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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Painful Diabetic Neuropathy

Intervention / Treatment
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* Drug: ISA specific


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent. Legally Authorized Representatives (LARs) will not be permitted. 18 years of age and older Diagnosis of diabetes mellitus Meets the Toronto Criteria for probable clinical sensorimotor polyneuropathy, with PDPN symptoms present for at least six months. 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: a. 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. b. Decreased distal sensation is satisfied by any of the following: i. Yes is checked at least once under Question 3 of the DN4 which queries hypoesthesia to touch and pinprick. ii. 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 c. 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 meets study criteria (to be established using a centrally-administered screening algorithm) which may 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 may be included if they meet at least one of the following criteria (note that individual ISAs may specify more stringent measures to prevent pregnancy): a. Are not of childbearing potential, defined as one or more of the following: i. Post-menopausal for at least 1 year ii. Surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) iii. XY genotype iv. Turner syndrome v. Uterine agenesis. b. Are completely abstinent from sexual activity capable of resulting in pregnancy (as part of their preferred and usual lifestyle). This will include females whose sole sexual partner is a male who has undergone surgical sterilization or vasectomy. c. Women of childbearing potential will agree to practice an effective form of two types of birth control, which are defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. This must be done before, throughout, and for 30 days after the last dose of study drug. Acceptable methods are: i. Hormonal methods such as the vaginal ring, or 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. ii. Intrauterine device. iii. Barrier method of contraception: condoms with or without a spermicidal agent, diaphragm or cervical cap with spermicide Specific requirements of male participants (regarding contraception) will be defined in the ISAs based on the potential toxicity profile of the asset. Exclusion Criteria: 3.1.1. Neuropathy Confound Exclusion Criteria Peripheral neuropathy caused by a condition 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 which interferes with the participant's ability to rate the neuropathy pain. If there is any amputation please contact the MM. The presence of any current foot ulcer. Significant peripheral vascular disease defined as symptoms consistent with intermittent claudication. 3.1.2. 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 (for the treatment of PDPN). Use of the capsaicin patch in a manner that is not expected to interfere with the measurement of PDPN severity is allowed. 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) for the treatment of conditions other than PDPN is allowed. If the treatment is for PDPN it 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. 3.1.3. 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). Screening ECG and lab results may be repeated without requiring a rescreen, as long as the participant is still within the screening window. 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. Clinically significant surgery planned during the study period. If a surgery is planned, please contact the MM. History of or currently active malignancy or other medical condition 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). Pregnant or nursing (lactating) women. 3.1.4. 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.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EN21-01 ISA<br>The EN21-01 Intervention Specific Analysis is detailed in the protocol (NCT#) | Drug: ISA specific<br>* ISA specific interventions will be listed in their protocols.<br>|
| Placebo Comparator: Placebo Comparator<br>Each ISA will detail the use of the Placebo Comparator. | Drug: ISA specific<br>* ISA specific interventions will be listed in their protocols.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily 0-10 pain NRS | 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. | Past 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain, Enjoyment, and General activity scale (PEG) | 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. | Past 24 hours | 
| Pain Catastrophizing Scale - Short Form 6 (PCS-SF6) | 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. | Past 24 hours | 
| PROMIS Physical Functioning Short-Form 6b | 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). | Past 24 hours | 
| Pain Health Questionnaire (PHQ-2) | 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. | Past 24 hours | 
| Generalized Anxiety Disorder - 2 item scale (GAD-2) | 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. | Past 24 hours | 
| Patient Global Impression of Change (PGIC) | 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). | Past 24 hours | 
| Tobacco, Alcohol, Prescription medication, and other Substance use Tool (TAPS-1) | 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. | Past 24 hours | 
| PROMIS Sleep Disturbance - 6A | 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). | Past 24 hours | 
| Sleep Duration | 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. | Past 24 hours | 
| Opioid Use Questionnaire (OUQ) | 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 | Past 24 hours |