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BackToBasic: Infliximab in Chronic Low Back Pain and Modic Changes

Primary Purpose

Low Back Pain

Status

Completed

Phase

Phase 3

Locations

Norway

Study Type

Interventional

Intervention

Biosimilar Infliximab

Placebo

About this trial

This is an interventional treatment trial for Low Back Pain focused on measuring Modic changes, biomarkers, treatment, infliximab, chronic low back pain

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Haukeland University Hospital
Vestre Viken Hospital Trust Drammen
Østfold Hospital Trust
Oslo University Hospital Ullevål
University Hospital of North Norway
St. Olavs Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Infliximab

Placebo

Arm Description

Intravenous infusion(biosimilar infliximab). Each participant will be given 4 infusions, at day 0, day 14, day 42 and day 98, unless unacceptable toxicity is encountered.

Intravenous infusion (NaCl intravenous infusion). Each participant will be given 4 infusions, at day 0, day 14, day 42 and day 98.

Outcomes

Primary Outcome Measures

Change in Oswestry Disability Index (ODI) from baseline to 5 months

ODI is a disease-specific disability score. Scale is measured 0-100, better to worse respectively.

Secondary Outcome Measures

Change in Short tau inversion recovery (STIR) signal (intensity and extent) of Modic Changes from baseline to 5 months.

Based on Magnetic Resonance Imaging (MRI). STIR result from evaluations of fat-water separation and T1 weighted fat-saturated post-contrast images, MC signal intensity standardized against the intensity of normal vertebral body marrow and cerebrospinal fluid, MC high signal craniocaudal size and volume.

Change in low back pain intensity from baseline to 5 months

Measured on a Numeric Rating Scale (NRS: 0-10); mean of three NRS scales; current LBP, the worst LBP within the last 2 weeks, and usual/mean LBP within the last 2 weeks (at baseline, post-treatment and at one year after start of treatment). Will also be monitored weekly during the intervention period, and the the wording "last 2 weeks" will then be replaced by "the last week". Better (0) to worse (10) respectively.

Change in Roland Morris Disability Questionnaire (RMDQ) from baseline to 5 months

RMDQ is a Self-reported disease-specific disability score, scale 0-24, better to worse respectively.

Change in Health-related quality of life from baseline to 5 months

EuroQoL-5D-5L (version 2.0), range -0.59 to 1.0, worse to better respectively.

Number and type of co-interventions (other pharmacological treatment (ATC-coded) and non-pharmacological treatment)

Will be reported by patients monthly during the study period for health-economical calculations

Days with sick leave

Self-reported by patients; how many days patients were on sick-leave last month (if patients are sick listed; degree / % sick listed will also be registered).

Incidence of adverse events (AEs) and serious AE (SAEs) during the study period

Adverse events frequency. The nature of the event(s) will be described by the investigator in precise standard medical terminology, duration and intensity will also be registered. In the evaluation, we will also consider serum infliximab concentration and vital signs.

Full Information

NCT ID

NCT03704363

First Posted

September 19, 2018

Last Updated

September 29, 2023

Sponsor

Oslo University Hospital

Collaborators

Haukeland University Hospital, St. Olavs Hospital, University Hospital of North Norway, Vestre Viken Hospital Trust, Ostfold Hospital Trust, Clinical Trial Unit (CTU), Oslo University Hospital, Diakonhjemmet Hospital

1. Study Identification

Unique Protocol Identification Number

NCT03704363

Brief Title

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

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

December 12, 2018 (Actual)

Primary Completion Date

July 27, 2023 (Actual)

Study Completion Date

September 29, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Oslo University Hospital

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Low Back Pain

Keywords

Modic changes, biomarkers, treatment, infliximab, chronic low back pain

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

A computer-generated randomised allocation sequence will be imported into an electronic case report form (eCRF) system (Viedoc) and made available exclusively to a study nurse (mixing nurse) authorised by the local principal investigator to prepare infusions. The mixing nurse is otherwise not involved in the treatment of the patient. The infusion bags containing the study medication will be prepared by the mixing nurse in identical infusion bags, and applied labels with patient number and dose such that blinding of the participants is secured. The Investigational Medicinal Products (IMPs) have the same color and will look the same. After preparing the IMP, the mixing nurse will hand over the IMP to another nurse, blinded to allocation, and authorised by the local principal investigator to administer the infusion.

Allocation

Randomized

Enrollment

128 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Infliximab

Arm Type

Experimental

Arm Description

Intravenous infusion(biosimilar infliximab). Each participant will be given 4 infusions, at day 0, day 14, day 42 and day 98, unless unacceptable toxicity is encountered.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intravenous infusion (NaCl intravenous infusion). Each participant will be given 4 infusions, at day 0, day 14, day 42 and day 98.

Intervention Type

Drug

Intervention Name(s)

Biosimilar Infliximab

Intervention Description

Intravenous infusion(5 mg/kg). Each participant will be given 4 infusions, at day 0, day 14, day 42 and day 98, unless unacceptable toxicity is encountered.

Intervention Type

Other

Intervention Name(s)

Placebo

Other Intervention Name(s)

NaCl intravenous infusion

Intervention Description

Intravenous infusion. Each participant will be given 4 infusions, at day 0, day 14, day 42 and day 98,

Primary Outcome Measure Information:

Title

Change in Oswestry Disability Index (ODI) from baseline to 5 months

Description

ODI is a disease-specific disability score. Scale is measured 0-100, better to worse respectively.

Time Frame

0, 1, 2, 3, 4, 5 and 9 months

Secondary Outcome Measure Information:

Title

Change in Short tau inversion recovery (STIR) signal (intensity and extent) of Modic Changes from baseline to 5 months.

Description

Time Frame

0 and 5-6 months

Title

Change in low back pain intensity from baseline to 5 months

Description

Time Frame

0 + weekly during intervention period, 3, 5 and 9 months

Title

Change in Roland Morris Disability Questionnaire (RMDQ) from baseline to 5 months

Description

RMDQ is a Self-reported disease-specific disability score, scale 0-24, better to worse respectively.

Time Frame

0, 3, 5 and 9 months

Title

Change in Health-related quality of life from baseline to 5 months

Description

EuroQoL-5D-5L (version 2.0), range -0.59 to 1.0, worse to better respectively.

Time Frame

0, 3, 5 and 9 months

Title

Number and type of co-interventions (other pharmacological treatment (ATC-coded) and non-pharmacological treatment)

Description

Will be reported by patients monthly during the study period for health-economical calculations

Time Frame

Will be registered every month up to 5 months and at 9 months

Title

Days with sick leave

Description

Self-reported by patients; how many days patients were on sick-leave last month (if patients are sick listed; degree / % sick listed will also be registered).

Time Frame

Will be registered at baseline and monthly until last follow-up

Title

Incidence of adverse events (AEs) and serious AE (SAEs) during the study period

Description

Time Frame

2, 6, 14, 22 and 40 weeks after start of treatment

Other Pre-specified Outcome Measures:

Title

Change in Leg pain intensity from baseline to 5 months

Description

Numeric Rating Scale (NRS: 0-10, better to worse respectively); leg pain last week.

Time Frame

0, 3, 5 and 9 months

Title

Change in Hours with low back pain during the last 4 weeks from baseline to 5 months

Description

Number of days during the last 28 days (4 weeks) the participant had experienced LBP (0-28 days), and, on an typical day, how many of the hours awake they experienced LBP (0-16 h). The number of days and hours are multiplied (a 0-448 scale).

Time Frame

0, 3, 5 and 9 months

Title

Change in Symptom-specific well-being from baseline to 5 months

Description

Measured on a 5-point Likert scale with 'very satisfied', 'some satisfied', 'neither satisfied nor dissatisfied', 'some dissatisfied' or 'very dissatisfied'

Time Frame

0, 3, 5 and 9 months

Title

Patients' satisfaction

Description

Rated on a 5-point Likert scale; patients rate satisfaction with treatment

Time Frame

Will be measured at 3, 5 and 9 months after start of treatment

Title

Global perceived effect from baseline

Description

Global Rating of Change is rated on a 7-point Likert scale to quantify a patient's self-judged improvement from baseline.

Time Frame

Will be measured at 3, 5 and 9 months after start of treatment

Title

Perceived treatment

Description

Patients will be asked about which study medicine (Infliximab / placebo / unsure) they think they received during the intervention period of the study.

Time Frame

Seven days after start of treatment, post-treatment (14 weeks after start of treatment) and at 5 months after start of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Overall Study Officials: