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Periganglionic Resiniferatoxin for the Treatment of Intractable Pain Due to Cancer-induced Bone Pain

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ClinicalTrials.gov Identifier: NCT02522611
Recruitment Status : Recruiting
First Posted : August 13, 2015
Last Update Posted : April 4, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )

Tracking Information
First Submitted Date  ICMJE August 12, 2015
First Posted Date  ICMJE August 13, 2015
Last Update Posted Date April 4, 2019
Study Start Date  ICMJE August 12, 2015
Estimated Primary Completion Date February 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
The primary outcome is to achieve a dose-response relationship for safety [ Time Frame: 30, 60, 90, and 180 days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02522611 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 12, 2015)
substantially reduced pain; improved pain relief; substantially reduced concomitant opioid analgesic consumption; improved quality of life [ Time Frame: 30, 60, 90, and 180 days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Periganglionic Resiniferatoxin for the Treatment of Intractable Pain Due to Cancer-induced Bone Pain
Official Title  ICMJE An Open-Label, Phase 1b Safety and Efficacy Trial of Periganglionic Resiniferatoxin for the Treatment of Intractable Pain Due to Cancer-Induced Bone Pain
Brief Summary

Background:

Cancer-induced bone pain (CIBP) is common in people with cancer. Bone cancer can also lead to anxiety, depression, and reduced mobility and quality of life. Researchers believe a research drug called resiniferatoxin (RTX) may be able to help.

Objective:

To learn whether RTX is safe and can reduce cancer induced bone pain.

Eligibility:

People ages 18 and older with CIBP that is not relieved by standard treatments

Design:

Participants will have up to 6 outpatient visits over about 7 months. These will include:

Medical history

Physical exam

Blood and urine tests.

Thermal testing: a disk placed on the skin to test ability to sense temperature in and around the area of pain

Chest x-ray

EKG: stickers are placed on the chest to measure heart signals

ECG: measures electrical activity of the heart

Participants will have 1 inpatient visit lasting 2-4 days. This will include:

Catheter inserted into a vein in the arm. They are given anesthesia, sedation, and x-ray contrast.

A needle is passed through the skin of the back to inject the RTX.

Participants will keep a log of the pain medications they take after surgery.

Participants will be called 1 week and 2, 3, and 4 months after the injection.

Participants will be mailed surveys and questionnaires to complete 2, 3, and 4 months after the injection.

Detailed Description

Cancer-induced bone pain (CIBP) is a common clinical problem.1 While primary osteosarcoma is relatively uncommon, bone metastases frequently cause cancer-related pain with metastatic spread to bone in 60-84% of cases. 2 Resiniferatoxin (RTX) is an ultrapotent agonist analog of capsaicin that targets a receptor expressed on specific dorsal root sensory ganglia (DRG) neurons and is expected to reduce pain within the targeted zone. The overall program goal is to develop a new treatment for intractable chronic pain below the mid-thoracic level resulting from CIBP that has not been controlled with conservative treatments.

Primary Objectives

To determine the maximum tolerated dose (MTD) of RTX when injected near one or more DRGs, and to characterize its safety/toxicity profile and identify any dose-limiting toxicity (DLT).

Study Population

Up to 30 adult subjects are estimated to be necessary for enrollment to have up to 16 subjects who will receive RTX and provide study-related assessment results through the 30-day time point.

Design

The study is a single center, open-label Phase 1b dose escalation safety and efficacy trial for adult subjects with intractable pain due to CIBP below the mid-thoracic level who meet all other eligibility criteria.

Subjects who have undergone the informed consent (IC) process and signed the approved IC form for the study will be assigned a Screen # (S1, S2, etc.). Those subjects who meet all inclusion and exclusion criteria will undergo various study procedures and then be scheduled for the unilateral periganglionic (PG) DRG injection(s) (a maximum of 3 contiguous levels) under fluoroscopic guidance to treat the targeted DRGs demonstrated to be responsible for the chronic CIBP.

Subjects who are screen failures and those who prematurely terminate participation will be replaced until 16 subjects have received the injection(s) and completed study-related assessments through the day 30 (D30) time point.

Outcome Measures

The primary outcome is to achieve a dose-response relationship for safety, although data for pain reduction will be obtained as a secondary outcome measure. All subjects will receive RTX. There is no placebo group because of the invasive nature of the injection and the dose escalation performed in the study.

This dose escalation safety study is based upon 4 progressive dose levels (0.8 microg/ganglion; 1.6 microg/ganglion; 3.2 microg/ganglion, and 6.4 microg/ganglion.

The adaptive dose selection design is employed to establish the primary outcome, the MTD for RTX. MTD will be defined as 1 dose level below that at which DLT is observed in more than one-third of the subjects.

The efficacy outcome variable will be evaluated by establishing dose-response curves, with dose plotted on the x-axis and changes in efficacy endpoints (between before and D30, D60, D90 and D180 after treatment) plotted on the y-axis. If, at the end of the study, all dose levels of RTX have equal pain-relieving efficacy, the Data Safety Monitoring Committee (DSMC) may determine it is appropriate to include a dose lower than 0.8 mcg and/or a control group. On the other hand, if the dose-response curves show that higher doses could result in greater pain-relieving efficacy, the protocol may be amended to include higher doses of RTX.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Intractable Pain
  • Palliative Care
  • Neoplasm Metastasis
  • Questionnaires &Amp; Surveys
Intervention  ICMJE Drug: Resiniferatoxin
Resiniferatoxin (RTX) is an ultrapotent agonist analog of capsaicin that targets a receptor expressed on specific dorsal root sensory ganglia (DRG) neurons and is expected to reduce pain within the targeted zone.
Study Arms  ICMJE Experimental: Resiniferatoxin
Patient receives one dose of Resiniferatoxin intrathecally
Intervention: Drug: Resiniferatoxin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 12, 2015)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2020
Estimated Primary Completion Date February 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

    1. Male or female subjects must be at least 18 years of age or older.
    2. Must be diagnosed with histologically-confirmed cancer-induced bone pain producing intractable chronic pain in the target area (mid thoracic or chest level down to lower extremities) which was poorly responsive to conservative therapies based on patient report, such as analgesic medication management with potent opioids with or without prior radiotherapy, bisphosphonates, or radioisotope therapy. Additionally, pain that is non-responsive to non-opioid drugs in situations where opioids were not tolerated. Conservative therapies do not include invasive treatments, such as neurolytic procedure, including surgical neurolysis, percutaneous regional or neuraxial continuous infusions (whether opioid or local anesthetic), and peripheral neuromodulation or spinal cord stimulation, but may include temporary diagnostic or therapeutic procedures.
    3. Must have moderate to severe pain that is not relieved by standard treatments.
    4. The chronic pain must result in an average score of at least 5 on the Brief Pain Inventory (BPI) Pain Interference (BPI-PI) Items. The score across the 7 BPI-PI items is averaged: the number (0 to 10) that describes how, during the past week, the subject s pain has interfered with the following: general activity, mood, walking ability, normal work (whether work outside the home or housework), relations with other people, sleep, and enjoyment of life.
    5. The subject must have undergone a diagnostic periganglionic injection(s) with a long-acting local anesthetic (e.g., bupivacaine) under fluoroscopic guidance which resulted in at least a 30% temporary pain reduction in the targeted pain region lasting for the expected duration of the local anesthetic used, prior to study drug treatment. Evidence of pain relief by bipuvicaine validates that a ganglia is involved in transmitting the pain signal from the site of cancer to the central nervous system.
    6. Must be healthy enough to tolerate study procedures in the judgment of the investigator.
    7. Subjects taking aspirin, non-steroidal anti-inflammatory medications, or vitamin supplements that include vitamin E or any prophylactic anticoagulant (including but not limited to Coumadin, heparin, or Xarelto) will be counseled either to stop taking these at least 7 days before surgery or be given instructions on dosing changes if applicable. In addition, if patients are currently taking a Factor Xa inhibitor (such as Xarelto) a hematology consult will be obtained. Subjects must be willing to comply with this requirement, which is standard clinical practice when undergoing elective surgical procedures to avoid surgical and post-surgical bleeding complications.
    8. If able to become pregnant or to father a child, agree to use a reliable/accepted method of birth control (i.e. hormonal contraception (birth control pills, injected hormones, vaginal ring), intrauterine device, barrier methods with spermicide (diaphragm with spermicide, condom with spermicide) or surgical sterilization (hysterectomy, tubal ligation, or vasectomy) for the duration of the study. Subjects must be willing and capable of understanding and cooperating with the birth control requirements of the study.
    9. Medical clearance from referring physician.
    10. Must be willing and able to participate in all study procedures.
    11. Must be capable of understanding and cooperating with the requirements of the study.
    12. Subjects must be able to understand and complete study-related forms and adequately communicate in English.
    13. Subjects must have provided written informed consent which includes signing the institutional review board (IRB)-approved consent form prior to participating in any study-related activity.
    14. Must have the capacity to provide informed consent.

EXCLUSION CRITERIA:

  1. Subjects must not be undergoing or have plans to undergo any active treatment for their cancer during the study until after the day 30 assessment timepoint, after the RTX injection.
  2. Subjects must not have had prior surgical procedures, such as posterior spinal fusions in the area of the injection site that could impair the ability to perform the periganglionic injection.
  3. Subjects must not have evidence of a coagulopathy or hemostasis problem as evidenced by the following blood laboratory values within the week prior to the planned injection:

    PT/INR > 1.5 times upper limit normal range (ULNR)

    PTT > 35 seconds

  4. Platelet count less than 50,000 Subjects must not have a total neutrophil count (TNC) < 1500. 1500. The US Clinical Practice Guideline for lumbar puncture is a platelet count of 50,000, which is higher risk for hemorrhage than periganglionic injection.

    4.5.Patients with TNC<1500 (neutropenia) may be eligible later if their TNC level becomes greater than 1500 spontaneously or after use of medications stimulating granulocyte production, such as Neupogen (granulocyte colony stimulating factor: G-CSF).

  5. Subjects must not be febrile or have other evidence of an infection within 7 days of the planned periganglionic injection.
  6. Subjects must not have an allergy or hypersensitivity to chili peppers, capsaicin or radiographic contrast agents.
  7. Female subjects must not be pregnant or breastfeeding
  8. Subjects with any medical condition that, in the Investigator s opinion, could adversely impact the subject s participation or safety, conduct of the study, or interfere with the pain assessment, such as poorly controlled diabetes or hypertension. Patients can be re-assessed for eligibility if these conditions can be controlled medically.
  9. Subjects who participated in a clinical trial of an investigational drug or device within 30 days of screening visit or are scheduled to receive an investigational product while participating in this study.
  10. Subjects must not have received invasive treatments, such as a neurolytic procedure, including surgical neurolysis, percutaneous regional or neuraxial continuous infusions (whether opioid or local anesthetic), peripheral neuromodulation or spinal cord stimulation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Fredric K Cantor, M.D. (301) 451-1184 cantorf@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02522611
Other Study ID Numbers  ICMJE 150175
15-N-0175
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
Study Sponsor  ICMJE National Institute of Neurological Disorders and Stroke (NINDS)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: John D Heiss, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date September 24, 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP