| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pain associated with diabetic peripheral neuropathy (DPN). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pain associated with diabetic peripheral neuropathy (DPN). |
|
| 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 |
|
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of GRC 17536 administered BID in patients with painful DPN
2. To investigate the effect of GRC 17536 on time to sustained improvement in pain, night-time pain, neuropathic pain symptoms (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 the effect of GRC 17536 on the use of rescue medication in patients with painful DPN
6. To investigate the effect of GRC 17536 in patients with painful DPN who have mechanical hyperalgesia and /or cold allodynia |
|
| 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 (post menopausal/surgically sterile only) 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 and < 9 as measured on an 11 point pain intensity NRS. The baseline score is the calculated as mean of the 24-hour daily average pain scores during the 7 days prior to randomisation. The patient must record at least 4 assessments of the 24-hour daily average pain intensity score during the 7-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 entire duration of study starting from washout period till end of study visit. Discontinuation of ongoing diabetic neuropathy pain medications during the study (from wash-out period to visit 8) must be medically justifiable and appropriate (eg, inadequate pain control, AEs, contra indication etc). Patients who are stable on the ongoing pain medications and have no medical justification to withdraw these medications will not be included in the study.
9) Stable glycaemic control for three months prior to randomisation (for subjects with HbA1c < 8%) as defined by:
a) Insulin: <25% change of their mean 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 up to 1 oral hypoglycaemic agent at its therapeutic dose to the existing treatment regimen.
Patients with HbA1c of 8 to 11% are eligible if attempts to improve diabetic control with optimal treatment with authorized drugs have failed.
Diabetic regimens may be changed after randomisation to maintain glycaemic control. Patients will receive guideline-based diabetes control that is individually adapted to their comorbidity and risk profile.
10) Patients detected to have mechanical hyperalgesia and/or cold allodynia on the basis of appropriate methodology: The study will intend to randomise at least 38 patients with either mechanical hyperalgesia and/or cold allodynia out of the total 138 planned patients.
11) Women must be of non child-bearing potential, defined as post menopausal or surgically sterile.
Menopause is defined as 12 months of spontaneous amenorrhea with a serum follicular stimulating hormone (FSH) level >40 mIU/L
Surgically sterile women: defined as 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.
12) It is required that all male patients 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:
• Male patients must have had a vasectomy for more than 6 months
• Female partner who meets one of the following conditions:
a) has had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy;
b) is post-menopausal;
c) 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
13) 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. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria must not be enrolled in the study:
1) 24-hour daily average pain intensity of ≥ 9 on the 11-point NRS at
visits 1 or 3
2) Other chronic pain conditions not associated with DPN that may
confound the assessment of neuropathic pain. Patients will not be
excluded if:
a) pain condition is located at a different region of the body (other than
lower limbs), and
b) 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) diffuse peripheral neuropathy caused by alcoholism, malignancy,
human immunodeficiency virus (HIV), syphilis, drug abuse, peripheral
ischaemia, Vitamin B 12 deficiency, abnormal folate, 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 within 7 days prior to start with the baseline pain
intensity assessment
a) Antidepressants, anticonvulsants or mexiletine (exceptions: fluvoxamine, norfluoxetine, nefazodone, carbamazepine, barbiturates, phenytoin and oxcarbazepine-patients on these medications at screening will be excluded)
b) Opioids or morphinomimetics
c) Fatty acid supplements, primrose oil, myoinositol, chromium picolinate, alpha-lipoic acid, benfotiamine, actovegin that are known to be used in neuropathic pain
d) Acetyl salicylic acid except up to 325 mg/day for myocardial infarction or 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]).
6) Use of herbal medication/supplements, St Johns wort and grape-fruit juice (more than 0.9 L/day) within 3 weeks prior to visit 2
7) Capsaicin use within 3 months of screening
8) Diabetic foot ulcer of ≤ 3 months duration
9) Lower extremity amputation other than toes
10) 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 or
Hepatitis C Core Antigen 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 SBP >160 mmHg
and/or sitting 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.
11) Participation in another study with an investigational compound
within the previous 90 days prior to study medication administration, or
concurrent participation in another clinical study
12) Major depression.
13) 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.
14) HbA1C>11 %
15) Patients on strong or moderate inhibitors of CYP3A4
16) Patients on inducers of CYP3A4
17) Patients on statins who have abnormal creatine kinase (CK) levels.
18) Patients who have undergone gastro-intestinal tract surgery that
could affect the absorption of investigational product
19) Patients in whom rescue medication is contraindicated
20) Patients with a history of HIV infection |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change from baseline to end of treatment (i.e., baseline to end of week 4) in the mean 24-hour average pain intensity (API) score based on an 11 point pain intensity numeric rating scale (NRS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to end of week 4
|
|
| E.5.2 | Secondary end point(s) |
1) Secondary endpoints
1. Change from baseline at the end of week 1, 2, 3, 4 and 6 in:
2. 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
3. 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.
4. Mean sleep interference Score (patient diary): An 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.
5. Mean daily dose of rescue medication (patient diary)
6. Number of patients who are responders on the PGIC questionnaire (visits)
7. Number of patients who are responders on the CGIC questionnaire (visits)
8. Number of patients achieving various levels of percent reduction from baseline in the mean 24-hour API score (derived from NRS score)
9. Time to onset of sustained improvement in the 24-hour daily average pain intensity Score: Sustained improvement is defined as a reduction of ≥ 2 points from baseline for ≥ 2 consecutive days on the 24-hour daily API scores on NRS.
10. NPSI (visits)
11. Quantitative sensory testing (QST) assessments
12. Change from baseline in the 24 hour daily API on NRS at the end of week 1, 2, 3 and 6
13. 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 and case record form (CRF)
14. Safety endpoints:
a) Physical examination including body weight
b) Vital signs (including blood pressure [BP], heart rate, , temperature)
c) Electrocardiogram (ECG)
d) Clinical laboratory safety analysis (haematology, coagulation, biochemistry and urinalysis)
e) Adverse events (AEs)
15. PK endpoints: Plasma pharmacokinetics: Cmax, Tmax, AUC0-tau, AUC0-24 will be estimated for GRC 17536 based on the rich PK group. The relevant PK parameters relying on the terminal phase may be determined based on the data as appropriate. Both the rich and the sparse PK samples may be used for the future population PK model building and analyses |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline, end of week 1, 2, 3, 4 and 6 |
|
| 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 | No |
| 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 | 2 |
| 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 | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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