Antibiotics In Modic Changes
Condition: Low Back Pain; Modic Changes Type I or II Seen on MRI
MeSH terms: Back Pain; Low Back Pain
Study type: Interventional
Phase: Phase 3

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:

             -  RMDQ at one year (12 months) follow-up separately in patients previously undergoing
                back surgery for disc herniation and patients NOT previously undergoing back
                surgery for disc herniation.

             -  other outcome measures not mentioned above (leg pain intensity, hours with LBP
                during the last 4 weeks, bothersomeness, days with sick leave, co-interventions,
                patients' satisfaction, global perceived effect) at one year (12 months) follow-up
                in the whole cohort of included patients

             -  secondary outcome measures at one year (12 months) follow-up separately in patients
                with type I and type II MCs at baseline, respectively

             -  primary and secondary outcomes measures posttreatment (100 days after start of
                treatment) in the whole cohort and separately in patients with type I and type II
                MCs at baseline, respectively.

        -  Further radiological objectives and endpoints: To assess whether characteristics of MCs
           on baseline MRI predict change in ODI, or change in intensity of LBP from baseline to
           one year (12 months) follow-up. To compare change in characteristics of MCs from
           inclusion to one year (12 months) follow-up between treatment groups, and to assess
           whether this change in MCs is related to change in RMDQ, ODI, and pain intensity from
           baseline to one year (12 months) follow-up. To determine the reliability of different
           MCs characteristics by different MRI methods. To assess the relationships of these MC
           characteristics to each other and to clinical variables.

      Genetic objectives and endpoints: To investigate the effect of Amoxicillin on epigenetic
      patterns, longitudinal gene- and protein expression, genetic variation, from baseline to
      post-treatment (100 days after start of treatment) and from baseline to one year (12 months)
      follow-up in patients with MCs type I or II, and to evaluate correlations with clinical data.

      Randomization lists will be created using STATA 13 (StatCorp LP, College Station, TX, USA)
      and will be stratified by MODIC type (1/2) and previous surgery (yes/no) with a 1:1:1:1
      allocation and random block sizes of 4 and 6. This will ensure similar numbers of patients
      receiving antibiotics or placebo within each stratum (1-MCs type I, no previous back surgery
      for disc herniation, 2-MCs type I, previous back surgery for disc herniation, 3-MCs type II,
      no previous back surgery for disc herniation, and 4-MCs type II, previous back surgery for
      disc herniation). Investigators intend to recruit two equally large patient groups, one with
      type I MCs and one with type II MCs, in order to evaluate treatment effect separately in each
      MC type group and not only in the total sample. Investigators will achieve this by stratified
      randomization as explained above, and investigators will stop the inclusion of the two MCs
      type II strata (with and without previous surgery) when investigators have enough MCs type II
      patients, and continue the inclusion of the two MCs type I strata (or vice versa). Patients
      are stratified for previous back surgery for disc herniation (Yes/No) since it is not clear
      how the low virulent anaerobic organisms gain access to the disc (during normal bacteraemia
      or as a result of intraoperative contamination). Hence, stratifying for previous back surgery
      for disc herniation will ensure balanced distribution of this potential source of infection
      between groups.

      Investigators have designed the study with enough power to evaluate the treatment effect
      separately in the MC type I group and in the MC type II group (investigators will include
      equally many Modic I and Modic II patients in the trial), but the main analysis will be in
      the whole cohort of patients with MCs type I or II. In power calculations for each MC type
      group, investigators used a two-sided alfa of 0.05 and a power of 0.90 and wished to be able
      to identify a difference in mean RMDQ of 4 (SD 5) between the two treatment groups at 12
      months follow-up. The minimal important difference in mean RMDQ between groups is not clear,
      but a change in RMDQ of 2-3 in individual patients over time is very unlikely to be important
      and may represent measurement error. Investigators therefore used a difference of 4 in mean
      RMDQ between groups in the power calculations. The SD of 5 is within the upper range of
      commonly reported SDs for RMDQ in patients with persistent LBP.

      A to-sided alfa 0.05 (i.e. 95 % Confidence Interval), a power 90, ratio of sample size 1
      (antibiotic group / placebo group) and a difference in RMDQ 4 (SD 5) results in a sample size
      of 33 in each treatment group, or 66 in both treatment groups; i.e. 132 in the total sample
      (both MC type groups). The Danish RCT by Albert et al 2013 had 11 % dropouts. Adding 20 % for
      dropouts (26 patients) investigators calculated that they need to include 158 patients in the
      study, rounded up to 160 patients: 80 patients with type I MCs and 80 patients with type II
      MCs. The study continue inclusion until 80 patients are included in the MC type group that is
      slowes to recruit, implying inclusion of at least 80 patients in the other MC type group and
      at least 160 patients in total.

      Data on main outcome will be analysed by a statistician who is blinded to group status. The
      primary analyses (main outcome) will be by intention-to-treat in the whole cohort of patients
      with MCs type I or II using an ANCOVA analysis adjusted for baseline RMDQ-score. The
      significance level will be 0.05. Investigators will report the p value with 95 % CI. ANCOVA
      analysis, adjusted for baseline RMDQ-score, will also be used to examine main outcome
      separately in the sub-samples of type I and II MSc. The significance level will still be
      0.05. Investigators will report the exact p value with 95 % CI for each of the two
      sub-samples. For the secondary outcome measures also ANCOVA analysis will be used with
      adjustment for baseline values and in accordance to intention to treat (ITT). The analysis
      will be carried out in the whole cohort of patients with MCs type I or II with a significance
      level of 0.05, and separately in the two sub-samples of type I and II MSc. Investigators will
      report the p value with 95 % CI. Analyses of MRI results will include observer agreement
      analyses (kappa, McNemars test, Bland Altmann plots) and multiple regression analyses to
      assess relationships with clinical variables.

      As secondary analysis, investigators will perform responder analyses of RMDQ to supplement
      the interpretability of the main analysis. They will analyze if a higher proportion of
      patients with MCs type I or II at baseline reports a clinically relevant improvement of their
      RMDQ-score from baseline to one year (12 months) follow-up in the antibiotic treatment group
      than in the placebo group. Analysis (chi-square test) will be performed for three different
      cut-offs (>75%, >50% and >30% improvement of RMDQ score from baseline to one year follow-up,
      respectively). Intention-to-treat (ITT) principles will be used and the significance level
      will be 0.05. Investigators will report the exact p value and the number needed to treat
      (NNT) with 95 % CI.

      Analyses of MRI results will include observer agreement analyses (kappa, McNemars test, Bland
      Altmann plots) and multiple regression analyses to assess relationships with clinical
      variables. Cost-effectiveness will be analyzed as the difference in costs between the 2
      treatment groups divided by their difference in QALYs gained. The results will be presented
      as an incremental cost-effectiveness ratio (ICER).

      In addition to outcome measured listed, the following will be evaluated:

        -  To check Blinding: Patients will be asked which study medicine (Amoxicillin / placebo /
           unsure) they think they received. Points of time: post-treatment (100 days after start
           of intervention), and one year (12 months) after start of intervention.

        -  To evaluate Compliance to the medicine protocol; Patients will be asked every week
           during the intervention period how many days the last week they took the study
           medication (0-7)). At post-treament (100 days after start of treatment); Capsule count
           will be performed by a pharmacist.

        -  Adverse events will be Registered and CTC-coded at every study visit (=monthly) during
           the intervention period by the principal investigators.

      EudraCT no: 2013-004505-14
    

Intervention name(s): Amoxicillin (Amoksicillintrihydrat); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Amoxicillin tablets 750 mg 1x3 for 100 days (oral intake).; Placebo tablets 1x3 for 100 days (oral intake).
Other intervention name(s): Amimox "Meda"
Intervention MeSH terms: Amoxicillin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Low back pain; Chronic; Modic Changes; MRI; epigenetics; antibiotics; randomized placebo controlled trial