| Eligibility |
Inclusion Criteria:
1. Male or female patients 18 years of age and older.
2. Documented diagnosis of erythromelalgia, as characterized by redness, warmth, and
burning pain of the extremities (most commonly feet), typically precipitated by heat
or exercise and relieved by cooling.
3. Mean pain attack intensity, measured on the 11-point NPRS, of =4 and =9 at baseline
and =4 pain attacks per week as documented through eDiary use during the 3 weeks prior
to randomization (Day -21 to Day -1).
4. Use of concomitant medications, with the exception of topical agents applied to the
hands or feet, are permitted if the dose has been stable for at least 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).
5. Patients having signed a written informed consent prior to any study related
procedure.
6. Male patients 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 visit. Male
patients should agree not to donate sperm until 90 calendar days after the last dose
of study drug.
7. Females must comply with the following in order to be enrolled:
1. WOCBP with negative pregnancy test results can be enrolled only if willing to use
an acceptable contraceptive method, i.e. 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 the completion of the study.
2. Or surgically sterilized for at least 6 months.
3. Or menopausal, for at least 1 year.
Exclusion Criteria:
1. Clinical evidence of a pre-existing pain disorder in the extremities resulting from
another cause than erythromelalgia, e.g. complex regional pain syndrome (CRPS),
diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN).
2. Evidence of skin breakdown, ulcers, papules and > +2 pitting edema of the affected
limbs.
3. Presence of glaucoma.
4. Presence of urinary retention (or significant prostatic hypertrophy at risk of urinary
retention).
5. History of coronary artery disease.
6. History and /or presence of major depressive episode.
7. The patient has suicidal risk in the opinion of the investigator based upon clinical
interview and the Columbia Suicide-Severity Rating Scale.
8. Pregnant or lactating women.
9. Abnormality in the 12-lead electrocardiogram (ECG) at screening that in the opinion of
the investigator increases the risk of participating in the study, such as a corrected
QT Fridericia (QTcF) interval >430 ms for males or >450 ms for females.
10. A history of additional risk factors for Torsade de Pointe (e.g. heart failure,
hypokalemia, family history of Long QT Syndrome).
11. 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 (e.g. quinidine, disopyramide, procainamide) and Class 3
antiarrhythmics (e.g. amiodarone, sotalol), antihistamines, antipsychotics known to
prolong QT interval, and antimalarials (e.g. mefloquine, quinine), tricyclic
antidepressants (e.g. AMT), tetracyclic antidepressants (e.g. maprotiline), cisapride.
12. 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.
13. The use of opioids within 4 weeks (or the equivalent of 5 half-lives) prior to Day 1
and/or during the study.
14. History of illicit drug use or confirmed drugs of abuse at screening. Positive urine
drug screen for prescribed medication is allowed at the discretion of the
investigator.
15. Use of more than 2 analgesics (regardless of the route of administration) from
different drug classes (including antidepressants and antiepileptics) on top of study
drug.
16. Treatment with oral or topical amitriptyline or nortriptyline in the past 4 weeks or
current treatment with any other tricyclic antidepressant.
17. Any known hypersensitivity to amitriptyline (regardless of the route of
administration) in any salt form or to any constituent of the topical formulation.
18. Use of glutathione, vitamin E, minocycline, or calcium magnesium supplements within 12
weeks of screening.
19. Any topical treatment on treated extremities for any indication, other than cosmetic
use of creams and lotions, within the 12 weeks prior to screening.
20. Any topical treatment for pain including use of:
1. over-the-counter capsaicin on extremities within 12 weeks of screening,
2. and/or Qutenza within 24 weeks of screening,
3. and/or nonsteroidal anti-inflammatory drugs, menthol, methyl salicylate, local
anesthetics within 1 week of screening.
21. Implanted active medical device (eg, spinal cord stimulator, intrathecal pump, or
peripheral nerve stimulator) for the treatment of pain or any etiology.
22. Regional anesthetic block for pain of any etiology within 3 months prior to screening.
23. Intake in the 4 weeks preceding screening visit of any medication susceptible to
inhibit or induce cytochrome P450 CYP2D6.
24. Poor metabolizers of CYP2D6 substrates.
25. Treatment with an investigational drug in the previous 4 weeks or greater, according
to local requirements
26. Any condition that the investigator feels would place the patient at increased risk if
the investigational therapy is initiated, such as, but not limited to,
hyperthyroidism, convulsive disorder, advanced hepatic disease, pylorus, stenosis, or
paralytic ileus.
27. 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.
28. The patient is unable to apply the study drug on feet and/or hands.
29. The patient is an employee of the investigator, study site, sponsor, or contract
research organization 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.
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