STTEPP: Safety, Tolerability and Dose Limiting Toxicity of Lacosamide in Patients With Painful Chronic Pancreatitis (STTEPP)

September 22, 2023 updated by: Evan Fogel, Indiana University
The investigators propose to conduct a dose-escalation trial of an FDA-approved antiepileptic drug, lacosamide, added to opioid therapy in patients with chronic abdominal pain from chronic pancreatitis (CP). This pilot trial will test the feasibility of the study design and provide reassurance regarding the tolerability and safety of lacosamide used concomitantly with opioids in this patient population to reduce the condition known clinically as opioid-induced hyperalgesia (OIH).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

One rather pronounced adverse off-target effect of opioids is an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli, known clinically as opioid-induced hyperalgesia (OIH). Based on pre-clinical published data, therapeutic targeting of the sodium channel NaV1.7 may address one of the mechanisms that limits opioid efficacy for controlling pain. The investigators hypothesize that lacosamide, an FDA-approved antiepileptic drug that targets NaV1.7, used concomitantly with opioids will improve the opioid efficacy for controlling pain in patients with chronic pancreatitis (CP). However, there are no preliminary data available evaluating lacosamide in this patient population. Therefore, a phase 1 trial is necessary.

The investigators will employ the Bayesian optimal interval (BOIN) design to find the Maximum Tolerated Dose (MTD). The investigators will enroll and treat patients in cohorts of size 3. The initial dose will be 50mg po bid (100mg/day), followed by incremental increases of 100mg/day in two divided doses. The maximum daily dose of lacosamide will be 400mg/day. Duration of lacosamide administration will be 7 days at each dose level. Follow-up laboratory parameters (as obtained at study entry) will be obtained on day 8 (with a 3 day window) after therapy is completed. A follow-up phone visit will occur on day 21 (with a 3-day window) to assess for adverse events and medication changes.

It is anticipated that lacosamide will prove to be safe and well-tolerated. The results of this pilot study will then support proceeding with a subsequent phase 2 trial assessing the efficacy of lacosamide added to opioid therapy to alleviate abdominal pain from CP. The investigators further anticipate that lacosamide combined with opiates will substantially lower the opioid dose necessary for adequate pain relief and serve to substantially improve the safety profile of opioid use for CP.

Study Type

Interventional

Enrollment (Estimated)

24

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Evan L Fogel, MD, MSc
  • Phone Number: 317-944-2816
  • Email: efogel@iu.edu

Study Contact Backup

  • Name: Fletcher A White, MS, PhD
  • Phone Number: 317-274-5164
  • Email: fawhite@iu.edu

Study Locations

  • United States
    • California
      • Stanford, California, United States, 94305
        • Recruiting
        • Stanford University
        • Principal Investigator:
          • Walter Park, MS, MD
        • Contact:
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • Indiana University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Evan Fogel, MD, MSc
        • Principal Investigator:
          • Fletcher White, MS, PhD
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic
        • Contact:
        • Principal Investigator:
          • Santhi Vege, MD
        • Contact:
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Recruiting
        • Ohio State University
        • Contact:
        • Principal Investigator:
          • Samuel Y. Han, MD, MS
        • Contact:
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213
        • Recruiting
        • University of Pittsburgh Medical Center
        • Principal Investigator:
          • Dhiraj Yadav, MD, MPH
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. written informed consent and HIPAA authorization for release of personal health information;
  2. ≥ 18 years old at the time of informed consent;
  3. suspected (YELLOW 2 or 3) or definite diagnosis of CP, as per CPDPC PROCEED study definition with ongoing symptoms of abdominal pain;
  4. patients must be maintained on an opioid (except methadone or suboxone) for 4 weeks prior to enrollment for treatment of abdominal pain related to pancreatitis, with a daily morphine equivalent dose of 20-120mg;
  5. ongoing symptoms of abdominal pain even with opioid use (VAS and BPI average score ≥4, at enrollment);
  6. ECOG Performance Status of 0-2;(Oken et al., 1982)
  7. ability to swallow and tolerate oral tablets;
  8. females of childbearing potential must have a negative pregnancy test;
  9. the following laboratory parameters must be met: WBC count ≥ 3.0 K/mm3, absolute neutrophil count ≥ 1.5 K/mm3, hemoglobin ≥ 9 g/dL, platelets ≥ 75 K/mm3, creatinine ≤ 1.5 mg/dl, bilirubin ≤ 1.5 x ULN, AST ≤ 3 x ULN, ALT ≤ 3 x ULN; normal PR interval on baseline 12-lead EKG.

Exclusion Criteria:

  1. subjects with indeterminate CP (YELLOW 1) as per PROCEED criteria;
  2. treatment with any investigational agent within 30 days prior to registration, or concurrent participation in a clinical trial which involves another investigational agent;
  3. rapidly escalating pain that requires hospitalization or intravenous opioid therapy;
  4. known hypersensitivity/allergic reaction to lacosamide, carbamazepine or oxcarbazepine;
  5. pregnant or breastfeeding;
  6. patient who has a diagnosis of epilepsy and/or is currently taking anti-epileptic drugs;
  7. abdominal surgery or pain intervention (ERCP with sphincterotomy/stent/stone removal; celiac plexus block) within 90 days of enrollment.
  8. hospitalization for pancreatitis exacerbation or pain management within 90 days of enrollment
  9. patient who currently takes Suboxone or Methadone.
  10. other factors which might explain the patient's ongoing symptoms, at the discretion of the enrolling physician.
  11. history of autoimmune or traumatic pancreatitis, or sentinel attack of acute necrotizing pancreatitis which results in suspected disconnected duct syndrome.
  12. primary pancreatic tumors- pancreatic ductal adenocarcinoma, suspected cystic neoplasm (>1cms in size or main duct involvement), neuroendocrine tumors, and other uncommon tumors.
  13. pancreatic metastasis from other malignancies.
  14. history of solid organ transplant, HIV/AIDS.
  15. known isolated pancreatic exocrine insufficiency (e.g. in the absence of any eligible inclusion criteria).
  16. participants must not have medical or psychiatric illnesses or ongoing substance abuse that in the investigator's opinion would compromise their ability to tolerate study interventions or participate in follow-up.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose Escalation Level
In the first 3-patient cohort, the dose of lacosamide given is 50mg/d BID. Enrollment to the next higher dose cohort will be initiated only if none of the 3 participants exhibits a DLT in the 21 ±3 days following completion of the 7 day drug therapy. Dose escalation will proceed according to the Bayesian optimal interval (BOIN) design at incremental increase of 100mg/day in two divided doses. The maximum daily dose of lacosamide will be 400mg/day.
Drug: Lacosamide
Study Visit 1: Baseline study assessments will be made and questionnaires completed in person, on day 0. Drug treatment days will then occur on days 1-7. Study Visit 2: Following completion of the 7-day drug treatment period, participants will have a face-to-face clinic visit on day 8 (with a 3 day grace period), where similar assessments and questionnaires will again be completed. Participants will return all unused drug at this visit, for disposal and to monitor compliance. A follow-up phone visit will occur on day 21 (with a 3 day window) to assess for adverse events and medication changes
Other Names:
  • VIMPAT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose-limiting toxicity of lacosamide in combination with opioids in CP patients will be measured by the number of grade 3 or4 toxicities reported via the CTCAE v5.0, between Day 1 through 21 day follow up.
Time Frame: Day 1, 21 day follow up
Dose-limiting toxicity of combination lacosamide and opioids. Patients will be examined and graded for subjective/objective evidence of developing grade 3 or 4 toxicities according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Day 1, 21 day follow up
Tolerability of lacosamide in combination with opioids in CP patients will be evaluated by the percentage of compliance in taking lacosamide pills as directed between Day 1 and Day 7.
Time Frame: Day 1, Day 7
Tolerability will be assessed by compliance with the intervention. Subjects will be evaluated for completing the 7-day trial. The percent of subjects taking 100%, 75%, 50% and <50% of tablets will be recorded.
Day 1, Day 7
Feasibility of performance of a pilot study adding lacosamide to opioid therapy in CP patients based on recruitment rate: measured by the proportion of eligible patients who continue from the screening visit to the enrollment visit.
Time Frame: Screening visit, Enrollment visit
Recruitment rate (proportion of eligible patients approached who agree to participate)
Screening visit, Enrollment visit
Feasibility of performance of a pilot study adding lacosamide to opioid therapy in CP patients based on retention rate measured by the change from the screening visit to the 21 day follow-up visit.
Time Frame: Screening visit, 21 day follow-up
Dropout rate, including qualitative assessment of barriers to retention.
Screening visit, 21 day follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of adding lacosamide to opioid therapy for the treatment of abdominal pain due to CP by a 50% decrease in the VAS score from the Screening visit to the Follow-up visit day 8..
Time Frame: Screening visit, Day 8

Visual Analog Score (VAS) - a 50% decrease in score from Screening visit to Follow-up visit day 8.

The visual analog scale (VAS) is a validated, subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between "no pain" and "worst pain."
Screening visit, Day 8
Efficacy of adding lacosamide to opioid therapy for the treatment of abdominal pain due to CP by a 50% decrease in BPI-SF average pain score from the Screening visit to the Day 8 visit.
Time Frame: Screening visit, Day 8
Brief Pain Inventory (BPI), short form average score - a 50% decrease in total score from Screening visit to Follow-up visit day 8 The BPI-SF is a validated self-reported tool that evaluates pain severity and pain interference with daily activities at the time of assessment. Possible scores for pain severity range from 0 to 10 (higher scores reflect more severe pain)
Screening visit, Day 8
Efficacy of adding lacosamide to opioid therapy for the treatment of abdominal pain due to CP by a 50% decrease in total score of the Compat-SF pain severity from the Screening visit to Follow-up visit day 8.
Time Frame: Screening visit, Day 8
Compat-SF total score - a 50% decrease in total score from Screening visit to Follow-up visit day 8 The COMPAT-SF is a validated self-reported tool specifically designed for patients with pancreatic disease. Scores for pain severity (average, worst, and least) range from 0 to 10 (higher corresponds to more pain); scores for pain triggers (including food, exercise, and thermal changes) are scored on a scale from never to always (never, rarely, sometimes, very often, always); scores for pain symptom characteristics (cramping, shooting, stabbing) are scored on a scale from 0 (none) to 10 (worst possible).
Screening visit, Day 8
Efficacy of adding lacosamide to opioid therapy for the treatment of abdominal pain due to CP by a 25% decrease in morphine milligram equivalents (MME) of opioid use from the Screening visit to Follow-up visit day 8.
Time Frame: Screening visit, Day 8
Opioid use will decrease by 25% from screening visit to Follow-up visit day 8. Patients will be asked to track all opioids taken on a drug diary from the screening visit through day 8 of study intervention. MME will be calculated to compare level of MME from screening visit to day 8.
Screening visit, Day 8

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Indiana University

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

  • Study Director: Aynur Unalp-Arida, MD, PhD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 17, 2023

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

October 18, 2022

First Submitted That Met QC Criteria

October 31, 2022

First Posted (Actual)

November 3, 2022

Study Record Updates

Last Update Posted (Actual)

September 25, 2023

Last Update Submitted That Met QC Criteria

September 22, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SHHBRBAPSM35
  • 1R01DK132709-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified patient data may be shared with investigators from outside institutions for ancillary studies upon request. Requests should be made to study principal investigator at efogel@iu.edu.

IPD Sharing Time Frame

Data will be available at the close of the study and for 5 years subsequent.

IPD Sharing Access Criteria

Individual requests for data sharing can be made to: efogel@iu.edu

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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