Pregabalin Treatment for RDEB Pain and Itch

Neuropathic pain and itch are significant symptoms that affect RDEB patients' quality of life. To date, there is no evidence on what the best agent is to control these symptoms.

Based on the anecdotal data and the safety profile, the investigator believes that pregabalin is a therapeutic agent that will be effective and safe in this population.

This is a pilot, randomized, double-blinded, cross-over trial of pregabalin vs placebo for the treatment of RDEB associated neuropathic pain and itch. The study will run for 24 weeks and will have 4 separate phases with 6 overall visits: 1. Observation/wash out period (2 weeks); 2. ARM-1, ½ of the patients will receive pregabalin(A) and ½ the placebo (B) (10 weeks); 3. Wash out period (2 weeks) and 4. ARM-2 (patients who received placebo will receive pregabalin and pregabalin will receive placebo (10 weeks).

Patients will be recruited during the regular clinic visits or invited to participate via a letter followed by 2 phone calls.

• Screening/Wash out period #1 (Visit 0)to assess eligibility criteria and the background pain and itch level (2 weeks), as well as the effectiveness of patients' "standard pain/itch interventions". Throughout this phase and the rest of the study, patients will receive pain and itch medications, except those that interfere with the pregabalin (see exclusion criteria).

• Investigators will assess the eligibility criteria, including having moderate to severe pain (>4/10), the evidence of neuropathy using a thermal roller device ROLLTEMP2, Sometic, and a screening tool for neuropathic pain, the DN4 questionnaire 15 (Appendix 2).
• Investigators will collect basic demographic data, medication information and disease severity using iscorEB clinician portion, a valid outcome measure that evaluates the disease severity 16 and EBDASI 17 ( Data collection form: Baseline/Screening Form)
• Patients will be asked to report on their disease severity using iscorEB patient portion (all ages) that includes pain and itch domains and QOLEB 18 for those over 18 years of age (validated only for the adult population).
• Patients will be instructed how to collect daily assessments of pain and itching for 14 days before the next visit. For the overall pain intensity assessment, the investigators will use a 100mm VAS, where 0 is no pain and 10- the worst pain ever experienced. For itch assessments, the investigators will ask patients to score each day, before going to bed, the degree of itching experienced that day using a 100 mm horizontal VAS where 0 is no itch and 10 is the worst itch.19 The investigators chose the single item for its reliability, validity and responsiveness to change. These values will represent patient's baseline pain (AvePain-00) and itch (AveItch-00).
• ARM1 intervention study period (Visits 1 & 2): ½ of the patients will receive the active intervention (Pregabalin) and ½ the placebo. This phase will be of 10 weeks duration and will consist of 4 weeks of escalating dose until the desired maximum, 4 weeks of active treatment and 2 weeks of titration down (see titration schedule in the Appendix 1)Patients will receive either active intervention (pregabalin) or placebo including instruction of how to administer them.

Visit 1: (Week 2)

• Investigator will collect the data on pain and itching from the 2 weeks wash-out and will determine the average pain and itching of approximately 14 days prior to the study visit 1(AvePain-00, AveItch-00)
• Patients will be asked to report on their disease severity using iscorEB patient portion and QOLEB for those over 18 years of age.
• A team member will call patient twice a week during the escalation phase to inquire about adverse events
• Patients will be instructed to collect daily assessments of pain, and itch for 7 days before next visit (~from weeks 9-10).

Visit 2: (Week 10)

• Patients will be instructed to contact investigator if experiencing any adverse events.
• Investigator will collect the data on pain and itching from approximately 7 days prior to visit 2 (~weeks 9-10) and will determine the average pain and itching (AvePain-02, AveItch-02)
• Patients will be asked to report on their disease severity using iscorEB patient portion and QOLEB for those over 18 years of age.
• Adverse events (see potential risks, DCF follow up, patient's diary)
• Patients will be instructed to collect daily assessments of pain, and itch for 7 days before next visit (~from weeks 13-14)
• Wash out period #2 (2 weeks) Visit 3 (Week 14)

• Investigator will collect the data on pain and itching and will determine the average pain and itching of approximately 7 days prior to the study visit 3 (AvePain-03, AveItch-03)
• Patients will be asked to report on their disease severity using iscorEB patient portion and QOLEB for those over 18 years of age.
• Investigator will collect adverse events (see potential risks, DCF follow up, patient's diary)
• Patients will be instructed to collect daily assessments of pain, and itch for 7 days before next visit (~from weeks 21-22)
• All study procedures at visit 3 will be similar to visit 1.
• ARM2 intervention study period (Visits 4 & 5 (Week 22 and 24): patients randomized to placebo will receive pregabalin and those on placebo will get the pregabalin conducted similarly as in ARM1

• All study procedures at visit 4 will be similar to visit 2
• The outcome measures will be similar, but will be recorded as (AvePain-04, AveItch-04)
• Weaning will be similar to ARM1
• End of the Study visit: Visit 5 (Week 24) The outcome measures will be similar, but will be recorded as AvePain-05, AveItch-05)

Inclusion criteria

• Age: > 8 - 40 years (we selected this range due to lack of data in younger population and the difficulty in getting patient reported outcomes in younger patients)
• Diagnosis of RDEB (by a dermatologist and/or EB specialist and/or genetic confirmation)
• Evidence of neuropathy defined by: thermal sensory loss (determined by a thermal roller, ROLLTEMP2, Sometic, Sweden) 14 and > 4/10 score using a screening tool for neuropathic pain, the DN4 questionnaire 15
• Pain intensity of > 4/10 on a 0-10 VAS scale measured daily (reduced frequency is also acceptable) at night over 2 weeks
• Itch intensity of > 4/10 on a 0-10 VAS scale measures daily (reduced frequency is also acceptable) at night over 2 weeks
• Consent to follow with study procedures

Exclusion criteria

• Intolerance and/or allergy to Pregabalin or gabapentin
• Lactose intolerance (placebo capsules contain lactose)
• Pregabalin use within 2 weeks before study enrolment
• Ongoing treatment with gabapentin, amitriptyline, duloxetine, nortriptyline, other tricyclics or SNRIs
• Medical conditions that would be considered as contraindications for pregabalin treatment (ischemic heart disease, cardiac dysrhythmia, glaucoma, history of urinary retention)
• Pregnancy
• History of use of restrictive substances or alcohol abuse
• Allergy to gelatin