Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation

A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation

The study is a phase 2/3, multicenter, double-blind, parallel assignment study. It involves 100 adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT).

The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by the proportion of insulin-independent patients following IAT. The safety of reparixin in the specific clinical setting will be also evaluated.

Study Overview

• Status: Completed
• Conditions: Pancreatectomy for Chronic Pancreatitis
• Intervention / Treatment: Drug: Reparixin; Drug: Placebo

Detailed Description

In contrast to allo-transplantation in type 1 diabetes patients, where immunological mechanisms involving allo- and auto-antibodies affect long-term graft function, outcome in IAT (Islet Auto-Transplantation) is independent from immunological processes and does not require immunosuppression management. On the other hand, early inflammatory events intrinsic to the intra-portal islet infusion have been demonstrated to impact islet engraftment. Among possible mechanisms, PMNs have been found to be the predominant cell types infiltrating the liver in a syngeneic model of islet transplantation in mice.

Data obtained in experimental models of islet transplantation in mice demonstrate a clear effect of reparixin in improving graft survival and function. Protection from the loss and/or deterioration of transplanted islets was evident regardless of the immunological mechanisms involved in islet damage, suggesting that the ability of reparixin to modulate early inflammatory responses readily impact graft outcome.

Thus, the use of reparixin may emerge as a potential useful medication in the control of non specific inflammatory events surrounding the early phases of IAT.

The goal of this study is to reach a total of 100 adult patients who are randomized and receive IAT after total or completion pancreatectomy. Patients will be randomly (1:1) assigned to receive either reparixin [continuous i.v. infusion for 7 days (168hrs)], or matched placebo (control group),starting approximately 12hrs before islet infusion. The two groups will be balanced within each centre. All patients who are randomized and receive the Investigational Product (either reparixin or placebo) will be included in the ITT analysis. Patients will be in the ITT analysis whether or not they receive IAT, because exclusions cannot be made for events occurring after randomization that could be influenced by the randomized assignment.

Recruitment will be competitive among the study sites, until the planned number of patients is enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and to account for any difference in transplant rate among study sites. Each centre will enroll patients as rapidly as possible, up to a maximum of 40 patients (as per the randomization list). A maximum of 48 patients is allowed for the site of the Primary Investigator.

Each patient will be involved in the study for 7 day hospital stay during pancreatectomy followed by islet transplantation, for all required measurements up to hospital discharge and for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the transplant.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2C8
      • University of Alberta, Clinical Islet Transplant Program
• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California. Department of Surgery, Division of Transplantation
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Schulze Diabetes Institute University of Minnesota Medical School
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The University of Cincinnati Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients eligible for an IAT following total (or completion) pancreatectomy.
• Ages > 18 years.
• Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
• Patients who have given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

Exclusion Criteria:

• Recipients of a previous IAT (if completion pancreatectomy).
• Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic benign diseases other than chronic pancreatitis, including insulinomas, etc.
• Patients with inadequate renal reserve as per calculated creatinine clearance (CLcr) < 60 mL/min according to the Cockcroft-Gault formula (1976).
• Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x upper limit of normal (ULN) or increased total bilirubin above the upper limit at local laboratory). Patients with Gilbert's syndrome (elevated unconjugated bilirubin levels in the absence of any evidence of hepatic or biliary tract disease) are not excluded.
• Patients with a preoperative International Normalized Ratio (INR) > 1.5 or any known coagulopathy.

• Hypersensitivity to:

  1. ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID).
  2. medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.
• Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome).
• Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use of <5mg prednisone daily or equivalent dose of hydrocortisone, for physiological replacement only) or with any immune modulators in the 4 weeks prior to enrolment.
• Patients with pre-existing diabetes or evidence of impaired β-cells function, based on pre-operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%, or requiring treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 weeks prior to enrolment.
• Use of any investigational agent in the 4 weeks prior to enrolment, including any anti-cytokine/chemokine agents.
• Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males). (NB: pregnancy should be avoided in patients or partners during the first month after completing the treatment with the Investigational Product; no other specific warnings are described, considering the treatment course of the Investigational Product, its PK profile, and the lack of significant adverse effects on mating performance and fertility in animal studies).
• Patients with past or current history of alcohol abuse based on clinical history and/or past treatment for alcohol addiction.
• Patients with evidence of pre-operative portal hypertension as per clinical history and abdominal/liver imaging by ultrasound techniques.

Sites will comply with any additional or more restrictive exclusion criteria locally accepted, as per centre practice.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Physiologic solution	Drug: Placebo; Physiologic solution administered at 0.25 mL/kg/hour
Experimental: Reparixin; Solution for intravenous (IV) infusion with active compound	Drug: Reparixin; Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour; Other Names: DF1681Y

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant.	Insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: a glycated hemoglobin (HbA1c) level <6.5%;; fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week (based on a minimum of one daily measurement;; a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past week (based on a minimum of one daily measurement);; a laboratory fasting glucose in the non-diabetic range (<126 mg/dL).	day 365±14 after the transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant	AUC for the serum C-peptide level is calculated during the first 4 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg	day 75±14 after the transplant
Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant	AUC for the serum C-peptide level is calculated during the first 4 hours of a mixed meal tolerance test (MMTT), normalized by the number of Islet Equivalent (IEQ)/kg	day 365±14 after the transplant
Average Daily Insulin Requirements at Day 75±14 After the Transplant	Daily insulin is reported as IU/kg and intake averaged over the previous week.	day 75±14 after the transplant
Average Daily Insulin Requirements at Day 365±14 After the Transplant	Daily insulin is reported as IU/kg and intake averaged over the previous week.	day 365±14 after the transplant
Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant	Data of this outcome are reported as "model estimates over all timepoints". This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).; 15 min; N=42; 46; 30 min; N=40; 46; 60 min; N=40; 46; 90 min; N=40; 46; 120 min; N=41; 46; 180 min; N=40; 46; 240 min; N=39; 44	day 75±14 after the transplant
Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant	Data are reported as "model estimates over all timepoints" This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: basal; N=34; 42 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).; 15 min; N=34; 41; 30 min; N=34; 41; 60 min; N=34; 41; 90 min; N=34; 41; 120 min; N=34; 41; 180 min; N=33; 41; 240 min; N=33; 41	day 365±14 after the transplant
Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant	Data are reported as "model estimates over all timepoints". This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: basal; N=44; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).; 15 min; N=43; 47; 30 min; N=41; 47; 60 min; N=42; 47; 90 min; N=42; 47; 120 min; N=42; 47; 180 min; N=41; 47; 240 min; N=40; 44	day 75±14 after the transplant
Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant	Data are reported as "model estimates over all timepoints". This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: basal; N=33; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).; 15 min; N=34; 41; 30 min; N=34; 41; 60 min; N=33; 41; 90 min; N=34; 41; 120 min; N=34; 41; 180 min; N=33; 40; 240 min; N=33; 41	day 365±14 after the transplant
Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant	Data are reported as "model estimates over all timepoints". This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal).; 15 min; N=43; 47; 30 min; N=41; 47; 60 min; N=41; 47; 90 min; N=41; 47; 120 min; N=42; 47; 180 min; N=41; 47; 240 min; N=40; 44	day 75±14 after the transplant
Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant	Data are reported as "model estimates over all timepoints". This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: basal; N=34; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal); 15 min; N=34; 41; 30 min; N=34; 41; 60 min; N=34; 41; 90 min; N=34; 41; 120 min; N=34; 41; 180 min; N=33; 41; 240 min; N=33; 40	day 365±14 after the transplant
β-cell Function at Day 75±14 After the Transplant	This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for: fasting plasma glucose,; HbA1c,; stimulated C-peptide; insulin requirement subscales. The higher the total score, the better the outcome.; Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome); HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome); Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome); Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome)	day 75±14 after the transplant
β-cell Function at Day 365±14 After the Transplant	This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for glucose, HbA1c, stimulated C-peptide and insulin requirement subscales. The higher the total score the better the outcome.; Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome); HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome); Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome); Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome)	day 365±14 after the transplant
Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant	Percentage of patients with a glycated haemoglobin (HbA1c) <6.5% at day 365±14 after the transplant.	day 365±14 after the transplant
Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant	A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.	from day 75±14 to day 365±14 after the transplant
Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant AND Free of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant Inclusive	Percentage of patients with an HbA1c <6.5% at day 365±14 after the transplant AND free of severe hypoglycemic events from day 75±14 to day 365±14 after the transplant inclusive.A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.	from day 75±14 to day 365±14 after the transplant
Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study	The percentages of patients with any treatment emergent adverse events (TEAE, serious and non serious) and with serious TEAE by severity are presented. Patients with multiple events within a particular system organ class or preferred term were counted only under the category of their most severe event within that system organ class or preferred term. A serious AE was defined as any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening (ie, the patient was at risk of death at the time of the event); Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above	up to day 365±14 after the transplant
Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant	Malnutrition risk levels are defined as: Poor prognosis = pre-albumin level <5.0 mg/dL; Significant risk = pre-albumin level 5.0 to 10.9 mg/dL; Increased risk = pre-albumin level 11.0 to 15.0 mg/dL; Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL	day 75±14 after the transplant
Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant	Malnutrition risk levels are defined as: Poor prognosis = pre-albumin level <5.0 mg/dL; Significant risk = pre-albumin level 5.0 to 10.9 mg/dL; Increased risk = pre-albumin level 11.0 to 15.0 mg/dL; Normal = pre-albumin level > 15.0 (up to 35.0) mg/dL	day 365±14 after the transplant
Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant	Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as: No steatorrhea;; Steatorrhea few times per week;; Steatorrhea daily;; Stool incontinence.	day 75±14 after the transplant
Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant	Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as: No steatorrhea;; Steatorrhea few times per week;; Steatorrhea daily;; Stool incontinence.	day 365±14 after the transplant
Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant	The following definition applies: - Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration <70mg/dL.	from day 75±14 to day 365±14 after the transplant
Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant	The following definition applies: - Documented symptomatic hypoglycemia = An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <70mg/dL.	from day 75±14 to day 365±14 after the transplant
Cumulative Number of Diabetic Ketoacidosis-related Events	A diabetic ketoacidosis event is defined as the presence of: hyperglycemia (blood glucose >200 mg/dL);; pH <7.3 or HCO3 <15;; ketones positive in the serum or urine.	from day 75±14 to day 365±14 after the transplant
Peak C-peptide at Day 75 After the Transplant	Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.	Day 75±14 after the transplant
Peak C-peptide at Day 365 After the Transplant	Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.	Day 365±14 after the transplant
Time-to-peak C-peptide at Day 75 After the Transplant	The time-to-peak value in minutes was computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test Case Report Form.	day 75±14 and day 365±14 after the transplant
Time-to-peak C-peptide at Day 365 After the Transplant	The time to peak value in minutes will be computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test CRF.	Day 365±14 after the transplant
Change From Baseline in Post-transplant Alanine Aminotransferase (ALT)	Data are reported as "model estimates over all timepoints". This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: baseline; N=50; 52; Day 2 post-transplant; N=49; 51; Day 3 post-transplant; N=47; 50; Day 7 post-transplant; N=47; 50; Day 75 post-transplant; N=44; 47	Baseline, Days 2, 3, 7, 75 ±14 after the transplant
Change From Baseline in Post-transplant Aspartate Aminotransferase (AST)	Data are reported as "model estimates over all timepoints". This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: baseline; N=50; 52; Day 2 post-transplant; N=49; 51; Day 3 post-transplant; N=47; 50; Day 7 post-transplant; N=47; 50; Day 75 post-transplant; N=44; 47	Baseline, Days 2, 3, 7, 75±14 after the transplant
Number of Treatment Emergent Adverse Events Related to Investigational Product	Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called "Adverse reactions" (ADR). An adverse reaction is defined as any untoward medical occurrence in a patient or clinical investigation patient, which has a causal relationship with the administered medicinal product.	Throughout the study From Day -1 to hospital discharge
Number of Serious Treatment Emergent Adverse Events Related to Investigational Product	Serious Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called serious "Adverse reactions". A serious adverse reaction is defined as any untoward medical occurrence with a causal relationship with the administered medicinal product, that at any dose: Resulted in death; Was life-threatening (ie, the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.); Required patient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above	Throughout the study From Day -1 to hospital discharge for all adverse events, and from then to day 365 post-transplantation only for serious adverse events

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Principal Investigator: Melena Bellin, MD, Schulze Diabetes Institute; University of Minnesota Amplatz Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2014
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: October 18, 2013
• First Submitted That Met QC Criteria: October 18, 2013
• First Posted (Estimated): October 23, 2013

Study Record Updates

• Last Update Posted (Actual): November 2, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Pancreatic islet auto-transplantation
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease Attributes; Pancreatic Diseases; Chronic Disease; Pancreatitis; Pancreatitis, Chronic
• Other Study ID Numbers: REP0112

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No