A multicenter randomized, double-blind, placebo-controlled Phase 2 study to evaluate efficacy, safety, tolerability, pharmacokinetics and target engagement of GSK3858279 in adult participants with chronic Diabetic Peripheral Neuropathic Pain (DPNP) / NEPTUNE-17.

Trial ID: 2022-502313-28-00
Protocol: 214221
Sponsor: Glaxosmithkline Research & Development Limited

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Diseases & Conditions

Diabetic neuropathy

Objectives

The primary objective of this multicenter, randomized, double-blind, placebo-controlled Phase 2 study is to **characterize the efficacy** of GSK3858279 on pain compared to placebo in adult participants with **Diabetic Peripheral Neuropathic Pain** (DPNP). This objective is clinically relevant as it aims to assess the potential of GSK3858279 to alleviate pain associated with DPNP, a common and debilitating complication of diabetes that significantly impacts patients' quality of life. The study evaluates the therapeutic effect of GSK3858279, administered via subcutaneous injection, in comparison to a placebo, thereby providing insights into its potential role in pain management for this condition.

Participants

The clinical trial involves a total of **160 participants** diagnosed with **Diabetic Peripheral Neuropathic Pain** (DPNP). The study population includes both male and female subjects, aged between **18 and 75 years**. Participants are required to have Type I or Type II diabetes with painful, distal, symmetrical, sensory-motor neuropathy attributed to diabetes, persisting for at least six months. The trial population was selected based on specific criteria, including a stable anti-diabetic medication regimen and a body mass index (BMI) within the range of 18 to 40 kg/m². Participants must have a documented history of insufficient pain relief from, or inability to tolerate, or contraindication to current standard of care therapy. The trial includes individuals who are capable of understanding and participating in all scheduled evaluations and procedures. Both genders are included, and the study considers vulnerable populations. Participants' general health status is monitored, ensuring no recent unplanned hospitalizations due to noncompliance or uncontrolled diabetes. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 2 study designed to evaluate the efficacy, safety, tolerability, pharmacokinetics, and target engagement of GSK3858279 in adult participants with chronic **Diabetic Peripheral Neuropathic Pain** (DPNP). The trial aims to assess the change from baseline in the weekly average of average daily pain intensity at Week 12, using the Numeric Rating Scale (NRS). The study is expected to commence recruitment on May 18, 2024, and conclude by June 24, 2025, with a maximum treatment period of 12 weeks.

Participants will be involved in a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diabetes type, pain characteristics, and medication regimen. The screening will include a positive Douleur Neuropathique 4 (DN4) questionnaire and a pain score assessment. Following the screening, eligible participants will enter a run-in period to further evaluate pain scores and rescue medication use. Subsequent visits will occur at regular intervals to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will finalize data collection and assess the primary endpoint.

Participant involvement is expected to last approximately 12 weeks, with conditions for early termination including non-compliance with the study protocol, adverse events, or withdrawal of consent. The study will utilize GSK3858279 administered via **subcutaneous injection**, with a maximum daily dose of 400 mg. Participants will be monitored for any adverse reactions and overall treatment efficacy throughout the trial duration.

Treatment

The clinical trial involves the administration of **GSK3858279**, an investigational medication developed by GlaxoSmithKline. This experimental drug is formulated as an injection and is administered via **subcutaneous injection**. The dosage for GSK3858279 is set at a maximum of 400 mg per day, with the treatment period extending up to 12 weeks. The active substance in GSK3858279 is a protein of other origin, specifically designed to target chronic Diabetic Peripheral Neuropathic Pain (DPNP). Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study employs a **placebo** control, which is a **Sterile 0.9% (w/v) Sodium Chloride** solution. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the experimental drug, via subcutaneous injection, to maintain consistency in the administration process. The use of a placebo is critical in evaluating the efficacy and safety of GSK3858279 by providing a baseline for comparison.

Efficacy

The efficacy of GSK3858279 in the treatment of chronic **Diabetic Peripheral Neuropathic Pain (DPNP)** will be assessed through a primary endpoint focused on the change from baseline in the weekly average of average daily pain intensity. This will be measured at Week 12 using the Numeric Rating Scale (NRS), a validated tool for quantifying pain intensity. Participants will record their pain levels daily, and these scores will be averaged weekly to monitor changes over the course of the trial. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled Phase 2 study, ensuring rigorous evaluation of the treatment's efficacy compared to placebo. Data collection will be systematic and consistent, adhering to the trial protocol to ensure the reliability and validity of the efficacy assessments.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18-75 years of age inclusive, at the time of signing the informed consent. 2. Type I or Type II diabetes with painful, distal, symmetrical, sensory-motor neuropathy attributed to diabetes, of at least 6 months duration; a. Pain must have begun in bilateral distal lower limbs. b. Pain is not related to underlying infection or trauma. c. Diagnosis confirmed by a positive Douleur Neuropathique 4 [DN4] questionnaire at screening. d. Levels of glycosylated haemoglobin A1c (HbA1c) less than 97 mmol/mol (<11%). 3. On a stable anti-diabetic medication regimen (unchanged dose over the last 30 days for diabetes) prior to screening. Adjustment of insulin dose is acceptable, however, resumption of insulin treatment is not allowed since 30 days prior to screening. 4. No unplanned recent hospitalizations due to noncompliance or uncontrolled diabetes. 5. At screening, a pain score ≥4 and ≤9 by the 11-point NRS (0-10) for average daily pain intensity over the past 24 hours. 6. During the run-in period; An average of the average daily pain score of ≥4 and ≤9 by the 11-point NRS (0-10). Rescue medication use (if required) must be within the permitted allowance.
Documented history of insufficient pain relief from, or inability to tolerate, or contraindication to current standard of care therapy, e.g. antidepressants (tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) OR antiepileptic (anticonvulsant) drugs. 8. Participant must be willing and able to understand and participate in all scheduled evaluations and to complete all required tests and procedures including the use of patient eDiary. This will be judged by the Investigator during the screening period. 9. BMI within the range of 18 to 40 kg/m2 (inclusive). 10. Male or Female participant; A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP). OR • Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4 during the study intervention period and for at least 16 weeks after the last dose of study intervention. The Investigator should evaluate potential for contraceptive method failure (e.g. noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention. • Additional requirements for pregnancy testing during and after study intervention are located in protocol. • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

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Exclusion Criteria

History of significant medical illness 2. Participant has current painful peripheral neuropathy due to a cause other than diabetes 3. Participant has any lower extremity amputation. 4. Participant has a current or previous foot ulcer within the past 3 months 5. Participants who have complications of diseases that are considered to affect the assessment of diabetic peripheral neuropathic pain. 6. Current immunodeficiency diseases 7. History of recurrent/chronic infections 8. Symptomatic herpes zoster within 3 months prior to screening. 9. Current or previous active Mycobacterium tuberculosis infection regardless of treatment. 10. Evidence of latent tuberculosis (TB) as documented by medical history, examination and TB testing: either a positive (not indeterminate) QuantiFERON TB Gold Plus test or a positive (not indeterminate) T-SPOT test. 11. History of significant allergies to monoclonal antibodies. 12. History, diagnosis, signs or symptoms of any clinically significant psychiatric disorder 13. History or evidence of clinically significant multiple or severe drug allergies, or severe post-treatment hypersensitivity reactions 14. Malignancy • History of malignancy within the last 5 years, except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. • Breast cancer within the past 10 years.
Liver • Alanine Aminotransferase (ALT) >1.5× ULN at screening. • Bilirubin >1.5× ULN at screening (isolated bilirubin >1.5× ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 16. Hematological laboratory values at screening • White blood cell (WBC) count <3.0×109/L • Hemoglobin <10.0 g/dL • Platelet count <125×109/L 17. Myocardial infarction or unstable angina, or cerebrovascular event within 6 months prior to screening. 18. Unstable or life-threatening cardiac arrhythmia requiring intervention within 3 months prior to screening. 19. New York Heart Association (NYHA) Class III or IV heart failure. 20. Corrected QT interval according to Fridericia’s formula (QTcF) >450 msec or QTcF >480 msec in participants with bundle branch block, at screening or Day 1 visit. 21. Estimated creatinine clearance <45 mL/min/1.73 m2 at screening 22. Planned surgical procedure over the duration of the study. 23. Major surgery within 3 months prior to first dose of study intervention. 24. Participants with a recurrent or chronic infection 25. Use of any analgesic medication is prohibited 26. Recent immunomodulator use within pre-specified timeframes 27. Received live or live attenuated vaccine(s) use within pre-specified timeframes 28. Use of pain interventions within 4 weeks of screening.
Current enrollment or past participation in a clinical study of an Investigational Medicinal Product within the last 30 days or 5 half-lives (whichever is longer) 30. Exposure to more than 4 new IMPs within 12 months prior, or any previous exposure to GSK3858279. 31. Participants who are a family member of the Investigator or any associate, colleague, and employee assisting in the conduct of the study 32. Participants who cannot be contacted by phone in an emergency. 33. Participants who are unlikely to comply with the protocol 34. Positive human immunodeficiency virus (HIV) antibody test. 35. Has a positive test for active hepatitis B virus. 36. Positive hepatitis C antibody test result. 37. Positive hepatitis C RNA test result 38. Active or suspected COVID-19 infection. 39. A positive drug screen at screening. 40. Pregnant or lactating, or women planning to become pregnant or initiating breastfeeding. 41. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or dependence within a year 42. Sensitivity to any of the study interventions, or components thereof, or drug