A study of oral GRC 17536 in treatment of painful diabetic peripheral neuropathy to find an effective dose of GRC 17536 to reduce the level of pain
Scientific Title of Study
A Phase 2b, randomized, double-blind, placebo controlled dose-finding study to evaluate efficacy, safety and tolerability of GRC 17536 in patients with painful diabetic peripheral neuropathy.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
GRC 17536-206, Version 2.0, Dated 18 Jun 2021
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Dr Kanhei Charan Sahoo
Designation
DGM-Clinical Development
Affiliation
Glenmark Pharmaceuticals Ltd
Address
Glenmark House, B D Sawant Marg
Chakala, Andheri (East)
District: Mumbai
Post Graduate Institute of Medical Education & Research (PGIMER)
Department of Endocrinology and Metabolism, PGIMER, Chandigarh-160012
Chandigarh CHANDIGARH
9781001046
ashuendo@gmail.com
Dr Prakash Kurmi
Shivam Hospital
C-4, Satyanarayan Society, Gor No Kuvo, Jashoda nagar Cross Road, Mani nagar East, Ahmedabad-380008 Ahmadabad GUJARAT
9825047692
dr_prakashkurmi@yahoo.co.in
Dr Surender Kumar
Sir Ganga Ram Hospital
Sir Ganga Ram Hospital Marg,
Old Rajinder Nagar, New Rajinder
Nagar, New Delhi-110060 New Delhi DELHI
9810195147
doctorsuren@yahoo.co.uk
Dr Amit Yeole
Supe Heart & Diabetes Hospital
Opp.Adhar Ashram, Near Rungtha High School, Gharpure Ghat, Ashokstambh, Nashik-422002 Nashik MAHARASHTRA
7588554530
amit_yeole37@rediffmail.com
Dr Lily Rodrigues
Surakshaka Multi-Speciality And Diabetes Hospitals
Surakshaka Diabetic Centre PVT LTD, MIG 218, KPHB Colony, Hyderabad- 500072, India Hyderabad TELANGANA
9704799955
drrlily@gmail.com
Dr Sunil Jain
TOTALL Diabetes Hormone Institute
A unit of Diabetes Thyroid Hormone Research Institute Pvt. Ltd., BCM Health Island, PU 4,
Scheme 54, Behind Prestige Management Institute, Near Bombay Hospital, Indore- 452010 Indore MADHYA PRADESH
(1) ICD-10 Condition: G892||Chronic pain, not elsewhere classified,
Intervention / Comparator Agent
Type
Name
Details
Intervention
GRC 17536
GRC 17536 (270 mg BID): 3 capsules of GRC 17536 (90 mg each capsule): in the morning and evening; orally for 12 weeks
Intervention
GRC 17536
GRC 17536 (30 mg BID): 1 capsule of 30mg GRC 17536 and 2 capsules of placebo: in the morning and in the evening; orally for 12 weeks
Intervention
GRC 17536
GRC 17536 (90 mg BID): 1 capsule of 90 mg GRC 17536 and 2 capsules of placebo: in the morning and in the evening ; orally for 12 weeks
Comparator Agent
Placebo
3 capsules of placebo in the morning and evening administered orally for 12 weeks.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Both
Details
Each subject must meet all of the following criteria to be randomized in the study:
1. Subject voluntary willing to provide written informed consent; and willing to comply with all aspects of the protocol.
2. Type 1 or Type 2 diabetes mellitus male and female (post-menopausal/surgically sterile females only) subjects with age between 18 and 75 years (inclusive of both) at the time of informed consent.
3. A history of pain for at least 6 months and no greater than 5 years attributed to DPN.
4. Subjects with cold detection and warm detection present.
5. Douleur Neuropathique en 4 questions (DN4) score ≥4.
6. Moderate to severe pain due to DPN.
7. Treatment naïve subjects or subjects on treatment with DPN pain medication with pain not adequately controlled with the medication.
8. HbA1c (glycosylated hemoglobin) level ≤8%.
9. Must be willing to use appropriate contraceptive precautions as defined in the study protocol.
ExclusionCriteria
Details
A subject who meets any of the following criteria must not be entered into the run-in phase/randomized in the study:
1. Other chronic pain conditions not associated with DPN that may confound the assessment of pain in DPN.
2. Use of a capsaicin patch within 6 months prior to Screening.
3. Subjects who are currently taking opioids for their painful DPN.
4. Recent hospitalization due to hypo or hyperglycemia within the last 3 months prior to the Screening Visit.
5. Complex regional pain syndrome or trigeminal neuralgia.
6. Active diabetic foot ulcer.
7. Subject has any of the following laboratory abnormalities, medical conditions, or disorders:
a) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or alkaline phosphatase (ALP) ≥1.5x upper limit of normal (ULN) or total bilirubin ≥1.2x ULN.
b) Folate or Vitamin B12 levels < lower limit of normal (LLN).
c) Chronic hepatitis B or C with a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C Core Antigen Antibody (Hep C antibody).
d) Blood urea nitrogen ≥1.5x the ULN.
e) Creatinine clearance (CrCL) ≤60 mL/min as determined by the central laboratory using the modified Cockcroft-Gault equation.
j) SARS-CoV2 infection within 4 weeks before Screening and any persisting post-infection symptoms at the time of Screening.
11. Current diagnosis of major depression or taking medications for it.
12. Presence or history of cancer within the past 5 years
13. Subjects who have undergone gastrointestinal surgery that could affect the absorption of investigational product (e.g., bariatric surgery).
14. Subjects with a history of human immunodeficiency virus (HIV) infection.
15. Subject is positive for urine opioid/cannabinoid tests.
16. History of alcohol abuse/dependence as assessed by the Investigator.
17. Participants answering "Yes" to any of the questions about active suicidal ideation/intent/behaviors occurred within the past month.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
Change from baseline in mean 24-hour API score as measured by 11-point NRS
Week 12
Secondary Outcome
Outcome
TimePoints
Change from baseline in mean 24-hour API score
Week 3, 6, 9, and 16
Proportion of subjects achieving 30% reduction in the mean 24-hour API score
Week 3, 6, 9, 12, and 16
Proportion of subjects achieving 50% reduction in the mean 24-hour API score
Week 3, 6, 9, 12, and 16
Time to onset of sustained improvement in the 24-hour API score
Day of onset of sustained improvement
Change in mean worst pain intensity (WPI) in last 24 hours [Time points
Week 3, 6, 9, 12, and 16
Change in mean night-time API score
Week 3, 6, 9, 12, and 16
Change in mean night-time WPI score
Week 3, 6, 9, 12, and 16
Change in mean sleep interference score
Week 3, 6, 9, 12, and 16
Proportion of subjects who are responders on the Patient Global Impression of Change questionnaire
Week 6, 12, and 16
Change in Neuropathic Pain Symptom Inventory (NPSI) score
Week 6 and 12
Change in quality of life parameters as per SF-12 score
Week 6 and 12
Cmax, Tmax, AUC, AUC0-tau, and AUC0-24 for GRC 17536.
PK sampling time points: Day 3, 4, 7, 9, 15, 18, 25 and Day 29
Adverse events by type, severity, causality and seriousness
From Study initiation to end of study
Columbia-Suicide Severity Rating Scale (C-SSRS)
From baseline to Week 12
Target Sample Size
Total Sample Size="472" Sample Size from India="472" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
Diabetic peripheral neuropathy (DPN) represents a diffuse symmetric and length-dependent injury to peripheral nerves that has major implications on quality of life (QOL), morbidity, and costs from a public health perspective. Diabetic peripheral neuropathy (DPN) is a common complication of both Type 1 and 2 diabetes mellitus, which affects 30% to 90% of the diabetic patients. Pharmacological agents used in the management of painful DPN mainly include tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, opioid, and anti-epileptic drugs. In general, the available treatment options do not provide total relief, are not effective in all patients, and only about one-third of patients may achieve more than 50% pain relief. Hence newer therapies are required for the treatment of painful DPN. GRC 17536 is a novel small molecule targeting TRPA1 as an antagonist and is undergoing clinical development for treatment of painful DPN.
The proposed Phase 2b trial will assess dose-range effect of GRC 17536 for treatment of painful DPN and the study will be conducted across multiple centres in India.
The primary outcome measures will be the change from baseline to end of treatment in the mean 24-hour average pain intensity.