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

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

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.

Study Overview

• Status: Completed
• Conditions: Radiation Induced Brachial Plexopathy
• Intervention / Treatment: Drug: Pentoxifylline; Drug: Tocopherol acetate; Drug: Clodronic Acid; Drug: Pentoxifylline placebo; Drug: Tocopherol placebo; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Hopital Saint-Louis
  • Paris, France
    • Groupe Hospitalier Pitie-Salpetriere

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Sylvie Delanian, MD, PhD, Oncologie-Radiothérapie, Hôpital Saint Louis , Paris, France

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): May 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: February 2, 2011
• First Submitted That Met QC Criteria: February 7, 2011
• First Posted (Estimate): February 8, 2011

Study Record Updates

• Last Update Posted (Actual): December 8, 2017
• Last Update Submitted That Met QC Criteria: December 7, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Wounds and Injuries; Neuromuscular Diseases; Peripheral Nervous System Diseases; Radiation Injuries; Brachial Plexus Neuropathies; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Vitamin E; Tocopherols; alpha-Tocopherol; Tocotrienols; Clodronic Acid; Pentoxifylline
• Other Study ID Numbers: P081239