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

Indiana University

Status and phase: Enrolling; Phase 1

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

Treatments: Drug: Lacosamide

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05603702

SHHBRBAPSM35

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

Details and patient eligibility

About

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).

Full 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.

Enrollment: 24 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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;
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 parenteral (intravenous or intramuscular) opioid therapy within 30 days of enrollment;
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 (other than gabapentin and pregabalin);
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 30 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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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24 participants in 1 patient group

Dose Escalation Level

Experimental group

Description:

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.

Treatment:

Drug: Lacosamide