Potential effect modifier | Biological rationale |
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Primary analyses | |
1. Modic changes type I | |
We expected a larger treatment effect in type I compared to type II. | Type I Modic changes are more strongly associated with low back pain [11]. In animal models, injecting C.acne into intervertebral discs induced type I Modic changes [12, 13]. |
2. Previous disc surgery at level with Modic changes | |
We expected a larger treatment effect in patients with previous disc surgery compared to those without. | Low-grade discitis might be a complication of disc surgery due to introduction of bacteria into the disc during the surgical procedure. The randomised trial from 2013 with a high number of patients with previous surgery found effect of antibiotic treatment [4], while a case series with few patients with previous surgery was negative [14]. |
3. Positive pain provocation test | |
We expected a larger treatment effect in patients with a positive Springing test (patient reported pain with pressure applied to lumbar transverse processes) compared to those with a negative Springing test. | Spinal tenderness may indicate regular spondylodiscitis [15]. Springing test is found to be borderline significant discriminator between patients with and without Modic changes [16]. |
4. Elevated CRP (C-reactive protein) | |
We expected a larger treatment effect in those with higher CRP. The predefined cut-off values for CRP were changed from 3 mg/L and 10 mg/L to 5 mg/L due to too few patients in the predefined categories. | CRP in serum is associated with bacterial infection and inflammation. |
Exploratory analyses | |
1. Disturbed sleep | |
We expected a larger treatment effect in those with disturbed sleep than in those without. Disturbed sleep was defined as a ≥ 2 score on the Oswestry Disability Index item 7 (sleep scale), i.e. less than 6 h sleep to no sleep because of pain. | Night-time pain may indicate infectious spondylodiscitis [15]. |
2. Constant low back pain | |
We expected a larger treatment effect in those patients with constant low back pain compared to those with fluctuating low back pain. | Constant pain may indicate regular spondylodiscitis [15]. |
3. Short duration of low back pain | |
We expected a larger treatment effect in those with short duration of symptoms compared to those with longer duration of symptoms. The predefined categorization (< 1 year, 1–2 years and ≥ 2 years) was dichotomized into < 2 years and ≥ 2 years due to too few patients with symptoms < 1 year. | Recent disc herniation could have increased perfusion in the disc as part of disc repair, thereby increasing absorption of amoxicillin. |
4. Younger age | |
We expected a larger treatment effect in patients < 40 years of age compared to those ≥40 years of age. | C.acne could be more prevalent in discs of young patients [17]. |
5. Male gender | |
We expected a larger treatment effect in men compared to women. | C.acne could be more prevalent in discs in men than in women [17]. |