| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pain associated with diabetic peripheral neuropathy (DPN). |
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| E.1.1.1 | Medical condition in easily understood language |
| Pain associated with diabetic peripheral neuropathy (DPN). |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012683 |
| E.1.2 | Term | Diabetic peripheral neuropathy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of GRC 17536 in the treatment of pain associated with diabetic peripheral neuropathy (DPN). |
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of GRC 17536 administered once daily (OD) or twice daily (BID) in patients with painful DPN
2. To investigate the effect of GRC 17536 on time to sustained improvement in pain, night time pain, intensity of pain on neuropathic pain symptoms inventory (NPSI), and sleep interference in patients with painful DPN.
3. To evaluate number of patients who are responders on the Patient Global Impression of Change (PGIC) Questionnaire, Clinician Global Impression of Change (CGIC) Questionnaire; and number of patients who achieve various levels of percent reduction in pain
4. To investigate the pharmacokinetics (PK) of GRC 17536 in patients with DPN
5. To investigate effect of GRC 17536 on the use of rescue medication in patients with painful DPN
6. To investigate effect of GRC 17536 in patients with painful DPN who have mechanical hyperalgesia and /or cold allodynia
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Patients willing to provide voluntary written informed consent
2) Male and female (women of non child-bearing potential) patients ≥18 yrs and ≤ 75 yrs
3) Patients with diabetes mellitus (type 1 or 2) with distal symmetric chronic sensorimotor painful peripheral neuropathy
4) A history of pain for at least 6 months and no greater than 5 years attributed to DPN (Note this requirement refers to duration of pain, not the duration of DPN).
5) DN4 (Douleur Neuropathique en 4 questions) score of ≥4
6) A baseline 24-hour average daily pain intensity score ≥5 as measured on a 11 point pain intensity NRS. The baseline score is the calculated mean of the 24-hour daily average pain scores during the 7 days prior to randomization. The patient must record at least 4 assessments of the 24-hour daily average pain intensity score during the seven-day placebo run-in period in the patient diary.
7) Pain uncontrolled with up to 2 medications for the treatment of pain associated with DPN. The patient’s medical history may indicate that the pain was not controlled with:
a) 1 medication for painful DPN or
b) 2 medications for painful DPN taken over different time-periods in the past or
c) 2 medications for painful DPN taken over the same time-periods in the past (ie combination therapy using 2 drugs)
8) Patients willing to withdraw their neuropathy medications for the whole duration of study starting from washout period till end of study visit.
9) Stable glycaemic control for three months prior to randomization (diabetic regimens may be changed after randomization to maintain glycaemic control) as defined by:
a) Insulin: <25% change of their current insulin dose to maintain glycaemic control
b) Oral antidiabetic agents: <50% change of their current oral dose to maintain glycaemic control.
c) Addition of 1 oral hypoglycaemic agent at its therapeutic dose to the existing treatment regimen.
10) Patients detected to have mechanical hyperalgesia and/or cold allodynia on the basis of appropriate methodology: The study will intend to randomize at least 5 patients with either mechanical hyperalgesia and/or cold allodynia into each of the 3 treatment arms (90 mg, 250/30 mg and placebo).
11) HbA1c level <11
12) Women must be of non child-bearing potential, defined as post menopausal or surgically sterile.
• Menopause is defined as:
• 12 months of spontaneous amenorrhea or
• 6 months of spontaneous amenorrhea with a serum follicular stimulating hormone (FSH) level >40 mIU/L
• Surgically sterile: Females who have a documented hysterectomy and/or bilateral oophorectomy at least 6 weeks before screening. Tubal ligation does not constitute non-child bearing potential.
13) It is required that all male patients with partners of child-bearing capacity use the following methods of contraception from the first dose of study medication and until 90 days after the last dose as shown below:
All sexually active males must use a condom in addition to one of the following conditions:
1) Male patients must have had a vasectomy for more than 6 months
2) Female partner who meets one of the following conditions:
• has had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy;
• is post-menopausal;
• uses one of the following forms of contraception:
1. consistent use of oral, injected or implanted hormonal methods of contraception
2. Placement of intra-uterine device (IUD) or intra-uterine system (IUS)
3. Barrier methods only when used with spermicidal foam/gel/film/cream or suppository. Barrier methods such as condom or occlusive cap (diaphragm or cervical/vault caps) are acceptable
14) Male patients (including men who have had vasectomies) whose partners are pregnant should use condoms from the first dose of study medication and until 90 days after last dose of study medication.
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| E.4 | Principal exclusion criteria |
1) Patients with a 24-hour daily average pain intensity of ≥ 9 on the 11-point NRS at visit 1 or visit 3
2) Other chronic pain conditions not associated with DPN that may confound the assessment of neuropathic pain. However, the patient will not be excluded if:
a)The pain condition is located at a different region of the body (other than lower limbs), and
b) The pain intensity of this condition is not greater than the pain intensity of DPN, and
c) The patient can assess pain due to DPN independently of their other pain condition.
3) Other causes of neuropathy or lower extremity pain which may include, but not be limited to:
a) Lower extremity pain of any severity caused by: osteoarthritis of the ankle or foot, gout, bursitis, or fasciitis.
b) Past medical history or known current medical condition of diffuse peripheral neuropathy caused by alcoholism, malignancy, human immunodeficiency virus (HIV), syphilis, drug abuse, peripheral ischaemia, Vitamin B 12 deficiency, hypothyroidism, liver disease, chemotherapy or radiation therapy.
c) Focal neuropathy in the lower extremities including nerve entrapment or local trauma.
d) Acute or chronic inflammatory polyradiculopathy.
e) Multiple sclerosis or other conditions associated with central neuropathic pain.
f) Pain associated with distal limb ischaemia including intermittent claudication.
4) Complex regional pain syndrome or trigeminal neuralgia
5) Use of the following drugs within 7 days prior to start with the baseline pain intensity assessment ( i.e, 7 days prior to visit 2)
a) Antidepressants, anticonvulsants or mexiletine
b) Opioids or morphinomimetics
c) Fatty acid supplements, primrose oil, myoinositol, chromium picolinate that are known to be used in neuropathic pain
d) Acetyl salicylic acid (ASA) except up to 325 mg/d post myocardial infarction or prevention, transient ischaemic attack prophylaxis
e) Benzodiazepines other than indicated at low doses for sleep disorders
f) Lidocaine patch
g) Non-drug therapies or procedures (i.e. nerve blocks, trans cutaneous electrical nerve stimulation [TENS]) for the relief of pain of DPN for the required run in period and throughout the duration of the study.
h) Herbal medication/supplements, St Johns wort and grape fruit juice (more than 1 quart/day)
6) Capsaicin use within last 03 months of screening
7) Diabetic foot ulcer of ≤ 3 months duration. Diabetic foot ulcer of > 3months can be included in the study only if the ulcer has been stable for a period of at least 3 months prior to screening.
8) Lower extremity amputations other than toes
9) Has any of the following laboratory abnormalities, medical conditions or disorders:
a) Alanine aminotransferase (ALT) > 1.5x upper limit of normal (ULN) or direct bilirubin > 1.5x ULN.
b) Chronic hepatitis B or C with a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C Core Antigen Antibody (Hep C antibody).
c) Serum creatinine >150 μmol/L
d) Corrected QT (QTc) interval using Bazett’s correction >430 msec in males >450msec in females based on single or average QTc value of triplicate electrocardiograms (ECGs) obtained over a brief recording period.
e) Uncontrolled hypertension at screening (sitting systolic blood pressure [SBP] >160 mmHg and/or sitting diastolic blood pressure [DBP] >90 mmHg.
f) Current diagnosis of active epilepsy or any active seizure disorder requiring chronic therapy with antiepileptic drug(s).
g) Patients with clinically significant or uncontrolled hepatic, gastrointestinal, cardiovascular, respiratory, neurological (other than neuropathy), psychiatric, hematological, renal, or dermatological disease, or any other medical condition that according to Investigator’s medical judgment:
• Could interfere with the accurate assessment of safety or efficacy, or,
• Could potentially affect a patient's safety or study outcome.
10) Participation in another study with an investigational compound within the previous 30 days prior to study medication administration, or concurrent participation in another clinical study
11) Major depression.
12) Presence or history of cancer within the past 5 years with the exception of adequately treated localized basal cell skin cancer or in situ uterine cervical cancer.
13) Patients with past medical history or known current medical condition of abnormal folate, vitamin B12, or elevated thyrotropin (TSH), (hypothyroidism) level that could be the cause of the neuropathic pain, and needs to be corrected.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The co-primary efficacy variables (endpoints) are change from baseline to end of each treatment (i.e., baseline to end of week 2; from end of week 2 to end of week 4; and baseline to end of week 4) in the mean 24-hour API score based on a 11-point pain intensity NRS |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 Baseline to end of week 2
2 End of week 2 to end of week 4
3 Baseline to end of week 4
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| E.5.2 | Secondary end point(s) |
1) Efficacy variables (endpoints):
a) Change from baseline at the end of week 1, 2, 3, 4 and 6 in:
• Mean night-time API Score (patient diary): night-time is defined as the time between going to bed at night and rising in the morning
• Mean night-time worst pain intensity Score (patient diary): worst pain is defined as the patient’s assessment of their worst pain intensity for the time period.
• Mean sleep interference Score (patient diary): A 11-point scale that asks patients to select the score that best describes how much the pain interfered with sleep during the past 24 hours. A score 0=Did not interfere with sleep, 10=unable to sleep due to pain.
• Mean daily dose of rescue medication (patient diary)
• Number of patients who are responders on the Patient Global Impression of Change (PGIC) Questionnaire (visits)
• Number of patients who are responders on the Clinician Global Impression of Change (CGIC) Questionnaire (visits)
• Number of patients achieving various levels of percent reduction from baseline in the mean API score (derived from NRS score)
• Time to onset of sustained improvement in the 24-hour daily average pain intensity Score.
• Pain intensity as assessed by the neuropathic pain symptom inventory (NPSI)
• QST assessments
b) Change from baseline in the 24 hour daily API on NRS at the end of week 1, 3 and 6
• Other: In addition, at all visits from visit 2 onwards until visit 8, the investigator will ask the patient “Compared to the previous visit, has your pain characteristic changed?” If the response to this question is yes, the patient must be asked to describe the pain in his/her words. This must be documented in the patient source files.
2) Safety variables (endpoints):
a) Physical examination – body weight
b) Vital signs (including BP, HR, temperature)
c) ECG
d) Clinical laboratory safety analysis (haematology, coagulation, biochemistry and urinalysis)
e) Adverse events
3) Pharmacokinetic Variable (endpoints):
Assessment of plasma pharmacokinetics: Cmax, Tmax, AUC0–tau, AUC0-24 will be estimated for GRC 17536. The relevant PK parameters relying on the terminal phase may be determined based on the data.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline, end of week 1, 2, 3, 4 and 6 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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