Clinical trial NCT03704363: BackToBasic: Infliximab in Chronic Low Back Pain and Modic Changes
Official title: The Effect of Infliximab in Patients With Chronic Low Back Pain and Modic Changes. A Randomized, Double Blind, Placebo-controlled, Multicenter Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Low Back Pain
Keywords: Modic changes
biomarkers
treatment
infliximab
chronic low back pain
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Haukeland University Hospital
name: St. Olavs Hospital
name: University Hospital of North Norway
name: Vestre Viken Hospital Trust
name: Ostfold Hospital Trust
name: Clinical Trial Unit (CTU), Oslo University Hospital
name: Diakonhjemmet Hospital
First posted: 2018-10-12
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Low-Back Pain (LBP) is the leading cause of disability worldwide. Even though LBP relates to different underlying pathologies, there are a substantial number of patients with chronic complaints that have vertebral bone marrow lesions visualized as Modic changes (MC) on magnetic resonance imaging (MRI). Despite the clinical evidence that MC is painful, the etiology is unknown and there is currently no established treatment. It has been suggested that MCs are secondary to a biomechanically induced degradation with a subsequent autoimmune response, supported by evidence showing that Tumor necrosis factor (TNF)-α plays a critical role in intervertebral disc degeneration and MCs. Clinical trials suppressing inflammation with TNF-alfa blockers in patients with acute low back pain and sciatica provide evidence to support the initiation of a clinical trial assessing the effect of TNF-alfa blockers in patients with chronic low-back pain and MCs. Since TNF-alfa blockers is an established treatment for immune-mediated disorders like spondyloarthritis by reducing pain as well as bone marrow lesions, the researchers aim to assess whether this treatment is effective for chronic LBP with MCs. In addition refine diagnostic assessment and explore potential biomarkers, which will provide an increased understanding of underlying factors causing LBP, and ultimately result in better management and treatment for one of the most costly and challenging patient populations.

Detailed description: The following information will be collected at baseline, in addition to pre-specified efficacy assessments: age, gender, BMI (measured at site), ethnicity, marital status, children, educational level, work status, physical work load, leisure time activity, smoking habits, expectations about treatment effect and characteristics of pain (duration, agrevating factors, morning stiffness, morning pain, relief by NSAIDs, night time pain and former treatment). Emotional distress will be measured using the Hopkins Symptom Checklist-25 at baseline. The researchers will measure fear-avoidance beliefs about physical activity and work with Fear-avoidance beliefs Questionnaire (FABQ) at baseline. Subjective health complaints (SHC) will be measured using a formal inventory which consists of 29 questions concerning severity and duration of subjective somatic and psychological complaints and will be measured at baseline. In addition, routine clinical investigations (pain provocation tests (springing test, active flexion / extension of the lumbar spine) and neurological tests (strength, toe-/heel walking, sensibility, reflexes, straight leg raising test, reverse Lasegue test)) will be structured and registered in the CRF at baseline.

Eligibility criteria: Inclusion Criteria:

* Age between 18 and 65 years
* LBP of \> 50% of days for \> 6 months duration in the area below the 12th rib and above the gluteal folds with:

Numerical Rating Scale (NRS) pain intensity score of at least 5 (mean of three NRS scales; current LBP, the worst LBP within the last 2 weeks, and usual/mean LBP within the last 2 weeks) and/or ODI-score of at least 25

- Modic change of craniocaudal size \>= 10% of vertebral height and of primary or secondary type 1 in the vertebral body at a level of the lumbar spine (superior or inferior endplate, Th12-S1).

Exclusion criteria:

* Fever or ongoing infection
* Allergy or hypersensitivity against any products of the medication
* Previous infliximab treatment
* Any serious adverse events with other immunosuppressive treatment (including cytostatics, antibodies, drugs acting on immunophilins, Interferons, mycophenolate and any other DMARDs)
* Any specific diagnosis that may explain patient's low back symptoms (e.g. tumor, fracture, spondyloarthritis, infection, spinal stenosis).
* Former low back surgery (L1 - S1) for other reasons than disc herniation or decompression (e.g fusion, disc prosthesis).
* Former surgery for disc herniation or decompression within the last 12 months
* Any known rheumatic disease
* Current pregnancy or lactation
* For women of childbearing potential (WOCBP); inadequate birth control, pregnancy, and/or breastfeeding. WOCBP is defined as those who are fertile (with uterus, fallopian tubes and at least one intact functional ovary), following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Documentation of surgical procedure or physical examination is required for subjects who have had such an operation. Adequate contraception must be used by WOCBP during the entire intervention period and 6 months after the last administration of study drug, and includes oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device or system, vasectomized partner or sexual abstinence.
* Ongoing systemic glucocorticoid or other immunosuppressive treatments (see list above)
* Regular use of opioids with the exception of codeine and tramadol
* Other immunosuppressive treatment last year (see list above)
* Active or latent (known or suspected) tuberculosis (all participants will be screened for latent tuberculosis)
* Previous infection with Hepatitis B virus (HBV) (all participants will be screened for HBV-carrier state)
* Live vaccination within the last 4 weeks or planned live vaccination during treatment period
* Planned surgical procedure
* Increased transaminases (ASAT/ALAT)
* Ongoing or previous malignant disease at any time (i.e. skin cancer, cervical cancer etc.)
* Known increased risk of malignant disease
* Diabetes
* Immunodeficiency (I.e primary immunodeficiency diseases, human immunodeficiency virus/acquired immunodeficiency syndrome, splenectomy)
* Heart failure (NYHA class III - IV)
* Previous or ongoing psoriasis
* Ulcerative colitis or Crohns disease
* Existing or recent demyelination diseases (I.e. MS or Guillain-Barres)
* Abnormal hemoglobin or abnormal platelet, leucocyte or neutrophil count
* Not able to understand written and spoken Norwegian
* Not able to complete treatment or follow-ups in the study (i.e. severe psychiatric disease, drug abuse or plans of moving address)
* Contraindications for MRI (ie. pacemaker, metal implants, claustrophobia)
* Abnormal creatinine level

Primary outcomes:
measure: Change in Oswestry Disability Index (ODI) from baseline to 5 months
timeFrame: 0, 1, 2, 3, 4, 5 and 9 months
Secondary outcomes:
measure: Change in Short tau inversion recovery (STIR) signal (intensity and extent) of Modic Changes from baseline to 5 months.
timeFrame: 0 and 5-6 months
measure: Change in low back pain intensity from baseline to 5 months
timeFrame: 0 + weekly during intervention period, 3, 5 and 9 months
measure: Change in Roland Morris Disability Questionnaire (RMDQ) from baseline to 5 months
timeFrame: 0, 3, 5 and 9 months
measure: Change in Health-related quality of life from baseline to 5 months
timeFrame: 0, 3, 5 and 9 months
measure: Number and type of co-interventions (other pharmacological treatment (ATC-coded) and non-pharmacological treatment)
timeFrame: Will be registered every month up to 5 months and at 9 months
measure: Days with sick leave
timeFrame: Will be registered at baseline and monthly until last follow-up
measure: Incidence of adverse events (AEs) and serious AE (SAEs) during the study period
timeFrame: 2, 6, 14, 22 and 40 weeks after start of treatment
Other outcomes:
measure: Change in Leg pain intensity from baseline to 5 months
timeFrame: 0, 3, 5 and 9 months
measure: Change in Hours with low back pain during the last 4 weeks from baseline to 5 months
timeFrame: 0, 3, 5 and 9 months
measure: Change in Symptom-specific well-being from baseline to 5 months
timeFrame: 0, 3, 5 and 9 months
measure: Patients' satisfaction
timeFrame: Will be measured at 3, 5 and 9 months after start of treatment
measure: Global perceived effect from baseline
timeFrame: Will be measured at 3, 5 and 9 months after start of treatment
measure: Perceived treatment
timeFrame: Seven days after start of treatment, post-treatment (14 weeks after start of treatment) and at 5 months after start of treatment
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Drammen
country: Norway
facility: Vestre Viken Hospital Trust Drammen
city: Moss
country: Norway
facility: Østfold Hospital Trust
city: Oslo
country: Norway
facility: Oslo University Hospital Ullevål
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St. Olavs Hospital
Study officials:
affiliation: Vestre Viken Hospital Trust Drammen
name: Anne Froholdt, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ostfold Hospital Trust
name: Anne Julsrud Haugen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Haukeland University Hospital
name: Jan Sture Skouen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oslo University Hospital
name: Jens Ivar Brox, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Olavs Hospital, Trondheim
name: Gunn Hege Marchand, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of North Norway Tromsø
name: Gunnstein Bakland, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Oslo University Hospital, Oslo, Norway
name: John-Anker Zwart, PhD
role: STUDY_CHAIR
References:
citation: Gjefsen E, Braten LCH, Goll GL, Wigemyr M, Bolstad N, Valberg M, Schistad EI, Marchand GH, Granviken F, Selmer KK, Froholdt A, Haugen AJ, Dagestad MH, Vetti N, Bakland G, Lie BA, Haavardsholm EA, Nilsen AT, Holmgard TE, Kadar TI, Kvien T, Skouen JS, Grovle L, Brox JI, Espeland A, Storheim K, Zwart JA. The effect of infliximab in patients with chronic low back pain and Modic changes (the BackToBasic study): study protocol of a randomized, double blind, placebo-controlled, multicenter trial. BMC Musculoskelet Disord. 2020 Oct 21;21(1):698. doi: 10.1186/s12891-020-03720-5.