Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy

This study has been terminated.
(See termination reason in detailed description.)
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01049217
First received: January 13, 2010
Last updated: August 27, 2013
Last verified: August 2013
  Purpose

The purpose of this study is to evaluate the efficacy of pregabalin compared to placebo in reducing neuropathic pain associated with HIV neuropathy.


Condition Intervention Phase
Neuropathy
Drug: pregabalin
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Trial Of Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy (Pregabalin A0081244)

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Change From Baseline in Mean Pain Score at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Mean pain score was defined as the mean of the last 7 daily diary pain ratings. Participants rated their Human Immunodeficiency Virus (HIV) neuropathy pain over the past 24 hours on an 11-point numeric rating scale ranging from 0 = no pain to 10 = worst possible pain. A rating of 1-3 was considered as mild pain; 4-6 = moderate pain; and 7-10 = severe pain. Endpoint was the last observation for a participant assessed using specified imputation method, modified Baseline Observation Carried Forward (mBOCF).


Secondary Outcome Measures:
  • Number of Participants With Categorical Scores on Patient Global Impression of Change (PGIC) [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
    PGIC: participant rated instrument to measure participant's change in overall status on a 7-point scale; range from 1 (very much improved) to 7 (very much worse). Number of participants in each category is reported.

  • Number of Participants With Categorical Scores on Clinician Global Impression of Change (CGIC) [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
    The CGIC scale measures a physician's global impression of a participant's clinical condition at final visit in terms of change relative to the start of treatment (CGIC). At final visit, the participants CGIC will be categorized into a three point scale as: improvement: CGI response of very much improved, much improved or minimally improved; no change: CGI response of no change; worsening: CGI response of very much worse, much worse or minimally worse. Number of participants in each category is reported.

  • Change From Baseline in Numeric Rating Scale (NRS)-Sleep Interference Score at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and Endpoint (up to Week 16) [ Time Frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Weekly mean sleep interference score was defined as the mean of the daily sleep interference diary ratings split into 7 day intervals. Participants rated how HIV neuropathy pain has interfered with their sleep during the past 24 hours on an 11-point NRS ranging from 0 = does not interfere with sleep to 10 = completely interferes (unable to sleep due to pain). Endpoint was the last observation for a participant assessed using specified imputation method.

  • Change From Baseline in Numeric Rating Scale (NRS)-Current Pain Score at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and Endpoint (up to Week 16) [ Time Frame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Weekly current pain score was defined as the mean of the daily current pain diary ratings split into 7 day intervals. Participants rated current ("right now") HIV neuropathy pain an 11-point NRS ranging from 0 = no pain to 10 = worst possible pain. A rating of 1-3 was considered as mild pain; 4-6 = moderate pain; and 7-10 = severe pain. Endpoint was the last observation for a participant assessed using specified imputation method.

  • Change From Baseline in Brief Pain Inventory-Short Form (BPI-sf) Score at Week 4, 8, 12, 16 and Endpoint (up to Week 16) [ Time Frame: Baseline, Week 4, 8, 12, 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    BPI-sf:5-item self-administered questionnaire to assess severity,impact of pain on daily functions. Pain Severity Index (PSI):average of Question 1-4 each measured severity of pain over past 24-hours on 11-point scale (0=no pain to 10=worst possible pain). Pain Interference Index (PII):average of 7 pain interference items of Question 5 that measured level of interference of pain on daily function on 11-point scale (0=does not interfere to 10=completely interferes). For PSI, PII range:0-10 higher score=higher pain/interference. Endpoint=last observation for participant as per imputation method.

  • Change From Baseline in Neuropathic Pain Symptom Inventory (NPSI) Item Scores at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    NPSI: participant-rated questionnaire to evaluate different symptoms of neuropathic pain. It includes 10 descriptors and 2 temporal items. Results reported for the 10 descriptors (burning, squeezing, pressure, electric shocks, stabbing, light touching of area, pressure of area, cold of area, pins and needles, tingling) quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) scale. Endpoint was the last observation for a participant assessed using specified imputation method.

  • Neuropathic Pain Symptom Inventory (NPSI): Change From Baseline in Number of Participants With Duration of Spontaneous Pain and Number of Pain Attacks at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    NPSI: participant-rated questionnaire to evaluate different symptoms of neuropathic pain. It includes 10 descriptors, and 2 temporal items. Results reported for categorical change in temporal items assessed on 5-point scale for duration of spontaneous pain (1=continuously, 2=8-12 hours [hrs], 3=4-7 hrs, 4=1-3 hrs, 5=less than 1 hr), numbers of pain attacks (1=more than 20, 2=11-20 attacks, 3=6-10 attacks, 4=1-5 attacks, 5=no attack). Change data categorized as worsened (negative change), unchanged (no change), and improved (positive change). Endpoint=last observation as per imputation method.

  • Change From Baseline in Neuropathic Pain Symptom Inventory (NPSI) Subscales and Total Intensity Score at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    NPSI: participant rated questionnaire to evaluate different symptoms of neuropathic pain (subscales: burning [superficial] spontaneous pain, pressing [deep] spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dyesthesia [P/D]). Includes 10 descriptors quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) and 2 temporal items assessing duration of spontaneous ongoing and paroxysmal pain. The relevant subscales and total score were transformed to 0-1, higher score indicates a greater intensity of pain. Endpoint=last observation for participant as per imputation method.

  • Total Sleep Time (TST) and Minutes of Interrupted Sleep (MIS) [ Time Frame: Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Total sleep time is the number of minutes asleep between time of sleep onset to morning awakening and MIS is the number of minutes spent awake after sleep onset to final awakening. TST and MIS were determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method.

  • Sleep Fragmentation Index (SFI) [ Time Frame: Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    SFI is a measure to quantify sleep restlessness. SFI calculated from analysis of the periods that participant was not moving (immobile bouts). It is number of immobile bouts that were exactly 1 minute long divided by total number of immobile bouts. Value ranges from 0-100 percent, with low number representing more restful sleep. SFI determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on wrist like a watch. It was programmed to record movements while device was being worn. Endpoint was the last observation for a participant assessed using imputation method.

  • Sleep Efficiency [ Time Frame: Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Sleep efficiency is the time spent asleep divided by total time between sleep onset and sleep end, multiplied by 100. Sleep efficiency was determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method.

  • Total Activity Counts [ Time Frame: Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Activity counts are the units of motion. It is equal to the sum of peak accelerations each second during the epoch (60 seconds). Total activity counts per day is the sum of the activity counts for each epoch (60 seconds) during the "day" (non sleep period). A total activity count was determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method.

  • Percentage Day Time Above Sedentary Level [ Time Frame: Baseline (Day -14 to 1), Week 1 through Week 4, Week 12 through Week 16, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Percentage of time above sedentary level is number of epochs (60 seconds) with greater than (>) 200 activity counts per minute divided by total number of epochs during the "day" (non sleep period) multiplied by 100. This was determined by actigraphy. Actigraphy was performed with an accelerometer that was worn on the wrist like a watch. It was programmed to record movements while the device was being worn. Endpoint was the last observation for a participant assessed using specified imputation method.

  • Change From Baseline in Medical Outcomes Study-Sleep Scale (MOS-SS) at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    Participant-rated 12-item questionnaire to assess constructs of sleep over past week; 7 subscales: sleep disturbance (range 0-100), snoring (range 0-100), awaken short of breath (SOB) or with headache (range 0-100), sleep adequacy (range 0-100), somnolence (range: 0-100); sleep quantity (range: 0-24), optimal sleep (yes/no), and 9 item index measures of sleep disturbance provide composite scores: sleep problems index (range 0-100). Except adequacy, optimal sleep and quantity, higher scores=more impairment. Endpoint was the last observation for a participant assessed using imputation method.

  • Medical Outcomes Study-Sleep Scale (MOS-SS): Number of Participants With Optimal Sleep [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    MOS-SS: participant-rated 12 item questionnaire to assess constructs of sleep over past week. It included 7 subscales: sleep disturbance, snoring, awaken short of breath or with headache, sleep adequacy, somnolence, sleep quantity, optimal sleep, and 9 item index measures of sleep disturbance provide composite scores: sleep problems index. Participants responded whether their sleep was optimal or not optimal by choosing yes or no. Endpoint was the last observation for a participant assessed using imputation method.

  • Change From Baseline in Hospital Anxiety and Depression Scales (HADS) at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    HADS: participant rated questionnaire with 2 subscales. HADS-A assesses state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assesses state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicates greater severity of anxiety and depression symptoms. Endpoint was the last observation for a participant assessed using imputation method.

  • Change From Baseline in 36-Item Short-Form Health Survey (SF-36) at Endpoint (up to Week 16) [ Time Frame: Baseline, Endpoint (up to Week 16) ] [ Designated as safety issue: No ]
    SF-36 is a standardized survey evaluating 8 domains of functional health and well being: physical and social (So) functioning (Fn), physical and emotional role (role-physical [R-P], role-emotional [R-E]) limitations, bodily pain (BP), general health (GH), vitality (Vit), mental health (MnH). Two summary scores include Physical Component (Ph C) and Mental Component (Mn C). The score for a section is an average of the individual question scores. Score range for domain scores and summary scores: 0-100 (100=highest level of functioning).

  • Number of Participants Who Were Employed or Unemployed Assessed by Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) Questionnaire [ Time Frame: Baseline, Week 16, 17 ] [ Designated as safety issue: No ]
    WPAI: 6-question participant rated questionnaire to determine the degree to which specific health problem (SHP) affected work productivity while at work and affected activities outside of work. It assesses amount of absenteeism, presenteeism and daily activity impairment attributable to a HIV neuropathy pain. Number of participants who responded "Yes/No" to Question 1: Are you currently employed (working for pay)? are reported.

  • Absenteeism and Presenteeism Assessed by Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) Questionnaire [ Time Frame: Baseline, Week 16, 17 ] [ Designated as safety issue: No ]
    WPAI: 6-question participant rated questionnaire to determine the degree to which SHP affected work productivity while at work and affected activities outside of work. It assesses amount of absenteeism, presenteeism and daily activity impairment attributable to a HIV neuropathy pain. Question 2 and 3 assesses absenteeism as: Hours of work missed in past 7 days due to leg/foot pain or other reason, respectively. Question 4 assesses presenteeism as: Hours of work performed in past 7 days. A participant who had responded 'no' to question 1 regarding employment status reported hours of work and as this was a self-reported questionnaire the source data were included.

  • Productivity and Activity Impairment Assessed by Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) Questionnaire [ Time Frame: Baseline, Week 16, 17 ] [ Designated as safety issue: No ]
    WPAI: 6-question participant rated questionnaire to determine the degree to which SHP affected work productivity while at work and affected activities outside of work. It assesses amount of absenteeism, presenteeism and daily activity impairment attributable to a HIV neuropathy pain. Question 5 and 6 assesses: How much leg/foot pain affect productivity and daily activity, respectively in past 7 days? on 11-point scale, where 0 (not affected/no impairment) to 10 (completely affected/impaired).

  • Diagnostic Neuropathy Assessment [ Time Frame: Screening ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Number of Participants With Treatment-Emergent (TE) Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 28 days after last dose ] [ Designated as safety issue: Yes ]
    An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An 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. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

  • Number of Participants With Abnormal Laboratory Test Findings [ Time Frame: Screening up to Week 17 ] [ Designated as safety issue: Yes ]
    Laboratory tests included hematology, chemistry, cluster of differentiation 4 (CD4) count and cluster of differentiation 8 (CD8) count, HIV plasma viral load, B12, Venereal Disease Research Laboratory (VDRL), toxic screens for drugs and alcohol, reflex thyroid-stimulating hormone (TSH), urinalysis. Number of participants with a laboratory abnormality meeting specified criteria while on study treatment or during lag time was reported.

  • Number of Participants With Positive Serum and Urine Pregnancy [ Time Frame: Screening for serum pregnancy test, Week 1 for urine pregnancy test ] [ Designated as safety issue: Yes ]
    Serum pregnancy test (regardless of childbearing potential) and urine pregnancy test for all female participants were performed.

  • Number of Participants With Abnormal Physical Examination Findings [ Time Frame: Screening, Week 8, 17 ] [ Designated as safety issue: Yes ]
    A physical examination included an examination of the general appearance, skin, chest, pulses, pulmonary, cardiovascular, head, eyes, ears, nose, throat, abdominal, and extremities.

  • Body Weight [ Time Frame: Screening, Week 1, 4, 8, 12, 16, 17 ] [ Designated as safety issue: Yes ]
  • Sitting Systolic and Diastolic Blood Pressure [ Time Frame: Screening, Week 1, 4, 8, 12, 16, 17 ] [ Designated as safety issue: Yes ]
    Systolic Blood Pressure (SBP) is the blood pressure (pressure exerted by circulating blood on the walls of blood vessels) when heart is contracting; it is the maximum arterial pressure during contraction of left ventricle of heart. Diastolic Blood Pressure (DBP) is the blood pressure (pressure exerted by circulating blood on the walls of blood vessels) when heart is relaxing; it is the minimum arterial pressure during relaxation and dilation of ventricles of heart.

  • Sitting Heart Rate [ Time Frame: Screening, Week 1, 4, 8, 12, 16, 17 ] [ Designated as safety issue: Yes ]
  • Number of Participants With Neurological Examination Findings [ Time Frame: Screening ] [ Designated as safety issue: Yes ]
    A neurological examination consisted of examination of the mental state, cranial nerve function, motor function (reflexes of patellar, achilles, biceps, babinski and coordination) and sensory function (sharp sensation of dorsal surface of right and left great toe, light touch of lower extremities [LE], right and left first metatarsal joint position sense, and vibration sensation [vibration is felt for < 6 seconds = markedly diminished, 6 to 10 seconds = mild loss, > 10 seconds = normal]).

  • Number of Participants Who Met Mini-International Neuropsychiatric Interview (MINI) Criteria [ Time Frame: Screening ] [ Designated as safety issue: Yes ]
    MINI: short structured clinical interview to make diagnoses of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) or International Classifications of Disease-10 (ICD-10). In the MINI Modules, participants were asked a series of Yes/No questions.

  • Number of Participants With Response to Sheehan-Suicidality Tracking Scale (S-STS) Mapped to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categories [ Time Frame: Screening, Post-Baseline (Week 4 up to Week 17) ] [ Designated as safety issue: Yes ]
    S-STS:8-item clinician/participant administered prospective rating scale to assess TE suicidal(Su) ideation(ID),behavior(BHV).Items 1a,2-6,7a,8 scored on 5-point Likert scale 0(not at all) to 4(extremely). Items 1,1b,7 require yes/no response. S-STS total score range 0-30. Lower score=reduced Su tendency. Responses on S-STS were mapped to Columbia Classification Algorithm of Suicide Assessment(C-CASA) as 1:Completed Su; 2: Su attempt; 3: Preparatory acts; 4: Su ID; 5: Self-injurious (SI) BHV, intent unknown; 6: Not enough information; 7: SI BHV, no Su intent; 8: Other, no deliberate self harm.

  • Number of Participants With Response to Patient Health Questionnaire-8 (PHQ-8) [ Time Frame: Screening ] [ Designated as safety issue: No ]
    PHQ-8: 8-item self-administered validated subset of PHQ-9, which comprises first 8 items of measure. Participant rated "Over past 2 weeks, how often bothered by any of following problems?": little interest in doing things(1); feeling down(2); trouble falling or staying asleep/sleeping too much(3); feeling tired(4); poor appetite/overeating(5); feeling bad about self(6); trouble concentrating(7); moving or speaking slowly or being so fidgety/moving around more than usual (8). Each item scored on scale of 0(not at all)-3(nearly every day). Total score range: 0-24, higher score=greater severity.


Enrollment: 377
Study Start Date: April 2010
Study Completion Date: May 2012
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Active drug Drug: pregabalin
Pregabalin 75 mg-300mg twice daily during the course of the study.
Placebo Comparator: Control Drug: placebo
Subjects may be assigned to placebo during this study. The study duration is approximately 19 weeks.

Detailed Description:

Based on DMC interim efficacy analysis results indicating a low probability for success the study was terminated on April 2, 2012; the termination was unrelated to any safety findings that could impact patient health.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men and women, ages of 18 or greater
  • Documented evidence of HIV-1 infection
  • Documented diagnosis of HIV-associated Distal Symmetrical Polyneuropathy (DSP) with subjective sensory symptom of pain
  • Pain starts in the feet

Exclusion Criteria:

  • Subject has untreated vitamin B12 deficiency (serum B12 level <200 pg/ml) or if treated B12 deficiency -treatment is less than 6 months of B12 supplementation (injection or intranasal B12) prior to screening
  • Diabetes mellitus requiring regular medical treatment (other than diet and exercise) or HbA1C >6.9
  • Subjects with peripheral neuropathic pain that is not associated with HIV infection; including subjects with conditions such as: Post Herpetic Neuralgia (PHN), Diabetic Peripheral Neuropathy (DPN), familial neuropathies; compression related neuropathy, radicular pain, other infection related neuropathies (eg, leprosy); neuropathy related to: metabolic abnormalities; nutritional factors; vascular insults; inflammation; autoimmune disease; and malignancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01049217

  Show 63 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01049217     History of Changes
Other Study ID Numbers: A0081244
Study First Received: January 13, 2010
Results First Received: May 6, 2013
Last Updated: August 27, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
neuropathy
pain
HIV-1
HIV Infections

Additional relevant MeSH terms:
Neuralgia
Demyelinating Diseases
Polyneuropathies
Nerve Compression Syndromes
Neurologic Manifestations
Neurotoxicity Syndromes
Pain
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Signs and Symptoms
Poisoning
Substance-Related Disorders
Pregabalin
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anticonvulsants

ClinicalTrials.gov processed this record on July 29, 2014