Novel Treatment Option for Neuropathic Pain

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the EGFR-inhibitor cetuximab is better than placebo for the treatment of neuropathic pain.

Official Title
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A Randomized, Cross-over, Placebo-controlled, Double-blind, Single-center, Phase II Study of Cetuximab in Patients With Treatment-refractory, Non-malignant Severe Chronic Neuropathic Pain

Conditions
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Neuralgia, Complex Regional Pain Syndromes

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent and anticipated compliance. Pain defined as definite neuropathic pain, according to the Special Interest Group on Neuropathic Pain guidelines or defined as probable NP, according to the guidelines, if the confirmatory test was a positive diagnostic test. Complex regional pain syndrome can be included despite lack of an offending lesion, as long as the Budapest criteria are fulfilled Neuropathic Pain associated with compressive nerve states (including failed surgery) or CRPS (according to the Budapest criteria) PainDETECT score of at least 13 with average pain intensity of at least 6 /10 over the last four weeks. In addition, a painDETECT pattern indicating that the underlying neuropathic pain is constantly present. Worst pain intensity higher than 6 for five of seven days during the screening phase, according to Brif Pain Inventory. The patient should be able to distinguish between the neuropathic pain and other pain conditions, including elements of nociceptive pain caused by the same disease process. Neuropathic pain duration of between six and thirty months, deemed chronic and likely to be irreversible by clinical history and findings. No new or increased neuropathic pain treatment for the last four weeks. Standard medical treatments for the patients' underlying condition or neuropathic pain must have been considered or tried and must, according to the opinion of the referring or a consulted pain specialist, be judged to be inappropriate or of insufficient potential efficacy. Referring physician agreement to follow up the patient after study completion according to the best possible and available pain treatment and care. Women of childbearing potential and men must use an acceptable method of contraception throughout the study, and for 30 days after the last study drug administration. Negative pregnancy test within 7 days before each treatment period where appropriate. White blood cell count ≥ 3 × 109 with neutrophils ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L and hemoglobin ≥ 6.21 mmol/L (10 g/dL). Total bilirubin ≤ 1.5 × upper limit of reference range and AST and ALT ≤ 2.5 × upper limit of reference range within the last 28 days before inclusion. Aged 18 or above Exclusion Criteria: Neuropathic pain origin in the central nervous system. Phantom limb pain or a significant component of nociceptive pain. Ascending distal small fiber peripheral neuropathy. Patients primarily experiencing pain 'attacks', i.e. pattern of neuropathic pain depicted in picture 3 of the painDETECT. Other pain state that may interfere with evaluation of the studied neuropathic pain condition. Any underlying medical or psychiatric condition, clinical disorder or laboratory finding, which in the opinion of the investigator may interfere with study objectives. Uncontrolled or unstable diabetes. Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias Severe cerebrovascular disease during the six months prior to inclusion. Active and ongoing eye and skin disorders or newly diagnosed gastric ulcer that may interfere with the study treatment. History of allergic reaction to any of the study treatment components, red meat or tick bites. Previous treatment with any EGFR-pathway inhibitor. Women who are pregnant or breastfeeding. Participation in another clinical trial within the past 90 days. Use of any investigational agent within 90 days prior to day 1 of study drug. Known drug abuse/alcohol abuse, legal incapacity or limited legal capacity or any other reason that, in the opinion of the investigator precludes the subject from participating.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: active drug first<br>Cetuximab in treatment period 1, placebo in treatment period 2, and open-label cetuximab in treatment period 3. | Drug: Cetuximab<br>* Randomized cross-over between cetuximab and placebo<br>* Other names: Erbitux;Drug: Placebo<br>* Randomized cross-over between cetuximab and placebo<br>|
| Experimental: B: placebo first<br>Placebo in treatment period 1, cetuximab in treatment period 2, and open-label cetuximab in treatment period 3. | Drug: Cetuximab<br>* Randomized cross-over between cetuximab and placebo<br>* Other names: Erbitux;Drug: Placebo<br>* Randomized cross-over between cetuximab and placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in average neuropathic pain score using an 11-point numeric rating scale. |  | Days 4-8 after each infusion of cetuximab and placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of frequency, in all patients on active treatment of at least a 30% reduction of average neuropathic pain score using an 11-point numeric rating scale. |  | Days 4-8 after each infusion of cetuximab and placebo | 
| Comparison of frequency in all patients on active treatment of at least a 50% reduction of average neuropathic pain score using an 11-point numeric rating scale. |  | Days 4-8 after each infusion of cetuximab and placebo | 
| Comparison of change in average worst neuropathic pain score using an 11-point numeric rating scale. |  | Days 4-8 after each infusion of cetuximab and placebo | 
| Comparison of frequency, in all patients on active treatment of at least a 30% reduction of average worst neuropathic pain score using an 11-point numeric rating scale. |  | Days 4-8 after each infusion of cetuximab and placebo | 
| Comparison of frequency in all patients on active treatment of at least a 50% reduction of average worst neuropathic pain score using an 11-point numeric rating scale. |  | Days 4-8 after each infusion of cetuximab and placebo | 
| Patient Global Impression of Change. |  | 7 days after each infusion. | 
| Brief Pain Iinventory (short form) interference scores, comparing cetuximab to the placebo. |  | Days 4-8 after each infusion during treatment periods 1 and 2. | 
| Brief Pain Iinventory (short form) total scores, comparing cetuximab to the placebo. |  | Days 4-8 after each infusion during treatment periods 1 and 2. | 
| 2-hourly waking time 11-point numeric rating scale (item #6 from the Brief Pain Inventory) in the first 24 hours and daily thereafter. |  | 2-hourly in first 24 hours after infusion and daily thereafter until end of study (day 86). | 
| Number of AE and SAE recording |  | From signing informed consent (within 28 days prior to first study treatment) and until 30 days after the last study infusion. |