Antibiotic Treatment in Patients With Chronic Low Back Pain and Modic Changes: a Randomized Double-blind Placebo Controlled Trial
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Enrollment
- 180
- Locations
- 1
- Primary Endpoint
- Roland Morris Disability Questionnaire
Study Overview
Brief Summary
Low-back pain (LBP) is the single leading cause for disability worldwide, affects all age groups and has increased from 58 million years lived with disability (YLDs) in 1990 to 83 million YLDs in 2010. The burden is accordingly substantially higher than previously assessed, causing activity limitation and work absence with subsequently enormous economic burden. Norwegian expenses reach at least NOK 24 billions annually whereof a substantial part is hospital costs. The research project responds to this challenge and aim to conduct a multicenter randomized placebo-controlled trial, complemented by a study of epigenetic and molecular biomarkers, to re-examine the finding of a recent randomized controlled trial that antibiotic treatment can cure patients with chronic low back pain (LBP), a former disc herniation and present Modic Changes (MCs). The hypothesis is that MCs is caused by low virulent anaerobic organisms in the disc. Investigators also want to add important new knowledge to the research field beyond the only former RCT by broadening the inclusion criteria to include both patients with type I and type II MCs, improving the MRI assessment of MCs, further clarifying the pathogenesis of MCs by studying genetic variability, gene and protein expression of inflammatory biomarkers, and conducting health economic analysis.
Detailed Description
Pre-defined research questions / hypothesis and endpoints:
Main objective and endpoint: To evaluate the effect of Amoxicillin versus placebo on disease-specific disability evaluated by the Roland Morris Disability Questionnaire (RMDQ) at one year (12 months) follow-up in patients with chronic LBP and MCs type I or II adjacent to a previously herniated disc (Hypothesis A).
Thus, the projects Main objective is to re-examine the clinical effect of antibiotic treatment reported in the former Danish study at one year (12 months) follow-up. Investigators will use the same primary outcome measure (RMDQ), but the effect will be evaluated in patients with MCs type I or MCs type II since, as outlined above, investigators argue that some MCs type I patients may be classified as MCs type II patients and vice versa dependent on the magnet strength of MRI machines used, and MCs type I and type II most likely represent a common process (that can be influenced by a common treatment) (hypothesis A). As a secondary objective (SO 1) investigators will evaluate the effect of Amoxicillin versus placebo on RMDQ at one year (12 months) follow-up separately in patients with type I and type II MCs, respectively (hypotheses B and C).
Exploratory and key supportive objectives (KSOs) and endpoints):
- KSO 2. To evaluate the effect of Amoxicillin versus placebo on Oswestry Disability Index (ODI) at one year (12 months) follow-up in the whole cohort of included patients (hypothesis D).
- KSO 3. To evaluate the effect of Amoxicillin versus placebo on LBP intensity at one year (12 months) follow-up in the whole cohort of included patients (hypothesis E).
- KSO 4. To evaluate whether the short tau inversion recovery (STIR) signal (intensity and extent) of MCs on baseline MRI predicts change in RMDQ from baseline to one year (12 months) follow-up (hypothesis F).
- KSO 5. To assess whether change in STIR signal (intensity and extent) of MCs at one year (12 months) follow-up is related to change in RMDQ from baseline to one year (12 months) follow-up (hypothesis G).
- KSO 6. To evaluate the effect of Amoxicillin versus placebo on health-related quality of life (the EQ-5D) at one year (12 months) follow-up in the whole cohort of included patients (hypothesis H).
- To evaluate cost-effectiveness of Amoxicillin versus placebo at one year (12 months) follow-up in the whole cohort of included patients.
- To evaluate whether positive pain provocation tests at baseline predicts change in RMDQ at one year (12 months) follow-up.
- To evaluate the difference in incidence of AEs and SAEs between the two intervention groups from inclusion to one year (12 months) follow-up in the whole cohort of included patients.
- To evaluate, separately in the two intervention groups, whether lack of a clinically important improvement in RMDQ, ODI, and LBP intensity, respectively, from baseline to post-treatment (100-das after start of treatment) is associated with lack of a clinically important improvement in these outcomes from baseline to one-year (12 months) follow-up.
- Further clinical objectives and endpoints: To evaluate the effect of Amoxicillin versus placebo on:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- •Allergy to penicillin or cefalosporins
- •Allergy/hypersensitivity to any of the excipients of the study drug
- •Current pregnancy or lactation
- •Elevated kidney (creatinine) or hepatic (ALAT/ASAT) values outside normal range
- •Phenylketonuria (Følling disease)
- •Mononucleosis or leukaemia
- •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 (e.g fusion, decompression, disc prosthesis).
- •Former surgery for disc herniation, but < 12 months have elapsed since surgery.
- •Former surgery for disc herniation, but MC located at non-operated level(s) only.
- •Reservation against intake of gelatine (the capsules contains gelatine, which among other things is produced by ingredients from pigs)
- •Regular use of glucocorticoids
- •Regular use of opioids with the exception of codeine and tramadol
- •Not understanding Norwegian language
- •Unlikely to adhere to treatment and/ or complete follow-up (e.g ongoing serious psychiatric disease, drug abuse, plans to move)
- •Antibiotic treatment within the preceding one month before treatment start
- •Contraindications to MRI (e.g. cardiac pacemaker electrodes, metal implant in eye or brain, claustrophobia).
- •Unwilling to participate
Arms & Interventions
Amoxicillin
Amoxicillin (Amoksicillintrihydrat) tablets 750 mg 1x3 for 100 days (oral intake). The tablets will be encapsulated in Capsugel DB-caps AAel Swedish orange.
Intervention: Amoxicillin (Amoksicillintrihydrat) (Drug)
Placebo
Placebo capsules for 100 days of daily (1x3), oral intake. The placebo tablets will also be encapsulated in Capsugel DB-caps AAel Swedish orange.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Roland Morris Disability Questionnaire
Time Frame: Evaluated at baseline, post-treatment (100 days after start of intervention), 6, 9 and 12 months after start of treatment.
Self-reported disease-specific disability evaluated by the Roland Morris Disability Questionnaire (RMDQ, scale 0-24, Norwegian translation) from baseline to one year (12 months) follow-up in patients with chronic LBP and MCs type I or II adjacent to a previously herniated disc. The effect will be evaluated in the whole sample (hypothesis A) and in MC type I and II sub-groups (hypothesis B and C). RMDQ will also be evaluated from baseline to post-treatment and used in health economic analysis and in relation to MRI. Primary endpoint of the study is change in RMDQ from baseline to one year (12 months) after start of intervention.
Secondary Outcomes
- Oswestry Disability Index(Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
- Lumbar pain: Numeric Rating Scale(Evaluated at baseline, post-treatment (100 days after start of intervention), 6, 9 and 12 months after start of treatment, and weekly during the treatment period.)
- Health-related quality of life: EuroQoL-5D-5L(Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
- STIR signal on MRI(Evaluated 6-2 weeks before start of intervention and 12-13 months after start of treatment.)
- Leg pain: Numeric Rating Scale(Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
- Number of hours with low back pain during the last 4 weeks(Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
- Global perceived effect(Evaluated post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
- Patient's satisfaction: 5-point Likert scale(Evaluated post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
- Days with sick leave(Evaluated monthly during the whole 12-months study period.)
- Longitudinal changes in gene (RNA) and protein expression(Evaluated at baseline, post-treatment (100 days after start of intervention), and 12 months after start of treatment.)
Investigators
Kjersti Storheim
Head of section
Oslo University Hospital