NEW Diabetes and Pain Medication Study

(EN21-01 Trial)

Recruiting at 23 trial locations

Overseen By Jesse Lipnick, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Trial Phase: Phase 2

Sponsor: James P. Rathmell, MD

Must not be taking: Prohibited medications

Disqualifiers: Substance abuse, Renal impairment, Heart disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 13 weeks

122 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a daily pill called NRD135S.E1 for people with painful nerve damage from diabetes. The study will see if taking this pill for a few months can safely reduce their pain. Researchers aim to understand how well the drug works and if it is safe to use.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that taking prohibited medications listed in Appendix A is not allowed. It's best to consult with the trial coordinators for specific guidance.

Do I need to stop my current medications to join the trial?

The trial protocol mentions that participants cannot take certain prohibited medications, as described in Appendix A. However, it does not specify which medications are prohibited, so it's unclear if you need to stop your current medications. It's best to discuss this with the trial coordinators.

What data supports the idea that NRD135SE.1 for Peripheral Neuropathy is an effective treatment?

The available research does not provide any data supporting the effectiveness of NRD135SE.1 for Peripheral Neuropathy. The studies mentioned focus on other treatments and conditions, such as cardiovascular disease and lipid management, but do not address NRD135SE.1 or its impact on Peripheral Neuropathy. ^{1 2 3 4 5}

What safety data is available for NRD135SE.1 treatment for peripheral neuropathy?

The safety data for NRD135SE.1, also known as NRD.E1, comes from three phase I studies. These studies included a single-ascending-dose study, a multiple-dose study, and a food interaction study. In these studies, NRD.E1 was well tolerated with no discontinuations due to treatment-emergent adverse events. The studies showed rapid absorption and fast elimination of the drug, with increased exposure when taken with food and no significant accumulation after daily administration. Overall, NRD.E1 demonstrated good tolerability in healthy volunteers. ^{6 7 8 9 10}

Is NRD135SE.1 safe for humans?

NRD135SE.1, also known as NRD.E1, was tested in healthy volunteers and was well tolerated with no participants stopping due to side effects. The studies showed that it was absorbed quickly and eliminated from the body without significant issues. ^{6 7 8 9 10}

Is the drug NRD135SE.1 a promising treatment for Peripheral Neuropathy?

The information provided does not directly address the effectiveness of the drug NRD135SE.1 for treating Peripheral Neuropathy. The articles focus on the prevalence and associations of Peripheral Neuropathy with other conditions, but do not evaluate the drug NRD135SE.1 itself. ^{10 11 12 13 14}

Research Team

Jessica Robinson-Papp, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for people with Type 2 Diabetes who have been experiencing pain in their legs, feet, toes, or ankles due to diabetic peripheral neuropathy for at least six months. They should score ≥3 on a specific neuropathy screening and report a certain level of pain over the last week.

Inclusion Criteria

A score ≥3 on the Michigan Neuropathy Screening Instrument (MNSI) part B. Diagnosis must be carried out by trained personnel.

Do you have Type 2 Diabetes?

Patient-reported daily 11-point NRS (for average pain over the last 24 hours) meets the criteria specified in Appendix B: Blinded Information during both the 7-day screening and 7-day baseline periods

Exclusion Criteria

Do you have Type 2 Diabetes?

Do you have Type 2 Diabetes?

Do you have pain in your lower extremities (legs, feet, ankles, toes, etc.)?

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NRD135S.E1 80 mg daily or placebo for 13 weeks to assess safety and efficacy in treating painful diabetic peripheral neuropathy

13 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• NRD135SE.1
• Placebo

Trial Overview The study tests NRD135S.E1 (a new medication) against a placebo to see if it can safely reduce pain from diabetic nerve damage. Participants will take either the medication or placebo once daily for 13 weeks.

Participant Groups

Group I: NRD135S.E1 80mg/day Experimental Treatment 1 Intervention

NRD135S.E1 as a potential treatment for moderate to severe painful diabetic peripheral neuropathy (PDPN). While the activity of NRD135S.E1 has been extensively studied, its molecular target is not known, though it does not appear to work through any of the opioid receptors or molecular pathways currently targeted by available analgesics. The best evidence suggests it may act, at least in part, through modulating the Lyn kinase signaling pathway In clinical studies, NRD135S.E1 has been well tolerated at all dose levels tested in single-dose (up to 1,200 mg) and repeat-dose regimens (up to 300 mg/day over 5 days or 150 mg over 3 weeks), and it has been shown to have predictable pharmacokinetics with dose-dependent increases in exposure.

Group II: Matching placebo Placebo Group 1 Intervention

A matching placebo comparator will be used.

Who Is Running the Clinical Trial?

James P. Rathmell, MD

Lead Sponsor

Trials

2

Recruited

240+

Icahn School of Medicine at Mount Sinai

Collaborator

Trials

933

Recruited

579,000+

New York University

Collaborator

Trials

249

Recruited

229,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Findings from Research

In a hypothetical cohort of 1,000 male patients with established cardiovascular disease, combining ezetimibe with statin therapy could prevent significant cardiovascular events, including 43 nonfatal heart attacks and 26 cardiovascular deaths over a lifetime.

The cost-effectiveness analysis suggests that this combination therapy could provide additional quality-adjusted life-years (QALYs) at a cost of approximately £27,475 per QALY gained, indicating potential economic viability compared to increasing statin doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating the health benefits and costs associated with ezetimibe coadministered with statin therapy compared with higher dose statin monotherapy in patients with established cardiovascular disease: results of a Markov model for UK costs using data registries. Ara, R., Pandor, A., Tumur, I., et al.[2016]

In the 6-year 'IMPROVE-IT' trial involving patients after an acute coronary syndrome, the combination of ezetimibe and simvastatin led to a 1.6% reduction in nonfatal myocardial infarctions compared to simvastatin alone.

However, this combination treatment did not result in a reduction in overall mortality, indicating that while it may help prevent heart attacks, it does not necessarily improve survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ezetimibe + statin: insufficient benefit. [2019]

Only about 50% of patients with peripheral artery disease (PAD) are prescribed statins, despite guidelines recommending their use for lipid lowering and plaque stabilization, which can reduce limb-related complications by 24%.

For patients who experience statin intolerance, alternatives like bempedoic acid and PCSK9 inhibitors are available, and all adults should have their lipoprotein(a) levels checked at least once, as high levels are linked to PAD progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Update on lipid lowering therapy in peripheral artery disease]. Mühlberg, KS.[2023]

Niacin effectively improves lipid profiles by increasing HDL and lowering triglycerides and LDL through unique mechanisms, making it a strong candidate for combination therapy with other lipid-lowering medications.

Recent studies show that an extended-release formulation of niacin is as effective as immediate-release versions but offers better tolerability, and it is safe for use in patients with type 2 diabetes, who typically have low HDL levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The benefits of niacin in atherosclerosis. Tavintharan, S., Kashyap, ML.[2019]

The ENHANCE trial demonstrated that the combination of ezetimibe and simvastatin effectively lowers total and low-density lipoprotein cholesterol levels, but it did not show a significant reduction in carotid intima-media thickness, which was the primary endpoint.

The clinical effectiveness of adding ezetimibe to statin therapy in reducing cardiovascular events is still uncertain, with further insights expected from the upcoming IMPROVE-IT trial involving 18,000 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carotid intima-media thickness (cIMT): a useful clinic tool or research luxury? Another view of the ENHANCE trial. Toutouzas, P., Richter, D.[2019]

NRD135S.E1 (NRD.E1) is a new oral medication developed for treating painful diabetic peripheral neuropathy, showing rapid absorption and good tolerability in three phase I studies involving healthy male and female subjects.

The studies demonstrated that NRD.E1's absorption is dose-dependent and increases when taken with food, with no significant accumulation in the body after daily doses, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Human Single-Ascending-Dose, Multiple-Dose, and Food Interaction Studies of NRD.E1, an Innovative Nonopioid Therapy for Painful Diabetic Peripheral Neuropathy. Tiecke, E., Rainisio, M., Guentert, T., et al.[2023]

In a phase 2a study involving 88 patients with painful diabetic peripheral neuropathy (PDPN), NRD.E1 demonstrated clinically relevant pain reductions at doses of 40 mg and 150 mg/day compared to placebo, indicating its potential efficacy as a treatment option.

NRD.E1 was well tolerated, with minimal side effects reported, suggesting it may offer a safer alternative to existing pain management therapies for PDPN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NRD.E1, an innovative non-opioid therapy for painful diabetic peripheral neuropathy-A randomized proof of concept study. Tiecke, E., Rainisio, M., Eisenberg, E., et al.[2022]

Statins, commonly used to lower cholesterol and prevent cardiovascular issues, can cause rare but serious side effects like muscle damage and peripheral polyneuropathy, which may include sensory impairment and reduced muscle strength.

Although peripheral polyneuropathy is a rare side effect, affecting about 1 in 10,000 patients treated for a year, discontinuing statins often leads to improvement in symptoms after ruling out other causes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral neuropathy and statins. [2007]

A pooled analysis of approximately 700 patients receiving antibody-drug conjugates (ADCs) revealed that the risk of developing clinically significant peripheral neuropathy (grade ≥ 2) increases with higher ADC exposure and longer treatment duration.

Demographic factors such as body weight and history of peripheral neuropathy also contribute to the risk, suggesting that dosing adjustments and treatment duration modifications could help minimize the incidence of this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates. Kågedal, M., Samineni, D., Gillespie, WR., et al.[2023]

In a study of 90 patients with erectile dysfunction (ED), 68.9% were found to have neurological issues, with 61.1% specifically diagnosed with peripheral neuropathy, indicating a significant link between these conditions.

Patients with more severe peripheral neuropathy symptoms had worse erectile function scores (IIEF-5) and required more aggressive treatments, highlighting the importance of assessing nerve function in ED management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral neuropathy: an underdiagnosed cause of erectile dysfunction. Valles-Antuña, C., Fernandez-Gomez, J., Fernandez-Gonzalez, F.[2019]

In a study of 1213 men aged 40 and older, peripheral neuropathy was found to be significantly associated with erectile dysfunction, with an odds ratio of 1.71, indicating that men with decreased lower extremity sensation are at a higher risk for erectile dysfunction.

The prevalence of peripheral neuropathy was notably higher in men with diabetes (51.2%) compared to those without diabetes (22.5%), but the association between peripheral neuropathy and erectile dysfunction was still significant in men without diabetes, suggesting it is a risk factor independent of diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Peripheral Neuropathy with Erectile Dysfunction in US Men. Hicks, CW., Wang, D., Windham, BG., et al.[2021]

In a study of 4000 Type 2 diabetes patients in Korea, the prevalence of diabetic peripheral neuropathy was found to be 33.5%, indicating a significant health concern among this population.

Many patients with neuropathy (69.8%) were receiving treatment, but only 12.6% were aware of their condition, highlighting the need for better awareness and management strategies among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea. Won, JC., Kwon, HS., Kim, CH., et al.[2022]

In a study of 1200 patients with mitochondrial disorders, 12.4% were found to have peripheral neuropathy, making it one of the most common symptoms associated with these conditions.

Specific genetic mutations, such as POLG, TYMP, and SURF1, are linked to different types of peripheral neuropathy, which can help guide diagnosis and treatment strategies for affected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

"Mitochondrial neuropathies": A survey from the large cohort of the Italian Network. Mancuso, M., Orsucci, D., Angelini, C., et al.[2022]

In a study of 772 adults diagnosed with inflammatory bowel disease (IBD) over 12,476 person-years, the incidence of peripheral neuropathy was found to be low, with only 9 cases reported, resulting in an incidence rate of 72 cases per 100,000 IBD person-years.

Neuropathy in IBD patients was typically diagnosed long after the onset of the disease, often during periods of bowel disease inactivity, suggesting that other causes of neuropathy should be considered in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral neuropathy incidence in inflammatory bowel disease: a population-based study. Figueroa, JJ., Loftus, EV., Harmsen, WS., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Estimating the health benefits and costs associated with ezetimibe coadministered with statin therapy compared with higher dose statin monotherapy in patients with established cardiovascular disease: results of a Markov model for UK costs using data registries. [2016]

2. France pubmed.ncbi.nlm.nih.gov

Ezetimibe + statin: insufficient benefit. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

[Update on lipid lowering therapy in peripheral artery disease]. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

The benefits of niacin in atherosclerosis. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Carotid intima-media thickness (cIMT): a useful clinic tool or research luxury? Another view of the ENHANCE trial. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

First-in-Human Single-Ascending-Dose, Multiple-Dose, and Food Interaction Studies of NRD.E1, an Innovative Nonopioid Therapy for Painful Diabetic Peripheral Neuropathy. [2023]

7. England pubmed.ncbi.nlm.nih.gov

NRD.E1, an innovative non-opioid therapy for painful diabetic peripheral neuropathy-A randomized proof of concept study. [2022]

8. France pubmed.ncbi.nlm.nih.gov

Peripheral neuropathy and statins. [2007]

9. United States pubmed.ncbi.nlm.nih.gov

Time-to-Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E Antibody-Drug Conjugates. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Peripheral neuropathy: an underdiagnosed cause of erectile dysfunction. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Association of Peripheral Neuropathy with Erectile Dysfunction in US Men. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea. [2022]

13. England pubmed.ncbi.nlm.nih.gov

"Mitochondrial neuropathies": A survey from the large cohort of the Italian Network. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Peripheral neuropathy incidence in inflammatory bowel disease: a population-based study. [2021]