| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chemotherapy-induced peripheral neuropathy (CIPN) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Neuropathic pain resulting from cancer therapy. |
|
| 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 efficacy of ATX01 compared to placebo in treating neuropathic pain in target study extremities in patients with CIPN. |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
1_The effects of ATX01 on pain and neuropathic pain symptoms, global patient improvement, and QoL.
2_The safety and tolerability of ATX01 10% and ATX01 15%. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients of 18 years and older.
2. Patients having signed a written informed consent prior to any study-related procedure.
3. Body mass index (BMI) of 18 and 32 kg/m2 (inclusive).
4. With an estimated life expectancy ≥6 months at study entry.
5. Patients with painful sensory CIPN resulting from prior treatment of cancer with taxanes or platins. A diagnosis of CIPN should be supported by i) onset of pain in hands or feet after exposure to taxanes or platins, ii) presence of painful symptoms in a symmetrical stocking and/or glove distribution, AND iii) painful symptoms may be accompanied by nonpainful symptoms (eg, tingling/pins and needles intensity and numbness intensity).
6. Patients who have stopped their chemotherapy treatment with taxanes or platins or any other neurotoxic chemotherapy for ≥24 weeks at the time of the screening visit.
7. Patients with CIPN pain for ≥24 weeks at the time of the screening visit.
8. Patients with a mean value of pain intensity ≥4 and ≤9 in target study extremities (left and right feet or left and right hands) on the 11-point NPRS at baseline.
9. Patients with symmetrical stocking or glove distribution pain, NPRS (≤1 point difference) in the target study extremities at screening.
10. Neuropathic Pain (Douleur Neuropathique 4 [DN4]) score ≥4 in the target study extremities (hands or feet) at the screening visit.
11. Treatment naïve patients or patients in whom any prior CIPN treatment (except oral AMT) has not been modified during the 4 weeks preceding the screening visit and is planned to be maintained at the same regimen during the course of the study (prior treatment includes pharmacological and nonpharmacological treatments).
12. Male patient should agree to use a condom along with another medically acceptable contraceptive method, where applicable according to local guidelines, if he is engaged in sexual activity with a woman of childbearing potential (WOCBP) from the day of the signature of the informed consent and up to 90 days after the End of Study (EoS) Visit. Male patient should agree not to donate sperms until 30 calendar days after the last dose of study drug.
13. Females must comply with the following in order to be enrolled:
a. WOCBP with negative serum pregnancy test results can be enrolled only if willing to use an acceptable contraceptive method, ie, oral contraceptives, patch contraceptives, injection contraceptives, implantable hormonal contraceptives, male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, vaginal contraceptive ring, intrauterine device or system, surgical sterilization (hysterectomy, bilateral oophorectomy, and/or bilateral salpingectomy), tubal ligation/occlusion, vasectomized partner, or sexual abstinence, if this is the patient’s current practice, from at least 14 days prior to the screening visit and throughout the study and for at least 30 days after completion of the study.
b. Or surgically sterilized for at least 6 months.
c. Or menopausal for at least 1 year.
|
|
| E.4 | Principal exclusion criteria |
1.Patients who are not compliant in completion of pain ratings during the screening period. Patients having <5 of 7 records of average pain intensity in the target study extremities .
2.Clinical evidence of a preexisting painful peripheral neuropathy resulting from another cause than chemotherapy, eg, diabetic neuropathy, posttraumatic neuropathy, carpal/tarsal tunnel syndrome, radiculopathy, spinal stenosis, brachial plexopathy, or other preexisting symptomatic neuropathy due to alcoholism, vitamin B deficiency, hypothyroidism, human immunodeficiency virus (HIV).
3.Skin abnormality, irritation, or lesions of any type on the hands or feet (or only on the hands if the study drug is not applied on the feet and vice versa [only on the feet if the study drug is not applied on the hands]).
4.Presence of glaucoma.
5.Presence of urinary retention (or at risk of urinary retention).
6.History of coronary artery disease.
7.History and/or presence of major depressive episode. Patients with a medical history of bipolar disorder, alcohol abuse, or psychotic disorder.
8.Patients at significant risk of suicide, or is a danger to self or others, in
the opinion of the investigator, based upon clinical interview and C-SSRS (Affirmative to suicidal ideation Q4 & 5) within the last 6 months.
9.Pregnant or lactating women.
10.Abnormality in the 12-lead ECG at screening that in the opinion of the investigator increases the risk of participating in the study, such as QTcF interval >430 msec for males or >450 msec for females.
11. A history of additional risk factors for Torsade de Pointe (eg, heart failure, hypokalemia, family history of long QT syndrome).
12.The use of concomitant medications within 24 weeks prior to Day 1 and/or during the study or the equivalent of 5 half-lives that prolong the QT/QTc interval, eg, Class 1 antiarrhythmics (eg, quinidine, disopyramide, procainamide) and Class 3 antiarrhythmics (eg, amiodarone, sotalol), antihistamines, antipsychotics known to prolong QT interval, and antimalarials (eg, mefloquine, quinine), tricyclic antidepressants (eg, AMT), tetracyclic antidepressants (eg, maprotiline), cisapride.
13.The use of Monoamine Oxidase Inhibitors within 24 weeks (or the equivalent of 5 half-lives) prior to Day 1 and/or during the study.
14.The use of opioids within 4 weeks (or the equivalent of 5 half-lives) prior to Day 1 and/or during the study.
15.History of illicit drug use or confirmed drugs of abuse at screening.
16.Patients likely to require neurotoxic chemotherapy treatment or any other treatment during the study, which may interfere with compliance to the protocol, ability to complete the study and study assessments except treatments authorized in inclusion criterion #11.
17.Failure to respond to more than 2 analgesics from different drug classes (including antidepressants and anticonvulsants) due to lack of efficacy or intolerability to treat CIPN at any time in the past.
18.Treatment with oral or topical AMT or nortriptyline in the past 4 weeks.
19.Any known hypersensitivity to AMT in any salt form or to any constituent of the topical formulation.
20.Any contraindication to the use of acetaminophen/paracetamol.
21.Use of glutathione, vitamin E, minocycline, or calcium magnesium supplements within 12 weeks of screening.
22.Any topical treatment on treated extremities for any indication, other than cosmetic use of creams and lotions, within the previous 12 weeks.
23.Any topical treatment for pain including use of:
a.over-the-counter (OTC) capsaicin on extremities within 12 weeks of screening, b.and/or Qutenza within 24 weeks of screening, c.and/or nonsteroidal anti-inflammatory drugs, menthol, methyl salicylate, local anesthetics within 1 week of screening.
24.Poor metabolizer for cytochrome P450 CYP2D6
25.Intake in the 4 weeks preceding the screening visit of any strong inhibitor of cytochrome P450 CYP2D6.
26.Treatment with an investigational drug in the previous 4 weeks or greater.
27.Any condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated
28.The investigator considers the patient unfit for the study as a result of the medical interview, physical examination, or screening investigations, in particular any status or disease making the patient unable to follow instructions.
29.The patient is unable to apply the study drug on hands or feet.
30.The patient is an employee of the investigator, study site, sponsor, or CRO with direct involvement in the proposed study or other studies under the direction of the investigator, study site, or sponsor, or a family member of the site employee or the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline to Week 12 in the weekly mean of the daily NPRS score assessing average pain intensity in target study extremities related to CIPN in the past 24 hours. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1_Percentage of patients achieving ≥30% pain reduction from baseline in the weekly mean NPRS average pain intensity related to CIPN at Week 12.
2_Percentage of patients achieving ≥50% pain reduction from baseline in the weekly mean NPRS average pain intensity related to CIPN at Week 12.
3_Mean change from baseline to each visit in tingling/pins and needles intensity and numbness intensity in target study extremities as measured by the numerical rating scale (NRS) assessing each symptom.
4_Proportion of patients achieving various percentages of reduction in average pain intensity in target study extremities (cumulative responder curve) throughout the study.
5_Change from baseline to Week 4 and 8 in the weekly mean of the daily NPRS score assessing average pain intensity in target study extremities related to CIPN in the past 24 hours.
6_Change from baseline to each visit in the weekly mean of the daily NPRS assessing worst pain intensity in target study extremities related to CIPN in the past 24 hours.
7_Percentage of patients with at least “improved” on the Patient Global Impression of Change (PGI-C) at each visit.
8_Mean change from baseline to each visit in pain interference with daily life using the Brief Pain Inventory Short Form questionnaire (BPI-SF item 9 only).
9_Mean change from baseline to each visit in the calculated mean NPRS average pain intensity in the nontarget study extremities.
10_Mean change from baseline to Week 12 in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN 20-item scale (EORTC QLQ CIPN20).
11_Use of rescue medication including the proportion of patients using rescue medication, the frequency, and amount used
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Most of them from Baseline to week 12 |
|
| 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 | No |
| 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 | 3 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| United States |
| France |
| Poland |
| Spain |
| Czechia |
| Italy |
| Belgium |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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