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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Chronic Pain, Chronic Pain Syndrome, Chronic Pancreatitis, Hyperalgesia, Opioid Use Disorder, Opioid-Related Disorders, Opioid Dependence, Chronic Abdominal Pain, ERCP, Pancreatic Surgery

Intervention / Treatment
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* Drug: Lacosamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: written informed consent and HIPAA authorization for release of personal health information; ≥ 18 years old at the time of informed consent; suspected (YELLOW 2 or 3) or definite diagnosis of CP, as per CPDPC PROCEED study definition with ongoing symptoms of abdominal pain; 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; ongoing symptoms of abdominal pain even with opioid use (VAS and BPI average score ≥4, at enrollment); ECOG Performance Status of 0-2;(Oken et al., 1982) ability to swallow and tolerate oral tablets; females of childbearing potential must have a negative pregnancy test; 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: subjects with indeterminate CP (YELLOW 1) as per PROCEED criteria; treatment with any investigational agent within 30 days prior to registration, or concurrent participation in a clinical trial which involves another investigational agent; rapidly escalating pain that requires hospitalization or intravenous opioid therapy; known hypersensitivity/allergic reaction to lacosamide, carbamazepine or oxcarbazepine; pregnant or breastfeeding; patient who has a diagnosis of epilepsy and/or is currently taking anti-epileptic drugs; abdominal surgery or pain intervention (ERCP with sphincterotomy/stent/stone removal; celiac plexus block) within 90 days of enrollment. hospitalization for pancreatitis exacerbation or pain management within 90 days of enrollment patient who currently takes Suboxone or Methadone. other factors which might explain the patient's ongoing symptoms, at the discretion of the enrolling physician. history of autoimmune or traumatic pancreatitis, or sentinel attack of acute necrotizing pancreatitis which results in suspected disconnected duct syndrome. primary pancreatic tumors- pancreatic ductal adenocarcinoma, suspected cystic neoplasm (>1cms in size or main duct involvement), neuroendocrine tumors, and other uncommon tumors. pancreatic metastasis from other malignancies. history of solid organ transplant, HIV/AIDS. known isolated pancreatic exocrine insufficiency (e.g. in the absence of any eligible inclusion criteria). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients in the first cohort are treated at dose level 1. Once a cohort of three patients has been recruited at a given dose level, recruitment will temporarily be held until all three patients have been evaluated for delayed adverse events, at 21 ±3 days following completion of drug therapy. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation according to BOIN design rules. Repeat step 2 until the maximum sample size of 24 is reached or stop the trial if the number of patients treated at the current dose reaches 15.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Level<br>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<br>* 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<br>* Other names: VIMPAT;|

What is the study measuring?
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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. | 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. | 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. | 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. | 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.. | 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. | 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. | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatitis, Pancreatitis, chronic, Chronic pain, Pain, Pancreatic Diseases, Digestive System Diseases