Trial of Combined Pentoxifylline-tocopherol-clodronate vs Placebo in Radiation-induced Brachial Plexopathy

Study Overview
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Brief Summary
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Radiation-induced brachial plexopathy (RIP) is a rare and severe delayed peripheral nerve complication of radiotherapy, that is spontaneously irreversible with no medical treatment to limit or reduce symptoms. The investigators planed in RIP a randomized double blind clinical trial, using a pentoxifylline (P)- tocopherol (E)- clodronate combination versus placebo, to assess a possible symptomatic regression by a sensory-motor neurological quantifiable and reproducible score (modified Subjective Objective Medical management Analytic, SOMA). The investigators previously developed a successful PE treatment in symptomatic RI injuries via the antioxidant pathway, in clinical phase II and III trails and experiments obtaining a major significant radiation-induced fibrosis regression, then the PE clodronate combination (PENTOCLO), obtaining a rapid and significant healing of mandible osteoradionecrosis and significant neurological signs regression (- 35% modified SOMA score at 18 months) in 50 partial RIP. The aim of this phase III randomized clinical trial is to show PENTOCLO efficiency and its tolerance in long survival patients irradiated before for cancer and presenting with partial RIP of upper or lower legs. The investigators calculated to include 60 patients to show a significant clinical difference between the two groups after 18 months of treatment: PENTOCLO[Pentoxifylline 400 (2x/d) + vitamine E 500 (2x/d) + intermittent Clodronate 800 (2/d, 5d/7)] versus triple placebo, with prednisone 20 (2d/7) for all patients. RIP is assessed before treatment and every 6 months by a standardized sensory-motor neurological (SOMA 95 modified by NCI-CTC 99) score used for main criteria at M18, and various neurological scales of assessment (Visual Analog Scale for pain / VAS for paresthesia, Neuropathic Pain Symptom Inventory [NPSI], Overall Disability Sum Score [ODSS], muscle testing, Nine hole peg test / Timed 25-Foot Walk), quality of life (SF36, Patient Global Impression of Change and Clinical Global impression of Change [PGIC/ CGIC]) and electrophysiology.

Detailed Description
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The aim of this phase III randomized clinical trial is to show PENTOCLO efficiency and its tolerance in long survival patients irradiated before for cancer and presenting with partial RIP of upper or lower legs. We calculated to include 60 patients to show a significant clinical difference between the two groups after 18 months of treatment: PENTOCLO [Pentoxifylline 400 (2x/d) + vitamine E 500 (2x/d) + intermittent Clodronate 800 (2/d, 5d/7)] versus triple placebo, with prednisone 20 (2d/7) for all patients. RIP is assessed before treatment and every 6 months by a standardized sensory-motor neurological (SOMA 95 modified by NCI-CTC 99) score used for main criteria at M18, and various neurological scales of assessment (Visual Analog Scale [VAS] for pain / VAS for paresthesia, Neuropathic Pain Symptom Inventory [NPSI], Overall Disability Sum Score [ODSS], muscle testing, Nine hole peg test / Timed 25-Foot Walk), quality of life (SF36, Patient Global Impression of Change and Clinical Global impression of Change [PGIC/ CGIC]) and electrophysiology.

Official Title
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Randomized Clinical Trial Evaluating Combined Pentoxifylline-tocopherol-clodronate vs Placebo in Radiation-induced Brachial Plexopathy: the PENTOCLO Trial

Conditions
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Radiation Induced Brachial Plexopathy

Intervention / Treatment
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* Drug: Pentoxifylline placebo
* Drug: Pentoxifylline
* Drug: Tocopherol acetate
* Drug: Clodronic Acid
* Drug: Tocopherol placebo
* Drug: Clodronate placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Past-history of post-operative or exclusive irradiation (RT) for currently in remission cancer, in particular breast cancer with breast or thoracic anterior wall RT; axilla-subclavicular lymph nodes RT; sometimes lung or head/neck cancer Lymphoma (Hodgkin or non Hodgkin) with axilla-subclavicular RT (upper limb) or lumbar-aortic (lower limbs) or testis tumor Delay RT-RIP more than 6 months, but partial RIP Neurological injury in irradiated volume confirmed by EMG Patient living within distance compatible with day-hospitalization Use of effective contraception for fertile women Signed written informed consent (in case of motor paralysis informed consent is signed by a witness) Exclusion Criteria: Localized or metastatic cancer recurrence (axillar MRI or PET scan) Complete plexus injury with total motor paralysis of upper/ lower limb for more than 2 years Associated neurological disease that may interferer with the assessment of endpoints Hemorrhage, disease with hemorrhagic risk, unbalanced diabetes Known hypersensitivity to Pentoxifylline, one of the excipients or biphosphonates Renal failure, liver failure or decompensated heart failure Taking another biphosphonate Evolving virosis (hepatitis, herpes, zona) or live vaccine (influenza) Uncontrolled psychotic condition Informed consent not obtained Fertile women who do not want or cannot use effective contraception during the administration of study drugs Women pregnant or nursing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PENTOCLO<br>Association pentoxifylline, tocopherol and clodronate | Drug: Pentoxifylline<br>* Pentoxifylline 400 mg: 1 cp twice a day (7d/7)<br>* Other names: Pentoxifylline 400 mg: 1 cp twice a day (7d/7);Drug: Tocopherol acetate<br>* Tocopherol alpha-acetate, 500 mg: 1 capsule twice a day (7d/7)<br>* Other names: Tocopherol alpha-acetate;Drug: Clodronic Acid<br>* Clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday)<br>* Other names: Clodronate disodium;|
| Placebo Comparator: Placebo<br>Triple placebo | Drug: Pentoxifylline placebo<br>* Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7)<br>* Other names: Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7);Drug: Tocopherol placebo<br>* Placebo for Tocopherol alpha-acetate, 500 mg: 1 capsule twice a day (7d/7)<br>Drug: Clodronate placebo<br>* Placebo for clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensory-motor neurological clinical assessment | Sensory-motor neurological clinical assessment of RIP patients as measured with SOMA scale (Subjective Objective Medical management Analytic involving tools) modified by NCI-CTC99 scale | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain VAS | Visual analog scale for pain | 6, 12, 18 months | 
| NPSI scale | NPSI (Neuropathic Pain Symptom Inventory) pain scale to assess neuropathic pain by a self-questionnaire [Reference: Bouhassira et al. Development and validation of the neuropathic pain symptom inventory. Pain 2004;108(3):248-57] | 6, 12, 18 months | 
| Paresthesia VAS | Visual analog scale for paresthesia | 6, 12, 18 months | 
| Frequence of paresthesia | Evaluated on a 4-item scale: Never Occasional (several times each week or month) Intermittent (several times a day) Permanent (all day long and night) | 6, 12, 18 months | 
| ODSS | Overall disability sum score: Checklist for upper limb (5 items) and lower limb (7 items) | 6, 12, 18 months | 
| Muscle testing | Semi-quantitative manual muscle strength assessment on a 0 to 5 scale, separately for each muscle. | 6, 12, 18 months | 
| Neurological examination | Evaluation of sensitivity, motricity and reflex | 6, 12, 18 months | 
| Motor assessment of complex movements | Evaluated by two separate tests according to upper vs lower limb involvement: Nine Hole Peg test for brachial injury Timed 25-Foot Walk for lower limb symptoms | 6, 12, 18 months | 
| Quality of life | Global quality of life as evaluated by SF36 questionnaire | 6, 12, 18 months | 
| Global clinical impression | Patient global impression of change (PGIC) and clinical global impression of change (CGIC) | 6, 12, 18 months | 
| Electromyography | Electromyography of upper / lower limbs | 6, 12, 18 months | 
| Clinical symptoms evaluation | Clinical evaluation looking for upper digestive disorders (nausea, vomiting, epigastralgia), lower digestive disorders (diarrhea), vascular disorders (cephalalgia, vertigo, flush, deep asthenia), bleeding (hematoma) | 6, 12, 18 months | 
| Biological evaluation | evaluation of biological parameters: blood cell count, platelets, sedimentation velocity, C-reactive protein, prothrombin time, TCK, calcemia, protidemia, LDH, creatininemia, phosphokinase creatine (CPK) | 6, 12, 18 months | 
| Cardiovascular evaluation | As evaluated by: Heart rate Blood pressure lying and standing after 5 minutes orthostatism Electrocardiogramm | 6, 12, 18 months |