| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chemotherapy-induced peripheral neuropathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chemotherapy-induced peripheral neuropathy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10079545 |
| E.1.2 | Term | Chemotherapy induced peripheral neuropathy |
| E.1.2 | System Organ Class | 100000004852 |
|
| 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 safety and tolerability of multiple oral (twice daily [BID]) doses of TRK-750 in oxaliplatin-treated colorectal cancer patients with chemotherapy-induced peripheral neuropathy (CIPN). |
|
| E.2.2 | Secondary objectives of the trial |
• to assess the efficacy of multiple oral (BID) doses of TRK-750 in reducing neuropathic symptoms, improving quality of life (QoL), and clinician-reported outcomes in oxaliplatin-treated colorectal cancer patients with CIPN.
• to study the relationship between plasma concentrations of TRK-750 and safety and efficacy variables in oxaliplatin-treated colorectal cancer patients with CIPN.
The exploratory objective of this study is:
• to assess the efficacy of multiple oral (BID) doses of TRK-750 on PD biomarker(s) in blood, psychophysical, electrophysiological, and histological parameters of neuropathy in oxaliplatin-treated colorectal cancer patients with CIPN. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patient between 18 and 80 years of age, inclusive.
2. Oxaliplatin-containing chemotherapy treatment for colorectal cancer in the adjuvant setting must have been completed ≥ 3 months, but not more than 3 years, prior to Screening.
3. A diagnosis of CIPN based on the following criteria:
a. onset of pain of any severity in hands and/or feet after exposure to oxaliplatin AND;
b. presence of painful symptoms of any severity in a symmetrical stocking and glove distribution beginning in lower extremities, which may progress to the upper extremities (the latter may or may not be present at study entry) AND;
c. painful symptoms are accompanied by non-painful symptoms (e.g., tingling or numbness) in a similar distribution.
4. Neuropathy of ≥ Grade 2 using the general guideline of grading scales defined in CTCAE (v5.0)
5. Pain or neuropathic symptoms of CIPN for a duration of ≥ 3 months, for which the patient wants intervention.
6. Body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive.
7. Females of childbearing potential will agree to use highly effective
contraception from the time of signing the ICF until 90 days after the
Follow-up visit. Males who are sexually active with female partners of
childbearing potential will agree to use a male condom with spermicide from Day 1 until 90 days after the Follow-up visit.
8. Be either CIPN pain-treatment naïve or have important side effects or inadequate relief from their current CIPN pain medication (stable over
last month).
9. Has not used non-pharmacological therapy for the treatment of any pain condition (e.g., chiropractic therapies, alternative medicine therapies, or acupuncture) for at least 2 weeks prior to start of the baseline days (Days -14 to -1), and a willingness to refrain from using these therapies throughout the study. The use of physical activity or other short-acting, symptomatic non-pharmacological therapy is permitted provided the patient is willing to maintain the same regimen or usage pattern consistently throughout the study.
10. Able to comprehend and willing to sign an Informed Consent Form (ICF) and to abide by the study restrictions.
11. Patients have a life expectancy of at least 12 months.
12. An EORTC QLQ-CIPN20 score of ≥ 25 based on an average of 2 assessments during the Screening period and Day 1 prior to randomisation.
13. At least one of the following:
a. a mean value of pain intensity ≥ 4 on the 11-point NRS based on the average of once-daily assessments for 7 days, with no more than 2 missing records, between Days -7 and -1. Patients must score ≥ 4 on at least 4 out of 7 measurements between Days -7 and -1 OR;
b. a mean value of intensity of tingling and numbness or uncomfortable neuropathic symptoms ≥ 4 on the 11-point NRS based on the average of once-daily assessments for 7 days, with no more than 2 missing records, between Days -7 and -1. Patients must score ≥ 4 on at least 4 out of 7 measurements between Days -7 and -1. |
|
| E.4 | Principal exclusion criteria |
1. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol, ability to complete the study, and study assessments.
2. Presence of skin conditions in the affected dermatome that, in the judgement of the Investigator, could interfere with evaluation of the neuropathic pain condition.
3. Presence of non-CIPN pain that may interfere with study assessments and/or self-evaluation of peripheral neuropathic pain.
4. Known history of significant hypersensitivity, intolerance, or allergy.
5. Peripheral neuropathy caused by tumour infiltration or compression of spinal nerves or surgical trauma.
6. Active clinically significant infection
7. Unstable cardiac disease or myocardial infarction within 6 months prior to study entry.
8. Patients with uncontrolled major psychiatric disorders, such as major depression or psychosis.
9. History of pre-existing symptomatic neuropathy prior to chemotherapy, including neuropathy due to alcoholism, vitamin B deficiency, diabetes, hypothyroidism, human immunodeficiency virus (HIV), congenital neuropathy, and toxic neuropathy.
10. Female patients who are pregnant (including a positive urine pregnancy test at Screening or on Day 1) or lactating.
11. Inadequate haematological function, defined as neutrophil count < 1.0 × 10^9/L and platelet count < 50 × 10^9/L with measured values of these in the clinical laboratory tests conducted at Screening. At Screening, haematology assessments may be repeated once.
12. Inadequate renal function, defined as estimated glomerular filtration rate (eGFR) ≤ 59 mL/min, i.e., Creatinine Clearance (CrCl) as calculated using the Cockcroft-Gault equation with measured values of these in the clinical laboratory tests conducted at Screening:
a. [1.23 × (140 - age) × (weight in kg)] ÷ (serum creatinine in μmol/L) – if male.
b. [1.04 × (140 - age) × (weight in kg)] ÷ (serum creatinine in μmol/L) – if female.
At Screening, clinical laboratory assessments may be repeated once.
13. History of substance abuse within 1 year prior to Screening.
14. Positive test results for drugs of abuse at Screening (confirmed by
repeat) or Day 1, unless consistent with use of prescription medication
and approved by the Sponsor (or delegate). A repeated positive test
result for cocaine, phencyclidine, methadone, or amphetamines, for
nonmedical use, is unconditionally exclusionary.
15. Positive test for hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCV), or HIV antibody at Screening. NOTE: Patients who test positive for hepatitis C antibody may be eligible for inclusion in the study provided that hepatitis C antibody RNA PCR is negative to demonstrate that the infection is not current (or that the result was a false positive). HCV RNA PCR counts as a rescreening attempt.
16. Use of any medication in the absence of appropriate washout periods that, in the opinion of the Investigator, may influence the result of the study, or the patient's ability to participate in the study.
17. Has received an investigational product or has been treated with an investigational device within 90 days prior to first drug administration and will not start any other investigational product or device study within 90 days after last study drug administration.
18. Likely to require chemotherapy during the study period or any other treatment that may interfere with compliance with the protocol, ability to complete the study, and study assessments.
19. Plans to change current medications or any other intervention intended to treat or relieve CIPN signs or symptoms from Screening to end of study.
20. Has previously received TRK-750. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary safety and tolerability endpoints for this study include AEs, patient withdrawals and drug discontinuations, use of concomitant medication(s) and therapy(ies), vital sign measurements, 12-lead electrocardiograms (ECGs), clinical laboratory evaluations, and physical examinations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
For neuropathic symptoms:
x absolute change and percentage change from baseline in neuropathic symptoms.
o for pain intensity: weekly average of NRS daily (evening) assessments o for distressing neuropathic symptoms such as tingling and numbness intensity: weekly average of NRS of daily (evening) assessments.
x proportion of patients with a reduction of at least 30% relative to baseline in neuropathic symptoms intensity on weekly average of NRS daily assessments.
x change from baseline in EORTC QLQ-CIPN20 patient-reported outcome scale.
x proportion of patients with 2 points or more improvement relative to baseline in EORTC QLQ-CIPN20 sensory subscale assessments.
For QoL:
x change from baseline in EORTC QLQ-C30
For clinician-reported outcomes:
x change from baseline in TNSc.
x change from baseline in CTCAE (v5.0) neuropathy grade.
For the study of the relationship between plasma concentrations and other variables:
x plasma concentrations of TRK-750.
The exploratory PD endpoints are as follows:
For psychophysical parameters:
x change from baseline in QST parameters (optional):
o thermal detection
x cold detection threshold (qC)
x warm detection threshold (qC)
o mechanical detection
• mechanical detection threshold (Von Frey filament detection [mN])
• vibration detection threshold (Hz)
o thermal hyperalgesia
• cold pain threshold (*C)
• heat pain threshold (*C)
o mechanical hyperalgesia
• mechanical pain threshold (mN)
• pressure pain threshold (kPa)
For electrophysiological parameters:
• change from baseline in electrophysiological amplitude (mV and microV; motor and sensory nerve, respectively) and conduction velocity
(m/sec) in the sural, superficial radial, and tibial nerves (optional).
For histological parameters:
• punch skin biopsies (optional).
For biomarkers of neuropathy:
• NfL
The assessment of psychophysical and electrophysiological parameters will be study site dependant. For sites with the ability to perform these assessments, all patients will be evaluated.
The assessment of pharmacogenomics and histological parameters will solely be at the discretion of the patient. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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
|
| The end of the study is defined as the date of the last patient’s last assessment (scheduled or unscheduled) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 24 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 24 |
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