Trial Outcomes & Findings for Safety And Efficacy Study Of Once Daily Controlled Release Pregabalin In The Treatment Of Patients With Postherpetic Neuralgia (NCT NCT01270828)

Last Updated: 2021-01-28

Results Overview

Loss of Therapeutic Response (LTR) is defined as \<30% pain response relative to the single blind phase baseline or patient discontinuation due to lack of efficacy or adverse events in the double blind phase of the study. For the calculation of \<30% pain response relative to baseline, baseline will be defined as the mean of the last 7 observations prior to the start of SB treatment, which will be compared with the 7 days rolling average of pain response in DB phase. Participants may be discontinued due to lack of efficacy in this study at the discretion of the study physician.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

806 participants

Primary outcome timeframe

13 Weeks

Results posted on

2021-01-28

Participant Flow

A total of 129 centers in 17 countries screened subjects for the study, including 68 in the US, 6 in Bulgaria, 6 in Poland, 6 in Russia, 6 in the Ukraine, 5 in India, 5 in South Africa, 5 in Sweden, 4 in Slovakia, 3 in Colombia, 3 in Croatia, 3 in Germany, 2 in Denmark, 2 in Hong Kong, 2 in Serbia, 2 in Taiwan, and 1 in the Czech Republic.

The study consisted of 4 phases: Baseline (1 week \[wk\]): to determine study entry criteria; Single Blind (SB) (6 wks): to determine optimized dose; Double Blind (DB) (13 wks): responders with at least 50% improvement in pain at SB were considered and randomized to pregabalin or matching placebo; and DB taper phase (1 wk).

Participant milestones

Participant milestones
Measure	Pregabalin Controlled Release (CR) DB Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Pregabalin CR SB STARTED	0	0	806
Pregabalin CR SB COMPLETED	0	0	660
Pregabalin CR SB NOT COMPLETED	0	0	146
Double Blind Phase STARTED	208	205	0
Double Blind Phase COMPLETED	182	160	0
Double Blind Phase NOT COMPLETED	26	45	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Pregabalin Controlled Release (CR) DB Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Pregabalin CR SB Reason Unspecified	0	0	8
Pregabalin CR SB Enrolled but not treated	0	0	5
Pregabalin CR SB Related adverse event	0	0	46
Pregabalin CR SB Lack of Efficacy	0	0	32
Pregabalin CR SB Withdrawal by Subject	0	0	29
Pregabalin CR SB Lost to Follow-up	0	0	10
Pregabalin CR SB Unrelated AE	0	0	8
Pregabalin CR SB Protocol Violation	0	0	8
Double Blind Phase Death	0	1	0
Double Blind Phase Protocol Violation	0	1	0
Double Blind Phase Protocol and GCP non-compliance	4	3	0
Double Blind Phase Reason Unspecified	7	4	0
Double Blind Phase Withdrawal by Subject	6	15	0
Double Blind Phase Lost to Follow-up	1	2	0
Double Blind Phase Lack of Efficacy	2	11	0
Double Blind Phase Adverse event not related to study drug	1	1	0
Double Blind Phase Adverse event related to study drug	5	7	0

Baseline Characteristics

Safety And Efficacy Study Of Once Daily Controlled Release Pregabalin In The Treatment Of Patients With Postherpetic Neuralgia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pregabalin CR DB n=208 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Total n=413 Participants Total of all reporting groups
Age, Customized <18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Customized 18-44 years	26 Participants n=5 Participants	24 Participants n=7 Participants	50 Participants n=5 Participants
Age, Customized 45-64 years	86 Participants n=5 Participants	78 Participants n=7 Participants	164 Participants n=5 Participants
Age, Customized ≥65 years	96 Participants n=5 Participants	103 Participants n=7 Participants	199 Participants n=5 Participants
Sex: Female, Male Female	134 Participants n=5 Participants	122 Participants n=7 Participants	256 Participants n=5 Participants
Sex: Female, Male Male	74 Participants n=5 Participants	83 Participants n=7 Participants	157 Participants n=5 Participants

PRIMARY outcome

Timeframe: 13 Weeks

Population: The full analysis set (FAS) was the primary efficacy analysis set and consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=208 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Number of Participants With Loss of Therapeutic Response.	29 Participants	63 Participants	—

SECONDARY outcome

Timeframe: 13 Weeks

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase

A secondary LTR endpoint (S-LTR) was defined as the 5 day rolling average pain score during DB, compared to the 5 day randomization baseline pain score. As a secondary endpoint, S-LTR was defined as: 1. At least a 30% increase in the 5 days rolling average pain score during DB relative to the 5 Day randomization baseline pain score 2. A 5 days rolling average pain score ≥4. Participants who discontinue due to lack of efficacy or adverse events in the DB phase of the study will also be counted as an LTR.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=208 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Participants With Secondary LTR Based on 5 Day Rolling Average Diary Results	49 Participants	87 Participants	—

SECONDARY outcome

Timeframe: 13 Weeks

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The 30% pain responders were defined as participants with at least a 30% reduction in the mean pain score from SB baseline to DB endpoint.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=206 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=204 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Percentage of Participants With 30% Reduction in the Mean Pain Score.	95.6 Percentage of participants	83.8 Percentage of participants	—

SECONDARY outcome

Timeframe: 13 Weeks

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The 50% pain responders were defined as participants with at least a 50% reduction in the mean pain score from SB baseline to DB endpoint.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=206 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=204 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Percentage of Participants With 50% Reduction in the Mean Pain Score.	88.3 Percentage of participants	68.6 Percentage of participants	—

SECONDARY outcome

Timeframe: SB Baseline (Enrollment) to Week 19 and DB Baseline (Week 6) to Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The pain numeric rating scale (NRS Pain) consists of an 11 point NRS ranging from 0 (no pain) to 10 (worst possible pain). A rating of 1-3 is considered mild pain; 4-6, moderate pain; and 7-10, severe pain

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=206 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change From Baseline to Endpoint in Weekly Mean Pain Score. SB Baseline to Week 19	-4.89 Units on a scale Standard Error 0.12	-3.95 Units on a scale Standard Error 0.12	—
Change From Baseline to Endpoint in Weekly Mean Pain Score. DB Baseline to Week 19	-0.04 Units on a scale Standard Error 0.11	0.87 Units on a scale Standard Error 0.11	—

SECONDARY outcome

Timeframe: SB Baseline (Enrollment) to Week 19 and DB Baseline (Week 6) to Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=195 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in the Weekly NRS-Pain (1-Week Recall). DB Baseline to Week 19	-0.1 Units on a scale Standard Error 0.13	0.9 Units on a scale Standard Error 0.13	—
Change in the Weekly NRS-Pain (1-Week Recall). SB Baseline to Week 19	-5.0 Units on a scale Standard Error 0.13	-3.9 Units on a scale Standard Error 0.14	—

SECONDARY outcome

Timeframe: SB Baseline (BL) (Enrollment) to Week 19 and DB Baseline (Week 6) to Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase. N in the below table refers to number of participants analyzed: 203 in Pregabalin DB CR group and 195 in Placebo DB group, unless otherwise specified.

The MOS-SS is a validated self administered questionnaire consisting of 12 items that assess key constructs of sleep. The scale has been found reliable and valid with good overall measurement properties. Instrument scoring yields 7 subscales (sleep disturbance, snoring, awaken short of breath or with a headache, quantity of sleep, optimal sleep, sleep adequacy, and somnolence) as well as a 9 item overall sleep problems index assessing sleep over the past week. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range multiplied by 100); total score range = 0 to 100; higher score indicates greater intensity of attribute.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=195 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Sleep Problems Index I-SB BL to wk 19(N=202,195)	-19.9 Units on a scale Standard Error 1.09	-16.7 Units on a scale Standard Error 1.13	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Sleep Problems Index I-DB BL to wk 19(N=202,195)	1.2 Units on a scale Standard Error 1.05	4.4 Units on a scale Standard Error 1.09	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). SleepProblems Index II-SB BL to wk 19(N=202,195)	-21.2 Units on a scale Standard Error 1.07	-17.4 Units on a scale Standard Error 1.11	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). SleepProblems Index II-DB BL to wk 19(N=202,194)	0.2 Units on a scale Standard Error 1.01	4.3 Units on a scale Standard Error 1.05	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Sleep Disturbance-SB BL to wk 19	-28.3 Units on a scale Standard Error 1.42	-21.1 Units on a scale Standard Error 1.48	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Sleep Disturbance-DB BL to wk 19	-1.1 Units on a scale Standard Error 1.31	7.6 Units on a scale Standard Error 1.36	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Snoring-SB BL to wk 19(N=202,194)	-3.3 Units on a scale Standard Error 1.57	-4.7 Units on a scale Standard Error 1.64	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Snoring-DB BL to wk 19(N=201,194)	-0.6 Units on a scale Standard Error 1.41	0.8 Units on a scale Standard Error 1.46	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Awaken short of breath/headache-SB BL to wk 19	-11.9 Units on a scale Standard Error 1.21	-10.4 Units on a scale Standard Error 1.26	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Awaken short of breath/headache-DB BL to wk 19	-1.2 Units on a scale Standard Error 1.23	-0.2 Units on a scale Standard Error 1.27	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Sleep adequacy-SB BL to wk 19	19.9 Units on a scale Standard Error 1.83	17.5 Units on a scale Standard Error 1.90	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Sleep adequacy-DB BL to wk 19(N=202,195)	-3.3 Units on a scale Standard Error 1.82	-6.0 Units on a scale Standard Error 1.89	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Somnolence-SB BL to wk 19(N=202,195)	-12.0 Units on a scale Standard Error 1.19	-12.0 Units on a scale Standard Error 1.23	—
Change in the Medical Outcomes Study-Sleep Scale (MOS-SS). Somnolence-DB BL to wk 19(N=203,194)	-0.7 Units on a scale Standard Error 1.15	-0.9 Units on a scale Standard Error 1.19	—

SECONDARY outcome

Timeframe: SB Baseline (BL) (Enrollment) to Week 19 and DB Baseline (Week 6) to Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The MOS-SS is a validated self administered questionnaire consisting of 12 items that assess key constructs of sleep. The scale has been found reliable and valid with good overall measurement properties. Instrument scoring yields 7 subscales (sleep disturbance, snoring, awaken short of breath or with a headache, quantity of sleep, optimal sleep, sleep adequacy, and somnolence) as well as a 9 item overall sleep problems index assessing sleep over the past week. The item "Quantity of sleep" of MOS-SS is presented here.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=192 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in the MOS-SS-Quantity of Sleep. Quantity of sleep-SB BL to wk 19(N=203,192)	0.9 Hours Standard Error 0.09	0.7 Hours Standard Error 0.10	—
Change in the MOS-SS-Quantity of Sleep. Quantity of sleep-DB BL to wk 19(N=202,192)	-0.1 Hours Standard Error 0.08	-0.4 Hours Standard Error 0.09	—

SECONDARY outcome

Timeframe: Week 6 and Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The MOS-SS is a validated self administered questionnaire consisting of 12 items that assess key constructs of sleep. The scale has been found reliable and valid with good overall measurement properties. Instrument scoring yields 7 subscales (sleep disturbance, snoring, awaken short of breath or with a headache, quantity of sleep, optimal sleep, sleep adequacy, and somnolence) as well as a 9 item overall sleep problems index assessing sleep over the past week. The optimal sleep score is a dichotomous 'Yes' or 'No' rating, where 'Yes' indicates optimal sleep (average 7-8 hours per night) and 'No' indicates not optimal sleep. The "percentage of participants with optimal sleep" is presented here.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=208 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
The MOS-SS-Optimal Sleep. Week 6 (N=208,205)	58.7 Percentage of participants 0.09	62.4 Percentage of participants 0.10	—
The MOS-SS-Optimal Sleep. Week 19 (N=204,197)	54.9 Percentage of participants 0.08	54.8 Percentage of participants 0.09	—

SECONDARY outcome

Timeframe: Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The PGIC is a participant-rated instrument that has been used in chronic pain and fibromyalgia studies to rate change in a patient's overall status. This single item instrument uses a 7 point Likert scale, anchored by (1) very much improved, to (7) very much worse.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=195 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score Minimally improved	16.7 Percentage of participants	19.0 Percentage of participants	—
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score Very much improved	31.5 Percentage of participants	23.1 Percentage of participants	—
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score Much improved	36.9 Percentage of participants	30.3 Percentage of participants	—
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score No change	10.3 Percentage of participants	12.8 Percentage of participants	—
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score Minimally worse	2.5 Percentage of participants	7.2 Percentage of participants	—
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score Much worse	1.5 Percentage of participants	7.2 Percentage of participants	—
Percentage of Participants With Change in the Patient Global Impression of Change (PGIC) Score Very much worse	0.5 Percentage of participants	0.5 Percentage of participants	—

SECONDARY outcome

Timeframe: Week 19

The SF 36 is a self administered, validated questionnaire that measures each of the following 8 health aspects: Physical functioning, role limitations due to physical problems, social functioning, bodily pain, mental health, role limitations due to emotional problems, vitality, and general health perception over the past week. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning) where, higher scores indicate a better health related quality of life.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=195 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in the Short Form 36 Health Survey (SF-36) General Health Perception-SB BL to wk19(N=202,195)	11.3 Units on a scale Standard Error 1.05	8.2 Units on a scale Standard Error 1.08	—
Change in the Short Form 36 Health Survey (SF-36) General Health Perception-DB BL to wk19(N=202,195)	1.4 Units on a scale Standard Error 0.96	-4.0 Units on a scale Standard Error 1.00	—
Change in the Short Form 36 Health Survey (SF-36) Vitality-SB BL to wk 19(N=202,195)	13.7 Units on a scale Standard Error 1.25	10.7 Units on a scale Standard Error 1.30	—
Change in the Short Form 36 Health Survey (SF-36) Vitality-DB BL to wk 19(N=202,195)	-3.5 Units on a scale Standard Error 1.21	-6.5 Units on a scale Standard Error 1.25	—
Change in the Short Form 36 Health Survey (SF-36) Social Functioning-SB BL to wk 19	18.5 Units on a scale Standard Error 1.35	15.7 Units on a scale Standard Error 1.39	—
Change in the Short Form 36 Health Survey (SF-36) Social Functioning-DB BL to wk 19	-2.1 Units on a scale Standard Error 1.28	-4.3 Units on a scale Standard Error 1.32	—
Change in the Short Form 36 Health Survey (SF-36) Role-Emotional-SB BL to wk 19	15.0 Units on a scale Standard Error 1.43	11.6 Units on a scale Standard Error 1.47	—
Change in the Short Form 36 Health Survey (SF-36) Role-Emotional-DB BL to wk 19	-1.4 Units on a scale Standard Error 1.42	-5.4 Units on a scale Standard Error 1.47	—
Change in the Short Form 36 Health Survey (SF-36) Mental Health-SB BL to wk 19(N=202,195)	11.1 Units on a scale Standard Error 1.05	9.5 Units on a scale Standard Error 1.08	—
Change in the Short Form 36 Health Survey (SF-36) Mental Health-DB BL to wk 19(N=202,195)	-1.3 Units on a scale Standard Error 1.04	-3.7 Units on a scale Standard Error 1.08	—
Change in the Short Form 36 Health Survey (SF-36) Physical Component-SB BL to wk 19(N=202,195)	7.5 Units on a scale Standard Error 0.54	5.6 Units on a scale Standard Error 0.56	—
Change in the Short Form 36 Health Survey (SF-36) Physical Component-DB BL to wk 19(N=202,195)	0.1 Units on a scale Standard Error 0.51	-2.3 Units on a scale Standard Error 0.53	—
Change in the Short Form 36 Health Survey (SF-36) Mental Component-SB BL to wk 19(N=202,195)	6.4 Units on a scale Standard Error 0.62	5.5 Units on a scale Standard Error 0.64	—
Change in the Short Form 36 Health Survey (SF-36) Mental Component-DB BL to wk 19(N=202,195)	-1.1 Units on a scale Standard Error 0.62	-2.2 Units on a scale Standard Error 0.64	—
Change in the Short Form 36 Health Survey (SF-36) Physical functioning-SB BL to wk 19	11.7 Units on a scale Standard Error 1.44	8.9 Units on a scale Standard Error 1.49	—
Change in the Short Form 36 Health Survey (SF-36) Physical functioning-DB BL to wk 19	-1.4 Units on a scale Standard Error 1.25	-4.9 Units on a scale Standard Error 1.29	—
Change in the Short Form 36 Health Survey (SF-36) Role-Physical-SB BL to wk 19	18.9 Units on a scale Standard Error 1.62	13.9 Units on a scale Standard Error 1.67	—
Change in the Short Form 36 Health Survey (SF-36) Role-Physical-DB BL to wk 19	-2.4 Units on a scale Standard Error 1.54	-7.7 Units on a scale Standard Error 1.60	—
Change in the Short Form 36 Health Survey (SF-36) Bodily pain-SB BL to wk 19	31.0 Units on a scale Standard Error 1.51	23.6 Units on a scale Standard Error 1.56	—
Change in the Short Form 36 Health Survey (SF-36) Bodily pain-DB BL to wk 19	1.4 Units on a scale Standard Error 1.38	-6.2 Units on a scale Standard Error 1.43	—

SECONDARY outcome

Timeframe: Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The pain related sleep interference item rating scale is scored on an 11 point numeric rating scale (NRS Sleep). It is self administered by the subject in order to rate how pain has interfered with their sleep during the past 24 hours, ranging from 0 (pain does not interfere with sleep) to 10 (completely interferes (unable to sleep due to pain)). Participants are to describe how their pain has interfered with their sleep during the past 24 hours by choosing the appropriate number on the numeric rating scale.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=206 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=204 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in Mean Daily Sleep Interference Scores SB Baseline to Week 19 (N=205,203)	-4.5 Units on a scale Standard Error 0.11	-3.5 Units on a scale Standard Error 0.11	—
Change in Mean Daily Sleep Interference Scores DB Baseline to Week 19 (N=206,204)	-0.2 Units on a scale Standard Error 0.10	0.7 Units on a scale Standard Error 0.10	—

SECONDARY outcome

Timeframe: Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The HADS is a self administered questionnaire that was designed to screen for the presence of a mood disorder in medically ill patients. To distinguish psychiatric presentations from physical illness, the items focus on subjective disturbance of mood rather than physical signs. The HADS contains 14 items rated on 4 point Likert type scales. Two subscales assess depression and anxiety. Each subscale consists of 7 statements, rated on a scale of 0 to 3 (0 = No anxiety or depression, to 3 = Severe feelings of anxiety or depression). Separate scores are calculated for each subscale ranging from 0 to 21. Higher scores denote greater severity of depression or anxiety

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=195 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in Hospital Anxiety and Depression Scales (HADS) HADS-Anxiety-SB Baseline to Week 19	-1.8 Units on a scale Standard Error 0.21	-1.1 Units on a scale Standard Error 0.21	—
Change in Hospital Anxiety and Depression Scales (HADS) HADS-Anxiety-DB Baseline to Week 19	0.1 Units on a scale Standard Error 0.19	0.9 Units on a scale Standard Error 0.20	—
Change in Hospital Anxiety and Depression Scales (HADS) HADS-Depression-SB Baseline to Week 19	-1.8 Units on a scale Standard Error 0.20	-1.2 Units on a scale Standard Error 0.21	—
Change in Hospital Anxiety and Depression Scales (HADS) HADS-Depression-DB Baseline to Week 19	0.2 Units on a scale Standard Error 0.19	0.8 Units on a scale Standard Error 0.19	—

SECONDARY outcome

Timeframe: Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The BPI sf is a self-administered questionnaire developed to assess the severity of pain and the impact of pain on daily functions during a 24 hour period prior to evaluation. The BPI sf consists of 5 questions. Questions 1, 2, 3, and 4 measure pain on an 11 point scale from 0 (no pain) to 10 (worst pain possible). Question 5 consists of 7 item subsets which measure the level of interference of pain on daily functions on an 11 point scale from 0 (Does not interfere) to 10 (Completely interferes).

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=203 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=195 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Change in the Brief Pain Inventory (BPI-sf) Pain Severity Index-SB Baseline to Week 19	-18.0 Units on a scale Standard Error 0.47	-13.8 Units on a scale Standard Error 0.49	—
Change in the Brief Pain Inventory (BPI-sf) Pain Severity Index-DB Baseline to Week 19	-0.7 Units on a scale Standard Error 0.43	3.1 Units on a scale Standard Error 0.44	—
Change in the Brief Pain Inventory (BPI-sf) Pain Interference Index-SB Baseline to Week 19	-21.9 Units on a scale Standard Error 0.71	-17.2 Units on a scale Standard Error 0.74	—
Change in the Brief Pain Inventory (BPI-sf) Pain Interference Index-DB Baseline to Week 19	-0.2 Units on a scale Standard Error 0.67	4.0 Units on a scale Standard Error 0.70	—

SECONDARY outcome

Timeframe: Week 19

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

The BSW is administered by the study physician or designated site personnel and consists of three single item measures designed to capture the patient's perception of the effect of treatment in terms of the relative benefit, their satisfaction, and their intention or willingness to continue on therapy.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=201 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=193 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Percentage of Participants With Benefit From Treatment, Satisfaction With Treatment and Willingness to Continue Treatement (BSW) Benefit from treatment	98.5 Percentage of participants	93.3 Percentage of participants	—
Percentage of Participants With Benefit From Treatment, Satisfaction With Treatment and Willingness to Continue Treatement (BSW) Satisfaction with treatment	96.0 Percentage of participants	90.7 Percentage of participants	—
Percentage of Participants With Benefit From Treatment, Satisfaction With Treatment and Willingness to Continue Treatement (BSW) Willingness to continue treatment	87.6 Percentage of participants	81.3 Percentage of participants	—

SECONDARY outcome

Timeframe: Baseline to Week 20

Population: The SB Analysis Set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis.

An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A serious adverse event is any untoward medical occurrence at any dose that: Results in death; Is life-threatening (immediate risk of death); Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); or Results in congenital anomaly/birth defect. The study physician used the adjective "severe" to those AEs that interfere significantly with participant's usual function.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=208 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Pregabalin CR SB n=801 Participants The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Number of Participants With Adverse Events Participants with AEs	80 Participants	63 Participants	441 Participants
Number of Participants With Adverse Events Participants with Serious AEs	7 Participants	3 Participants	17 Participants
Number of Participants With Adverse Events Participants with Severe AEs	9 Participants	3 Participants	35 Participants

SECONDARY outcome

Timeframe: Baseline, Weeks 6, 11, 15, 19 and 20

Population: The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study drug in the DB phase.

Percentage of participants with suicidal behavior/ideation were noted as Baseline, Weeks 6, 11, 15, 19 and 20.

Outcome measures

Outcome measures
Measure	Pregabalin CR DB n=208 Participants Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 Participants Participants received matching placebo	Pregabalin CR SB The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Percentage of Participants With Suicidal Behaviour/Ideation SB BL(N=208,205)	0 Percentage of participants	0.5 Percentage of participants	—
Percentage of Participants With Suicidal Behaviour/Ideation Week 6 (N=208,205)	0 Percentage of participants	0 Percentage of participants	—
Percentage of Participants With Suicidal Behaviour/Ideation Week 11 (N=194,178)	0 Percentage of participants	0 Percentage of participants	—
Percentage of Participants With Suicidal Behaviour/Ideation Week 15 (N=183,167)	0 Percentage of participants	0 Percentage of participants	—
Percentage of Participants With Suicidal Behaviour/Ideation Week 19 (N=204,197)	0 Percentage of participants	0 Percentage of participants	—
Percentage of Participants With Suicidal Behaviour/Ideation Week 20 (N=199,194)	0 Percentage of participants	0 Percentage of participants	—

Adverse Events

Pregabalin CR DB

Serious events: 7 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo DB

Serious events: 3 serious events

Other events: 1 other events

Deaths: 0 deaths

Pregabalin CR SB

Serious events: 17 serious events

Other events: 202 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Pregabalin CR DB n=208 participants at risk Possible doses for participants with normal creatinine clearance (CLcr) (≥60 mL/min) during the DB fixed dose phase were pregabalin CR 165 mg/day, 330 mg/day, 495 mg/day CR or 660 mg/day CR. Doses for participants with low CLcr (\>30 - \<60 mL/min) were pregabalin 82.5 mg/day, 165 mg/day, 247.5 mg/day, or 330 mg/day CR.	Placebo DB n=205 participants at risk Participants received matching placebo	Pregabalin CR SB n=801 participants at risk The participants with normal CLcr (≥60 mL/min) were treated with pregabalin 165 mg/day CR; those with low CLcr (\>30 - \<60 mL/min) received 82.5 mg/day pregabalin CR. Subsequently, the pregabalin doses were increased based on efficacy and tolerability at each weekly visit.
Nervous system disorders Dizziness	3.4% 7/208 • Baseline to Week 20 The SB analysis set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis	0.49% 1/205 • Baseline to Week 20 The SB analysis set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis	17.1% 137/801 • Baseline to Week 20 The SB analysis set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis
Nervous system disorders Somnolence	0.48% 1/208 • Baseline to Week 20 The SB analysis set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis	0.00% 0/205 • Baseline to Week 20 The SB analysis set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis	11.4% 91/801 • Baseline to Week 20 The SB analysis set (SBAS) consisted of all participants who were enrolled into the SB phase of the study and received at least 1 dose of study medication; The FAS consisted of all participants randomized to the DB phase who received at least 1 dose of study medication in the DB phase. Both SBAS and FAS were included in this analysis

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
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