EPPIC-Net: Platform Protocol to Assess Treatments for Painful Diabetic Peripheral Neuropathy

New York University, Icahn School of Medicine at Mount Sinai, National Institute of Neurological Disorders and Stroke (NINDS)

This is a Platform Protocol to perform Phase II clinical trials in The Early Phase Pain Investigation Clinical Network (EPPIC-Net), under The Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM, related to the treatment of Painful Diabetic Peripheral Neuropathy (PDPN) in a platform setting to test multiple assets under a single protocol.

This is a Platform Protocol that allows evaluation of more than one treatment in a single trial structure, to be run within EPPIC-Net. Instead of testing individual assets in a series of clinical trials, this Platform Protocol sets out the framework for testing multiple assets related to PDPN. This provides an efficient approach to evaluate multiple therapies under a single infrastructure in a timely fashion. The Platform Protocol also allows efficiencies by creating the possibility of sharing information across assets, such as data from control conditions. This Platform Protocol is for a platform design to allow for the testing of multiple assets. Some platform trials allow direct comparisons of competing therapies for the same condition. However, for this EPPIC-Net platform trial, there will not be direct comparisons of assets to one another. Instead, assets will only be compared to a placebo. This is in service to the EPPIC-Net primary goal of accelerating the development of pain treatment because, based on feedback from asset-holders, the possibility of comparison of assets to one another or to an active drug would be a deterrent for asset-holders' participation in EPPIC-Net.

The Platform Protocol is intended to potentially accommodate different design plans for different assets. In addition, it is anticipated that the protocol may evolve over time, as lessons learned from earlier assets are used to fine tune the study design for later assets in an adaptive approach. For reasons of generalizability (including consideration of minimizing participant burden and being attractive to asset holders), a parallel-group design will typically be employed, and it is the current intention that designs should provide 80% power to detect an effect size of 0.35 on the primary efficacy outcome

Randomization assignment within an ISA will be blinded from study participants, staff from clinical sites, investigators, asset owners, IND sponsors, and/or designees. This blinding will be accomplished by providing identical investigational product and packaging for each asset and its corresponding control treatment. The use of IXRS will ensure the blinding is accomplished.

Typically, the primary efficacy endpoint for this Platform Protocol will be based on the daily 0-10 pain NRS. Participants will respond to the following every evening before going to bed: "Select the number that best describes your average neuropathy pain during the past 24 hours." "Select the number that best describes your worst neuropathy pain during the past 24 hours." Typically, the primary efficacy endpoint for this Platform Protocol will be based on the daily 0-10 pain NRS. Participants will respond to the following every evening before going to bed: "Select the number that best describes your average neuropathy pain during the past 24 hours." "Select the number that best describes your worst neuropathy pain during the past 24 hours."

The PEG is a three-item (each scored 0-10) multidimensional pain measure designed and validated for use in primary care and other ambulatory clinic patients, as a practical and useful tool to improve assessment and monitoring of chronic pain in primary care.

Catastrophizing is a pain-specific psychosocial construct comprising cognitive and emotional processes such as helplessness, pessimism, rumination about pain-related symptoms, and magnification of pain reports. The PCS-SF6 is a 6-item, self-report measure of catastrophic thinking associated with pain. Scores range from 0-24, with higher scores indicating more catastrophizing.

The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Functioning short form is a 6-item scale that is widely used in pain research. It is a unidimensional scale that shows broad coverage of the physical function construct, good construct validity, and high levels of temporal stability. The PROMIS Physical Function Scale is expressed as a T-score, with a population mean of 50 and SD of 10. Higher scores represent better physical functioning; possible T scores in this distribution range from 21 to 59 (PROMIS, 2020).

The 2-item PHQ-2 is a brief depression screening tool that correlates strongly with PHQ-9 scores and shows good sensitivity for identifying individuals with depressive disorders in the general population in a variety of medical samples. Scores range from 0-6, with higher scores indicating more depressive symptomatology.

The GAD-2 is a 2-item screening tool that is widely used to screen for clinically significant anxiety symptoms and anxiety disorders in clinical settings. It shows good sensitivity and specificity as a screening tool for anxiety disorders. Scores range from 0-6, with higher scores indicating more anxiety symptomatology.

The PGIC is a single-item measure of patient-reported improvement that is widely used as a general outcome measure in studies of chronic pain patients. It is often used as an index of treatment-associated change, and patient-reported improvements in the form of PGIC scores correlate robustly with significant improvement in pain intensity, pain interference with activities of daily living, mood, and quality of life (Perrot and Lanteri-Minet, 2019).

The TAPS-1 is the screening component of the TAPS tool and consists of a single stem question with four items covering the frequency of past-12-month use of tobacco, alcohol, and illicit drugs, and non-medical use of prescription medications. Scores range from 0-4; higher scores indicate a higher likelihood of problematic substance use. The TAPS-1 shows good sensitivity and specificity for identifying substance use disorders.

The PROMIS Sleep Disturbance short form is a convenient 6-item scale that correlates strongly with the longer forms. The PROMIS Sleep Disturbance Scale is expressed as a T-score, with a population mean of 50 and standard deviation (SD) of 10. Possible T scores in this distribution range from 31.7 to 76.1 (PROMIS, 2021).

A single-item scale measuring the duration of actual sleep a participant has gotten, on average, over the past month. Numerical responses will be provided in hours and minutes.

The OUQ is an indicator of past or present use of any of the listed opioid medications. There are a total of three yes/no items where a yes indicates the use of such medications

The Norfolk QOL-DN is a validated 47-item, patient-reported outcome measure, sensitive to the different features of diabetic neuropathy (DN) including small fiber, large fiber, and autonomic function.

The neuropathy examination will be a single consolidated procedure consisting of visual inspection of the feet, brief distal motor exam, ankle and knee deep tendon reflexes, and a standardized sensory exam. This single exam will collect all the data needed to calculate several common scores including: the Michigan Neuropathy Screening Instrument (MNSI) Part B (Feldman et al., 1994; Herman et al., 2012), the Utah Early Neuropathy Scale (UENS) (Singleton et al., 2008), and the Toronto Clinical Scoring System (Toronto CSS) (Bril & Perkins, 2002). Disambiguation: Toronto CSS is the name given to the scale initially. In a subsequent publication (Bril et al, 2008) this scale is referred to as the Toronto Clinical Neuropathy Score (TCNS), and its modification as the modified Toronto Clinical Neuropathy Score (mTCNS).

Inclusion Criteria: (To be used in conjunction with ISA-specific criteria) Able to provide informed consent. Legally Authorized Representatives (LARs) will not be permitted. 18 years of age and older Diagnosis of Type II diabetes mellitus Stable treatment of diabetes for at least 3 months with no anticipated changes in medication regimen Meets the Toronto Criteria for probable clinical sensorimotor polyneuropathy. This is defined as a combination of symptoms and signs with any two or more of the following (must be present bilaterally in the distal lower extremities): neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes. Specifically: The presence of any neuropathic symptoms on either the "Douleur Neuropathique en 4 Questions" (DN4) or the EPPIC-Net Neuropathy Exam will suffice to demonstrate "neuropathic symptoms." Decreased distal sensation is satisfied by any of the following: "Yes" is checked at least once under Question 3 of the DN4 which queries hypoesthesia to touch and pinprick. At least one score of "reduced" or "absent" on the right AND at least one score of "reduced" or "absent" on the left in any of the following items from the EPPIC-Net Neuropathy Exam: Pin sensation in segments 1 or 2 (i.e. the toes and feet) Vibration at the great toe Joint position at the great toe Light touch/touch pressure at the great toe Temperature at the great toe Monofilament at the great toe Decreased or absent ankle reflexes is satisfied by a score of "reduced" or "absent" on the right AND left in the "Ankle reflex" item in the EPPIC-Net Neuropathy Exam. A score of at least 4 on the "Douleur Neuropathique en 4 Questions" (DN4). Pain reporting during a pre-defined 7 day screening period (see section 7.2) meets study criteria (to be established using a centrally-administered screening algorithm) which will account for mean pain intensity reported, variability in reported values, and adherence in reporting. Patient reported daily 11-point NRS (for average and worst pain over the last 24 hours) is completed on at least 5 out of the 7 days in the baseline period. Participants must be willing and able to comply with scheduled visits, the treatment schedule, laboratory testing, and other requirements of the study (e.g., completion of app-based daily reporting). Females not of childbearing potential, defined as post-menopausal for at least 1 year, or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or females of childbearing potential who are practicing, or are willing to begin practicing, one of the following medically acceptable methods of birth control before, throughout, and for 30 days after the last dose of study drug: Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the participant's usual menstrual cycle period) before study drug administration. Total abstinence from sexual intercourse since the last menses before study drug administration. Intrauterine device. Vaginal ring. Double barrier method (condoms, sponge, diaphragm, with spermicidal jellies or cream). Specific requirements of male participants will be defined in the ISAs based on the potential toxicity profile of the asset. Passes the State, Assessibility, Face and Ecological Validity and the Rule of the 3 Ps [persistent, pervasive, pathological] (SAFER) interview. Exclusion Criteria: To be used in conjunction with ISA-specific criteria) Participants must not meet any of the following exclusion criteria, organized by category: 3.2.1. Neuropathy Confound Exclusion Criteria Peripheral neuropathy caused by a condition other than diabetes and/or a known history of significant risk factors for neuropathy other than diabetes (e.g. HIV, cancer/chemotherapy-induced, other medication-induced, alcohol-induced, hereditary, autoimmune neuropathies, uncontrolled or untreated hypothyroidism). Note that participants will not be tested for HIV, this will be established by patient report or review of the medical record. Other significant pain conditions involving the same area as the neuropathy (e.g. physical deformity of the feet, plantar fasciitis, lumbosacral radiculopathy with distal lower extremity pain, fibromyalgia involving the lower limbs, Morton's neuroma). Other pain conditions not involving the same area as the neuropathy which (in the opinion of the investigator) interfere with the participant's ability to rate the neuropathy pain. Any amputation of the lower limb, or current or previous foot ulcer. Significant peripheral vascular disease defined as symptoms consistent with intermittent claudication. 3.2.2. Medication/Treatment Exclusion Criteria Use of other investigational drugs within 3 months before screening and throughout the study. Known or suspected hypersensitivity to all of the assets (active component and excipients) currently being tested in the Platform Protocol. Undergone neurolytic or neurosurgical therapy or used an implanted neurostimulating device for neuropathic pain in the distal lower limbs within 3 months of screening. Use of the high dose capsaicin patch (8%) in the 6 months before screening and throughout the study. Participants who receive and are unwilling to discontinue episodic or periodic treatments for pain in the distal legs and/or feet (e.g., injections of local anesthetics) will be excluded. Non-pharmacological pain treatment (e.g. relaxation/hypnosis, physical or occupational therapy, any exercise based therapy, any talk based therapy, acupuncture, TENS) is allowed if it has been stable for at least 4 weeks prior to screening and is expected to remain stable throughout the study. Active use of opioids or marijuana for any reason at screening and unwilling or unable to discontinue use. 3.2.3. Medical Exclusion Criteria Clinically significant ECG or laboratory abnormalities at the Screening Visit that would put the participant at undue risk or affect the ability of the participant to participate in the trial (in the opinion of the investigator). Participants whose glycemic control has been unstable within 3 months before screening (e.g. ketoacidosis requiring hospitalization, any recent episode of hypoglycemia requiring assistance through medical intervention). Proliferative retinopathy or maculopathy requiring acute treatment. Requiring dialysis. Myocardial infarction or stroke in the past 6 months. Known diagnosis of moderate to severe hepatic impairment (equivalent to Child-Pugh class B or C) OR aspartate aminotransferase or alanine aminotransferase ≥ 3 times the upper limit of normal. A clinically significant illness or operative procedure within 4 weeks of screening. Planned surgery (major or minor) during the study period. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there was evidence of local recurrence or metastases. Pregnant or nursing (lactating) women. 3.2.4. Psychosocial and Substance Use Disorders Exclusion Criteria A clinically significant psychiatric disease that would put the participant at undue risk or affect the ability of the participant to participate in the trial (in the opinion of the investigator). Alcohol use disorder or other substance use disorders (other than nicotine or caffeine) in accordance with DSM-5 criteria within 12 months of screening. Positive urine drug tests defined as follows: Two positive urine drug tests for prescription opioids or marijuana, prior to the initiation of investigational product (IP); or One positive urine drug test for any illegal drugs (other than marijuana) prior to the initiation of IP. Vulnerable persons defined as either of the following: Individuals whose willingness to volunteer in a clinical study may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Individuals whose judgment has been impaired by their physical, mental, or socio-economical condition and those incapable of giving informed consent.

The use of Global Unique Identifiers (GUIDs) allows data to be linked with a given research participant, without revealing any of the participant's identifiable information. All participants in NIH-funded research must have a GUID. This study is using the Biomedical Research Informatics Computing System (BRICS) GUID platform to assign GUIDs. This ID should be generated at the time of Informed Consent since it requires several pieces of patient information (e.g., last name at birth, first name at birth, sex at birth, day, month and year of birth, city and country of birth, etc.). The GUID will be a combination of letters and numbers to form a unique identifier, e.g. TBIAC412JJK. Sites should maintain a list to link the GUID to the participant.