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Prevalence, Intensity and Consequences of Bortezomib-induced Neuropathic Disorders. (PREVIB)

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ClinicalTrials.gov Identifier: NCT03344328
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : July 1, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Clermont-Ferrand

Brief Summary:

Cancer-induced peripheral neuropathies (CIPN) remain a real problem in oncology (Balayssac et al., 2011). These CIPN are induced by certain classes of anticancer drugs such as taxanes (paclitaxel and docetaxel), platinum salts (cisplatin and oxaliplatin), alkaloids of Madagascar periwinkle (vincristine), bortezomib, thalidomide and eribulin (Balayssac et al., 2011; Vahdat et al., 2013). These CIPN essentially translate into sensory disorders such as paresthesia, dysesthetics or numbness. More rarely, these CIPN may be associated with motor or vegetative disorders (Balayssac et al., 2011). According to the recent meta-analysis by Hershman et al., no treatment can be proposed as a "gold standard" for preventing or treating CIPN (Hershman et al., 2014). As a result, oncologists reduce or stop doses of neurotoxic anticancer drugs because patients with CIPN have a marked deterioration in quality of life and co-morbidities such as anxiety, depression and sleep disorders (Hong et al., 2014; Mols et al., 2014). Therefore, understanding the pathophysiology of CIPN is essential to propose new therapeutic strategies.

Among neurotoxic anticancer drugs, bortezomib remains relatively little studied in terms of pathophysiology compared to platinum salts or taxanes, while the neurotoxicity of bortezomib remains a limiting factor in treatment. Since 2012, the FDA and EMA have validated the administration of bortezomib subcutaneously instead of intravenously in order to limit the neurotoxicity of bortezomib (Minarik et al., 2015). Indeed, a large study (N=222) reported that subcutaneous administration of bortezomib allowed the same therapeutic efficacy to be maintained while improving the safety profile and in particular limiting peripheral neuropathies (CIPN all grades: 38% vs. 53%, p=0.044, grade> 2: 24% vs. 41%, p=0.012 and grade> 3: 6% vs. 16%, p=0.026) However, a recent retrospective study (N=446) reports that the prevalence of bortezomib-induced peripheral neuropathies after subcutaneous administration remains relatively high: all grade: 41%, grade> 2: 18%, grade> 3: 4%, and above all that this prevalence is not different between subcutaneous and intravenous routes (Minarik et al., 2015).


Condition or disease Intervention/treatment
Chemotherapy Induced Peripheral Neuropathy Multiple Myeloma Drug: Bortezomib

Detailed Description:

Only 2 studies evaluated quantitatively and qualitatively the sensitivity disorders in patients with bortezomib-induced peripheral neuropathy by intravenous (Boyette-Davis et al., 2011; Cata et al., 2007). In these 2 studies, the patients presented a distribution of the sensitive disorders characteristic of the so-called stocking-glove distribution of the CIPN affecting the distal extremities of the limbs. A quantification of the sensory thresholds (QST) was carried out and revealed a number of sensitive anomalies. Neuropathic patients suffer from deficits in tactile sensitivity and disorders of thermal sensitivity. In Cata et al. study, patients showed hypersensitivity to painful cold (CIPN patients vs. healthy controls: 10.4±2°C vs. 3±1°C, p<0.05), hot perception deficit (CIPN patients vs. healthy controls: 40.2±1.4°C vs. 37±0.74°C, p<0.05) and a painful hot sensitivity deficit. However, the cold sensory disorders would be more inconstant, because in neuropathic patients suffering from bortezomib-induced peripheral neuropathy, another study by the same team found only warm tactile and thermal sensory anomalies, but did not reveal a cold perception anomaly (Boyette-Davis et al., 2011). Finally, a few rare cases of bortezomib-induced hearing impairment have been described in the literature (Chim and Wong, 2008; Engelhardt et al., 2005). This ototoxicity is thought to be linked to an alteration in the functioning of peroxisomes (Lee et al., 2015).

No studies have actually evaluated the long-term prevalence of bortezomib-induced neuropathy. The only studies with long-term follow-up have carried out a cumulative assessment over 22 months (Pantani et al., 2014), 32 months (Dimopoulos et al., 2013) and 60 months (Wang et al., 2016) of the therapeutic response and adverse reactions induced by bortezomib. No studies dedicated to neurological adverse events have been conducted in the long term. Thus, the prevalence, duration, intensity and reversibility of bortezomib-induced neuropathy are poorly known in the long term (more than 5 years). On the other hand, a measurement tool such as the QLQ-CIPN20 questionnaire (EORTC) evaluating the intensity of sensory, motor and vegetative disorders associated with CIPN, a questionnaire presented as the most specific tool in the evaluation of CIPN (Lavoie Smith et al., 2013; Postma et al., 2005), has never been tested in this patient population.

This study project aims to provide precise knowledge on the prevalence, intensity and consequences of bortezomib-induced neuropathy in the short (2016-2014) and medium (2014-2012) term after subcutaneous injection and in the long term (2012-2008) after intravenous injection, knowing that at the Clermont-Ferrand University Hospital, the route of administration of bortezomib was intravenous. Retreat to at least 9 years of age could provide information on the kinetics of onset and disappearance of neuropathy after chemotherapy treatments (data unknown in the literature to date). Finally, these data acquired in a French context relating to bortezomib-induced neuropathy may be used in future studies evaluating new intervention strategies to prevent and/or treat bortezomib-induced neuropathy.

This observational study will combine retrospective treatment data from the CHIMIO® chemotherapy prescribing software with data obtained from patients by answering questionnaires.

Patients will be identified from the CHIMIO® chemotherapy prescription software database. The algorithm (computer query) will identify all patients who received bortezomib-based chemotherapy for the multiple myeloma indication between 2008 and 2016. All the questionnaires used are validated in the scientific literature.


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Study Type : Observational
Estimated Enrollment : 360 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Evaluation of the Prevalence, Intensity and Consequences of Bortezomib-induced Neuropathic Disorders: Monocentric Observational and Cross-sectional Study.
Actual Study Start Date : January 15, 2019
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : January 31, 2020



Intervention Details:
  • Drug: Bortezomib
    The algorithm (computer query) will identify all patients who received bortezomib-based chemotherapy for the multiple myeloma indication between 2008 and 2016. All the questionnaires used are validated in the scientific literature.


Primary Outcome Measures :
  1. Prevalence of peripheral neuropathy [ Time Frame: at day 1 ]

    Quality of Life Questionnaire - Chemotherapy-Induced Peripheral Neuropathy 20 (QLQ-CIPN20 ; EORTC- European Organisation for Research and Treatment of Cancer).

    The questionnaire is divided in 3 subscales: sensory, motor and vegetative. Severity scores summed from 0 to 100. A high score will correspond to the worst symptoms.

    • Sensory score CIPN20 ≤ 6 = grade 0 NCI-CTCAE
    • Sensory score CIPN20 > 6 and < 30 = grade 1 NCI-CTCAE
    • Sensory score CIPN20 ≥ 30 and < 80 = grade 2-3 NCI-CTCAE
    • Sensory score CIPN20 ≥ 80 = grade 4 NCI-CTCAE.


Secondary Outcome Measures :
  1. Chronic pain [ Time Frame: at day 1 ]
    Pain score rated by a Visual Analog Scale (VAS, 0 (no pain) - 10 (worst possible pain)). Pain will be defined for a score of 4/10.

  2. Screening of neuropathic pain [ Time Frame: at day 1 ]
    DN4 questionnaire interview (positive score> 3/7), if VAS pain> 4

  3. Anxiety and Depression Score [ Time Frame: at day 1 ]
    Hospital Anxiety and Depression Scale (HADS, summed score from 0 to 21). Score ≤ 7 = no symptomatology, score between 8-10 = suspect symptomatology and score ≥ 11 = consistent symptomatology.

  4. Hearing disorders [ Time Frame: at day 1 ]
    EVA and questions exploring possible hearing problems (professional or leisure activity exposing to noise, habit of having people repeat themselves, problems with telephone comprehension, need to increase television volume, difficulty following a conversation in the presence of noise).

  5. Health -related quality of life related to chemotherapy treatment. [ Time Frame: at day 1 ]

    Quality of Life Questionnaire - Chemotherapy 30 (QLQ-C30, EORTC-European Organisation for Research and Treatment of Cancer).

    The questionnaire is divided in 3 subscales: Global health, functional and symptomatic.

    Severity scores summed from 0 to 100. For the global health scale and the functional scale, a high score will correspond to a better quality of life. For the symptomatic scale, a high score will correspond to a lower quality of life.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients previously treated with bortezomib for multiple myeloma between 2008 and 2016 at Clermont-Ferrand University Hospital
Criteria

Inclusion Criteria:

  • - Patients previously treated with bortezomib for multiple myeloma between 2008 and 2016 at Clermont-Ferrand University Hospital.
  • Oral non-opposition of participation in the study

Exclusion Criteria:

  • Patient unable to understand or answer questionnaires.
  • Age < 18 years.
  • Neurological pathologies (e. g. Parkinson's syndrome, stroke, fibromyalgia, etc.).
  • Legal incapacity (person deprived of liberty or under guardianship).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03344328


Contacts
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Contact: Patrick LACARIN 04 73 75 11 95 placarin@chu-clermontferrand.fr

Locations
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France
CHU Clermont-Ferrand Recruiting
Clermont-Ferrand, France, 63003
Contact: Patrick LACARIN    04 73 75 11 95    placarin@chu-clermmontferrand.fr   
Principal Investigator: David BALAYSSAC         
Sponsors and Collaborators
University Hospital, Clermont-Ferrand
Investigators
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Principal Investigator: David BALAYSSAC University Hospital, Clermont-Ferrand

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Responsible Party: University Hospital, Clermont-Ferrand
ClinicalTrials.gov Identifier: NCT03344328     History of Changes
Other Study ID Numbers: CHU-359
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Clermont-Ferrand:
Chemotherapy
Bortezomib
Multiple myeloma

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Peripheral Nervous System Diseases
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Neuromuscular Diseases
Nervous System Diseases
Bortezomib
Antineoplastic Agents