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

• Status: Not yet recruiting
• Trial end date: 2025-01-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: James P. Rathmell, MD
• Collaborators: Icahn School of Medicine at Mount Sinai; National Institute of Neurological Disorders and Stroke (NINDS); New York University

Criteria

Inclusion Criteria:

(To be used in conjunction with ISA-specific criteria)

1. Able to provide informed consent. Legally Authorized Representatives (LARs) will not be permitted.

2. 18 years of age and older

3. Diagnosis of Type II diabetes mellitus

4. Stable treatment of diabetes for at least 3 months with no anticipated changes in medication regimen

5. 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.

6. A score of at least 4 on the "Douleur Neuropathique en 4 Questions" (DN4).

7. 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.

8. 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.

9. 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).

10. 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).

11. Specific requirements of male participants will be defined in the ISAs based on the potential toxicity profile of the asset.

12. 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

1. 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.

2. 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).

3. 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.

4. Any amputation of the lower limb, or current or previous foot ulcer.

5. Significant peripheral vascular disease defined as symptoms consistent with intermittent claudication.

3.2.2. Medication/Treatment Exclusion Criteria

6. Use of other investigational drugs within 3 months before screening and throughout the study.

7. Known or suspected hypersensitivity to all of the assets (active component and excipients) currently being tested in the Platform Protocol.

8. Undergone neurolytic or neurosurgical therapy or used an implanted neurostimulating device for neuropathic pain in the distal lower limbs within 3 months of screening.

9. Use of the high dose capsaicin patch (8%) in the 6 months before screening and throughout the study.

10. 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.

11. Active use of opioids or marijuana for any reason at screening and unwilling or unable to discontinue use.

3.2.3. Medical Exclusion Criteria

12. 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).

13. 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).

14. Proliferative retinopathy or maculopathy requiring acute treatment.

15. Requiring dialysis.

16. Myocardial infarction or stroke in the past 6 months.

17. 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.

18. A clinically significant illness or operative procedure within 4 weeks of screening.

19. Planned surgery (major or minor) during the study period.

20. 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.

21. Pregnant or nursing (lactating) women. 3.2.4. Psychosocial and Substance Use Disorders Exclusion Criteria

22. 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).

23. Alcohol use disorder or other substance use disorders (other than nicotine or caffeine) in accordance with DSM-5 criteria within 12 months of screening.

24. Positive urine drug tests defined as follows:

1. Two positive urine drug tests for prescription opioids or marijuana, prior to the initiation of investigational product (IP); or

2. One positive urine drug test for any illegal drugs (other than marijuana) prior to the initiation of IP.

25. Vulnerable persons defined as either of the following:

1. 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.

2. Individuals whose judgment has been impaired by their physical, mental, or socio-economical condition and those incapable of giving informed consent.