Acute Low Back Pain
Conditions
Brief summary
The aim of this study is to assess the efficacy and tolerability of Nicoboxil/Nonivamide ointment in comparison to Nicoboxil, Nonivamide, and placebo ointments for the treatment of acute low back pain.
Interventions
DRUGnicoboxil
2cm ointment line for a skin area of approximately 20 cm x 20 cm up to 3 times in a 24h period
DRUGplacebo matching nonivamide + nicoboxil
2cm ointment line for a skin area of approximately 20 cm x 20 cm up to 3 times in a 24h period
DRUGnonivamide + nicoboxil (Finalgon)
2cm ointment line for a skin area of approximately 20 cm x 20 cm up to 3 times in a 24h period
DRUGnonivamide
2cm ointment line for a skin area of approximately 20 cm x 20 cm up to 3 times in a 24h period
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients must sign and date an Informed Consent consistent with International Conference on Hermonisation (ICH)/Good Clinical Practice (GCP) guidelines and local regulation prior to participation in the trial. * Patients must agree to cooperate with all trial evaluations and perform all required tasks. * Acute low back pain for more than 2 days and less than 21 days (= 3 weeks) * Male or female patients aged 18 to 65 years * Low back pain rating \>5 on a 0-10 numerical rating scale (NRS). * Female patients of childbearing potential may participate only in case of availability of a negative urine pregnancy test and a confirmed menstrual period prior to study entry and using a highly effective method of birth control. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1 % per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, appropriate intrauterine devices, sexual abstinence or vasectomised partner. Barrier methods of contraception (e.g. condom, diaphragma or occlusive cap) are accepted if used in combination with spermicides (e.g. foam, gel). Female patients will be considered being of childbearing potential unless surgically sterilised by bilateral tubal ligation/salpingectomy or hysterectomy or post-menopausal for at least one year.
Exclusion criteria
* Multilocular pain or panalgesia * History of more than three low back pain episodes in the last six months * Abnormal findings in at least one of the following assessments: Achilles tendon reflex, patella reflex, heel walking, toe walking, cutaneous sensitivity of the legs (including gluteal region), paresis tests in supine position upon dorsiflexion, plantarflexion, hip flexion, knee extension * Bladder and/or rectum dysfunction * Acute low back pain due to vertebral collapse or neoplastic, inflammatory (ankylosing spondylitis), traumatic, or infective origins * Any condition, disease or concomitant treatment that in the judgement of the Investigator will affect the subject's ability to participate in the clinical trial or which will influence the test methodology used * Negative experience in the past with heat treatment for muscle complaints (e. g. hot water bottle, heat pads, hyperemisation-inducing topical creams, ointments or patches) * History of treatment of back pain with centrally acting analgesics (e. g. opioids) and muscle relaxants * Surgery due to back pain or rehabilitation due to back pain in the last 12 months * Spinal injection back pain treatment within 6 months prior to enrollment * Intake of antidepressant/antipsychotic medication within 4 weeks prior to enrollment * Treatment of the recent low back pain period with oral analgesics for more than 4 consecutive days * Locally applied medication to the back within 48 hours prior to enrollment (topical treatments, injections) * Administration of other analgesics within 24 h prior to enrollment (exception: acetyl salicylic acid (ASS) up to 100 mg/daily for anti platelet-aggregation therapy) * Non-pharmacological low back pain treatment (physiotherapy, heat treatment (e.g. hot water bottle, heat patch, or massages) within 12 h prior to enrollment * Participation in an investigational drug or device trial within 4 weeks prior to enrollment * Hypersensitivity to Nicoboxil, Nonivamide, or paracetamol * Known hypersensitivity to any other ingredient, especially to sorbic acid/sorbate, to citronella oil containing e.g. the fragrance compounds geraniol, citronellol and citronellal, or to relevant flowers containing these compounds such as geranium, lavender, jasmine or rose. For patients with known hypersensitivity to perfumes or known type IV hypersensitivity to fragrance-mix I, the application of the investigational product should be performed only with particular caution. * Skin lesions (e. g., rash, dermatitis, bruising, laceration) in the back region * Drug dependence and/or alcohol abuse * Severe hepatocellular insufficiency * Patients who are pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity Difference (PID) Between Pre-dose Baseline and 8hours After First Application | Baseline and 8 hours after first ointment application | Pain intensity (PI) was assessed on a 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible) at pre-dose baseline and 0.5, 1, 2, 3, 4, 6 and 8 hours after first ointment application. Means were adjusted for centre effect and baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Intensity Difference (PID) Between Pre-dose Baseline and 4 Hours After First Application | Baseline and 4 hours after first ointment application | Pain intensity was assessed on a 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible) at pre-dose baseline and 0.5, 1, 2, 3 and 4 hours after first ointment application. Means were adjusted for centre effect and baseline value. |
| Difference Between Baseline Pain Intensity and Average Pain Intensity on the Last Individual Treatment Day | Baseline and 1 to 4 days | Average pain intensity was assessed in the evening of days 1, 2, 3 and 4 on a 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible). The last individual treatment day is the last day with diary-recorded ointment application. Means were adjusted for centre effect and baseline value. |
| Patient Assessment of Efficacy on the Last Individual Treatment Day | 1 to 4 days | Patient assessment of efficacy was assessed on a 4-point verbal rating scale (VRS, 0 = 'poor', 1 = 'fair', 2 = 'good', 3 = 'very good' relief of the patients' low back pain) in the evening of days 1, 2, 3 and 4. The last individual treatment day is the last day with diary-recorded ointment application |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients treated with placebo ointment | 204 |
| Nicoboxil Patients treated with ointments containing 2.5% nicoboxil alone | 201 |
| Nonivamide Patients treated with ointments containing 0.4% nonivamide alone | 198 |
| Nicoboxil/Nonivamide Patients treated with ointments containing a combination of 2.5% nicoboxil and 0.4% nonivamide | 202 |
| Total | 805 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 9 | 13 |
| Overall Study | Lack of Efficacy | 84 | 60 | 35 | 15 |
| Overall Study | Other reasons than stated above | 1 | 1 | 0 | 2 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo | Nicoboxil | Nonivamide | Nicoboxil/Nonivamide | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.2 years STANDARD_DEVIATION 13.27 | 40.4 years STANDARD_DEVIATION 13.06 | 42.2 years STANDARD_DEVIATION 13.53 | 40.2 years STANDARD_DEVIATION 14.31 | 40.5 years STANDARD_DEVIATION 13.57 |
| Sex: Female, Male Female | 94 Participants | 91 Participants | 103 Participants | 100 Participants | 388 Participants |
| Sex: Female, Male Male | 110 Participants | 110 Participants | 95 Participants | 102 Participants | 417 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 204 | 0 / 201 | 0 / 198 | 0 / 202 |
| serious Total, serious adverse events | 0 / 204 | 0 / 201 | 1 / 198 | 0 / 202 |
Outcome results
Primary
Pain Intensity Difference (PID) Between Pre-dose Baseline and 8hours After First Application
Pain intensity (PI) was assessed on a 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible) at pre-dose baseline and 0.5, 1, 2, 3, 4, 6 and 8 hours after first ointment application. Means were adjusted for centre effect and baseline value.
Time frame: Baseline and 8 hours after first ointment application
Population: Patients from the Full Analysis Set (FAS): all randomised patients who used at least 1 dose of study medication and provided any post-treatment data for the pain intensity difference within 8 hours after first application.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pain Intensity Difference (PID) Between Pre-dose Baseline and 8hours After First Application | -1.049 units on a scale | Standard Error 0.106 |
| Nicoboxil | Pain Intensity Difference (PID) Between Pre-dose Baseline and 8hours After First Application | -1.428 units on a scale | Standard Error 0.109 |
| Nonivamide | Pain Intensity Difference (PID) Between Pre-dose Baseline and 8hours After First Application | -2.252 units on a scale | Standard Error 0.141 |
| Nicoboxil/Nonivamide | Pain Intensity Difference (PID) Between Pre-dose Baseline and 8hours After First Application | -2.410 units on a scale | Standard Error 0.138 |
p-value: <0.000195% CI: [-1.699, -1.025]Restricted Maximum Likelihood (REML)
p-value: <0.000195% CI: [-1.324, -0.642]Restricted Maximum Likelihood (REML)
p-value: 0.417195% CI: [-0.541, 0.225]Restricted Maximum Likelihood (REML)
Secondary
Difference Between Baseline Pain Intensity and Average Pain Intensity on the Last Individual Treatment Day
Average pain intensity was assessed in the evening of days 1, 2, 3 and 4 on a 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible). The last individual treatment day is the last day with diary-recorded ointment application. Means were adjusted for centre effect and baseline value.
Time frame: Baseline and 1 to 4 days
Population: Patients from FAS with evaluable data for the pain intensity at baseline and for the avarage pain intensity on the last individual treatment day.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Difference Between Baseline Pain Intensity and Average Pain Intensity on the Last Individual Treatment Day | -1.884 units on a scale | Standard Error 0.16 |
| Nicoboxil | Difference Between Baseline Pain Intensity and Average Pain Intensity on the Last Individual Treatment Day | -2.371 units on a scale | Standard Error 0.16 |
| Nonivamide | Difference Between Baseline Pain Intensity and Average Pain Intensity on the Last Individual Treatment Day | -3.074 units on a scale | Standard Error 0.161 |
| Nicoboxil/Nonivamide | Difference Between Baseline Pain Intensity and Average Pain Intensity on the Last Individual Treatment Day | -3.540 units on a scale | Standard Error 0.159 |
p-value: <0.000195% CI: [-2.064, -1.247]ANCOVA
p-value: <0.000195% CI: [-1.578, -0.759]ANCOVA
p-value: 0.025995% CI: [-0.875, -0.056]ANCOVA
Secondary
Pain Intensity Difference (PID) Between Pre-dose Baseline and 4 Hours After First Application
Pain intensity was assessed on a 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible) at pre-dose baseline and 0.5, 1, 2, 3 and 4 hours after first ointment application. Means were adjusted for centre effect and baseline value.
Time frame: Baseline and 4 hours after first ointment application
Population: Patients from FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pain Intensity Difference (PID) Between Pre-dose Baseline and 4 Hours After First Application | -0.650 units on a scale | Standard Error 0.077 |
| Nicoboxil | Pain Intensity Difference (PID) Between Pre-dose Baseline and 4 Hours After First Application | -0.968 units on a scale | Standard Error 0.091 |
| Nonivamide | Pain Intensity Difference (PID) Between Pre-dose Baseline and 4 Hours After First Application | -1.641 units on a scale | Standard Error 0.11 |
| Nicoboxil/Nonivamide | Pain Intensity Difference (PID) Between Pre-dose Baseline and 4 Hours After First Application | -1.699 units on a scale | Standard Error 0.109 |
p-value: <0.000195% CI: [-1.305, -0.793]Restricted Maximum Likelihood (REML)
p-value: <0.000195% CI: [-1.003, -0.459]Restricted Maximum Likelihood (REML)
p-value: 0.703795% CI: [-0.356, 0.241]Restricted Maximum Likelihood (REML)
Secondary
Patient Assessment of Efficacy on the Last Individual Treatment Day
Patient assessment of efficacy was assessed on a 4-point verbal rating scale (VRS, 0 = 'poor', 1 = 'fair', 2 = 'good', 3 = 'very good' relief of the patients' low back pain) in the evening of days 1, 2, 3 and 4. The last individual treatment day is the last day with diary-recorded ointment application
Time frame: 1 to 4 days
Population: Patients from FAS.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Placebo | Patient Assessment of Efficacy on the Last Individual Treatment Day | Poor | 125 participants | — |
| Placebo | Patient Assessment of Efficacy on the Last Individual Treatment Day | Good | 47 participants | — |
| Placebo | Patient Assessment of Efficacy on the Last Individual Treatment Day | Missing | 1 participants | — |
| Placebo | Patient Assessment of Efficacy on the Last Individual Treatment Day | Fair | 22 participants | — |
| Placebo | Patient Assessment of Efficacy on the Last Individual Treatment Day | Very good | 9 participants | 0.16 |
| Nicoboxil | Patient Assessment of Efficacy on the Last Individual Treatment Day | Fair | 20 participants | — |
| Nicoboxil | Patient Assessment of Efficacy on the Last Individual Treatment Day | Poor | 94 participants | — |
| Nicoboxil | Patient Assessment of Efficacy on the Last Individual Treatment Day | Missing | 1 participants | — |
| Nicoboxil | Patient Assessment of Efficacy on the Last Individual Treatment Day | Good | 67 participants | — |
| Nicoboxil | Patient Assessment of Efficacy on the Last Individual Treatment Day | Very good | 19 participants | 0.16 |
| Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Fair | 27 participants | — |
| Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Very good | 34 participants | 0.161 |
| Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Good | 85 participants | — |
| Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Poor | 52 participants | — |
| Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Missing | 0 participants | — |
| Nicoboxil/Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Poor | 42 participants | — |
| Nicoboxil/Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Good | 88 participants | — |
| Nicoboxil/Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Very good | 50 participants | 0.159 |
| Nicoboxil/Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Fair | 20 participants | — |
| Nicoboxil/Nonivamide | Patient Assessment of Efficacy on the Last Individual Treatment Day | Missing | 2 participants | — |
p-value: <0.000195% CI: [4.943, 11.032]Regression, Logistic
p-value: <0.000195% CI: [2.469, 5.308]Regression, Logistic
p-value: 0.012995% CI: [1.104, 2.303]Regression, Logistic