Milgamma® and Milgamma® Compositum Step-therapy in Patients With Acute Non-specific Low Back Pain Receiving Modern NSAID

Study Overview
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Brief Summary
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The purpose of this study is to assess the effectiveness and safety of add-on Milgamma®/ Milgamma® compositum step-therapy in patients with acute non-specific low back pain receiving modern NSAIDs in routine medical practice.

Detailed Description
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This is a multi-centre observational prospective study that was planned for assessment the effectiveness of neurotropic vitamins therapy with Milgamma®/ Milgamma® compositum in combination with modern NSAIDs (preferential/selective cyclooxygenase-2 (COX-2) inhibitors) in patients with acute non-specific back pain. Approximately 500 adult out-patients with acute non-specific low back pain who have been prescribed therapy consisting of (1) modern NSAIDs (preferential/selective COX-2 inhibitors) or (2) modern NSAIDs (preferential/selective COX-2 inhibitors) + Milgamma® / Milgamma® compositum will be enrolled in the study. Each patient will be observed over a period of approximately 94 days. 9 visits/phone contacts are planned to be conducted during this period. Information about patient's condition, pain intensity, pain flare-ups, satisfaction with the treatment, patient's disability, therapy used for acute back pain treatment, data on safety will be collected during these contacts. Pain intensity will be measured with Numeric Rating Scale (NRS), patients' disability will be evaluated with Roland Morris disability questionnaire, patients' satisfaction with the treatment will be assessed with 5-point verbal rating scale. Safety assessment will be based on frequency and severity of adverse drug reactions recorded during the study. Prior to the start of the study, neurologists (potential investigators) will be asked to fill out feasibility questionnaires to identify their individual routine practice regarding prescription or non-prescription of Milgamma® / Milgamma® compositum. Based on results of feasibility physicians will be divided to non-prescribers and prescribers of Milgamma® / Milgamma® compositum to the patients with acute non-specific low back pain. In each medical institution, such non-prescribers and prescribers will be proposed to participate in the study. Non-prescribers will be responsible for enrolling group (1) (NSAIDs alone), prescribers will be responsible for enrolling group (2) (NSAIDs + Milgamma® / Milgamma® compositum).

Official Title
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Observational Study of Effectiveness and Safety of Add-on Milgamma® and Milgamma® Compositum Step-Therapy in Routine Practice of Management of Adult Patients With Acute Non-Specific Low Back Pain Receiving Modern NSAIDs

Conditions
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Acute Non-specific Low Back Pain

Intervention / Treatment
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* Drug: Exposure of interest (within routine clinical practice):Vitamin B complexes Milgamma® and Milgamma® compositum


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent including data protection declaration according to the local legislation. Acute non-specific low back pain less than 21 days (= 3 weeks). Low back pain treatment with (1) modern NSAIDs (preferential/selective COX-2 inhibitors) or (2) modern NSAIDs (preferential/selective COX-2 inhibitors) + Milgamma®/ Milgamma® compositum prescribed (but not started yet) in frames of routine medical practice. Prescribed (but not started yet) step-therapy with Milgamma® to be followed by Milgamma® compositum in accordance with locally approved instruction for medical use (for the group planned to be treated with Milgamma®/ Milgamma® compositum step-therapy). Pain intensity according to Numerical Rating Scale (NRS) ≥4 points ≤9 at the time of enrollment. In case of presence of previous episodes of acute non-specific low back pain in medical history, the last one had resolved at least 30 days before the start of current episode. Exclusion Criteria: History or presence of any disease that, in the opinion of the investigator, might confound the results of the study, poses an additional risk to the subject during participation in the study or can change pain perception (examples of such possible conditions: any malignancy, stomach ulcer, duodenal ulcer, chronic heart failure, bronchial asthma, psychiatry disorders, epilepsy, Parkinson Disease etc). Spinal surgery/rehabilitation in the last 12 months. Acute back pain that is attributable to any known or suspected specific identifiable cause (e.g. discogenic radiculopathy, spondylolisthesis, osteomalacia, inflammatory arthritis, metabolic, neurological diseases or tumor). Severe scoliosis. Use of NSAIDs or vitamins B within 2 months prior to enrollment into the study. Necessity to use myorelaxants or antidepressants for treatment of acute non-specific low back pain. Prior use of non-pharmacological treatment (physiotherapy, heat treatment (e.g. heat patch, hot water bottle) or topically applied medicinal products to the back area, procaine blocks) within the last 3 days before study entry.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NSAIDs group<br>Patients with acute non-specific low back pain prescribed with modern NSAIDs (preferential/selective COX-2 inhibitors) | |
| NSAIDs+Milgamma+Milgamma compositum group<br>Patients with acute non-specific low back pain prescribed with modern NSAIDs (preferential/selective COX-2 inhibitors) + Milgamma® / Milgamma® compositum | Drug: Exposure of interest (within routine clinical practice):Vitamin B complexes Milgamma® and Milgamma® compositum<br>* Milgamma®: 2 mL injection solution containing thiamin hydrochloride 100 mg, pyridoxine hydrochloride 100 mg, cyanocobalamin 1 mg, lidocaine hydrochloride 20 mg. Milgamma® compositum: 1 tablet containing benfotiamine 100 mg, pyridoxine hydrochloride 100 mg.<br>* Other names: Non-Steroidal Anti-Inflammatory Drugs (celecoxib, etoricoxib, meloxicam, nimesulide);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Pain Intensity After 10 Days of Treatment | Pain intensity was measured using 0-10 point Numeric Rating Scale (NRS). NRS is 11-step scale for assessment of pain intensity at the moment of patient's examination ranging from 0 (no pain) to 10 (worst pain imaginable). Pain intensity was measured at baseline and at 10 days after the start of treatment. | Baseline; Visit 3 (10 days after the start of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Pain Intensity After 5, 24 and 38 Days of Treatment | Pain intensity was measured using 0-10 point Numeric Rating Scale (NRS). NRS is 11-step scale for assessment of pain intensity at the moment of patient's examination ranging from 0 (no pain) to 10 (worst pain imaginable). Pain intensity was measured at baseline, at 5, 24 and 38 days after the start of treatment.Changes of pain intensity from baseline to Day 5, from baseline to Day 24 and from baseline to Day 38 after the start of treatment were calculated separately. | Baseline; Visit 2 (5 days after the start of treatment), Visit 4 (24 days after the start of treatment); Visit 5 (38 days after the start of treatment) | 
| Change of Pain Intensity Over Time | Pain intensity was measured using 0-10 point Numeric Rating Scale (NRS). NRS is 11-step scale for assessment of pain intensity at the moment of patient's examination ranging from 0 (no pain) to 10 (worst pain imaginable). Pain intensity was measured at baseline, at 5, 10, 24 and 38 days after the start of treatment. A mixed model repeated measures was used to analyze change from baseline in pain intensity over time from Baseline to Visit 5 (38 days after the start of treatment) in each group. The model included a random effect for subject and fixed effect terms for treatment, visit, treatment-by-visit interaction, baseline pain intensity. An unstructured covariance structure was used to model the within-subject errors. P-value was calculated for the difference between treatment groups. | From Baseline to Visit 5 (38 days after the start of treatment) | 
| Percentage of Patients With 30% Low Back Pain Relief After 5, 10, 24 and 38 Days of Treatment. | Pain intensity was measured using 0-10 point Numeric Rating Scale (NRS). NRS is 11-step scale for assessment of pain intensity at the moment of patient's examination ranging from 0 (no pain) to 10 (worst pain imaginable). Relief in pain intensity was defined as 100%*(pain intensity at baseline - pain intensity at Visit 2, 3, 4 or 5)/ pain intensity at baseline. Percentage of patients showing at least 30% low back pain relief at Visit 2 (5 days after the start of treatment), at Visit 3 (10 days after the start of treatment), at Visit 4 (24 days after the start of treatment) and at Visit 5 (38 days after the start of treatment) were calculated separately. | Visit 2 (5 days after the start of treatment); Visit 3 (10 days after the start of treatment); Visit 4 (24 days after the start of treatment) and Visit 5 (38 days after the start of treatment) | 
| Change in Pain-related Disability After 10 Days of Treatment | Patients' disability was assessed using Roland Morris disability questionnaire (RMDQ). RMDQ is a 24-item self-administered disability measure in which greater level of pain-related disability is reflected by higher score. The RMDQ score ranges from 0 to 24 with a lower score indicating better function. | Baseline; Visit 3 (10 days after the start of treatment) | 
| Percentage of Patients With at Least One Pain Flare-up During the Study | Episode of pain flare-up was defined as presence of at least 1 day with low back pain following a period without pain lasting at least 4 weeks. Therefore pain flare-ups were registered no earlier than 4 weeks after the start of treatment, i.e. starting from Visit 5 (38 days after the start of treatment). The occurrence of pain flare-up was determined by the investigator. | From Visit 5 (38 days after the start of treatment) to Visit 9 (End of Study Visit, 94 days after the start of treatment) | 
| Percentage of Patients With at Least One Pain Flare-up Resulting in Consultancy With Physician, Resulting in Disruption of Daily Activity, and Resulting in NSAIDs Intake | Episode of pain flare-up was defined as presence of at least 1 day with low back pain following a period without pain lasting at least 4 weeks. Therefore pain flare-ups were registered no earlier than 4 weeks after the start of treatment, i.e. starting from Visit 5 (38 days after the start of treatment). The occurrence of pain flare-up was determined by the investigator. Percentages of patients with at least one pain flare-up resulting in consultancy with physician or professional management, resulting in disruption of daily activity, and resulting in NSAIDs intake were analyzed separately. | From Visit 5 (38 days after the start of treatment) to Visit 9 (End of Study Visit, 94 days after the start of treatment) | 
| Number of Treatment Days With NSAIDs | Number of treatment days with NSAIDs was calculated using the data collected on the NSAIDs intake during the study irrespective of the specific drug used. Duration of each intake period was determined as Stop date - Start date +1 and, finally, all individual duration values were summed up. In case medication intake was ongoing at the End of Study Visit, stop date was imputed by the date of study completion. | From Baseline to Visit 9 (End of Study Visit, 94 days after the start of treatment)/ Early Discontinuation Visit | 
| Prescribed and Actual Number of Milgamma® Injections | Prescribed number of Milgamma® injections was reported at Baseline visit. Actual number of injections was calculated by counting the number of injections administered and reported starting from Visit 2. If the treatment was interrupted, the days patient did not receive Milgamma® injections were not contribute to the total number of injections. | From Baseline to Visit 9 (End of Study Visit, 94 days after the start of treatment)/ Early Discontinuation Visit | 
| Prescribed and Actual Number of Treatment Days With Milgamma® Compositum | Prescribed number of treatment days with Milgamma® compositum intake was reported at Baseline visit. Actual number of treatment days was calculated by summing up all the individual periods of treatment with Milgamma® compositum (in days) reported starting from Visit 2. If the treatment was interrupted, the days patient did not receive Milgamma® compositum were not contribute to the total number of treatment days with Milgamma® compositum intake. | From Baseline to Visit 9 (End of Study Visit, 94 days after the start of treatment)/ Early Discontinuation Visit | 
| Patient Satisfaction With Treatment | Patient satisfaction with treatment was evaluated using a 5-point verbal rating scale (1= very dissatisfied, 2= dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied) after 5, 10, 38 days and 3 months (94 days) since the start of treatment. | Visit 2 (5 days after the start of treatment); Visit 3 (10 days after the start of treatment); Visit 5 (38 days after the start of treatment) and Visit 9 (94 days after the start of treatment) | 
| Percentage of Patients Prematurely Discontinued Milgamma®/ Milgamma® Compositum Treatment | Percentage of patients prematurely discontinued prescribed treatment with Milgamma®/ Milgamma® compositum was evaluated by reasons for discontinuation. | From Baseline to Visit 9 (End of Study Visit, 94 days after the start of treatment)/ Early Discontinuation Visit | 
| Reasons for Early Discontinuation of Study Participation | Percentage of patient prematurely discontinued study participation by the following reasons: patient lost to follow-up, patient withdrew consent, administrative reasons, pain resolution, adverse event, death, other reason. | From Baseline to Visit 9 (End of Study Visit, 94 days after the start of treatment)/ Early Discontinuation Visit | 
| Frequency and Severity of Adverse Drug Reactions (ADRs) | As this was a non-interventional study in which NSAIDs and Milgamma® / Milgamma® compositum were administered and managed within routine medical care, safety assessment was based on frequency and severity of Adverse Drug Reactions (ADRs) recorded during the study. ADR was defined as an adverse event (AE) suspected to be causally related to the medicinal product (Milgamma®, Milgamma® compositum or NSAID). The severity grade (mild, moderate or severe) of ADR was determined based on the investigator's judgement. Adverse events not related to the medicinal product were not monitored in this observational study. | From Baseline to Visit 9 (End of Study Visit, 94 days after the start of treatment)/ Early Discontinuation Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low back pain, Milgamma, NSAIDs