (ASDAS-CRP) of ≥1.1 from baseline; UC: a decrease in the partial Mayo score of ≥ 3 from baseline or a partial Mayo score of 0; CD: a decrease in the Harvey-Bradshaw (HBI) of ≥ 4 from baseline; Ps: Psoriasis Area and Severity Index (PASI) 50 (a 50% reduction in the PASI score from baseline); Investigator and patient consensus on improvement: If a patient does not fulfil the formal definition, but both the patient and the investigator agree that the patient has improved this should be considered as improvement but recorded separately in the CRF.
Patients have the right to withdraw from the study at any time for any reason. In the case that a patient decides to do so, they will be asked if they can still be contacted for further information, so that a final evaluation can be made with an explanation for the withdrawal, including assessment of possible adverse events.
The investigator may discontinue the patient from further study participation if such participation will put the patient at risk of medical injury or there has been a major protocol violation.
Outcomes
Primary outcomes
The primary outcome in NOR-DRUM A is remission at week 30, while the primary outcome in NOR-DRUM B is sustained disease control without disease worsening throughout the study period. Remission and disease worsening are defined as disease specific activity scores as summarised in Table 2.
Table 2 Definition of primary outcomes
Disease
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Disease activity scoring tool
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Value defining
remission
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Values defining
disease worsening
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RA
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Disease Activity Score using 28 joint (DAS 28)
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<2.6
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Increase ≥1.2 from inclusion and a minimum score of 3.2
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PsA
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Disease Activity Score using 28 joint (DAS 28)
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<2.6
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Increase ≥1.2 from inclusion and a minimum score of 3.2
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SpA
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Ankylosing Spondylitis Disease Activity Score with CRP (ASDAS-CRP)
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<1.3
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Increase of ≥1.1 from inclusion and a minimum of 2.1
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CD
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Harvey-Bradshaw Index (HBI) score
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≤4
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Increase of ≥ 3 points from inclusion and a minimum partial score of 5 points
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UC
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Partial Mayo score
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≤2 with no sub scores >1
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Increase of ≥ 3 points from inclusion and a minimum partial score of 5 points
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Ps
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Psoriasis Area and Severity Index (PASI)
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≤4
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Increase ≥4 points from inclusion and a minimum score of 7 points
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Abbreviations: CD: Crohn’s disease; Ps: Psoriasis; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; SpA: Spondyloarthritis; UC: Ulcerative colitis
Additionally, disease worsening can be recorded based on patient and investigator consensus: If a patient does not fulfil the formal definition, but experiences a clinically significant worsening according to both the investigator and patient that leads to a major change in treatment (i.e. switching from INX to another immunosuppressant/Disease-Modifying Anti-Rheumatic Drug (DMARD), adding a immunosuppressant/DMARD, increasing the dose of a concomitant immunosuppressant/DMARD, adding systemic glucocorticoids (po., iv. or im.), receiving more than one i.a. glucocorticoid injection at one visit or increasing INX for clinical reasons) this should be considered as a disease worsening but be recorded separately in the eCRF.
Secondary and exploratory outcomes
In NOR-DRUM A, secondary outcomes include generic outcomes; time to sustained remission (a status of remission on all consecutive visits following the initial obtained remission), patient’s and physician’s global assessment of disease activity, biochemical parameters of disease activity, occurrence of ADAb, occurrence of and reason for drug discontinuation, safety and cost effectiveness, utility and quality of life in addition to disease specific activity composite scores assessed at all visits; RA: DAS28, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Rheumatoid Arthritis Impact of Disease (RAID), Modified Health Assessment Questionnaire (MHAQ), PsA: DAS28, Psoriatic Arthritis Impact of Disease (PsAID) score-9, Disease Activity Psoriatic Arthritis (DAPSA) score, MHAQ, Dermatology Life Quality Index (DLQI), SpA: ASDAS, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), MHAQ, UC: Partial Mayo Score, Inflammatory Bowel Disease Questionnaire (IBDQ), CD: HBI, IBDQ, Ps: PASI, DLQI. In NOR-DRUM B secondary outcomes include generic outcomes; time to disease worsening, patient and physician global assessment of disease activity, biochemical parameters of disease activity, occurrence of ADAb, occurrence of and reason for drug discontinuation, safety and cost effectiveness, utility and quality of life in addition to disease specific activity scores assessed at all visits as listed above for NOR-DRUM A.
Study schedule and assessments
The schedule of enrolment, interventions and assessments in NOR-DRUM A and NOR-DRUM B are depicted in the SPIRIT figures 2 and 3. The study visits are carried out according to the patient’s INX treatment schedule and the number of visits varies depending on the infusion intervals. Extra study visits are arranged at the request of the patient and/or the investigator. If INX treatment is terminated, patients are assessed according to the original infusion plan (every 8. weeks). The assessments performed at each visit are shown in figure 2 and 3. The primary outcome in NOR-DRUM A (remission) will be recorded at the week 30 (+/- 2 weeks) visit. In NOR-DRUM B the primary outcome (occurrence of disease worsening) is recorded at every visit during the 12 month follow-up period. If the patients perceive increased disease activity, a non-scheduled visit will be arranged within one week in order to identify occurrence of disease worsening.
Laboratory assessments
Blood samples are collected at all visits prior to the infusion. Hematology and clinical chemistry parameters, as well as acute phase reactants and faecal calprotectin in IBD-patients, are analysed at the local hospital laboratory or referred to other laboratories according to local practice. Samples for bio banking and measurement of serum INX-levels and ADAb are sent to the Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet. Serum INX-levels (trough) and ADAb will be measured using in-house assays automated on the AutoDELFIA immunoassay platform (PerkinElmer, Waltham, MA) (33). Laboratory data are stored in the laboratory information system, and results for patients in the intervention group are reported to the local investigator. All results will be transferred to the principal investigator upon completion of the study.
Statistics
Sample size and power considerations
Sample sizes are determined for each of the two study parts separately. NOR-DRUM A: Under the assumption of an (absolute) increase in remission rate of 15% (from 40 to 55%) 358 completed patients are needed in order to reject the null hypothesis at a 5% significance level with 80% power. Adjusting for possible drop-outs, we plan to randomise 400 patients.
NOR-DRUM B: Under the assumption of an (absolute) decrease in proportion of patients with disease worsening of 12.5% (from 30 to 17.5%) 414 completed patients are needed in order to reject the null hypothesis at a 5% significance level with 85% power. Adjusting for possible drop-outs, we plan to randomise 450 patients.
Statistical plan
Separate statistical analysis plans (SAP) for each study part will provide further details on the planned statistical analyses. The SAPs will be finalised, signed and dated prior to data lock for each of the parts.
Populations
The primary outcomes of both study parts will be analysed in the intention to treat (ITT) population. The ITT population consists of all randomised patients who have been exposed to the intervention (completed first infusion visit in NOR-DRUM B or completed second infusion visit in NOR-DRUM A). The per-protocol (PP) population will in each of the two study parts consist of all randomised patients who sufficiently comply with the protocol. Criteria for inclusion in the PP population will be specified in the SAP, and the final criteria will be defined prior to database lock. The safety population consist of all patients who have been exposed to the intervention (same definition as the ITT population).
Statistical model
The primary outcomes will be analysed using logistic regression with strategy treatment group as primary explanatory variable, adjusted for stratification factors used at randomisation. Although this is a multicentre study, study site will not be used for stratification or adjustment in the analysis due to anticipated small sample sizes within site. However, sensitivity analyses will be performed to assess the impact of site on the study conclusions. Other pre-specified covariates included in sensitivity analyses include age, use of disease-specific co-medication (methotrexate, azathioprine or similar) and levels of ADAb at baseline (NOR-DRUM B only). The SAP will detail these procedures, as well as alternative and further supportive evaluations, such as analyses including unbalanced baseline predictors or modifications of the logistic regression model in case validity assumptions are not met.
Primary analyses
The primary analysis will be performed on the ITT population. There will be two primary hypotheses tested in this study, one for each of the two parts (NOR-DRUM A and B). No adjustment for multiplicity will be made, since each part will be regarded as answering an independent research question.
In NOR-DRUM A the statistical hypothesis tested is (superiority test): Null hypothesis: There is no difference in the proportion of patients in remission at week 30 between the intervention and control group. Alternative hypothesis: There is a difference in the proportion of patients in remission at week 30 between the intervention and control group. The hypothesis test will be evaluated by logistic regression analysis. A conclusion of superiority of either of the treatment strategies will be made if the null hypothesis is rejected at the 5% significance level. If the study fails to reject the primary null hypothesis, non-inferiority of TDM vs standard care will be assessed using a non-inferiority margin of 15%. Non-inferiority implies that the 95% confidence limits of the estimated adjusted risk difference of disease worsening lies fully within a non-inferiority margin of 15%.
In NOR-DRUM B the statistical hypothesis tested is (superiority test): Null hypothesis: There is no difference in proportion of patients in sustained disease control throughout the study period (without disease worsening) between the intervention and control group. Alternative hypothesis: There is a difference in proportion of patients in sustained disease control throughout the study period (without disease worsening) between the intervention and control group. The primary hypothesis will be evaluated by the p-value from the logistic regression analysis. A conclusion of superiority of eitherof the treatment strategies will be made if the null hypothesis is rejected on a significance level of 5%. If the study fails to reject the primary null hypothesis, non-inferiority of TDM vs standard care will be assessed, also using a 15% non-inferiority margin. Non-inferiority implies that the 95% confidence limits of the estimated adjusted risk difference of disease worsening lies fully within a non-inferiority margin of 15%.
Secondary analyses
Between-group comparisons will be performed for the primary endpoints on secondary populations in addition to secondary efficacy endpoints on both efficacy populations. The between-group comparisons for secondary variables will be tested as for the primary variable where applicable and additional analyses will be performed based on the following methods (but not limited to); repeated measures mixed models or appropriate non-parametric alternatives (continuous variables), logistic regression (possibly adjusting for within-subject dependencies by mixed model approaches) or chi-square/Mantel-Haenszel test for binary response variables, Kaplan-Meier method (Time-to-event variables) and comparisons between the two groups will be performed using the log rank test, Cox regression analyses and/or appropriate parametric models such as the Weibull model. Methods to handle missing data may include complete case analyses, last observation carried forward, worst case/best case imputation and multiple imputation techniques. For the primary analyses, worst case imputation will be used for missing observations. Further details on missing data will be given in the SAP.
Safety analyses will be descriptive and presented as summary tables by treatment group and (if applicable) by visit. Patient reported outcome measures (PROMs) and disability will be assessed using Short Form (36) Health Survey (SF-36) (generic), EuroQol 5 Dimensions (EQ-5D) (generic), MHAQ (RA, PsA, SpA), IBDQ (IBD) and DLQI (Ps). These scores will be summarised by descriptive summary tables at baseline and over time, and at the end of study. Missing data at end of study will be replaced by the last valid post-baseline assessment. We will perform subgroup analyses according to diagnoses groups (RA, SpA, PsA, UC, CD, Ps) on the appropriate primary and secondary variables using methods described above. Other exploratory subgroup analyses of primary, secondary and exploratory efficacy variables may be performed if appropriate. The decision to include such analyses will be made on basis of the collected data. Health economic analyses appropriate analyses as estimating the number of quality-adjusted-life-years (QALYs) obtained during the study period. For each patient we will estimate one year costs based on register data for utilisation of health care and the unit costs. The mean week QALYs and cost in the two treatment arms will be used to estimate an incremental cost-effectiveness ratio for all patients and according to diagnostic group.
Adverse events
Any adverse event (AE) encountered during the clinical study is reported in the eCRF. If the patient has experienced AE (s), the investigator records the following information in the eCRF: The nature of the event is described by the investigator in precise standard medical terminology. The duration of the event is described in terms of event onset date and event ended date. The intensity of the adverse event is graded as mild, moderate, severe, life threatening or death. The causal relationship of the event to the study medication is assessed as unrelated, unlikely, possible, probable or definite. Events which are definitely due to disease progression are not reported as an AE. Serious adverse events (SAEs) are reported to the central study coordinating team.
Data registration and monitoring
A web-based eCRF software solution is used to collect study data (Viedoc 4™, Uppsala, Sweden). The Principal Investigator at each study centre is responsible for assuring that data entered into the eCRF is complete, accurate, and that entry is performed in a timely manner. The electronic signature of the investigator will attest the accuracy of the data on each CRF. If any assessments are omitted, the reason for such omissions will be noted on the CRFs. Corrections, with the reason for the corrections will also be recorded. A complete list of authorised study personnel will be maintained during the study, and only study personnel authorised by the principal investigator or coordinating investigator will be allowed to sign the eCRF. Protocol, protocol amendments, investigator’s brochure, informed consent and all study-related documents have been reviewed by an institutional review board and a GCP (Good Clinical Practice) certified person. All participating centres will be monitored during and after the trial by GCP-trained personnel in order to ensure compliance with GCP, the protocol, and all other applicable regulations.
Publications
Upon study completion and finalisation of the study report the results of this study will be submitted for publication and posted in a publicly assessable database of clinical study results.
The results of this study will also be submitted to the Ethics Committee according to national regulations. All personnel who according to the ICMJE recommendations have contributed significantly in the planning and performance of the study will be included in the list of authors. Authorship will be based on scientific contribution and enrolment.