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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2011 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by:
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01291433
First received: February 2, 2011
Last updated: April 14, 2011
Last verified: April 2011
  Purpose

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.


Condition Intervention Phase
Radiation Induced Brachial Plexopathy
Drug: Pentoxifylline placebo
Drug: Pentoxifylline
Drug: Tocopherol acetate
Drug: Clodronic Acid
Drug: Tocopherol placebo
Drug: Clodronate placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Clinical Trial Evaluating Combined Pentoxifylline-tocopherol-clodronate vs Placebo in Radiation-induced Brachial Plexopathy: the PENTOCLO Trial

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Sensory-motor neurological clinical assessment [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Pain VAS [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Visual analog scale for pain

  • NPSI scale [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    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]

  • Paresthesia VAS [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Visual analog scale for paresthesia

  • Frequence of paresthesia [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]

    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)

  • ODSS [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Overall disability sum score: Checklist for upper limb (5 items) and lower limb (7 items)

  • Muscle testing [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Semi-quantitative manual muscle strength assessment on a 0 to 5 scale, separately for each muscle.

  • Neurological examination [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Evaluation of sensitivity, motricity and reflex

  • Motor assessment of complex movements [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]

    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

  • Quality of life [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Global quality of life as evaluated by SF36 questionnaire

  • Global clinical impression [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Patient global impression of change (PGIC) and clinical global impression of change (CGIC)

  • Electromyography [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: No ]
    Electromyography of upper / lower limbs

  • Clinical symptoms evaluation [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: Yes ]
    Clinical evaluation looking for upper digestive disorders (nausea, vomiting, epigastralgia), lower digestive disorders (diarrhea), vascular disorders (cephalalgia, vertigo, flush, deep asthenia), bleeding (hematoma)

  • Biological evaluation [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: Yes ]
    evaluation of biological parameters: blood cell count, platelets, sedimentation velocity, C-reactive protein, prothrombin time, TCK, calcemia, protidemia, LDH, creatininemia, phosphokinase creatine (CPK)

  • Cardiovascular evaluation [ Time Frame: 6, 12, 18 months ] [ Designated as safety issue: Yes ]

    As evaluated by:

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


Estimated Enrollment: 72
Study Start Date: March 2011
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PENTOCLO
Association pentoxifylline, tocopherol and clodronate
Drug: Pentoxifylline
Pentoxifylline 400 mg: 1 cp twice a day (7d/7)
Other Name: Pentoxifylline 400 mg: 1 cp twice a day (7d/7)
Drug: Tocopherol acetate
Tocopherol alpha-acetate, 500 mg: 1 capsule twice a day (7d/7)
Other Name: Tocopherol alpha-acetate
Drug: Clodronic Acid
Clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday)
Other Name: Clodronate disodium
Placebo Comparator: Placebo
Triple placebo
Drug: Pentoxifylline placebo
Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7)
Other Name: Placebo for pentoxifylline 400 mg, 1 cp twice a day (7d/7)
Drug: Tocopherol placebo
Placebo for Tocopherol alpha-acetate, 500 mg: 1 capsule twice a day (7d/7)
Other Name: Tocopherol placebo
Drug: Clodronate placebo
Placebo for clodronate disodium (clodronic acid) 800 mg: 2 cp per day, 5d/7 (from monday to friday)
Other Name: Clodronate placebo

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01291433

Contacts
Contact: Isabelle Brindel, PhD +33 (0)1 4484 1780 isabelle.bindel@sls.aphp.fr
Contact: Marc Legrand +33 (0)1 4484 1792 marc.legrand@sls.aphp.fr

Locations
France
Hôpital Saint-Louis Recruiting
Paris, France
Contact: Sylvie Delanian, MD, PhD       sylvie.delanian@sls.aphp.fr   
Principal Investigator: Sylvie Delanian, MD, PhD         
Groupe Hospitalier Pitié-Salpêtrière Recruiting
Paris, France
Contact: Pierre-François Pradat, MD, PhD       pierre-francois.pradat@psl.aphp.fr   
Principal Investigator: Pierre-François Pradat, MD, PhD         
Sub-Investigator: Thierry Maisonobe, MD         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Sylvie Delanian, MD, PhD Oncologie-Radiothérapie, Hôpital Saint Louis , Paris, France
  More Information

No publications provided by Assistance Publique - Hôpitaux de Paris

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Isabelle Brindel, Department of Clinical Research and Development
ClinicalTrials.gov Identifier: NCT01291433     History of Changes
Other Study ID Numbers: P081239
Study First Received: February 2, 2011
Last Updated: April 14, 2011
Health Authority: France: Ministry of Health

Additional relevant MeSH terms:
Brachial Plexus Neuropathies
Radiation Injuries
Radiation-Protective Agents
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Wounds and Injuries
Clodronic Acid
Pentoxifylline
Tocopherols
Vitamin E
Alpha-Tocopherol
Tocotrienols
Bone Density Conservation Agents
Physiological Effects of Drugs
Pharmacologic Actions
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Protective Agents
Vasodilator Agents
Cardiovascular Agents
Free Radical Scavengers
Antioxidants
Vitamins
Micronutrients
Growth Substances

ClinicalTrials.gov processed this record on July 26, 2014