A Prospective Clinical Series followed by A Multicenter Double-blind Randomised Placebo-Controlled Clinical Trial

Rationale and Objectives: To prove the hypothesis that Intradiscal Methylene
blue is capable of longer pain reduction than the best available treatment
(conservative treatment) in patients suffering from axial low back pain of
discogenic origin. Secondary objective will be to assess cost-effectiveness,
improvement in physical function, and quality of life. Tertiary objective is to
assess disc Magnetic Resonance imaging (MRI) and provocative discography in
patients with low back pain of discogenic origin.

Study design: Multicenter prospective Clinical Case series followed by a
randomized clinical trial . In this RCT intradiscal Methylene blue injection
will be compared to a sham treatment. The treatment group as well as the
control group will receive best treatment available.

Study population: Patients (age >18 and < 65 years) suffering from axial low
back pain from discogenic origin. This study will be done in the Pain
Management Centres of Arnhem; Rijnstate, Leiderdorp, Eindhoven, and Maastricht.

Main study parameters/endpoints: Main study parameter are pain, Global
Perceived Effect and disability at 6 months measured by a Numeric Rating Scale
weighted according to Jensen. Secondary outcome includes cost effectiveness,
the Oswestry Disability Index , the McGill Pain Questionnaire- Dutch Language
Version, and a Quality of Life questionnaire. Tertiary objectives are to assess
early disc degeneration between groups by MR imaging and to develop a
prediction model for success of intervention.
Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: After intake and treatment the patients will be
followed-up at 6 weeks and at 3, 6,12, and 24 months after the initial
intervention (6 site visits). During the intake visit a physical examination is
done. Before each visit questionnaires have to be filled in by the patient. The
treatment itself is performed under local analgesia and is generally well
tolerated without side effects or complications.
The treatment group has the opportunity to benefit from the possible positive
effects from the intradiscal methylene blue treatment, i.e. longer pain
relieve and better functional status,. Patients in the control group have the
possibility to benefit in the same way after 6 months.

Primary Objective:
To prove the hypothesis that Intradiscal Methylene blue is capable of longer
pain reduction and better global perceived effect in patients suffering from
chronic axial low back pain from discogenic origin then a placebo treatment. To
prove that MB treatment is safe and causes little side effects

Secondary Objective(s):
To establish the effect of MB treatment on disability, cost effectiveness, and
quality of life.

Tertiary Objective:
To compare MRI images before and after discography and objectify the presence
of anatomical disc alterations and signs of early disc degeneration.
To compare Magnetic Resonance imaging (MRI) and provocative discography in
patients with low back pain of discogenic origin.

3. STUDY DESIGN

This study starts with a prospective clinical case series(CS) to validate the
following randomized Clinical Trial (RCT) After proper inclusion in the CT a
group of 15 patients with one or two level discogenic low back pain will be
treated at the symptomatic level with MB. Assessments occur at 6 weeks, 3,6,12
and 24 months. Positive result of the prospective CS, defined as a decrease of
2 points in the NRS scores and GPE( global perceived effect) "much improved"
and "very much improved" will be used as determinants of a clinically important
difference (Farrar, Young et al. 2001) in at least two out of five patients ,
without complications or side effects, will be followed by a randomized
placebo-controlled clinical trial RCT . Results of the CS and RCT will be
published.
The RCT is designed as a multicentre randomised placebo-controlled clinical
trial with comparison of an Intradiscal Methylene Blue injection with an
intradiscal Placebo injection. Patients will be randomly selected for
treatment with MB or Placebo injection. Follow-up assessment will be at 6 weeks
and at 3 months, 6,12, and 24 months after the initial intervention. After six
months, patients in the control group are allowed to have the MB injection.
Finally, patients are asked by their treating physician to undergo a second
lumbar MRI scan to assess anatomical alterations or degeneration of the
intervertebral disc.

MB treatment group
All patients with discogenic LBP follow a standardized treatment schedule.The
conservative treatment consists of medication according the scheme of the World
health organisation ( WHO). Step 1 ( Paracetamol and eventually NSAID*s), and
step 2: non-opioid medication: Tramadol .
When there is no treatment effect patients receive provocative discography.
When a discography is positive the patient is included and randomised into the
MB or the placebo group. A discography is considered positive when the
patient's pain can be reproduced, with a minimal NRS score of 7 (or 70% of max
pain) according International Standards (ISIS) guidelines. At least one
adjacent disc should perform as a negative control disc. A maximum of two
positive discs are accepted in this study.
After proper patient selection and informed consent patients are scheduled for
this methylene blue (MB) study.
1: MB groep: intradiscale injectie van 1 ml methylene Blauw ( 10mg/ml) met 1ml
2% Lidocaine hydrochloride en 0.5 ml iohexol 300(contrast)
2: ( RCT) placebogroep: intradiscale injectie van 1ml isotoon zout met 1ml 2%
lidocaine hydrochloride en 0.5 ml iohexol 300(contrast)

Both patient and Anaesthesiologist are blinded to the injected material.
Because MB is blue the Anaesthesiologist who performs the discography will not
participate in the follow-up of the patients.
The procedure is performed in day-care. Patients are discharged 2 hours post
procedure.

Use of co-intervention
Up to six months, new medication is restricted to Paracetamol, NSAIDs or
Tramadol. Except for physiotherapy, no interventional therapies are allowed in
this period. After six months, the MB treatment is available for patients from
the control group and prescription of new medication is free.

Adverse and serious adverse events
All adverse events reported spontaneously by the subject or observed by the
investigator or his staff will be recorded.

All SAEs will be reported to the accredited METC that approved the protocol,
according to the requirements of that METC.

Theoretically there is a possibility that nerve damage (thermal or mechanical)
or discitis can occur after an intradiscal therapy. If so the best standard of
care for their specific complication will be provided to the subject.

Follow-up of adverse events
All adverse events will be followed until they have abated, or until a stable
situation has been reached. Depending on the event, follow up may require
additional tests or medical procedures as indicated, and/or referral to the
general physician or a medical specialist.