An Effectiveness and Safety Study of PF-04383119 for the Treatment of Pain in Interstitial Cystitis

Percent Change From Baseline in O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) Score at Week 2, 4, 6, 10 and 16

The ICSI contained 4 questions that measured symptom severity including urinary urgency, urinary frequency, nocturia and pain/burning/discomfort/pressure in the bladder. Each question in the ICSI was rated on a 0 (no symptoms) to 5 (severe symptoms) scale, with higher scores indicating greater symptom severity. The sum of the individual question ratings was the total score for the ICSI. Total score ranged from 0 (no symptoms) to 20 (severe symptoms), with higher score indicating greater symptom severity.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Number of Micturitions Per 24 Hours at Week 2, 4, 6, 10 and 16

The micturition frequency per 24 hours was calculated from the sum of voluntary voids divided by the number of diary days over which they were collected.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Number of Micturitions Per 24 Hours at Week 2, 4, 6, 10 and 16

The micturition frequency per 24 hours was calculated from the sum of voluntary voids divided by the number of diary days over which they were collected.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Number of Nocturnal Micturitions Per Night at Week 2, 4, 6, 10 and 16

The nocturnal frequency per night was calculated as the sum of voluntary voids that occurred during a night's sleep, divided by the number of nights over which this was collected.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Number of Nocturnal Micturitions Per Night at Week 2, 4, 6, 10 and 16

The nocturnal frequency per night was calculated as the sum of voluntary voids that occurred during a night's sleep, divided by the number of nights over which this was collected. Percent change from baseline was calculated for participants who reported greater than 0 episodes at baseline.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Number of Incontinence Episodes Per 24 Hours at Week 2, 4, 6, 10 and 16

The incontinence episode frequency per 24 hours was calculated as the sum of any incontinence episodes occurring during the diary period when this was measured, divided by the number of days over which they were recorded.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Number of Incontinence Episodes Per 24 Hours at Week 2, 4, 6, 10 and 16

The incontinence episode frequency per 24 hours was calculated as the sum of any incontinence episodes occurring during the diary period when this was measured, divided by the number of days over which they were recorded. Percent change from baseline was calculated for participants who reported greater than 0 episodes at baseline.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Mean Voided Volume Per Micturition at Week 2, 4, 6, 10 and 16

Mean voided volume per micturition was calculated as the total urine volume voided (resulting from a toilet \[voluntary\] void) during the diary period when this was measured, divided by the number of toilet voids over which this occurred.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Mean Voided Volume Per Micturition at Week 2, 4, 6, 10 and 16

Mean voided volume per micturition was calculated as the total urine volume voided (resulting from a toilet \[voluntary\] void) during the diary period when this was measured, divided by the number of toilet voids over which this occurred.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Mean Interstitial Cystitis Pain Severity Per Urinary Event at Week 2, 4, 6, 10 and 16

Mean interstitial cystitis pain severity per urinary event (toilet void, accidental urine loss, urgency episode) was calculated as the mean of all pain severities recorded during the diary period when these events were measured. For each urinary event (toilet void, accidental urine loss, urgency episode), participants marked their associated level of pain intensity (or pressure, aching, burning, discomfort) using an 11-point NRS ranging from 0 denoting none (no pain), and 10 denoting worst (pain as bad as you can imagine), where higher scores indicated higher pain. Total mean interstitial cystitis pain severity per urinary event score ranged from 0 (no pain) to 10 worst (pain as bad as you can imagine), where higher scores indicated more pain.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Mean Interstitial Cystitis Pain Severity Per Urinary Event at Week 2, 4, 6, 10 and 16

Mean interstitial cystitis pain severity per urinary event (toilet void, accidental urine loss, urgency episode) was calculated as the mean of all pain severities recorded during the diary period when these events were measured. For each urinary event (toilet void, accidental urine loss, urgency episode), participants marked their associated level of pain intensity (or pressure, aching, burning, discomfort) using an 11-point NRS ranging from 0 denoting none (no pain), and 10 denoting worst (pain as bad as you can imagine), where higher scores indicated higher pain. Total mean interstitial cystitis pain severity per urinary event score ranged from 0 (no pain) to 10 worst (pain as bad as you can imagine), where higher scores indicated more pain.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Urinary Urgency Episodes Per 24 Hours at Week 2, 4, 6, 10 and 16

The urinary urgency episode per 24 hours was calculated as the sum of any urgency episodes occurring during the diary period when this was measured, divided by the number of days over which they were recorded.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Urinary Urgency Episodes Per 24 Hours at Week 2, 4, 6, 10 and 16

The urinary urgency episode per 24 hours was calculated as the sum of any urgency episodes occurring during the diary period when this was measured, divided by the number of days over which they were recorded. Percent change from baseline was calculated for participants who reported greater than 0 episodes at baseline.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Average Sleep Disturbance Score Per 24 Hours at Week 2, 4, 6, 10 and 16

Average sleep disturbance score was calculated from the sleep disturbance experienced over the previous night. The average sleep disturbance score per night was determined from calculating the mean of all sleep disturbance scores in the 7 days prior to each assessment time point. Participants answered the following question: "Over the past 24 hours, how much did the symptoms that you associate with your interstitial cystitis disturb your sleep?" Participants responded on a 5-point scale ranging from 0 (not at all) to 4 (extremely); where higher scores indicated more sleep disturbance.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Average Sleep Disturbance Score Per 24 Hours at Week 2, 4, 6, 10 and 16

Average sleep disturbance score was calculated from the sleep disturbance experienced over the previous night. The average sleep disturbance score per night was determined from calculating the mean of all sleep disturbance scores in the 7 days prior to each assessment time point. Participants answered the following question: "Over the past 24 hours, how much did the symptoms that you associate with your interstitial cystitis disturb your sleep?" Participants responded on a 5-point scale ranging from 0 (not at all) to 4 (extremely); where higher scores indicated more sleep disturbance. Percent change from baseline was calculated for participants who reported greater than 0 score at baseline.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Average Pain Score Associated With Sexual Activity Per 24 Hours at Week 2, 4, 6, 10 and 16

The average pain score associated with sexual activity was determined from calculating the mean of sexual activity scores of 7 days prior to each assessment time point. Participants answered the following question: "Over the past 24 hours, how much pain did you experience during or after sexual activity?" Participants responded on a 5-point scale ranging from 0 (no pain) to 4 (extremely painful); where higher scores indicated higher pain.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Average Pain Score Associated With Sexual Activity Per 24 Hours at Week 2, 4, 6, 10 and 16

The average pain score associated with sexual activity was determined from calculating the mean of sexual activity scores in the 7 days prior to each assessment time point. Participants answered the following question: "Over the past 24 hours, how much pain did you experience during or after sexual activity?" Participants responded on a 5-point scale ranging from 0 (no pain) to 4 (extremely painful); where higher scores indicated higher pain. Percent change from baseline was calculated for participants who reported greater than 0 score at baseline.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in Pelvic Pain and Urgency/Frequency (PUF) Total Score at Week 2, 4, 6, 10 and 16

The pelvic pain and urgency/frequency (PUF) was a 12-item questionnaire used to measure the severity of symptoms and the degree to which participants were bothered. Symptom questions include 3, 4, or 5 ranked answers, with higher answers indicating more voids, or greater frequency of pain. The bother questions consisted of 4 ranked answers from 0-never to 3-always with higher answers indicating more bothering. Total score was calculated as the sum of symptom score and bother score and ranged from 0 (no symptoms/bother) to 35 (higher symptom severity/bother), where a higher score indicated greater symptom severity and higher bother from pelvic pain and frequency.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in Pelvic Pain and Urgency/Frequency (PUF) Symptom Total Score at Week 2, 4, 6, 10 and 16

The pelvic pain and urgency/frequency (PUF) was a 12-item questionnaire used to measure the severity of symptoms and the degree to which participants were bothered. Symptom questions include 3, 4, or 5 ranked answers, with higher answers indicating more voids, or greater frequency of pain. The bother questions each of 4 ranked answers from 0-never, to 3-always with higher answers indicating more bothering. Total score was calculated as the sum of symptom score and bother score and ranged from 0 (no symptoms/bother) to 35 (higher symptom severity/bother), where a higher score indicated greater symptom severity and higher bother from pelvic pain and frequency.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Change From Baseline in O'Leary-Sant Interstitial Cystitis Problem Index (ICPI) Score at Week 2, 4, 6, 10 and 16

The ICPI contained 4 questions that measured how problematic the symptoms (urinary urgency, urinary frequency, nocturnal and pain/burning/discomfort/pressure in the bladder) were for the participant. Each question in the ICPI was rated on a 0-4 scale, where 0= no problem and 4= big problem. The sum of the individual question ratings was the total score for the ICPI. Total score ranged from 0 (no problem) to 16 (big problem), with higher score indicating greater problematic symptom.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Percent Change From Baseline in O'Leary-Sant Interstitial Cystitis Problem Index (ICPI) Score Week 2, 4, 6, 10 and 16

The ICPI contained 4 questions that measured how problematic the symptoms (urinary urgency, urinary frequency, nocturia and pain/burning/discomfort/pressure in the bladder) were for the participant. Each question in the ICPI was rated on a 0-4 scale, where 0= no problem and 4= big problem. The sum of the individual question ratings was the total score for the ICPI. Total score ranged from 0 (no problem) to 16 (big problem), with higher score indicating greater problematic symptom.

Time frame: Baseline, Week 2, 4, 6, 10, 16

Number of Participants With Global Response Assessment (GRA) at Weeks 6, and 16

Participants were asked the following question: "Compared to when you began this trial, how would you rate your interstitial cystitis symptoms now?" Participants responded on a 7-point symmetric scale where 1 = markedly worse, 2 = moderately worse, 3 = slightly worse, 4 = no change, 5 = slightly improved, 6 = moderately improved and 7 = markedly improved; where higher scores indicated improvement. Participants who responded as 6 (moderately improved) or 7 (markedly improved) were defined as treatment responders. Number of participants with response based on GRA scale for all scale categories were reported in this outcome measure.

Time frame: Week 6, 16

Patient's Global Satisfaction Assessment

Participant global satisfaction was assessed using Patient Reported Treatment Impact (PRTI) which is a self-administered questionnaire containing 4 items to assess participant satisfaction, previous treatment, preference and willingness to continue using the study medication. Participants were asked the following question: "Overall, how satisfied are you with the drug that you received since you entered this trial?" Participant's response was rated on a 5-point scale where 1=extremely dissatisfied (dissatisfy), 2=dissatisfied, 3=neither satisfied nor dissatisfied (satisfy/dissatisfy), 4=satisfied and 5=extremely satisfied; where higher scores indicated more satisfaction. Number of participants with each response was reported in this outcome measure.

Time frame: Week 6, 16

Patient's Global Preference Assessment at Weeks 6, and 16

Participant global preference was assessed using PRTI which is self-administered questionnaire containing 4 items to assess participant satisfaction, previous treatment, preference and willingness to continue using study medication. Participant reported previous treatment under following categories: lifestyle interventions, physical therapies, toileting programs, drug given into bladder, drug taken by mouth, surgery and no treatment. Participants' preference was assessed using following categories: definitely prefer current drug, slightly prefer current drug, no preference, definitely prefer prior treatment and slightly prefer prior treatment. Number of participants under each of the categories was reported in this outcome measure. For previous treatment, a single participant may be represented in more than 1 category.

Time frame: Week 6, 16

Patient Willingness to Re-use Medicine Assessment

Participant willingness to re-use study medication was assessed using PRTI which is a self-administered questionnaire containing 4 items to assess participant satisfaction, previous treatment, preference and willingness to continue using the study medication. Participants were asked the following question: "In the future, would you be willing to use the same drug that you have received since you entered this trial for your interstitial cystitis?" Participant willingness to re-use study medication was assessed using following categories: definitely want to re-use, might want to re-use, not sure, might not want to re-use, and definitely would not want to re-use.

Time frame: Week 6, 16

Percentage of Participants Who Use Rescue Medication

In case of inadequate pain relief or worsening symptoms of interstitial cystitis, any United States Food and Drug Administration (US FDA) approved commercial product of acetaminophen 500 milligram (mg) tablet/capsule could be taken as rescue medication.

Time frame: Baseline up to Week 16

Ratio of Number of Days Rescue Medication Used

In case of inadequate pain relief or worsening symptoms of interstitial cystitis, any US FDA approved commercial product of acetaminophen 500 mg tablet/capsule could be taken as rescue medication. Results were normalized by days rescue medication was used relative to the total number of days participant was in the study.

Time frame: Baseline up to Week 16

Average Number of Doses Per Day of Rescue Medication Used

In case of inadequate pain relief or worsening symptoms of interstitial cystitis, any US FDA approved commercial product of acetaminophen 500 mg tablet/capsule could be taken as rescue medication. Results were normalized by doses of rescue medication used relative to the total number of days participant was in the study.

Time frame: Baseline up to Week 16

Amount of Rescue Medication Taken Per Day

In case of inadequate pain relief or worsening symptoms of interstitial cystitis, any US FDA approved commercial product of acetaminophen 500 mg tablet/capsule could be taken as rescue medication. Results were normalized by amount of rescue medication (in mg) relative to the total number of days participant was in the study.

Time frame: Baseline up to Week 16

Time to First Dose of Rescue Medication as a Proportion of Total Days in Study

In case of inadequate pain relief or worsening symptoms of interstitial cystitis, any US FDA approved commercial product of acetaminophen 500 mg tablet/capsule could be taken as rescue medication. Time to first dose of rescue medication was defined as the time (in days) from the first dose of study drug to the time of first dose of rescue medication use. Results were normalized by days (time \[in days\] to first dose of rescue medication) relative to the total number of days participant was in the study and reported in terms of proportion of total days in study.

Time frame: Baseline up to Week 16

Plasma and Urine Total Nerve Growth Factor (NGF) Concentration

Plasma Total NGF levels were assayed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Urine NGF was not analyzed because no reliable assay method was available for assessing urine NGF.

Time frame: Day 1 (1 hour pre-dose), Week 2, 4, 6, 10, 16

Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) Urine Concentration

HB-EGF urine concentration (in picogram per milliliter \[pg/mL\]) at specified time points is reported here.

Time frame: Day 1 (1 hour pre-dose), Week 2, 4, 6, 10, 16

Anti-Proliferative Factor (APF) Urine Concentration

APF activity was determined using 3 H-thymidine incorporation assay. The results were expressed as the percentage of inhibition of 3 H-thymidine incorporation in epithelial cells from urine specimens in the presence of anti proliferative factor.

Time frame: Day 1 (1 hour pre-dose), Week 2, 4, 6, 10, 16

Number of Participants With Clinically Significant Change From Baseline in Physical Examination

Physical examination included the examination of general appearance, skin, neck, eyes, ears, nose, throat, cardiovascular assessment including rhythm, and presence of other cardiac abnormalities (for example gallops, murmurs, cardiomegaly), respiratory system, gastrointestinal system, genitourinary system, musculoskeletal system and any additional assessments necessary to establish baseline status. Clinically significant change in physical examination was based on investigator's discretion.

Time frame: Baseline up to Week 16

Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Vital signs included the assessment of the following: body temperature, blood pressure, heart rate and respiratory rate. Clinically significant change in vital signs was based on investigator's discretion.

Time frame: Baseline up to Week 16

Number of Participants With Clinically Significant Change From Baseline in Body Weight

Clinically significant change in body weight was based on investigator's discretion.

Time frame: Baseline up to Week 16

Number of Participants With Clinically Significant Change From Baseline in Neurologic Examination

Neurological examination included the assessment of cranial nerve function, coordination, reflexes, mental state, motor function, proprioception, gait and station, and sensory function (sharp sensation, warm/cold sensation, light touch, deep pressure, and vibration sensation). Clinically significant change in neurologic examination was based on investigator's discretion.

Time frame: Baseline up to Week 16

Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)

Clinically significant criteria for ECG abnormality: PR interval (maximum increase from Baseline of \>=25% \[only if Baseline value was greater than 200 millisecond\] or otherwise 50%), QRS complex (maximum increase from Baseline of \>=25% \[only if Baseline value was greater than 200 millisecond\] or otherwise 50%), QT interval, QT interval corrected using the Fridericia's formula (QTcF) (maximum increase from Baseline of \>= 30 to \<60; or \>=60), QT interval corrected using the Bazett's formula (QTcB) (maximum increase from Baseline of \>= 30 to \<60; or \>=60) and RR interval.

Time frame: Baseline up to Week 16

Post-void Residual (PVR) Volume

PVR volume is an objective assessment of the amount of urine (in milliliter) left in the bladder after normal urination and monitored whether the active treatment had an adverse effect on lower urinary tract voiding function. The PVR volume was assessed using trans-abdominal ultrasound (for example, bladder scanner) with the participant in a supine position immediately after voluntary urination.

Time frame: Baseline, Week 2, 6, 16

Number of Participants With Laboratory Abnormalities

Criteria for laboratory abnormalities: Hematology parameters: red blood cell count: \<0.8\*lower limit of normal (LLN); reticulocytes count (absolute or percent): \<0.5\*LLN or greater than (\>) 1.5\*upper limit of normal (ULN); Platelets: \<0.5\*LLN or \>1.75\*ULN; white blood cell count: \<0.6\*LLN or \>1.5\*ULN; neutrophils (absolute or percent): \<0.8\*LLN or \>1.2\*ULN; basophils (absolute or percent): \>1.2\*ULN; lymphocytes (absolute or percent): \<0.8\*LLN or \>1.2\*ULN; monocytes (absolute or percent): \>1.2\*ULN. Serum Chemistry parameters: sodium: \<0.95\*LLN or \>1.05\*ULN, potassium, chloride, bicarbonate, calcium: \<0.9\*LLN or \>1.1\*ULN; magnesium: \>1.1\*ULN or \<0.9\*LLN; BUN (blood urea nitrogen): \>1.3\* ULN, creatinine: \>1.3\*ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase : \>3.0\*ULN ; total bilirubin: \>1.5\*ULN; albumin: \<0.8\*LLN or \>1.2\*ULN and glucose: \<0.6\*LLN or \>1.5\*ULN.

Time frame: Baseline up to Week 16

Number of Participants With Presence of Anti-Drug Antibody (ADA)

Human serum ADA samples were analyzed for the presence or absence of anti-tanezumab antibodies by using a semi quantitative enzyme-linked immunosorbent assay (ELISA).

Time frame: Day 1, Week 4, 6, 16

Plasma Concentration of Tanezumab

Time frame: 0 hour (pre-dose), 1, 2 hours post-dose on Day 1; and at Week 2, 4, 6, 10, 16