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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PENTOCLO | Experimental | Association pentoxifylline, tocopherol and clodronate |
|
| Placebo | Placebo Comparator | Triple placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pentoxifylline placebo | Drug | Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7) |
|
| 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 |
| 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] |
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Inclusion Criteria:
Past-history of post-operative or exclusive irradiation (RT) for currently in remission cancer, in particular
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:
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| Name | Affiliation | Role |
|---|---|---|
| Sylvie Delanian, MD, PhD | Oncologie-Radiothérapie, Hôpital Saint Louis , Paris, France | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Groupe Hospitalier Pitié-Salpêtrière | Paris | France | ||||
| Hôpital Saint-Louis |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22742890 | Derived | Pradat PF, Maisonobe T, Psimaras D, Lenglet T, Porcher R, Lefaix JL, Delanian S. [Radiation-induced neuropathies: collateral damage of improved cancer prognosis]. Rev Neurol (Paris). 2012 Dec;168(12):939-50. doi: 10.1016/j.neurol.2011.11.013. Epub 2012 Jun 27. French. |
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| Pentoxifylline | Drug | Pentoxifylline 400 mg: 1 cp twice a day (7d/7) |
|
|
| Tocopherol acetate | Drug | Tocopherol alpha-acetate, 500 mg: 1 capsule twice a day (7d/7) |
|
|
| Clodronic Acid | Drug | Clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday) |
|
|
| Tocopherol placebo | Drug | Placebo for Tocopherol alpha-acetate, 500 mg: 1 capsule twice a day (7d/7) |
|
| Clodronate placebo | Drug | Placebo for clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday) |
|
| 6, 12, 18 months |
| Paresthesia VAS | Visual analog scale for paresthesia | 6, 12, 18 months |
| Frequence of paresthesia | Evaluated on a 4-item scale:
| 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:
| 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:
| 6, 12, 18 months |
| Paris |
| France |
| ID | Term |
|---|---|
| C536265 | Radiation induced brachial plexopathy |
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| ID | Term |
|---|---|
| D010431 | Pentoxifylline |
| D024502 | alpha-Tocopherol |
| D004002 | Clodronic Acid |
| ID | Term |
|---|---|
| D013805 | Theobromine |
| D014970 | Xanthines |
| D011688 | Purinones |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D024505 | Tocopherols |
| D014810 | Vitamin E |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D004164 | Diphosphonates |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
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