Pregabalin Treatment for RDEB Pain and Itch
Condition: Pain, Neuropathic; Itch; Epidermolysis Bullosa
MeSH terms: Neuralgia; Epidermolysis Bullosa
Study type: Interventional
Phase: Phase 3

Summary: 
      Recessive dystrophic epidermolysis bullosa (RDEB) patients' quality of life is severely
      affected by neuropathic pain and itch, which have recently been demonstrated to be secondary
      to skin small fiber neuropathy. To date, there is no evidence on what the best agent is to
      control these symptoms. Based on the anecdotal data and safety profile, the investigators
      believe that pregabalin is a therapeutic agent that will be effective and safe in this
      population. The investigators propose to conduct a blinded study, using pregabalin versus
      placebo in which each patient serves as its own control (cross-over design). This is a
      feasibility study that will provide preliminary data on efficacy and safety of pregabalin in
      RDEB patients with neuropathic pain and itch and gather much needed data (dosage, titration
      schedule, outcome measures, etc) to inform the design of a larger cohort, controlled,
      multicenter trial.
    

Detailed description: 
      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.

        1. 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).

        2. 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)

        3. 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.

        4. 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)
    

Intervention name(s): Pregabalin
Intervention type(s): Drug
Intervention description(s): Pregabalin /placebo capsules will be taken by mouth and will be prescribed for the study participants in the doses, depending on their weight and treatment phase: Participant < 25 kg at baseline will start with 50 mg per day, increasing the dose by 50 mg each week until their maximum dose 200 mg per day; Participants who are greater than or equal to 25 kg at baseline will start with 100 mg per day, increasing their dose by 50 mg each week until their target dose 300 mg per day is achieved. The study medication will be taken twice per day.The dose will be weaned down every 1-2 days by 25 mg in the last two weeks of each treatment period.
Other intervention name(s): Placebo
Intervention MeSH terms: Pregabalin
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: there two treatment periods in the study. All of the study participants will receive pregabalin treatment during one of these two 10-week treatment periods, and placebo - during the other one.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment