Clinical trial NCT01291433: Trial of Combined Pentoxifylline-tocopherol-clodronate vs Placebo in Radiation-induced Brachial Plexopathy
Official title: Randomized Clinical Trial Evaluating Combined Pentoxifylline-tocopherol-clodronate vs Placebo in Radiation-induced Brachial Plexopathy: the PENTOCLO Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Radiation Induced Brachial Plexopathy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2011-02-08
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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 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

Primary outcomes:
measure: Sensory-motor neurological clinical assessment
timeFrame: 18 months
Secondary outcomes:
measure: Pain VAS
timeFrame: 6, 12, 18 months
measure: NPSI scale
timeFrame: 6, 12, 18 months
measure: Paresthesia VAS
timeFrame: 6, 12, 18 months
measure: Frequence of paresthesia
timeFrame: 6, 12, 18 months
measure: ODSS
timeFrame: 6, 12, 18 months
measure: Muscle testing
timeFrame: 6, 12, 18 months
measure: Neurological examination
timeFrame: 6, 12, 18 months
measure: Motor assessment of complex movements
timeFrame: 6, 12, 18 months
measure: Quality of life
timeFrame: 6, 12, 18 months
measure: Global clinical impression
timeFrame: 6, 12, 18 months
measure: Electromyography
timeFrame: 6, 12, 18 months
measure: Clinical symptoms evaluation
timeFrame: 6, 12, 18 months
measure: Biological evaluation
timeFrame: 6, 12, 18 months
measure: Cardiovascular evaluation
timeFrame: 6, 12, 18 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Groupe Hospitalier Pitié-Salpêtrière
city: Paris
country: France
facility: Hôpital Saint-Louis
Study officials:
affiliation: Oncologie-Radiothérapie, Hôpital Saint Louis , Paris, France
name: Sylvie Delanian, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.