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NCT Number: NCT01291433

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

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.

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Key information

Conditions

Radiation Induced Brachial Plexopathy

Age range

18 year–74 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Groupe Hospitalier Pitié-Salpêtrière, Paris, France

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Pentoxifylline placebo

Drug

Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7)

Other names: Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7)

Pentoxifylline

Drug

Pentoxifylline 400 mg: 1 cp twice a day (7d/7)

Other names: 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)

Other names: Tocopherol alpha-acetate

Clodronic Acid

Drug

Clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday)

Other names: Clodronate disodium

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)

Primary outcomes

  1. Sensory-motor neurological clinical assessment

    Time frame: 18 months

    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

Secondary outcomes

  1. Pain VAS

    Time frame: 6, 12, 18 months

    Visual analog scale for pain

  2. NPSI scale

    Time frame: 6, 12, 18 months

    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]

  3. Paresthesia VAS

    Time frame: 6, 12, 18 months

    Visual analog scale for paresthesia

  4. Frequence of paresthesia

    Time frame: 6, 12, 18 months

    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)

  5. ODSS

    Time frame: 6, 12, 18 months

    Overall disability sum score: Checklist for upper limb (5 items) and lower limb (7 items)

  6. Muscle testing

    Time frame: 6, 12, 18 months

    Semi-quantitative manual muscle strength assessment on a 0 to 5 scale, separately for each muscle.

  7. Neurological examination

    Time frame: 6, 12, 18 months

    Evaluation of sensitivity, motricity and reflex

  8. Motor assessment of complex movements

    Time frame: 6, 12, 18 months

    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

  9. Quality of life

    Time frame: 6, 12, 18 months

    Global quality of life as evaluated by SF36 questionnaire

  10. Global clinical impression

    Time frame: 6, 12, 18 months

    Patient global impression of change (PGIC) and clinical global impression of change (CGIC)

  11. Electromyography

    Time frame: 6, 12, 18 months

    Electromyography of upper / lower limbs

  12. Clinical symptoms evaluation

    Time frame: 6, 12, 18 months

    Clinical evaluation looking for upper digestive disorders (nausea, vomiting, epigastralgia), lower digestive disorders (diarrhea), vascular disorders (cephalalgia, vertigo, flush, deep asthenia), bleeding (hematoma)

  13. Biological evaluation

    Time frame: 6, 12, 18 months

    evaluation of biological parameters: blood cell count, platelets, sedimentation velocity, C-reactive protein, prothrombin time, TCK, calcemia, protidemia, LDH, creatininemia, phosphokinase creatine (CPK)

  14. Cardiovascular evaluation

    Time frame: 6, 12, 18 months

    As evaluated by:

    • Heart rate
    • Blood pressure lying and standing after 5 minutes orthostatism
    • Electrocardiogramm

Sponsors and collaborators

Lead sponsor

Assistance Publique - Hôpitaux de Paris

Other

Registry information

Official study title

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

Acronym: PENTOCLO

Important dates

Study start
2011
Primary completion
2017
Study completion
2017
First posted
Feb 8, 2011
Registry last updated
Dec 8, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.