Study to Evaluate the Efficacy and Safety of Lenalidomide in the Treatment of Complex Regional Pain Syndrome Type 1

Study Overview
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Brief Summary
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The purpose of this multicenter, double-blind, placebo-controlled study is to evaluate the efficacy and safety of Lenalidomide in adult subjects with Complex Regional Pain Syndrome (CRPS) Type 1.

Detailed Description
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This is a multicenter, double-blind, placebo-controlled study in adult subjects with Complex Regional Pain Syndrome (CRPS) Type 1. One hundred eighty (180) subjects diagnosed with unilateral CRPS Type 1 will be enrolled and randomized to receive orally either 10 mg/day of lenalidomide or placebo (90 subjects per treatment arm). For each subject, the study consists of three phases: Pre-randomization Phase (2 weeks), Treatment Phase (12 weeks) and Extension Phase where subjects have the opportunity to receive lenalidomide treatment as long as a benefit is derived from the drug. Subjects who complete all 12 weeks of the treatment phase may be eligible to receive lenalidomide in the extension phase. Subject may continue in the extension phase as long as a benefit is derived from the drug.

Official Title
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A Multicenter, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Lenalidomide in the Treatment of Complex Regional Pain Syndrome Type 1

Conditions
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Complex Regional Pain Syndrome, Type I

Intervention / Treatment
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* Drug: lenalidomide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years at the time of signing the informed consent form Understand and voluntarily sign an informed consent form A diagnosis of CRPS Type 1, as defined by modified International Association for the Study of Pain criteria for at least a one-year duration. Unilateral involvement of a distal limb (hand or foot) with or without proximal spread must be present. In the presence of upper and lower limb involvement, the most severely affected limb will be designated the CRPS-affected limb. Screening: CRPS pain intensity score in the CRPS-affected limb must be at least 4 on an 11-point (0-10) Pain Intensity Numerical Rating Scale (PI-NRS). Randomization: Average PI-NRS score for randomization purposes will be based on AM and PM assessments made during the 7 days prior to randomization. At least eight PI-NRS scores during this 7-day period are required and the Average PI-NRS score in the CRPS-affected limb during this period must be at least 4 on an 11-point (0-10) PI-NRS. Measurable (by electrophysiology methods) sural, median sensory, median motor and peroneal motor nerves at the screening nerve conduction study. Opioid analgesics, non-opioid analgesics, non-steroidal anti-inflammatory drugs, anticonvulsants, antidepressant drugs and other non-drug therapies may be continued provided that the subject is on stable doses/regimens for at least four weeks prior to the start of the Treatment Phase (Visit 2). Able to adhere to the study visit schedule and other protocol requirements. Women of childbearing potential (WCBP) must agree to practice complete abstinence from heterosexual intercourse or to use two methods of contraception beginning 4 weeks prior to the start of study drug (Day 1) while on study drug (including dose interruptions) and 4 weeks after the last dose of study drug. The two methods of contraception must include one highly effective method (i.e. intrauterine device [IUD], hormonal [birth control pills, injections, or implants only if used in conjunction with a low-dose (81 mg/day) aspirin regimen], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). If a hormonal method (birth control pills, injections, or implants) or IUD is not medically possible for the subject, two of the barrier methods will be acceptable. Women of childbearing potential (WCBP) must have two negative pregnancy tests (sensitivity of at least 50 mlU/mL) prior to starting study drug treatment. The first test should be performed within 10-14 days and the second within 24 hours of starting study drug. Once treatment has started, it is recommended that subjects have weekly pregnancy test during the first 4 weeks of treatment. Thereafter, subjects are required to have pregnancy testing every 4 weeks in females with regular menstrual cycles and every 2 weeks in females with irregular cycles. Males (including those who have had a vasectomy) must use barrier contraception (latex condoms) when engaging in reproductive sexual activity with WCBP while on study drug and for 4 weeks after the last dose of study drug. Exclusion Criteria: The presence of any of the following will exclude a subject from study enrollment: History of deep vein thrombosis (DVT) or stroke in the past 5 years. Documented peripheral neuropathies to include diabetic neuropathy and other metabolic or toxic neuropathies. Current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurological or cerebral disease. Any other serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. White blood cell count (WBC) < 3.5*10^9/L at screening. Bilirubin, alanine transaminase (ALT), aspartate transaminase (AST) or alkaline phosphatase levels more than two times the upper limit of the normal range at screening. Abnormal thyroid function test values at screening. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Use of concomitant medication(s), which could increase the risk for developing DVT, except for steroid-based contraceptives (oral injectable, implantable) and hormone replacement therapies only if used in conjunction with a low-dose (81 mg/day) aspirin regimen. Concurrent use of thalidomide. Prior development of an allergic reaction/hypersensitivity while taking thalidomide. Prior development of a moderate or severe rash or any desquamation while taking thalidomide. Prior treatment with lenalidomide.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lenalidomide<br>10 mg/day lenalidomide orally for up to 12 weeks in the double-blind treatment period. Participants who completed double-blind treatment had the option of continuing on lenalidomide in the open-label extension period for as long as benefit was derived from the drug or until study closure. | Drug: lenalidomide<br>* Two 5 mg capsules taken one time per day<br>* Other names: CC-5013;|
| Placebo Comparator: Placebo<br>Placebo orally for up to 12 weeks in the double-blind treatment period. Participants who completed double-blind treatment had the option of crossing over to lenalidomide 10mg in the open-label extension period for as long as benefit was derived from the drug or until study closure. | Drug: Placebo<br>* Two placebo capsules taken one time per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Have a >= 30% Reduction (Improvement) in the Complex Regional Pain Syndrome (CRPS) Pain Intensity Numeric Rating Scale (PI-NRS) Score From Baseline to the Last Assessment | Participants rated the intensity of pain in the CRPS-affected limb twice each day in a diary. The PI-NRS is an eleven point scale with 0=no pain and 10=worst pain imaginable. Responders are participants who completed 12 weeks of treatment and their week 12 PI-NRS score showed at least a 30% improvement from baseline. Participants who did not complete 12 weeks of treatment are considered non-responders. | Day 0, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Total Score of the Short Form McGill Pain Questionnaire (SF-MPQ) at Week 12 | Short Form McGill Pain Questionnaire (SF-MPQ) is comprised of 15 pain qualities that are rated by the participant on a 4 point scale with 0=none and 3=severe. The scale for the Total Score is 0-45. Week 12 values are compared to baseline values. Negative changes indicate improvement in level of pain. | Day 0, week 12 | 
| Change From Baseline in the Complex Regional Pain Syndrome (CRPS) Pain Intensity Numeric Rating Scale (PI-NRS) Score Using Averaged Morning and Evening Readings at Week 12 | Participants rated the intensity of pain in the CRPS-affected limb twice each day in a diary. Morning and evening scores are averaged. The PI-NRS is an eleven point scale with 0=no pain and 10=worst pain imaginable. Week 12 values are compared to baseline values. Negative changes indicate improvement in level of pain. | Day 0, week 12 | 
| Change From Baseline in the Morning Complex Regional Pain Syndrome (CRPS) Pain Intensity Numeric Rating Scale (PI-NRS) Score at Week 12 | Participants rated the intensity of pain in the CRPS-affected limb twice each day in a diary. The PI-NRS is an eleven point scale with 0=no pain and 10=worst pain imaginable. The morning pain ratings at baseline and Week 12 are compared. Negative changes indicate improvement in level of pain. | Day 0, week 12 | 
| Change From Baseline in the Evening Complex Regional Pain Syndrome (CRPS) Pain Intensity Numeric Rating Scale (PI-NRS) Score at Week 12 | Participants rated the intensity of pain in the CRPS-affected limb twice each day in a diary. The PI-NRS is an eleven point scale with 0=no pain and 10=worst pain imaginable. The evening pain ratings at baseline and Week 12 are compared. Negative changes indicate improvement in level of pain. | Day 0, week 12 | 
| Change From Baseline in Daily Sleep Assessment Average Score at Week 12 | Participants rated how much CRPS pain interfered with their sleep each day in a diary. The Sleep Assessment uses an eleven point scale for four questions. Questions concern ability to fall asleep, ability to stay asleep, how refreshed the participant feels upon waking and how alert the participant is during the day. All use a scale of 0-10, where the higher number is the positive response (e.g. 0=Pain completely interferes with sleep and 10=Pain does not interfere). The mean of all four responses was calculated if at least 3 of the 4 questions had a value. Week 12 values are compared to baseline values. Positive change values indicate improvement. | Day 0, week 12 | 
| Change From Baseline in Activity Level Rating Using a Numeric Rating Scale (NRS) at Week 12 | Participants rated how the activity level on a given day compares with their activity level prior to the start of treatment. A seven-point scale is used with -3=much worse and +3=much better. Positive change values indicate improvement. | Day 0, week 12 | 
| Change From Baseline in Participant Assessment of CRPS Symptoms Total Score at Week 12 | Participants rated twelve CRPS symptoms using a four-point rating scale in which 1=the most positive outcome and 4= the most negative outcome for a total scale of 12-48. Week 12 values are compared to baseline values. Negative change values indicate improvement. | Day 0, week 12 | 
| Change From Baseline in Mechanically Evoked (Allodynia) Numeric Rating Scale (NRS) Score at Week 12 | The investigator rated the degree of allodynia on both the CRPS-affected limb on an eleven-point scale where 0=no pain and 10=worst pain imaginable. This outcome compares the baseline values for the CRPS affected-limb to the values at week 12. Negative change values indicate improvement. | Day 0, week 12 | 
| Difference in Allodynia Rating Between the CRPS-affected Limb and the Normal Limb at Week 12 | The investigator rated the degree of allodynia on both the CRPS-affected limb and the normal (or less-affected) limb on an eleven-point scale where 0=no pain and 10=worst pain imaginable. This outcome compares the values for the CRPS affected-limb to the normal limb at week 12. | Week 12 | 
| Change From Baseline in the Brief Pain Inventory (BPI) Total Score at Week 12 | Participants completed the Brief Pain Inventory which asks twelve questions that are rated on an eleven-point scale in which 0=most positive outcome and 10=the most negative outcome for a total scale of 0-120. BPI contains questions that concern the level of pain over the last week and the level of pain right now, the extent to which pain interfered with sleep, normal activities, ability to work, relationships, walking etc. Week 12 values are compared to baseline values. Negative change values indicate improvement. | Day 0, week 12 | 
| Change From Baseline in the Profile of Mood States (POMS) at Week 12 | Participants completed the Profile of Mood States questionnaire that asks participants to rate how each of 65 words reflected their mood in the past week on a 5-point scale with 0=not at all and 4=extremely for a total scale of 0-260. Week 12 values are compared to baseline values. Negative change values indicate improvement. | Day 0, week 12 | 
| Patient Global Impression of Change (PGIC) at Week 12 | The Patient Global Impression of Change asks the question: Overall, how would you rate your CRPS condition since the start of study drug? Answers are represented on a seven-point scale with -3=much worst and +3=much better. | Week 12 | 
| Participants Who Had a Change to CRPS Pain Medication During the Treatment Period | Participants who had any change in CRPS medication during the double-blind treatment period (up to week 12) are summarized. Changes include additions, discontinuations or dosage change of CRPS medication(s). | Day 1 to week 12 | 
| Change From Baseline in the Maximal Composite Motor Nerve Conduction Velocity at Week 12 | An electrophysiological evaluation using standard electrophysiological and electromyography to measure the speed and extent of nerve conduction. Week 12 values are compared to baseline values for maximal motor nerve conduct velocity. | Day 0, week 12 | 
| Change From Baseline in the Maximal Composite Sensory Nerve Conduction Velocity at Week 12 | An electrophysiological evaluation using standard electrophysiological and electromyography to measure the speed and extent of nerve conduction. Week 12 values are compared to baseline values for maximal sensory nerve conduct velocity. | Day 0, week 12 | 
| Participants With Treatment-Emergent Adverse Events in the Double-Blind Period or the Extension Period | Counts of study participants who had adverse events (AEs) while treated in either the Double-blind or Extension Periods. The NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 was used by the investigator to grade the severity of the AEs: Grade 1=Mild AE, Grade 2=Moderate AE, Grade 3=Severe AE, Grade 4=Life-threatening or disabling AE, Grade 5=Death related to AE. AEs are also summarized by whether they were serious, related to treatment and whether the AE caused treatment to be altered. A serious AE (SAE) was any event that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or congenital anomaly/birth defect or was an important medical event could have jeopardized the patient's safety or required medical or surgical intervention to prevent one of the outcomes listed above. | Day 1 up to week 158 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRPS, RSDS, Pain, CC-5013, Revlimid, Complex Regional Pain Syndrome, Reflex Sympathy Dystrophy Syndrome, Lenalidomide, CRPS Type I, Celgene