Evaluation Of The Efficacy And Safety Of Single Doses Of PF-05089771 In Patients With Primary (Inherited) Erythromelalgia

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of single doses of PF-05089771 against placebo in treatment of pain in patients with primary, inherited erythromelalgia.

Official Title
-----------------
A RANDOMIZED, DOUBLE BLIND THIRD PARTY OPEN PLACEBO-CONTROLLED EXPLORATORY STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SINGLE DOSES OF PF-05089771 IN PATIENTS WITH PRIMARY (INHERITED) ERYTHROMELALGIA

Conditions
-----------------
Inherited Erythromelalgia

Intervention / Treatment
-----------------
* Drug: PF-05089771
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and or female subjects between the ages of 18-78 years Subject has clinical signs of IEM Minimum BMI 17.5kg/m2 and total body weight >50kg Exclusion Criteria: Other severe pain conditions, e.g. rheumatologic, that may impair subject's self-assessment of pain due to IEM. Evidence of clinically significant hypertension, clinically significant hematological, dermatological, renal, endocrine (except diabetes mellitus), pulmonary, gastrointestinal, cardiovascular, hepatic, neurological (other than IEM), or allergic disease (including drug allergies but excluding untreated asymptomatic seasonal allergies). Subjects with severe obesity.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 78 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05089771 1600 mg<br> | Drug: PF-05089771<br>* A single oral dose of PF-05089771 1600 mg solution to be administered on Day 1 of each treatment session. There are 2 treatment sessions, therefore 2 single oral doses of PF-05089771 will be adminstered.<br>|
| Placebo Comparator: Placebo comparator: matching placebo<br>Single oral dose of placebo for PF-05089771 1600 mg | Drug: Placebo<br>* Placebo for PF-05089771 1600 mg solution administered in each treatment session. There are 2 treatment sessions, therefore 2 single oral doses of placebo will be administered.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Pain Intensity Numerical Rating Scale (PI-NRS) Score - From 0 to 4 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10, where 0= no pain and 10= worst possible pain; higher scores signify more pain. The average pain score was calculated as the mean of the pain scores recorded every 15 minutes from 0 to 4 hours post-dose. | Every 15 minutes from 0 to 4 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average PI-NRS Score - From Post Evoked Pain Time Point 2 (EP2) to 8 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 2= first time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP2 is approximately a time point 4-5 hours post-dose. The average pain score was calculated as the mean of the pain scores recorded from EP2 to 8 hours post-dose. | Post EP2, every 5 minutes for the first hour, then every 15 minutes up to 8 hours post-dose | 
| Average PI-NRS Scores - From Post Evoked Pain Time Point 3 (EP3) to 10 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 3= second time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP3 is approximately a time point 8-9 hours post-dose. The average pain score was calculated as the mean of the pain scores recorded from EP3 to 10 hours post-dose. | Post EP3, every 5 minutes for the first hour, then every 15 minutes up to 10 hours post-dose | 
| Average PI-NRS Scores - From Post Evoked Pain Time Point 4 (EP4) to 28 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 4= third time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP4 is approximately a time point 24-25 hours post-dose. The average pain score was calculated as the mean of the pain scores recorded from EP4 to 28 hours post-dose. | Post EP4, every 5 minutes for the first hour, then every 15 minutes up to 28 hours post-dose | 
| Maximum PI-NRS Scores - From 0 Hour to 4 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Maximum pain score in 4 hours period post-dosing is reported. | From 0 hour to 4 hours post-dose | 
| Maximum PI-NRS Scores - From Post EP2 to 8 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 2= first time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP2 is approximately a time point 4-5 hours post-dose. Maximum pain score in period from post EP2 to 8 hours post-dose is reported. | From post EP2 to 8 hours post-dose | 
| Maximum PI-NRS Scores - From Post EP3 to 10 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 3= second time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP3 is approximately a time point 8-9 hours post-dose. Maximum pain score in period from post EP3 to 10 hours post-dose is reported. | From the end of EP3 to 10 hours post dose | 
| Maximum PI-NRS Scores - From Post EP4 to 28 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 4= third time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP4 is approximately a time point 24-25 hours post-dose. Maximum pain score in period from post EP4 to 28 hours post-dose is reported. | Post EP4, every 5 minutes for the first hour, then every 15 minutes up to 28 hours post-dose | 
| Duration When PI-NRS Scores Were Greater Than (>) 5 - From 0 Hour to 4 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. The duration of time that participants experienced PI-NRS score greater than 5 from the 0 hours to 4 hours post-dose. | From 0 hour to 4 hours post-dose | 
| Duration When PI-NRS Scores Were >5 - From Post EP2 to 8 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 2= first time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP2 is approximately a time point 4-5 hours post-dose. The duration of time that participants experienced PI-NRS score >5 from in period from post EP2 to 8 hours post-dose is reported. | Post EP2, every 5 minutes for the first hour, then every 15 minutes up to 8 hours post-dose | 
| Duration When PI-NRS Scores Were >5 - From Post EP3 to 10 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 3= second time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP3 is approximately a time point 8-9 hours post-dose. The duration of time that participants experienced PI-NRS score >5 from the post EP3 to 10 hours post dose. | Post EP3, every 5 minutes for the first hour, then every 15 minutes up to 10 hours post-dose | 
| Duration When PI-NRS Scores Were >5 - From Post EP4 to 28 Hours Post-dose | Participants rated severity of their pain at 11 point PI-NRS, by choosing a number between 0 and 10. Where 0= no pain and 10= worst possible pain; higher scores signify more pain. Evoked pain time point 4= third time point post-dose when pain was evoked using the participant specific heat pain stimulus. EP4 is approximately a time point 24-25 hours post-dose. The duration of time that participants experienced PI-NRS score >5 from post EP4 to 28 hours post-dose. | After EP4, every 5 minutes for the first hour, then every 15 minutes up to 28 hours post-dose | 
| Number of Participants With Participant's Global Satisfaction Score | Participant was asked How would you rate the study medication you received for pain?. The participant was provided the following choices as an answer: excellent=4; good=3; fair=2; poor=1. Response to this question, was participant's overall impression (global evaluation) of the study medication at 4 hour post-dose or at time of first rescue treatment or medication, which ever occurred first. | At 4 hour post-dose or at time of first rescue therapy, whichever occurred first | 
| Time to First Use of Rescue Therapy or Medication | Time to rescue medication (hour) was calculated as: date/time of rescue medication minus date/time of first dose for each period. If participant who did not receive rescue medication, the time of censoring was cut off at 24 hours or the time of withdrawal, whichever was earlier. Kaplan-Meier method was used for estimation. | Up to maximum of 24 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hour Post-dose (AUC24) of PF-05089771 |  | Predose, 0.5, 2, 4, 6, and 24 hours post-dose | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of PF-05089771 |  | Predose and 0.5, 2, 4, 6, and 24 hours post dose | 
| Maximum Observed Plasma Concentration (Cmax) of PF-05089771 |  | Predose and 0.5, 2, 4, 6, and 24 hours post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-05089771 |  | Predose and 0.5, 2, 4, 6, and 24 hours post dose | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. | Baseline up to a maximum of Day 83 | 
| Number of Participants With Laboratory Abnormalities | Laboratory abnormalities: Hemoglobin (Hgb), hematocrit, red blood cell count: less than(<)0.8*lower limit of normal(LLN), platelet: <0.5*LLN/greater than (>)1.75*upper limit of normal (ULN), white blood cell: <0.6*LLN/>1.5*ULN, lymphocyte, neutrophil (absolute, %):<0.8*LLN/>1.2*ULN, total neutrophil <0.8*LLN;basophil, eosinophil, monocyte (absolute, %):>1.2*ULN; mean corpuscular (MC) volume, mean cell hemoglobin, MC hemoglobin concentration, mean platelet volume: <0.9*LLN/>1.1*ULN; total bilirubin >1.5*ULN, aspartate aminotransferase (AT), alanine AT, gammaglutamyl transferase, alkaline phosphatase:> 3.0*ULN, total protein, albumin: <0.8*LLN/>1.2*ULN; blood urea nitrogen, creatinine:>1.3*ULN, uric acid >1.2*ULN; sodium <0.95*LLN/>1.05*ULN, potassium, chloride, calcium, magnesium, bicarbonate: <0.9*LLN/>1.1*ULN; glucose <0.6*LLN/>1.5*ULN; urine (specific gravity <1.003/>1.030, pH <4.5/>8, glucose, ketone, protein, blood/Hgb, urobilinogen, bilirubin, nitrite, leukocyte esterase >=1). | Baseline up to a maximum of Day 73 | 
| Number of Participants With Clinically Significant Changes From Baseline in Core Body Temperature | The minimum starting temperature to measure core body temperature used was 33 degree Celsius. Clinically significant changes from baseline in core body temperature was judged by investigator. | Baseline up to a maximum of Day 83 | 
| Number of Participants With Clinically Significant Changes From Baseline in Blood Pressure | Criteria for clinically significant blood pressure abnormalities: systolic blood pressure >=30 millimetre of Mercury (mmHg) change from baseline in same posture, systolic blood pressure <90 mmHg, diastolic blood pressure >=20 mmHg change from baseline in same posture, diastolic blood pressure <50 mmHg. | Baseline up to a maximum of Day 83 | 
| Number of Participants With Clinically Significant Changes From Baseline in Electrocardiogram (ECG) | Criteria for clinically significant abnormalities in ECG : PR interval >=300 millisecond (msec) and 25 percent (%) increase when baseline >200 msec, 50% increase when baseline less than or equal to (<=) 200 msec; QRS interval >=140 msec, >=50% increase from baseline; QT interval >=500 msec; QT interval corrected using the Fridericia formula (QTcF) 450 msec to <480 msec, >=480 msec, 30 to <60 msec increase from baseline, >=60 msec increase from baseline. | Baseline up to a maximum of Day 83 |