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Focused Ultrasound and RadioTHERapy for Noninvasive Palliative Pain Treatment in Patients With Bone Metastases (FURTHER)

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ClinicalTrials.gov Identifier: NCT04307914
Recruitment Status : Recruiting
First Posted : March 13, 2020
Last Update Posted : March 13, 2020
Sponsor:
Collaborators:
Turku University Hospital
Universitätsklinikum Köln
University of Roma La Sapienza
Istituto Ortopedico Rizzoli
University of Bologna
Isala
Information provided by (Responsible Party):
Helena M Verkooijen, UMC Utrecht

Brief Summary:
The FURTHER study aims to evaluate the effectiveness and cost-effectiveness of MR-HIFU (alone or in combination with EBRT) compared to EBRT alone, the standard-of-care, as a palliative treatment option to relieve CIBP. This multicenter, three-armed randomized controlled trial will be performed in six hospitals in four European countries, and will include a total of 216 patients with painful bone metastases.

Condition or disease Intervention/treatment Phase
Bone Metastases Bone Neoplasm Bone Lesion Bone Cancer Pain Cancer Induced Bone Pain Quality of Life Tumor Neoplasm Metastasis Radiation: External beam radiotherapy Procedure: MR-HIFU Phase 3

Detailed Description:

Rationale: Cancer induced bone pain (CIBP) as a result of bone metastases strongly interferes with quality of life and daily functioning of patients with advanced cancer. The current standard of care for patients with painful bone metastasis includes palliative external beam radiotherapy (EBRT). While EBRT is a well-established treatment option, it takes up to 4-6 weeks for EBRT to induce optimal pain relief, and 30-40% of patients do not respond to EBRT. Pain palliation may be improved by including magnetic resonance image guided high intensity focused ultrasound (MR-HIFU) as alternative or in addition to EBRT.

Study design: The FURTHER study is a multicenter, three-armed randomized controlled trial, performed in six hospitals in four European countries, all of which are partners in the FURTHER consortium. The UMC Utrecht is coordinating center. A total of 216 patients with painful bone metastases will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or EBRT followed by MR-HIFU.

Study population: The study will be performed in male and female adult (≥ 18 years) cancer patients capable of giving informed consent, who were referred to the department of radiation oncology for treatment of painful bone metastases (pain score on Numerical Rating Scale (NRS) ≥ 4).

Intervention: The intervention under study is MR-HIFU alone or in combination with EBRT. The intervention is aimed at rapid and persistent relief of CIBP. The intervention will be compared with standard treatment EBRT.

Main study endpoints: Primary outcome of the trial will be pain response at 14 days after completion of the treatment. Secondary outcomes include pain response at 14 days after inclusion, and pain scores, toxicity, adverse events, quality of life and survival in the first 6 months after treatment, and cost-effectiveness of the treatments.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 216 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: A total of 216 patients with painful bone metastases will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or EBRT followed by MR-HIFU.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Focused Ultrasound and RadioTHERapy for Noninvasive Palliative Pain Treatment in Patients With Bone Metastases
Actual Study Start Date : March 10, 2020
Estimated Primary Completion Date : January 1, 2024
Estimated Study Completion Date : June 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ultrasound

Arm Intervention/treatment
Active Comparator: External Beam Radiotherapy
In the control arm, patients will undergo standard radiotherapy for painful bone metastases.The radiation schedule is at the discretion of the treating radiation oncologist.
Radiation: External beam radiotherapy
The current standard of care for patients with uncomplicated painful bone metastases is palliative locoregional external beam radiotherapy, often in combination with systemic therapy and analgesics.

Experimental: MR-HIFU
In the intervention arm, patients will be offered MR-HIFU treatment instead of standard radiotherapy. Treatment will be given following the international guidelines for MR-HIFU.
Procedure: MR-HIFU
MR-HIFU is a non-invasive treatment modality that delivers acoustic energy to heat tissue to ablative temperatures of more than 60°C. The combination of focused ultrasound with magnetic resonance imaging (MRI) enables physicians to perform localized tumor tissue ablation, with real-time temperature monitoring using magnetic resonance (MR) thermometry.
Other Names:
  • MRgFUS
  • MR guided High Intensity Focused Ultrasound

Experimental: Combination EBRT + MR-HIFU
In the combination arm, patients will undergo standard radiotherapy followed by MR-HIFU in a short timeframe.
Radiation: External beam radiotherapy
The current standard of care for patients with uncomplicated painful bone metastases is palliative locoregional external beam radiotherapy, often in combination with systemic therapy and analgesics.

Procedure: MR-HIFU
MR-HIFU is a non-invasive treatment modality that delivers acoustic energy to heat tissue to ablative temperatures of more than 60°C. The combination of focused ultrasound with magnetic resonance imaging (MRI) enables physicians to perform localized tumor tissue ablation, with real-time temperature monitoring using magnetic resonance (MR) thermometry.
Other Names:
  • MRgFUS
  • MR guided High Intensity Focused Ultrasound




Primary Outcome Measures :
  1. Pain response - 14 days after completion of treatment [ Time Frame: 14 days ]
    Patient reported pain response will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable) and the pain severity index calculated from the Brief Pain Inventory (BPI) questionnaire [Cleeland 1994]. In addition, analgesic and anti-neuropathic drug use is recorded, and all opioid analgesics are expressed as the oral equivalent daily morphine use (OMED). The primary endpoint of the RCT will follow the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone metastases (Chow 2012). Patients will be categorized as responders when a complete or partial pain response is achieved. All other patients will be categorized as non-responders.


Secondary Outcome Measures :
  1. Pain response - 14 days after inclusion [ Time Frame: 14 days ]
    Patient reported pain response will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable) and the pain severity index calculated from the Brief Pain Inventory (BPI) questionnaire [Cleeland 1994]. In addition, analgesic and anti-neuropathic drug use is recorded, and all opioid analgesics are expressed as the oral equivalent daily morphine use (OMED). This endpoint will follow the International Consensus on Palliative Radiotherapy Endpoints for Future Clinical Trials in Bone metastases (Chow 2012). Patients will be categorized as responders when a complete or partial pain response is achieved. All other patients will be categorized as non-responders.

  2. Patient reported pain scores - patient pain diary [ Time Frame: 21 days ]
    Patient reported pain scores will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable). This will be assessed using a daily patient pain diary during the first 21 days after completion of treatment.

  3. Patient reported pain scores - BPI [ Time Frame: on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]
    Patient reported pain scores will be based on a Numeric Rating Scale (from 0 to 10 with 0 being no pain and 10 being the worst pain imaginable). This will be assessed using the Brief Pain Inventory (BPI) questionnaire at 7 time points during the total follow up of 6 months.

  4. Physician reported toxicity - CTCAE 5.0 [ Time Frame: at 3 days, at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]
    Assessed in seven telephone calls during the first six months following completion of treatment according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

  5. Patient reported quality of life - EORTC BM22 [ Time Frame: on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]
    During the follow up time of 6 months, patients will receive the EORTC BM22 quality of life questionnaire at baseline, one, two, four and six weeks, and three and six months following completion of treatment.

  6. Patient reported quality of life - EORTC C15-PAL [ Time Frame: on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]
    During the follow up time of 6 months, patients will receive the EORTC C15-PAL quality of life questionnaire at baseline, one, two, four and six weeks, and three and six months following completion of treatment.

  7. Patient reported quality of life - EQ-5D-5L [ Time Frame: on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]
    During the follow up time of 6 months, patients will receive the EQ-5D-5L quality of life questionnaire at baseline, one, two, four and six weeks, and three and six months following completion of treatment.

  8. Patient reported quality of life - PGIC [ Time Frame: at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]
    During the follow up time of 6 months, patients will receive the Patient Global Impression of Change scale (a 7 point likert scale about overall improvement after treatment) at one, two, four and six weeks, and three and six months following completion of treatment.

  9. Patient reported quality of life - HADS [ Time Frame: on baseline, at 1, 2, 4 and 6 weeks, and at 3 and 6 months ]

    During the follow up time of 6 months, patients will receive the Hospital Anxiety and Depression Scale (HADS) questionnaire at one, two, four and six weeks, and three and six months following completion of treatment.

    Assessed among patients, patients' partners and caregivers by the Hospital Anxiety and Depression Scale (HADS) at baseline, two and four weeks, and three and six months fol-lowing completion of treatment.


  10. Local tumour control [ Time Frame: 3 and 6 months ]
    Assessed using CT and/or MRI imaging at patient discretion at three and/or six months after completion of treatment.

  11. Cost-effectiveness of the treatment [ Time Frame: 6 months ]
    A hypothetical diagnosis related group (DRG) will be calculated from the perspective of the statutory health insurance (SHI).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient capable of giving informed consent
  • Referral to radiotherapy department due to painful metastatic bone lesion (NRS ≥ 4)
  • Pain from target lesion is distinguishable from other lesions
  • Target lesion location is ccessible for MR-HIFU and EBRT
  • Target lesion is visible on pre-treatment MR or CT imaging, with a maximum diameter of 8 cm
  • Participant is able to fit in the MRI gantry
  • Participant has a reasonable performance score (KPS ≥ 50% or Zubrod/ECOG/WHO < 3)
  • Life expectancy ≥ 3 months

Exclusion Criteria:

  • Previous surgery on the target location
  • Neurological symptoms due to nerve involvement of target lesion
  • Need for surgery of targeted location due to (impending) pathological fracture
  • Unavoidable critical structures or dense tissues in target area
  • Curative intention of treatment plan
  • Contra-indications for MRI or sedation/anesthesia
  • Participant enrolled in another clinical interventional study related to bone metastases treatment or pain relief treatment
  • Clinically relevant medical history or physical findings that could interfere with the patient's safety as judged by the treating physician

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): NCT04307914


Contacts
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Contact: Marcia Bartels, MD +31 88 75 500 55 m.m.t.bartels-6@umcutrecht.nl
Contact: Helena M Verkooijen, MD, PhD +31 88 75 595 75 h.m.verkooijen@umcutrecht.nl

Locations
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Finland
TUCH Turku Not yet recruiting
Turku, Finland
Contact: Mira Huhtala       mira.huhtala2@tyks.fi   
Contact: Heikki Minn       heikki.minn@tyks.fi   
Germany
University Hospital Cologne Not yet recruiting
Cologne, Germany
Contact: Sin Yuin Yeo       Sin.yeo@uk-koeln.de   
Contact: Holger Gruell       holger.gurell@uk-koeln.de   
Italy
IOR Not yet recruiting
Bologna, Italy
Contact: Alberto Bazzocchi       alberto.bazzocchi@ior.it   
Contact: Milly Buwenge       milly.buwenge2@unibo.it   
CSSP Not yet recruiting
Roma, Italy
Contact: Alessandro Napoli       alessandro.napoli@centrosana.it   
Contact: Francesca de Felice       francesca.defelice@uniroma1.it   
Netherlands
University Medical Center Utrecht Recruiting
Utrecht, Netherlands, 3508GA
Contact: Helena M Verkooijen, MD, PhD       h.m.verkooijen@umcutrecht.nl   
Contact: Marcia MT Bartels, MD       m.m.t.bartels-2@umcutrecht.nl   
Sub-Investigator: Marcia MT Bartels, MD         
Principal Investigator: Helena M Verkooijen, MD, PhD         
Isala Klinieken Zwolle Recruiting
Zwolle, Netherlands
Contact: Jorik Slotman    +31 38 424 44 92    d.j.slotman@isala.nl   
Contact: Martijn Boomsma    +31 38 424 28 82    M.F.Boomsma@isala.nl   
Sponsors and Collaborators
UMC Utrecht
Turku University Hospital
Universitätsklinikum Köln
University of Roma La Sapienza
Istituto Ortopedico Rizzoli
University of Bologna
Isala
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Responsible Party: Helena M Verkooijen, Principal Investigator, UMC Utrecht
ClinicalTrials.gov Identifier: NCT04307914    
Other Study ID Numbers: NL71303.041.19
First Posted: March 13, 2020    Key Record Dates
Last Update Posted: March 13, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Helena M Verkooijen, UMC Utrecht:
Bone Metastases
Cancer Induced Bone Pain
Pain palliation
Raiotherapy
Radiation oncology
Noninvasive
MR-HIFU
MRgFUS
HIFU
Focused Ultrasound
Additional relevant MeSH terms:
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Neoplasms
Neoplasm Metastasis
Neoplasms, Second Primary
Bone Neoplasms
Bone Marrow Diseases
Neoplastic Processes
Pathologic Processes
Neoplasms by Site
Bone Diseases
Musculoskeletal Diseases
Hematologic Diseases