Clinical trial NCT03407430
Conditions: Breast Cancer Lymphoma Pain
Keywords: Pregabalin Bone pain Pegfilgrastim Supportive care prevention
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2016-01-27; Completion date: 2017-07-20
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Purpose:

To evaluate the preventative effects of pregabalin on pegfilgrastim-induced bone pain in cycle 1. Because granulocyte colony stimulating factor (G-CSF) receptors are found at nerve endings which modulate the pain signal, blocking this with pregabalin is theorized to prevent the occurrence of this adverse effect.

Participants:

Patients will be at least 18 years of age with either a diagnosis of a non-myeloid hematologic malignancy scheduled to initiate a cycle of chemotherapy that requires prophylactic use of a G-CSF, or with a diagnosis of breast cancer scheduled to initiate dose-dense doxorubicin/cyclophosphamide chemotherapy or docetaxel/cyclophosphamide that requires prophylactic use of a G-CSF.

Procedures (methods):

This is a randomized (1:1), single center, placebo-controlled, double blind, crossover phase II study. The primary objective is to compare the proportion of patients who have an increase in pain score of ≥3 from baseline in cycle 1 between Arm A (pregabalin) and Arm B (placebo). In consultation with the treating physician, the PI will determine what day pegfilgrastim will be initiated in each eligible, consented patient. Pregabalin or placebo will begin 4 days prior to pegfilgrastim administration, and continue for 7 additional days starting the day of pegfilgrastim administration.

Detailed description:
\*\*Study Synopsis\*\*

This is a randomized, double-blind, placebo-controlled, single center, crossover phase II clinical trial investigating the prophylactic analgesic effects of pregabalin (Lyrica®) during the first two cycles of chemotherapy in cancer patients receiving pegfilgrastim (Neulasta®). The investigators have restricted enrollment in this trial to breast cancer patients and those with hematological malignancies, who require pegfilgrastim prophylactically. Pegfilgrastim is associated with bone pain (which can be severe) when used in these populations.

In this study 60 patients are randomized to Arm A (pregabalin in cycle 1; placebo in cycle 2) or Arm B (placebo in cycle 1; pregabalin in cycle 2). The primary objective is to compare the proportion of patients who have an increase in pain score of ≥3 from baseline through the end of study medication in cycle 1 between Arm A (pregabalin) and Arm B (placebo).

A secondary objective is to compare of the proportion of patients with an increase in pain score of ≥3 from baseline between pregabalin and placebo across the 2 cycles. Other outcomes evaluated are the safety of this combination, the proportion of patients with an increase in bone/joint pain score of ≥3 from baseline, the proportion of patients with severe pain, the maximum change in pain score, and time to and number of days of rescue (breakthrough) analgesics.

For measuring pain, the investigators will rely on a validated 10-point numerical pain scale that patients will complete prior to initiation of pregabalin in each cycle, and for 7 days starting the day of pegfilgrastim administration in each cycle.

Pegfilgrastim is a pegylated form of granulocyte colony-stimulating factor (G-CSF) which is FDA approved to decrease the duration of neutropenia, thus the incidence of infection, by stimulating granulocyte production in patients receiving myelosuppressive chemotherapy associated with a significant risk of febrile neutropenia. As a long-acting product, this pegylated version is administered once per chemotherapy cycle, 24-72 hours after chemotherapy is complete.

Bone and skeletal pain due to pegfilgrastim have been reported in early clinical trials at rates of 22-33%, with sites of pain commonly noted in the lower back, posterior iliac crest and sternum. However more recent studies have found incidences as high as 59-71% with 27% experiencing severe pain (pain greater than 5 on a 10-point scale). Notably, Kirshner and colleagues conducted a phase III randomized trial evaluating the non-steroidal anti-inflammatory (NSAID) naproxen for the prevention of pegfilgrastim-related bone pain in patients with nonmyeloid cancer. Patients completed questionnaires at home documenting any new bone or joint pain post pegfilgrastim. The majority enrolled (68%) had breast cancer, and 7% had hematological malignancies. In this study of 510 patients, (257 on naproxen and 253 on placebo), the overall pain incidence was 71.3% (27% severe) in the placebo group and 61.1 % (19.2% severe) in the naproxen group. While naproxen significantly reduced the incidence of all and severe bone pain, and reduced the duration of bone pain (from 2.4 to 1.9 days), the authors concluded that novel preventive strategies are needed given the high incidence of bone pain even when naproxen is used for treatment.

The average onset of bone pain is 4 days after initiation of pegfilgrastim and with a duration of between 2-3 consecutive days. Because patients get multiple cycles of chemotherapy every 14-28 days, these repeated episodes of bone pain can significantly hinder quality of life. In the case where pegfilgrastim is withheld because of severe bone pain, chemotherapy dose-intensity and schedule often cannot be maintained threatening efficacy in addition to an increased potential for infectious complications.

Bone pain secondary to pegfilgrastim is usually treated with NSAIDs such as ibuprofen or naproxen, or opioids. Opioids are often preferred over NSAIDs because patients may be thrombocytopenic and at risk for gastrointestinal bleeding, and NSAIDs increase the risk of both of these adverse events. In addition, NSAIDs have an antipyretic property which is problematic in neutropenic patients. Their use can mask febrile neutropenia, which could mean an important sign of infection is missed in immunocompromised hosts. Because there are no established predictive factors for development of bone pain, nearly all patients who get pegfilgrastim receive a prescription for opioids in case they experience pain. Patients do not take pain medications to prevent the pain, but instead generally wait until they experience pain before starting these analgesics. In general, pain is more difficult to control once it has started, thus a prophylactic strategy may be more advantageous. To avoid any impact on the dose and/or schedule of chemotherapy, it would be optimal to prevent bone pain occurring after administration of pegfilgrastim, rather than advising the patient to treat this pain if/when it happens.

Primary Objective

Compare the proportion of patients who have an increase in pain score of ≥ 3 from baseline through the end of study medication in cycle 1 between Arm A and Arm B

Secondary Objectives

* Compare the proportion of patients who have an increase in pain score of ≥ 3 from baseline between pregabalin and placebo across the 2 cycles
* Compare the proportion of patients who have an increase in bone/joint pain score of ≥ 3 from baseline through the end of study medication in cycle 1 between Arm A and Arm B
* Compare the number of days of breakthrough analgesic use between pregabalin and placebo within cycle 1 and across the 2 cycles
* Compare the proportion of patients with severe pain between pregabalin and placebo within cycle 1 and across the 2 cycles
* Compare the maximum change in pain score from baseline between pregabalin and placebo within cycle 1 and across the 2 cycles
* Compare the maximum neuropathic pain score between pregabalin and placebo within cycle 1 and across the 2 cycles
* Describe the safety (assessed via NCI CTCAE v4) of pregabalin when used in the prevention of bone pain secondary to pegfilgrastim

Exploratory Objective

* Compare pain measures between pregabalin and placebo in the breast cancer and hematological malignancy subgroups separately within cycle 1 and across the 2 cycles
* Compare the time to first breakthrough analgesic use between pregabalin and placebo during cycle 1

Primary Endpoint

Pain score is based on a 10-point numerical scale (see section 11.1) for pain as documented at baseline (at screening for cycle 1 and day 1 of study medication prior to cycle 2) and on patient log (see section 11.3) for 7 days starting the day of pegfilgrastim administration

Secondary/Exploratory Endpoints

* Bone/joint pain score is based on a 10-point numerical scale (see section 11.1) for pain as documented at baseline (at screening for cycle 1 and day 1 of study medication prior to cycle 2) and on patient log (see section 11.3) for 7 days starting the day of pegfilgrastim administration
* Severe pain will be measured using the 10-point numerical scale for pain (see section 11.1) as documented on the patient log (section 11.3; severe pain is defined as a score \>5 on this scale, similar to Kirshner and colleagues3)
* A day of breakthrough analgesic use is defined as any day in which patient increases the dose of any pain medication compared to baseline, or the addition of a new pain medication as documented on patient log (see section 11.3); time to first breakthrough analgesic use is defined as the time in days from pegfilgrastim administration to the first day patient uses breakthrough analgesic
* Neuropathic pain is assessed via the Neuropathic Pain Scale (see section 11.2) as documented from phone calls twice during study medication administration post pegfilgrastim administration.

Arms: arm 1: Pregabalin in cycle 1; placebo in cycle 2.

Pregabalin or matching placebo will be administered at 75 mg twice a day (BID) for 4 days, to patients receiving pegfilgrastim for hematologic malignancies or breast cancer patients on myelosuppressive chemotherapy . Starting the day of pegfilgrastim, the dose of study medication will be increased to 150 mg PO BID provided the patient is tolerating the lower dose (ie, they are not experiencing any pregabalin associated toxicities \>Grade 1). This will be determined by the research team on the day of pegfilgrastim administration. arm 2: Placebo in cycle 1; pregabalin in cycle 2.

Pregabalin or matching placebo will be administered at 75 mg BID for 4 days, to patients receiving pegfilgrastim for hematologic malignancies or breast cancer patients on myelosuppressive chemotherapy . Starting the day of pegfilgrastim, the dose of study medication will be increased to 150 mg PO BID provided the patient is tolerating the lower dose (ie, they are not experiencing any pregabalin associated toxicities \>Grade 1). This will be determined by the research team on the day of pegfilgrastim administration.
Interventions: intervention 1: Pregabalin intervention 2: Placebo
Intervention descriptions: intervention 1: During the first chemotherapy cycle, the patient will receive pregabalin 75mg (1 capsule) BID x 4 days before pegfilgrastim 6mg subcutaneous (SC) x1; then pregabalin 150mg (2 capsules) BID x 7 days. During the second chemotherapy cycle, the patient will receive placebo in the same dosing scheme. intervention 2: During the first chemotherapy cycle, the patient will receive placebo (1 capsule) BID x 4 days before pegfilgrastim 6mg SC x1; then placebo (2 capsules) BID x 7 days. During the second chemotherapy cycle, the patient will receive pregabalin in the same dosing scheme.

Protocol documents:
Prot_SAP_004.pdf: 
LINEBERGER COMPREHENSIVE CANCER CENTER 
December 7, 2016 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
PROTOCOL AMENDMENT #1 
December 7, 2016 
 
 
LCCC 1314: A phase II, placebo-controlled, double blind, randomized crossover 
trial of pregabalin for the prophylaxis of pegfilgrastim-induced bone pain 
 
AMENDMENT INCORPORATES (check all that apply): 
___ Editorial, administrative changes 
___ Scientific changes (IRB approval) 
_X_ Therapy changes (IRB approval) 
___ Eligibility Changes (IRB approval) 
 
AMENDMENT RATIONALE AND SUMMARY: 
 
To better support patient accrual into this study, we have made amendments to the dosing 
schedule of study medication. This new dosing schedule will continue to allow for 
titration of the study medications, helping to reduce study-related side effects, while still 
obtaining sufficient drug levels at the estimated time of drug-related bone pain onset 
(typically 4 days after Neulasta injection; patients will have been given pregabalin 150mg 
PO BID for at least 48 hours at theoretical onset). 
 
 
 
As such, we have made the following amendments to the study protocol (marked in red): 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
December 7, 2016 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
Schedule and Dose of Pregabalin: 
1.4.2 
Because we are interested in the prevention of pain, the duration of treatment 
with pregabalin for less than one week prior to pegfilgrastim with continued 
dosing for 10 days starting from the day of pegfilgrastim administration will be 
sufficient for primary prophylaxis.  See the Treatment Plan example at the front 
of this protocol for a graphic of dosing of study medication, chemotherapy and 
pegfilgrastim during a given chemotherapy cycle in a breast cancer patient 
receiving chemotherapy. 
 
The analgesic effect of pregabalin is dose-responsive often exerting its effect at 
an average oral dose of 150 mg BID.  For all approved indications of pregabalin, 
patients are generally started at a lower dose (e.g., 75 mg BID), with the dose 
increased to 150 mg BID to improve tolerance. Therefore, we will start all 
patients on 75 mg PO BID to begin on the day of chemotherapy prior to 
increasing the dose to 150 mg PO BID provided the patient is not experiencing 
>grade 1 pregabalin-associated side effects. 
 
Schema: 
4.1 
 
This is a randomized (1:1), single center, placebo-controlled, double blind 
crossover phase II study.  The primary objective is to compare the proportion of 
patients who have an increase in pain score of ≥3 from baseline in cycle 1 between 
Arm A (pregabalin) and Arm B (placebo). In consultation with the treating 
physician, the PI will determine what day pegfilgrastim will be initiated in each 
eligible, consented patient.  Pregabalin or placebo will begin on the day 
chemotherapy is adminstered, and continue for 10 days, with an increase in 
pregabalin or placebo dose after 4 days. Also see the Treatment Plan example at 
the front of this protocol for a graphic of dosing of study medication, 
chemotherapy and pegfilgrastim during a given chemotherapy cycle in a breast 


LINEBERGER COMPREHENSIVE CANCER CENTER 
December 7, 2016 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
cancer patient receiving chemotherapy. 
 
Pregabalin/Placebo Treatment Dosage and Administration: 
4.3 
Pregabalin or matching placebo will be administered at 75 mg BID for 4 days, to 
patients receiving pegfilgrastim for hematologic malignancies or breast cancer 
patients on myelosuppressive chemotherapy. Starting on the fifth day (after the 4 
days at 75mg), the dose of study medication will be increased to 150 mg PO 
BID provided the patient is tolerating the lower dose (ie, they are not 
experiencing any pregabalin associated toxicities > Grade 1).  This will be 
determined by the research team on the day of pegfilgrastim administration. See 
section 4.7 for additional information. 
 
At the time of consent and randomization, patients will be given two bottles of 
study medication, one labeled for cycle 1 and one for cycle 2.   They will be 
instructed on the specific date to initiate their first dose of study medication for 
each cycle, to start on the day of chemotherapy. 
 
Assessment of Efficacy: 
6.3 
Any patient who receives all pregabalin/matching placebo doses during the 4 
day titration period in cycle 1 will be evaluable for any efficacy objective 
concerning cycle 1.   Any patient who also receives all pregabalin/matching 
placebo doses during the 4 day titration period in cycle 2 will be evaluable for 
efficacy objectives across the 2 cycles. 
 
 
 
 
 
 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
December 7, 2016 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
Time and Events Table: 
6.1 
 
 
Cycle 1 & Cycle 2 
 
 
Screening 
Randomization 
Day of 
Chemotherapy 
Chemotherapy 
Pegfilgrastim 6mg SC x1 dose; dose scheduled in 
relation to chemotherapy in consultation with MD 
Day of 
Pegfilgrastim 
Phone Call 
#1 after 
Pegfilgrastim 
Phone Call 
#2 after 
Pegfilgrastim 
Informed consent 
X 
 
 
 
 
Confirm lack of bone 
metastases 
X 
 
 
 
 
Review of 
concomitant 
medication 
X 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
Serum creatinine 
X 
 
 
 
 
Pregabalin/Placebo 
 
X 
Continue study medication for 7 days starting 
from the day of pegfilgrastim 
10 point numerical 
pain scale & log 
X 
 
Patient maintains log of pain and pain 
medications for 7 days starting from the day of 
pegfilgrastim 
Patient adherence log 
Provide 
Patient begins 
diary of 
pregabalin 
Patient continues diary of pregabalin 
ID pain scale 
X 
 
 
X 
X 
Toxicity monitoring 
 
 
X 
X 
X 
X 
X 
 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
December 7, 2016 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC  1314: A phase II, placebo-controlled, double-blind, randomized crossover trial of 
pregabalin for the prophylaxis of pegfilgrastim-induced bone pain 
 
Principal Investigator 
Benyam Muluneh, PharmD, CPP 
101 Manning Drive, CB 7600 
Chapel Hill, NC 27599 
Phone: 919-445-5432 
Fax: 919-966-0304 
Email: bmuluneh@unch.unc.edu 
 
Principal Co-Investigator  
Hendrik van Deventer, MD 
Larry W. Buie, PharmD, BCOP, BCPS 
 
Co-Investigator(s) 
Jill Bates, PharmD, MS, BCOP 
Aimee Faso, PharmD, CPP, BCOP 
Matthew Foster, MD 
Hyman Muss, MD 
Stephen Bernard, MD 
Steven Park, MD 
Hyman Muss, MD 
Elizabeth Dees, MD 
Lisa Carey, MD 
Carey Anders, MD 
Katherine Reeder-Hayes, MD 
 
Biostatistician 
Dominic Moore 
UNC Lineberger Comprehensive Cancer Center, Room 20-014 
Chapel Hill, NC 27599 
Phone: (919) 966-8647; Fax:   919-966-4244 
dominic_t_moore@unc.edu 
 
Clinical Protocol Office 
Lineberger Comprehensive Cancer Center 
The University of North Carolina at Chapel Hill 
450 West Drive, 3rd Floor, CB# 7295 
Chapel Hill, NC 27599-7295 
 
Sponsor:  Lineberger Comprehensive Cancer Center 
 
Funding Source: Pfizer Co. (supply of pregabalin and placebo) 
Version: November 6, 2016 
 


LINEBERGER COMPREHENSIVE CANCER CENTER 
December 7, 2016 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC  1314: A phase II, placebo-controlled, double-blind, randomized crossover trial of 
pregabalin for the prophylaxis of pegfilgrastim-induced bone pain 
 
 
 
 
Principal Investigator 
Benyam Muluneh, PharmD, BCOP, CPP 
101 Manning Drive, CB 7600 
Chapel Hill, NC 27599 
Phone: 919-445-5432 
Fax: 919-966-0304 
Email: bmuluneh@unch.unc.edu 
 
 
 
Signature Page 
  
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
Principal Investigator (PI) Name: Benyam Muluneh, PharmD, BCOP, CPP 
 
PI Signature: 
 
Date: April 12, 2015


LINEBERGER COMPREHENSIVE CANCER CENTER 
 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
 
 
 
 
TREATMENT PLAN EXAMPLE FOR BREAST CANCER PATIENT 
-see schema for full study design 
 
 
 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
i 
TABLE OF CONTENTS 
1.0 
BACKGROUND AND RATIONALE ..................................................................4 
1.1 
Study Synopsis ......................................................................................................4 
1.2 
Pegfilgrastim-associated Bone Pain ......................................................................4 
1.3 
Pregabalin ..............................................................................................................5 
1.4 
Study Design .........................................................................................................6 
1.5 
Rationale................................................................................................................8 
2.0 
STUDY OBJECTIVES ...........................................................................................8 
2.1 
Primary Objective .................................................................................................8 
2.2 
Secondary Objectives ............................................................................................8 
2.3 
Exploratory Objective ...........................................................................................9 
2.4 
Primary Endpoint ..................................................................................................9 
2.5 
Secondary/Exploratory Endpoints ........................................................................9 
3.0 
PATIENT ELIGIBILITY ....................................................................................10 
3.1 
Inclusion Criteria .................................................................................................10 
3.2 
Exclusion Criteria ................................................................................................11 
4.0 
TREATMENT PLAN ...........................................................................................12 
4.1 
Schema ................................................................................................................12 
4.2 
Treatment Assignment and Blinding...................................................................12 
4.3 
Pregabalin/Placebo Treatment Dosage and Administration................................13 
4.4 
Pegfilgrastim Dosage and Administration ..........................................................13 
4.5 
Pain Measures .....................................................................................................14 
4.6 
Patient Phone Contact .........................................................................................14 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
ii 
4.7 
Pregabalin Toxicities and Dosing Delays/Dose Modifications...........................14 
4.8 
Concomitant Medications/Treatments ................................................................15 
4.9 
Duration of Pregabalin/Matching Placebo Therapy ............................................16 
4.10 
Duration of Follow Up ........................................................................................16 
4.11 
Removal of Patients from Protocol Therapy .......................................................16 
4.12 
Study Withdrawal ................................................................................................16 
5.0 
PREGABALIN DRUG INFORMATION ..........................................................17 
5.1 
Dosage and Administration .................................................................................17 
5.2 
Storage and Handling ..........................................................................................17 
5.3 
Adverse Events ....................................................................................................17 
6.0 
EVALUATIONS AND ASSESSMENTS ............................................................21 
6.1 
Time and Events Table ........................................................................................21 
6.2 
Footnotes for Time and Events Table .................................................................22 
6.3 
Assessment of Efficacy .......................................................................................22 
6.4 
Assessment of Safety ..........................................................................................22 
7.0 
ADVERSE EVENTS ............................................................................................23 
7.1 
Definitions ...........................................................................................................23 
7.2 
Documentation of non-serious AEs or SARs ......................................................24 
7.3 
SAEs or Serious SARs ........................................................................................25 
7.4 
Data and Safety Monitoring Plan ........................................................................26 
8.0 
STATISTICAL CONSIDERATIONS ................................................................27 
8.1 
Study Design and Accrual ...................................................................................27 
8.2 
Sample Size and Stopping Rule ..........................................................................27 
8.3 
Data Analysis Plans .............................................................................................28 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
iii 
9.0 
STUDY MANAGEMENT ....................................................................................29 
9.1 
Institutional Review Board (IRB) Approval and Consent ..................................29 
9.2 
Required Documentation.....................................................................................29 
9.3 
Registration Procedures.......................................................................................30 
9.4 
Data Management and Monitoring/Auditing ......................................................30 
9.5 
Adherence to the Protocol ...................................................................................30 
9.6 
Amendments to the Protocol ...............................................................................31 
9.7 
Record Retention .................................................................................................32 
9.8 
Obligations of Investigators ................................................................................32 
10.0 REFERENCES ......................................................................................................33 
11.0 APPENDICES .......................................................................................................34 
11.1 
Appendix 1: Numerical Scale for Pain6: .............................................................34 
11.2 
Appendix 2: Neuropathic Pain Scale (ID Pain)7: ................................................34 
11.3 
Appendix 3:  Model Patient Pain Monitoring Log ..............................................35 
11.4 
Appendix 4:  Model Pregabalin/Placebo Medication Compliance Diary ...........36 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
4 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
This is a randomized, double-blind, placebo-controlled, single center, crossover 
phase II clinical trial investigating the prophylactic analgesic effects of pregabalin 
(Lyrica®) during the first two cycles of chemotherapy in cancer patients receiving 
pegfilgrastim (Neulasta®). We have restricted enrollment in this trial to breast 
cancer patients and those with hematological malignancies, who require 
pegfilgrastim prophylactically.  Pegfilgrastim is associated with bone pain (which 
can be severe) when used in these populations. 
 
In this study 60 patients are randomized to Arm A (pregabalin in cycle 1; placebo 
in cycle 2) or Arm B (placebo in cycle 1; pregabalin in cycle 2).  The primary 
objective is to compare the proportion of patients who have an increase in pain 
score of ≥3 from baseline through the end of study medication in cycle 1 between 
Arm A (pregabalin) and Arm B (placebo).   
 
A secondary objective is to compare of the proportion of patients with an increase 
in pain score of ≥3 from baseline between pregabalin and placebo across the 2 
cycles. Other outcomes evaluated are the safety of this combination, the 
proportion of patients with an increase in bone/joint pain score of ≥3 from  
baseline, the proportion of patients with severe pain, the maximum change in pain 
score, and time to and number of days of rescue (breakthrough) analgesics.  
 
For measuring pain, we will rely on a validated 10-point numerical pain scale that 
patients will complete prior to initiation of pregabalin in each cycle, and for 7 
days starting the day of pegfilgrastim administration in each cycle.   
1.2 
Pegfilgrastim-associated Bone Pain   
Pegfilgrastim is a pegylated form of granulocyte colony-stimulating factor (G-
CSF) which is FDA approved to decrease the duration of neutropenia, thus the 
incidence of infection, by stimulating granulocyte production in patients receiving 
myelosuppressive chemotherapy associated with a significant risk of febrile 
neutropenia.1 As a long-acting product, this pegylated version is administered 
once per chemotherapy cycle, 24-72 hours after chemotherapy is complete.  
 
Bone and skeletal pain due to pegfilgrastim have been reported in early clinical 
trials at rates of 22-33%, with sites of pain commonly noted in the lower back, 
posterior iliac crest and sternum.  However more recent studies have found 
incidences as high as 59-71% with 27% experiencing severe pain (pain greater 
than 5 on a 10-point scale).2,3   Notably, Kirshner and colleagues conducted a 
phase III randomized trial evaluating the non-steroidal anti-inflammatory 
(NSAID) naproxen for the prevention of pegfilgrastim-related bone pain in 
patients with nonmyeloid cancer.  Patients completed questionnaires at home 
documenting any new bone or joint pain post pegfilgrastim.  The majority 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
5 
enrolled (68%) had breast cancer, and 7% had hematological malignancies. In this 
study of 510 patients, (257 on naproxen and 253 on placebo), the overall pain 
incidence was 71.3% (27% severe) in the placebo group and 61.1 % (19.2% 
severe) in the naproxen group.  While naproxen significantly reduced the 
incidence of all and severe bone pain, and reduced the duration of bone pain 
(from 2.4 to 1.9 days), the authors concluded that novel preventive strategies are 
needed given the high incidence of bone pain even when naproxen is used for 
treatment.3 
 
The average onset of bone pain is 4 days after initiation of pegfilgrastim and with 
a duration of between 2-3 consecutive days.3,4  Because patients get multiple 
cycles of chemotherapy every 14-28 days, these repeated episodes of bone pain 
can significantly hinder quality of life.  In the case where pegfilgrastim is 
withheld because of severe bone pain, chemotherapy dose-intensity and schedule 
often cannot be maintained threatening efficacy in addition to an increased 
potential for infectious complications. 
 
Bone pain secondary to pegfilgrastim is usually treated with NSAIDs such as 
ibuprofen or naproxen, or opioids.  Opioids are often preferred over NSAIDs 
because patients may be thrombocytopenic and at risk for gastrointestinal 
bleeding, and NSAIDs increase the risk of both of these adverse events.  In 
addition, NSAIDs have an antipyretic property which is problematic in 
neutropenic patients.  Their use can mask febrile neutropenia, which could mean 
an important sign of infection is missed in immunocompromised hosts.  Because 
there are no established predictive factors for development of bone pain3, nearly 
all patients who get pegfilgrastim receive a prescription for opioids in case they 
experience pain.  Patients do not take pain medications to prevent the pain, but 
instead generally wait until they experience pain before starting these analgesics.  
In general, pain is more difficult to control once it has started, thus a prophylactic 
strategy may be more advantageous.  To avoid any impact on the dose and/or 
schedule of chemotherapy, it would be optimal to prevent bone pain occurring 
after administration of pegfilgrastim, rather than advising the patient to treat this 
pain if/when it happens.  
1.3 
Pregabalin 
1.3.1 Introduction 
Pregabalin (Lyrica®) is a medication indicated for various types of nerve-related 
pain, and as an adjunctive therapy for patients with partial onset seizures. It binds 
to the alpha2-delta subunit of the voltage gated calcium channels within the 
central nervous system (CNS) and inhibits excitatory neurotransmitter release.  
Pregabalin is structurally related to gamma-aminobutyric acid (GABA) but does 
not bind to GABA or benzodiazepine receptors.  Pregabalin’s maximal analgesic 
onset of action is about one week.  Plasma levels of pregabalin peak in 1.5 hours 
(3 hours with food), and it has an elimination half-life of approximately 6 hours.  
Significant drug-drug interactions are not associated with pregabalin as it 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
6 
undergoes negligible metabolism prior to excretion in the urine, and does not bind 
to serum proteins.  
1.3.2 Safety 
Common toxicities associated with pregabalin include peripheral edema (≤16%), 
CNS effects (such as dizziness [8-45%], somnolence [4-36%], ataxia [1-20%], 
headache [5-15%], fatigue [5-11%]) and weight gain (≤16%).   Rare but serious 
toxicities associated with pregabalin include angioedema, hypersensitivity, 
thrombocytopenia, rhabdomyolysis, suicidal ideation, and visual disturbances.  
Pregabalin-induced adverse effects are likely to be more prominent when 
administered continuously long-term for chronic conditions versus intermittent 
use with a regimen of chemotherapy.  The rates of drug discontinuation due to 
toxicity in pregabalin placebo-controlled registrational trials were: 3-11% for 
pregabalin daily-dose of 150 mg, 16% for pregabalin daily-dose of 300 mg and 
and 5-10% for placebo.5 
 
No known drug-interaction exists between pregabalin and pegfilgrastim, and 
based on their mechanisms of action and pharmacokinetics, none is predicted.  
Based on experience of the investigators of this trial, the two drugs are often used 
in combination in cancer patients with no adverse outcomes.   
 
Dose-dependent increases in the incidence of hemangiosarcoma were reported in 
mice that received pregabalin at doses of 200-500 mg/kg for two years.  The 
lowest dose and AUC that correlated with the incidence of hemangiosarcomas 
was estimated to be at an equivalent human dose of 600 mg per day.  Of note, 
there have never been any reported cases of carcinogenicity with pregabalin and it 
is considered safe and often utilized for the management of neuropathic pain in 
cancer patients.    
 
Pregabalin can also rarely cause a modest decrease in platelet counts with an 
average drop of 20 x 103/μL as compared to 11 x 103/μL in the placebo arm from 
registrational clinical trials (pregabalin prescribing information).  Clinically 
significant decreased platelet counts (defined as 20% below baseline value and 
<150 × 10
3/μL) occurred in 3% of pregabalin-treated patients (compared to 2% in 
the placebo group).  We do not anticipate this will be an issue with LCCC1314 as 
pregabalin administration will be limited to 11 days duration during either cycle 1 
or cycle 2.  Further, in subjects enrolled with hematological malignancies, any 
effects on platelets from pregabalin will be dwarfed by those from the 
chemotherapy regimens this group receives, and we do not anticipate pregabalin 
will delay the time to recovery.   In addition, platelet counts will be obtained 
regularly as part of the post-chemotherapy standard of care.   
1.4 
Study Design 
This is a randomized, double-blind, placebo-controlled, crossover phase II clinical 
trial of 60 patients investigating the prophylactic analgesic effects of pregabalin 
(Lyrica®) during the first two cycles of chemotherapy in cancer patients receiving 


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pegfilgrastim (Neulasta®).  We have restricted enrollment in this trial to breast 
cancer patients and those with hematological malignancies, who require 
pegfilgrastim prophylactically.  This allows us to limit the variety of tumor types 
enrolled, and to restrict our analysis to pegfilgrastim, versus filgrastim. 
 
Similar to Kirshner3, we will not exclude patients who are receiving analgesics at 
the time of enrollment, but the type and doses of each at the time of screening will 
be recorded.  Patients who are enrolled and subsequently require an increase in 
analgesics due to the discomfort associated with placement of a chemotherapy 
port will be withdrawn from the study if they still require these analgesics on day 
1 (D1) of chemotherapy. The use of acetaminophen for blood transfusions will be 
allowed, with the dose and frequency documented. 
 
The primary objective of the trial will focus on cycle 1.  Using a crossover 
component may increase the rate of accrual and will give us more power to detect 
potential differences in pain measures between pregabalin and placebo. However, 
given that pegfilgrastim’s association with bone pain varies between cycles 1 and 
2, and given the possibility of increased analgesic use in the placebo group in 
cycle 1, evaluation of the data across 2 cycles will be secondary, and hypothesis 
generating.  
1.4.1 Focus on Cycle 1 
The oncology literature supports increased frequency of bone pain when 
pegfilgrastim is used in cycle 1 of chemotherapy compared to subsequent cycles.8 
In a retrospective review of 7 randomized controlled trials comparing filgrastim to 
pegfilgrastim, the incidence of bone pain was most common in the first cycle 
(46.2% for pegfilgrastim) of chemotherapy, decreasing in subsequent cycles 
(30.9% in cycle 2). Within the same study, the authors performed an exploratory 
analysis of 23 chemotherapy-induced neutropenia trials that incorporated 
pegfilgrastim.  Within this group of studies, the incidence of bone pain decreased 
from 35.1% (cycle 1) to 22.7% (cycle 2).8   Focusing our primary objective on 
cycle 1 should provide the best opportunity to compare the incidence of pain 
between pregabalin and placebo when using pregabalin as a prophylactic.   
 
We chose a change in pain score of ≥3 since this change is considered clinically 
meaningful by the research team based on clinical experience. 
1.4.2 Schedule and Dose of Pregabalin 
Because we are interested in the prevention of pain, the duration of treatment with 
pregabalin for less than one week prior to pegfilgrastim with continued dosing for 
10 days starting from the day of pegfilgrastim administration will be sufficient for 
primary prophylaxis.  See the Treatment Plan example at the front of this protocol 
for a graphic of dosing of study medication, chemotherapy and pegfilgrastim 
during a given chemotherapy cycle in a breast cancer patient receiving 
chemotherapy. 
 


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The analgesic effect of pregabalin is dose-responsive often exerting its effect at an 
average oral dose of 150 mg BID.  For all approved indications of pregabalin, 
patients are generally started at a lower dose (e.g., 75 mg BID), with the dose 
increased to 150 mg BID to improve tolerance. Therefore, we will start all 
patients on 75 mg PO BID to begin on the day of chemotherapy prior to 
increasing the dose to 150 mg PO BID provided the patient is not experiencing 
>grade 1 pregabalin-associated side effects.   
 
Given the short half-life of pregabalin, the schedule of administration as outlined 
in the schema allows a sufficient washout period between cycle 1 and initiation of 
study medication prior to cycle 2. 
1.4.3 Early Stopping Rule 
In this trial toxicity will be monitored continuously, with an early stopping rule 
for cycle 1 in place to avoid excess toxicity related to use of this prophylactic 
analgesic.  The early stopping rule, applied to each arm separately, is based on a 
maximum acceptable ≥ grade 2 pregabalin-associated toxicity rate of 25%.  
Pregabalin associated toxicities not included in this rate of 25% are weight gain or 
dry mouth.  In assessing adverse events and attribution during the course of this 
study, we will consider those adverse events commonly associated with 
pregabalin, the specific chemotherapy administered and pegfilgrastim. 
1.5 
Rationale 
The purpose of this study is to evaluate the preventative effects of pregabalin on 
pegfilgrastim-induced bone pain in cycle 1.  Because G-CSF receptors are found 
at nerve endings which modulate the pain signal, blocking this with pregabalin is 
theorized to prevent the occurrence of this adverse effect.9 
 
If the data suggest a role for pregabalin as a prophylactic analgesic in this setting, 
data generated from the primary objective along with the additional data collected 
from the crossover portion will be used to design a larger, multicenter study.   
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
2.1.1 Compare the proportion of patients who have an increase in pain score of ≥ 3 
from baseline through the end of study medication in cycle 1 between Arm A and 
Arm B  
2.2 
Secondary Objectives    
2.2.1 Compare the proportion of patients who have an increase in pain score of ≥ 3 
from baseline between pregabalin and placebo across the 2 cycles  


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2.2.2 Compare the proportion of patients who have an increase in bone/joint pain score 
of ≥ 3 from baseline through the end of study medication in cycle 1 between Arm 
A and Arm B  
2.2.3 Compare the number of days of breakthrough analgesic use between pregabalin 
and placebo within cycle 1 and across the 2 cycles  
2.2.4 Compare the proportion of patients with severe pain between pregabalin and 
placebo within cycle 1 and across the 2 cycles  
2.2.5 Compare the maximum change in pain score from baseline between pregabalin 
and placebo within cycle 1 and across the 2 cycles  
2.2.6 Compare the maximum neuropathic pain score between pregabalin and placebo 
within cycle 1 and across the 2 cycles  
2.2.7 Describe the safety (assessed via NCI CTCAE v4) of pregabalin when used in the 
prevention of bone pain secondary to pegfilgrastim 
2.3 
Exploratory Objective 
2.3.1 Compare pain measures between pregabalin and placebo in the breast cancer and 
hematological malignancy subgroups separately within cycle 1 and across the 2 
cycles  
2.3.2 Compare the time to first breakthrough analgesic use between pregabalin and 
placebo during cycle 1 
 
2.4 
Primary Endpoint 
2.4.1 Pain score is based on a 10-point numerical scale (see section 11.1) for pain as 
documented at baseline (at screening for cycle 1 and day 1 of study medication 
prior to cycle 2) and on patient log (see section 11.3) for 7 days starting the day of 
pegfilgrastim administration 
 
2.5 
Secondary/Exploratory Endpoints 
2.5.1 Bone/joint pain score is based on a 10-point numerical scale (see section 11.1) for 
pain as documented at baseline (at screening for cycle 1 and day 1 of study 
medication prior to cycle 2) and on patient log (see section 11.3) for 7 days 
starting the day of pegfilgrastim administration 
2.5.2 Severe pain will be measured using the 10-point numerical scale for pain (see 
section 11.1) as documented on the patient log (section 11.3; severe pain is 
defined as a score >5 on this scale, similar to Kirshner and colleagues3) 


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2.5.3 A day of breakthrough analgesic use is defined as any day in which patient 
increases the dose of any pain medication compared to baseline, or the addition of 
a new pain medication as documented on patient log (see section 11.3); time to 
first breakthrough analgesic use is defined as the time in days from pegfilgrastim 
administration to the first day patient uses breakthrough analgesic 
2.5.4 Neuropathic pain is assessed via the Neuropathic Pain Scale (see section 11.2) as 
documented from phone calls twice during study medication administration post 
pegfilgrastim administration.   
 
 
3.0 
PATIENT ELIGIBILITY  
3.1 
Inclusion Criteria 
Subject must meet all of the inclusion criteria to participate in this study:  
3.1.1 Age ≥18 years 
3.1.2 Diagnosis of a non-myeloid hematologic malignancy scheduled to initiate a cycle 
of chemotherapy that requires prophylactic use of a granulocyte colony-
stimulating growth factor (based on the provider’s discretion), provided the 
schedule of chemotherapy cycles allows the use of pegfilgrastim at a dose of 6 mg 
SC once per cycle 
 
OR 
 
Diagnosis of breast cancer scheduled to initiate dose-dense doxorubicin and 
cyclophosphamide (AC) chemotherapy or docetaxel and cyclophosphamide  (TC) 
chemotherapy that requires prophylactic use of a granulocyte colony-stimulating 
growth factor, provided the schedule of chemotherapy cycles allows the use of 
pegfilgrastim, at a dose of 6 mg SC once per cycle; pegfilgrastim scheduled for 24 
hours post chemotherapy. 
3.1.3 Schedule of chemotherapy and pegfilgrastim initiation can accommodate 
initiation of pregabalin 4 days prior to pegfilgrastim dose 
3.1.4 Baseline pain scores <7 as measured via 10-point numerical scale for pain (see 
section 11.1); pain score and use of any non-opioid pain medication must be self-
reported as stable (same dose and frequency) over the 7 days prior to screening; 
for opioids, patient must self-report the same dose and frequency over the 28 days 
prior to screening.  Patients who are receiving peri-procedural short-acting 
analgesics will still be included as long as they are no longer receiving analgesics 
by D1 of chemotherapy. 
 
 


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3.2 
Exclusion Criteria 
Any subject meeting any of the following exclusion criteria at baseline will be 
ineligible for study participation: 
3.2.1 A history of (within one month) or current pregabalin use 
3.2.2 Baseline pain scores ≥7 as measured via 10-point numerical scale for pain (see 
section 11.1) 
3.2.3 Unwilling to discontinue use of antihistamines from 7 days prior to D1 of study 
medication 
3.2.4 CrCl ≤60 ml/min (as measured via Cockcroft-Gault ) based on serum creatinine 
measured as part of standard of care prior to administration of chemotherapy 
3.2.5 Women of childbearing potential must have a negative serum pregnancy test prior 
to initiating therapy (note, this test should be standard of care prior to 
administration of chemotherapy) 
3.2.6 Patient is unable or unwilling to abide by the study protocol or cooperate fully 
with the investigator 
3.2.7 Eligible and agrees to enroll into therapeutic trial ongoing at LCCC (i.e., the 
treatment trial will take precedence over LCCC1314) 
3.2.8 Currently receiving therapeutic doses of anticoagulants (ie, prophylactic use of 
anticoagulants is allowed) due to possibility of dizziness and falls while on 
pregabalin 
3.2.9 Currently receiving aromatase inhibitors or agents targeted against Ph+ leukemias 
(i.e., imatinib, dasatinib, nilotinib, nolotinib, and ponatinib) or scheduled to start 
these drugs during cycle 1 of scheduled chemotherapy.  
3.2.10 Presence of bone metastases 
3.2.11 History of angioedema  
3.2.12 History of a seizure disorder 
 
 
 
 
 
 
 
 
 


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4.0 
TREATMENT PLAN 
4.1 
Schema 
 
 
 
This is a randomized (1:1), single center, placebo-controlled, double blind 
crossover phase II study.  The primary objective is to compare the proportion of 
patients who have an increase in pain score of ≥3 from baseline in cycle 1 
between Arm A (pregabalin) and Arm B (placebo). In consultation with the 
treating physician, the PI will determine what day pegfilgrastim will be initiated 
in each eligible, consented patient.  Pregabalin or placebo will begin on the day 
chemotherapy is administered, and continue for 10 days, with an increase in 
pregabalin or placebo dose after 4 days. Also see the Treatment Plan example at 
the front of this protocol for a graphic of dosing of study medication, 
chemotherapy and pegfilgrastim during a given chemotherapy cycle in a breast 
cancer patient receiving chemotherapy. 
4.2 
Treatment Assignment and Blinding 
At the end of the screening period, eligible patients will be randomly assigned in a 
1:1 ratio to Arm A or Arm B in a double-blind fashion such that neither the 
Investigator, Sponsor, nor the patient will know which agent is being 
administered.  The randomization will be assigned by the statistician(s) of record 
who will provide this information to UNC Investigational Drug Services.  A block 
randomization scheme will be utilized, and stratified by tumor type (breast cancer 
or hematological malignancy) and age (<65 or ≥65). Anecdotally, younger 
patients seem to self-report pain more frequently than older patients.  
Stratification by age ensures some comparability between arms related to this 
factor.  


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Pregabalin and placebo will be identical in appearance in order to preserve 
blinding. 
4.2.1 Emergency Unblinding 
Unblinding may occur for emergency purposes only.  Investigators should note 
that the occurrence of a SAE should not routinely precipitate the immediate 
unblinding of the label.  Patients will be unblinded as per the Unblinding Plan, a 
document provided separate to this protocol. 
4.3 
Pregabalin/Placebo Treatment Dosage and Administration 
Pregabalin or matching placebo will be administered at 75 mg BID for 4 days, to 
patients receiving pegfilgrastim for hematologic malignancies or breast cancer 
patients on myelosuppressive chemotherapy. Starting on the fifth day of 
pegfilgastim (after the 4 days at 75 mg), the dose of study medication will be 
increased to 150 mg PO BID provided the patient is tolerating the lower dose (ie, 
they are not experiencing any pregabalin associated toxicities >Grade 1).  This 
will be determined by the research team on the day of pegfilgrastim 
administration. See section 4.7 for additional information. 
 
At the time of consent and randomization, patients will be given two bottles of 
study medication, one labeled for cycle 1 and one for cycle 2.   They will be 
instructed on the specific date to initiate their first dose of study medication for 
each cycle, to start on the day of chemotherapy.  
 
Patients will be instructed to document their adherence by noting the time of each 
dose on a diary (see section 11.4 for model diary) and to take their first daily dose 
of pregabalin at approximately the same time each day. The second dose of 
pregabalin should be administered approximately 12 hours after the morning 
dose.  If a dose is vomited or if a dose is missed for any reason, the dose should 
not be made up. Patients should note any missed doses on their medication diary, 
see section 11.4.   
 
Pregabalin/matching placebo may be taken with or without a meal; tablets should 
be swallowed whole with a glass of water, and should not be chewed or crushed.   
4.4 
Pegfilgrastim Dosage and Administration 
Pegfilgrastim 6 mg SC is to be administered as per standard of care based on the 
judgment of the prescribing hematologist/oncologist.  It is being provided free of 
charge to study participants by Amgen. The date of administration of 
pegfilgrastim in relation to the chemotherapy regimen will be decided by the 
hematologist/oncologist.  For hematologic malignancy patients, pegfilgrastim is 
usually administered 24 to 72 hours after chemotherapy. For breast cancer 
patients receiving dose dense AC or receiving TC, pegfilgrastim is usually 
administered 24 hours after chemotherapy. See sections 7.2 and 7.4.3 regarding 


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required documentation and reporting of any safety issues (other than adverse 
events) associated with the pegfilgrastim product or its administration. 
4.5 
Pain Measures  
4.5.1 Ten-point numerical scale 
The ten-point numerical scale is scored from 0 to 10.   Patients will complete this 
scale at screening, and then on a daily basis for 7 days starting the day of 
pegfilgrastim administration in both cycles 1 and 2.  They will use this scale to 
rate their pain (and separately bone/joint pain) with 0 signifying “no pain” and 10 
signifying “the worst pain you can imagine.” See section 11.1 and section 11.3 for 
the model patient pain monitoring log. 
4.5.2 ID-Pain (Neuropathic Pain Scale) 
The ID-Pain scale is a 6-item, patient-completed screening tool designed to help 
differentiate nociceptive and neuropathic pain.  Details of the scale and scoring 
are located in section 11.2. Patients will complete this scale on the day of 
enrollment, and then will be asked the questions from this scale by the research 
team via telephone twice during study medication administration after 
pegfilgrastim administration in cycles 1 and 2. 
4.6 
Patient Phone Contact 
Patients will be contacted by a study team member twice during study medication 
administration after pegfilgrastim administration in cycles 1 and 2.  Patients will 
be asked about any side effects they may be experiencing from their study 
medication.  If the patient makes any mention of pain, the study coordinator will 
remind the patient to note this information using the pain logs.  Patients will also 
be reminded during these phone calls to complete the daily pain log and 
compliance diary  (see 11.3 and 11.4 for model pain monitoring log and model 
medication compliance diary) and will be asked the questions from the 
Neuropathic Pain Scale (see 11.2) by the research team.  Patients will also be 
reminded to complete the list and doses of each pain medication on the day they 
start their pre-cycle 2 study medication. 
4.7 
Pregabalin Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives at least one dose of pregabalin/matching placebo on this 
protocol will be evaluable for toxicity.  Each patient will be assessed regularly for 
the development of any toxicity according to the Time and Events tables (see 
Section 6.0). Toxicity will be assessed according to the NCI CTCAE, v4. 
 
In assessing adverse events and attribution during the course of this study, we will 
consider those adverse events commonly associated with pregabalin, the specific 
chemotherapy administered and pegfilgrastim. 
 
The most common adverse reactions in placebo controlled trials of pregabalin 
(≥5% and twice the frequency of placebo) include dizziness, somnolence, dry 


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mouth, edema, blurred vision, weight gain, and difficult with concentration/ 
attention.  For complete prescribing information, see www.pfizer.com.  See 
section 5.3 for additional information on pregabalin warnings and precautions. 
 
There have been postmarketing reports of hypersensitivity in patients shortly after 
initiation of treatment with pregabalin. Adverse reactions included skin redness, 
blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately 
in patients with these symptoms. 
 
In clinical trials, dizziness and somnolence generally began shortly after the 
initiation of pregabalin therapy and occurred more frequently at higher doses.   
 
If a patient experiences ≤grade 1 pregabalin associated toxicity, the patient should 
remain on the same dose of pregabalin/matching placebo, and be monitored daily 
via telephone contact until the side effect is resolved.  If a patient experiences 
grade ≥2 pregabalin associated toxicity, the dose can be reduced to 75 mg PO 
BID if they are receiving 150 mg PO BID.  Otherwise, study medication should 
be permanently discontinued and he/she should be followed up per protocol. See 
section 5.3 for specific information on pregabalin related adverse events.  See 
section 8.2 for details on the continuous toxicity monitoring for the study and 
early stopping rule. 
 
If the CrCl ≤60 ml/min at the start of cycle 2, then the patient should be 
withdrawn from study medication and followed up per protocol. 
 
4.8 
Concomitant Medications/Treatments 
4.8.1 Prohibited Medications 
Aromatase inhibitors and agents targeted against Ph+ leukemias (i.e., imatinib, 
dasatinib, nilotinib, nolotinib, and ponatinib) are prohibited as joint pain, stiffness 
and arthralgia are common side effects associated with this class of drugs. 
Antihistamines will also be prohibited as there is anecdotal evidence of analgesic 
effects from this class of drugs against growth-factor induced bone pain. 
4.8.2 Drug Interactions 
Pregabalin is predominantly excreted unchanged in the urine, undergoes 
negligible metabolism in humans (<2% of a dose recovered in urine as 
metabolites), and does not bind to plasma proteins.  Therefore its 
pharmacokinetics is unlikely to be affected by other agents through metabolic 
interactions or protein binding displacement. In vitro and in vivo studies showed 
that pregabalin is unlikely to be involved in significant pharmacokinetic drug 
interactions. 
 
No known drug-interaction exists between pregabalin and pegfilgrastim, and 
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Based on experience of the investigators of this trial, the two drugs are often used 
in combination in cancer patients with no adverse outcomes.   
 
4.9 
Duration of Pregabalin/Matching Placebo Therapy 
Treatment with pregabalin/matching placebo may continue until: 
 Patient continues to require pain medication related to port placement 
on D1 of chemotherapy 
 CrCl ≤60 ml/min at start of cycle 2 
 Patient has completed 11 days of pregabalin/matching placebo therapy 
during cycle 2 
 Intercurrent illness prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient decides to withdraw from treatment, OR 
 General or specific changes in the patient’s condition render the 
patient unacceptable for further treatment in the judgment of the 
investigator 
4.10 
Duration of Follow Up 
All enrolled patients for pregabalin prophylaxis will be followed up per protocol 
through the last day of pregabalin/placebo administration in cycle 2. Patients 
removed from study treatment for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.  
4.11 
Removal of Patients from Protocol Therapy 
Patients will be removed from study treatment when any of the criteria listed in 
section 4.9 apply. Notify the Principal Investigator, and document the reason for 
removal from study treatment and the date the patient was removed in the Case 
Report Form (CRF). The patient should be followed-up per protocol.     
 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in both the medical records and in the CRF. 
 
Excessive patient withdrawals from protocol therapy or from the study can render 
the study un-interpretable; therefore, unnecessary withdrawal of patients should 
be avoided. 
4.12 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol 
therapy) all efforts should be made to complete and report study assessments as 
thoroughly as possible. The investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as 
completely as possible the reason for the study withdrawal. A complete final 
evaluation at the time of the patient’s study withdrawal should be made with an 


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explanation of why the patient is withdrawing from the study. If the reason for 
removal of a patient from the study is an adverse event, the principal specific 
event will be recorded on the CRF 
5.0 
PREGABALIN DRUG INFORMATION 
See www.pfizer.com for the complete pregabalin prescribing information.   
5.1 
Dosage and Administration 
See section 4.3 for the doses to be used in the current study LCCC1314.  For its 
approved indications, the starting and optimal doses are listed in the table below.   
 
Indication 
Starting Dose 
Optimal Dose 
Diabetic Peripheral 
Neuropathy 
50 mg TID 
100 mg TID 
Postherpetic Neuralgia 
75 mg BID 
150 mg BID 
Partial Onset Seizures 
75 mg BID or 50 mg TID 
Titrate to efficacy and 
tolerability to maximum of 600 
mg daily 
Fibromyalgia 
75 mg BID 
300-450 mg daily 
 
5.1.1 Patients with Renal Impairment 
In view of dose-dependent adverse reactions and since pregabalin is eliminated 
primarily by renal excretion, dose is adjusted in patients with reduced renal 
function. In this study patients with impaired renal function (defined as CrCL ≤ 
60 mL/min) will be excluded.  
5.2 
Storage and Handling 
Recommended storage is at 25°C (77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F) per package insert recommendations.   
5.3 
Adverse Events 
In addition to the safety information in section 1.3 and below, see the prescribing 
information at www.pfizer.com for detailed safety information.    Most common 
adverse reactions (≥ 5% and twice placebo) from registrational trials were 
dizziness,  somnolence, dry mouth, edema, blurred vision, weight gain and 
abnormal thinking (primarily difficulty with concentration/attention).  In addition 
to its tumorigenic potential and its association with decreased platelet counts 
described in section 1.3, additional warnings and precautions related to the 
following are in the pregabalin prescribing information. 
5.3.1 Angioedema 
There have been postmarketing reports of angioedema in patients during initial 
and chronic treatment with pregabalin. Specific symptoms included swelling of 
the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were 
reports of life-threatening angioedema with respiratory compromise requiring 


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emergency treatment. Discontinue pregabalin immediately in patients with these 
symptoms. 
 
Exercise caution when prescribing pregabalin to patients who have had a previous 
episode of angioedema. In addition, patients who are taking other drugs 
associated with angioedema (e.g.,angiotensin converting enzyme inhibitors [ACE-
inhibitors]) may be at increased risk of developing angioedema. 
5.3.2 Hypersensitivity 
There have been postmarketing reports of hypersensitivity in patients shortly after 
initiation of treatment with pregabalin. Adverse reactions included skin redness, 
blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately 
in patients with these symptoms. 
5.3.3 Withdrawal of Antiepileptic Drugs (AEDs) 
As with all AEDs, if pregabalin is withdrawn abruptly or rapidly in patients with 
seizure disorders, there is a potential for increased seizure frequency. When used 
as an anti-seizure medication or in patients with a history of seizures, pregabalin 
should be withdrawn gradually over a minimum of 1 week. 
5.3.4 Suicidal Behavior and Ideation 
Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal 
thoughts or behavior in patients taking these drugs for any indication. Monitor 
patients treated with any AED for any indication for the emergence or worsening 
of depression, suicidal thoughts or behavior, and/or any unusual changes in mood 
or behavior. 
 
Should suicidal thoughts and behavior emerge during treatment, the prescriber 
needs to consider whether the emergence of these symptoms in any given patient 
may be related to the illness being treated.  Patients should be advised of the need 
to be alert for the emergence or worsening of the signs and symptoms of 
depression, any unusual changes in mood or behavior, or the emergence of 
suicidal thoughts, behavior, or thoughts about self-harm. These behaviors should 
be immediately reported to healthcare providers. 
5.3.5 Peripheral Edema 
Pregabalin treatment may cause peripheral edema. In short-term trials of patients 
without clinically significant heart or peripheral vascular disease, there was no 
apparent association between peripheral edema and cardiovascular complications 
such as hypertension or congestive heart failure. Peripheral edema was not 
associated with laboratory changes suggestive of deterioration in renal or hepatic 
function.  
 
In controlled clinical trials the incidence of peripheral edema was 6% in the 
pregabalin group compared with 2% in the placebo group. Weight gain was 
reported in 4% of patients on pregabalin in the overall safety database in studies 


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of pain associated with diabetic peripheral neuropathy.  In this population, the 
incidence of edema and weight gain is increased when patients are also on a 
thiazolidinedione class of antidiabetic drugs.  As the thiazolidinedione class of 
antidiabetic drugs can cause weight gain and/or fluid retention, possibly 
exacerbating or leading to heart failure, exercise caution when co-administering 
pregabalin and these agents. Because there are limited data on congestive heart 
failure patients with New York Heart Association (NYHA) Class III or IV cardiac 
status, exercise caution when using pregabalin in these patients. 
5.3.6 Dizziness and Somnolence 
Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-
related dizziness and somnolence may impair their ability to perform tasks such as 
driving or operating machinery.  
 
In the pregabalin controlled trials, dizziness was experienced by 30% of 
pregabalin-treated patients compared to 8% of placebo-treated patients; 
somnolence was experienced by 23% of pregabalin treated patients compared to 
8% of placebo-treated patients. Dizziness and somnolence generally began shortly 
after the initiation of pregabalin therapy and occurred more frequently at higher 
doses. Dizziness and somnolence were the adverse reactions most frequently 
leading to withdrawal (4% each) from controlled studies. In pregabalin-treated 
patients reporting these adverse reactions in short-term, controlled studies, 
dizziness persisted until the last dose in 30% and somnolence persisted until the 
last dose in 42% of patients. 
5.3.7 Weight Gain 
Pregabalin treatment may cause weight gain; in controlled clinical trials of up to 
14 weeks, a gain of 7% or more over baseline weight was observed in 9% of 
pregabalin-treated patients and 2% of placebo-treated patients. The pregabalin 
associated weight gain was related to dose  and duration of exposure, but did not 
appear to be associated with baseline BMI, gender, or age. Weight gain was not 
limited to patients with edema. 
5.3.8 Abrupt or Rapid Discontinuation 
Following abrupt or rapid discontinuation of pregabalin, some patients reported 
symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and 
diarrhea. It should be tapered gradually over a minimum of 1 week rather than 
discontinuing the drug abruptly. We do not anticipate this to be an issue with the 
short duration of pregabalin use in this study. 
5.3.9 Ophthalmological Effects 
In controlled studies, a higher proportion of patients treated with pregabalin 
reported blurred vision (7%) than did patients treated with placebo (2%), which 
resolved in a majority of cases with continued dosing. Although the clinical 
significance of the ophthalmologic findings is unknown, inform patients to  


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notify their physician if changes in vision occur. If visual disturbance persists, 
consider further assessment. 
5.3.10 Creatine Kinase Elevations 
Mean changes in creatine kinase from baseline to the maximum value were 60 
U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all 
controlled trials across multiple patient populations, 1.5% of patients on 
pregabalin and 0.7% of placebo patients had a value of creatine kinase at least 
three times the upper limit of normal. Three pregabalin treated subjects had events 
reported as rhabdomyolysis in premarketing clinical trials. The relationship 
between these myopathy events and pregabalin is not completely understood 
because the cases had documented factors that may have caused or contributed to 
these events. Instruct patients to promptly report unexplained muscle pain, 
tenderness, or weakness, particularly if these muscle symptoms are accompanied 
by malaise or fever. Discontinue treatment with pregabalin if myopathy is 
diagnosed or suspected or if markedly elevated creatine kinase levels occur. 
5.3.11 PR Interval Prolongation 
Pregabalin treatment was associated with PR interval prolongation. In analyses of 
clinical trial ECG data, the mean PR interval increase was 3–6 msec at pregabalin 
doses ≥300 mg/day. This  mean change difference was not associated with an 
increased risk of PR increase ≥25% from  baseline, an increased percentage of 
subjects with on-treatment PR >200 msec, or an increased  risk of adverse 
reactions of second or third degree AV block. 
 
 
 


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6.0 
EVALUATIONS AND ASSESSMENTS  
6.1 
Time and Events Table 
 
 
Cycle 1 & Cycle 2 
 
 
Screening 
Randomization 
Day of 
Chemotherapy 
Chemotherapy 
Pegfilgrastim 6mg SC x1 dose; dose scheduled in 
relation to chemotherapy in consultation with MD 
Day of 
Pegfilgrastim 
Phone Call 
#1 after 
Pegfilgrastim 
Phone Call 
#2 after 
Pegfilgrastim 
Informed consent 
X 
 
 
 
 
Confirm lack of bone 
metastases 
X 
 
 
 
 
Review of 
concomitant 
medication 
X 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
Serum creatinine 
X 
 
 
 
 
Pregabalin/Placebo 
 
X 
Continue study medication for 7 days starting 
from the day of pegfilgrastim 
10 point numerical 
pain scale & log 
X 
 
Patient maintains log of pain and pain 
medications for 7 days starting from the day of 
pegfilgrastim 
Patient adherence log 
Provide 
Patient begins 
diary of 
pregabalin 
Patient continues diary of pregabalin 
ID pain scale 
X 
 
 
X 
X 
Toxicity monitoring 
 
 
X 
X 
X 
X 
X 
 


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6.2 
Footnotes for Time and Events Table 
1. Twice during study medication administration after pegfilgrastim 
administration in cycles 1 and 2, a study team member will contact the patient 
for assessment of neuropathic pain and for pregabalin associated side effects. 
 
2. Confirmation of lack of bone metastases will come from consultation with 
treating physician.  Study subjects will not require any additional testing 
regarding bone metastases from enrollment into LCCC1314.   
 
3. Serum or urine pregnancy testing should be done per standard of care (SOC) 
in women of childbearing potential prior to initiating a new cycle of 
chemotherapy.  Results will be documented on the CRF from this SOC test.  If 
this test is not done, the patient will not be eligible for LCCC1314.  
 
4. Serum creatinine should be done per SOC in prior to initiating a new cycle of 
chemotherapy.  Results will be documented on the CRF from this SOC test.  If 
this test is not done, the patient will not be eligible for LCCC1314.  
 
5. See section 11.1. 
 
6. See section 11.3. 
 
7. See section 11.2. 
6.3 
Assessment of Efficacy  
Any patient who receives all pregabalin/matching placebo doses during the 4 day 
titration period in cycle 1 will be evaluable for any efficacy objective concerning 
cycle 1.   Any patient who also receives all pregabalin/matching placebo doses 
during the 4 day titration period in cycle 2 will be evaluable for efficacy 
objectives across the 2 cycles. 
6.4 
Assessment of Safety 
Any patient who receives at least one dose of pregabalin on this protocol will be 
evaluable for toxicity.  Each patient will be assessed regularly for the 
development of any toxicity according to the Time and Events tables (see Section 
6.0). Toxicity will be assessed according to the NCI CTCAE, v 4. 
 
 
 
 


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7.0 
ADVERSE EVENTS 
7.1 
Definitions  
7.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not related to the 
medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered 
AEs and should not be recorded as an AE.  Disease progression should not be 
recorded as an AE, unless it is attributable by the investigator to the study therapy. 
7.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
 Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
 One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon 
rupture); often more than once occurrence from one or multiple studies 
would be needed before the sponsor could determine that there is 
reasonable possibility that the drug caused the event.   
 An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group 
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7.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 
(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs 
or SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation.   
7.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
 Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions; 
 Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
7.2 
Other Pegfilgrastim Safety Concerns Associated with a Serious SAR 
Other safety concerns in this context means pegfilgrastim product complaints, 
medication errors, overdose (whether accidental or intentional), misuse, abuse, 
transmission of infectious agent, or unauthorized use.  See section 7.4.3 for 
information on reporting these concerns to the manufacturer, Amgen, when they 
are associated with a serious SAR. 


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7.3 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is 
discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for 
that patient.  Please include a description of the event, its severity or toxicity 
grade, onset and resolved dates (if applicable), and the relationship to the study 
drug.    Documentation should occur at least monthly.  
7.4 
SAEs or Serious SARs  
7.4.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout, or no treatment run-
in).  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment and 
continue through the 30 day follow-up period after treatment is discontinued.  
7.4.2 Documentation and Notification 
These events (SAEs or Serious SARs) must be recorded for that patient within 24 
hours of learning of its occurrence.   
7.4.3 Reporting  
IRB Reporting Requirements: 
UNC: 
 UNC will submit an aggregated list of all SAEs to the UNC IRB annually 
at the time of study renewal according to the UNC IRB policies and 
procedures. 
 
The UNC-IRB will be notified of all SAEs that qualify as an 
Unanticipated Problem as per the UNC IRB Policies using the IRB’s web-
based reporting system (see section 9.5.3) within 7 days of the Investigator 
becoming aware of the problem.   
 
Pfizer Reporting Requirements: To ensure patient safety, every SAE, 
regardless of suspected causality, occurring after the patient begins taking study 
drug and until 4 weeks after the patient has stopped study treatment must be 
reported to Pfizer within 24 hours of learning of its occurrence.  If the event is 
both a serious SAR and unexpected, the MedWatch 3500A form will be used.   
 
Reports to Pfizer should be faxed to Pfizer U.S. Clinical Trial Department using 
the Pfizer-provided Reportable Event Fax Cover Sheet at 866-997-8322. 


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FDA Expedited Reporting requirements for studies conducted under an IND: 
If an investigator deems that an event is both a serious SAR AND unexpected, it 
must be recorded on the MedWatch Form 3500A as per 21 CFR 312.32.  The 
MedWatch 3500a form can be accessed at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. 
(Please be sure and access form 3500a, and not form 3500).   UNC, as the Sponsor 
of the study, will make the final determination regarding FDA submission.   
 
Once the UNC Principal Investigator determines an event is a serious SAR AND 
unexpected, the MedWatch 3500A form will be submitted to the FDA.    
 
Amgen Reporting Requirements:  
Any safety concerns documented as defined in section 7.2 that are associated with 
a Serious SAR must be reported to Amgen within one working day of PI 
awareness.  
 
7.5 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of 
patients treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  


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Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
8.0 
STATISTICAL CONSIDERATIONS  
8.1 
Study Design and Accrual 
This is a randomized phase II, single center, placebo-controlled, double-blind 
crossover study.  Eligible patients will be randomly assigned in a 1:1 ratio to 
either Arm A (pregabalin in cycle 1; placebo in cycle 2) or Arm B (placebo in 
cycle 1; pregabalin in cycle 2).  The primary objective is to compare the 
proportion of patients who have an increase in pain score of ≥3 from baseline 
through the end of study medication in cycle 1 between Arm A (pregabalin) and 
Arm B (placebo). Comparisons in pain measures between pregabalin and placebo 
across the 2 cycles are secondary objectives. See sections 2.4 and 2.5 for the 
specific definitions of the pain endpoints. 
 
Based on our patient populations and referral patterns, and using the study 
resources available, we expect to be able to accrue 60 patients meeting the trial 
eligibility into this single center study within two years.  We anticipate that 
enrolling 60 patients (30 per arm) will ensure 52 evaluable patients. 
Using a crossover component may increase the rate of accrual and will give us 
more power to detect potential differences in pain measures between pregabalin 
and placebo.  However, given that pegfilgrastim’s association with bone pain 
likely varies between cycles 1 and 2, and the possibility of increased analgesic use 
in the placebo group in cycle 1, evaluation of the data across 2 cycles will be 
secondary, and hypothesis generating. 
8.2 
Sample Size and Stopping Rule 
The primary objective is to compare the proportion of patients who have an 
increase in pain score of ≥3 from baseline through the end of study medication in 
cycle 1 between Arm A (pregabalin) and Arm B (placebo).  A Fisher's exact test 
with a one-sided significance level of 0.05 will have 81% power to detect the 
difference between a proportion of 0.5 in the placebo group and a proportion of 
0.15 in the pregabalin group when the sample size in each group is 26. We plan to 
enroll 30 patients per arm (60 total) to ensure that we have 26 evaluable patients 
in each group. Based on clinical experience, it is reasonable to assume that 50% 
of patients receiving placebo will have an increase in pain score of ≥3. If this 
percentage was decreased to 15% with the use of pregabalin, this would be 
considered clinically meaningful. In addition, with 26 evaluable patients per arm, 
the maximum width of an exact 95% confidence interval will be 0.401.  In other 
words, we will be able to estimate the proportion with a pain score increase of ≥3 
within ~20% for each arm. 
 
Sequential boundaries will be used to suspend the trial if excessive toxicity is seen 
in either arm during cycle 1. If the study reaches a stopping boundary, it may be 
terminated by the PI, or submitted to the DSMC with a description of the 


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toxicities and a rationale for why the study should be continued. Toxicities ≥ 
grade 2 and deemed to be associated with pregabalin in cycle 1 will be counted in 
the toxicity rate for the purposes of early stopping. The unacceptable toxicities 
will not include weight gain or dry mouth. The accrual will be halted if the 
number of patients with toxicities ≥ grade 2 is equal to or exceeds bn out of n 
patients who have received at least one dose of pregabalin or placebo and have 
been monitored for toxicity in cycle 1 (see table below). This is a Pocock type 
stopping boundary that assumes that a toxicity rate of 0.25 is acceptable, but 
anything >25% is unacceptable. If the true toxicity rate is equal to 0.25, the 
probability of crossing the boundary is 0.05. 
 
 
 
 
 
Stopping Rule for Each Arm 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- 
- 
- 
4 4 5 5 6 6 7 7 7 8 8 9 9 9 10 10 10 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
11 11 11 12 12 12 13 13 14 14 
 
8.3 
Data Analysis Plans 
A Fisher’s exact test will be used to compare the proportion of patients who have 
an increase in pain score (overall and specifically bone/joint pain) of ≥3 from 
baseline through the end of study medication between pregabalin and placebo in 
cycle 1. The proportion of patients in each arm who have an increase in pain score 
of ≥3 from baseline through the end of study medication in cycle 1 will also be 
estimated and reported along with exact 95% confidence intervals. Frequency 
tables will be used to summarize safety data and any other patient characteristics 
of interest. Descriptive statistics, including means, standard deviations, medians, 
and ranges will also be utilized as appropriate. 
 
A Fisher’s exact tests will also be used to compare the proportion of patients with 
severe pain between pregabalin and placebo in cycle 1. The number of days of 
breakthrough analgesic use, the maximum change in pain score from baseline, 
and the maximum neuropathic pain score will be compared in cycle 1 between 
pregabalin and placebo using Wilcoxon Rank Sum tests. Time to first 
breakthrough analgesic use in cycle 1 will be analyzed using the method of 
Kaplan and Meier and will be compared between pregabalin and placebo using 
the log rank test. 
 
Comparisons between pregabalin and placebo across the 2 cycles will be made 
using standard analysis methods for crossover designs.  Specifically, McNemar’s 


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test or the Mainland-Gart test will be used when the outcome is binary (i.e. to 
compare proportions). The Wilcoxon Rank Sum test on the within patient 
differences will be used for continuous outcomes.   Mixed models may also be 
considered in this setting. 
 
As an exploratory analysis, and as the sample size allows, the procedures 
described above will be repeated for the breast and hematologic patients 
separately. 
 
 
 
 
 
 
9.0 
STUDY MANAGEMENT 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
9.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Protocol Office (CPO) at the University of North 
Carolina. 
 A copy of the official IRB approval letter for the protocol and 
informed consent 


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 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
 Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if UNC holds the IND.  
Otherwise, the Investigator’s signature documenting understanding of 
the protocol and providing commitment that this trial will be 
conducted according to all stipulations of the protocol is sufficient to 
ensure compliance) 
 CAP and CLIA Laboratory certification numbers and institution lab 
normal values 
 Executed clinical research contract 
9.3 
Registration Procedures 
All patients must be registered with the CPO at the University of North Carolina 
before enrollment to study.  To register a patient, call the Oncology Protocol 
Office at 919-966-4432 Monday through Friday, 9:00AM-5:00PM..   
9.4 
Data Management and Monitoring/Auditing 
The CPO of the UNC LCCC will serve as the coordinating center for this trial. 
Data will be collected through a web based clinical research platform, OnCore®.   
 
All data will be collected and entered into OnCore® by Clinical Research 
Associates (CRAs) from UNC LCCC.  The investigators will allow monitors to 
review all source documents supporting data entered into OnCore®.    
 
As an investigator initiated study, this trial will also be audited by the Lineberger 
Cancer Center audit committee every twelve months 
9.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
9.5.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC or their 
respective institution’s IRB/IEC approval/favorable opinion.   
 
For Institutions Relying on UNC’s IRB: 
For any such emergency modification implemented, a UNC IRB modification 
form must be completed by UNC Research Personnel within five (5) business 
days of making the change.   
9.5.2 Single Patient/Subject Exceptions 
For Institutions Relying on UNC’s IRB:  


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Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the UNC Principal Investigator and the UNC 
IRB. 
9.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
 Is generally noted or recognized after it occurs 
 Has no substantive effect on the risks to research participants 
 Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
 Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  
 Has harmed or increased the risk of harm to one or more research 
participants. 
 Has damaged the scientific integrity of the data collected for the study. 
 Results from willful or knowing misconduct on the part of the 
investigator(s). 
 Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
For Institutions Relying on UNC’s IRB: 
Protocol Deviations: UNC or Affiliate personnel will record the deviation in 
OnCore®, and report to any sponsor or data and safety monitoring committee in 
accordance with their policies.  Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
Unanticipated Problems: 
UNC 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
9.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 


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design or the potential risk to the patient, a revised consent form might be 
required.   
 
For Institutions Relying on UNC’s IRB: 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.   
9.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
9.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered into the eCRFs. 
Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper 
entry of data. At the completion of the study, all eCRFs will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
 
 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
33 
10.0 REFERENCES  
1. Amgen. Pegfilgrastim. Package Insert.  Accessed June 9, 2013. 
2. Kirshner J, Hickock J, Hofman M. Pegfilgrastim-induced bone pain: 
Incidence, risk factors, and management in a community practice. Comm Onc 
4:455-459, 2007. 
3. Kirshner J, Heckler CE, Janelsins MC et al.  Prevention of Pegfilgrastim-
Induced Bone Pain: A Phase III Double-Blind Placebo-Controlled 
Randomized Clinical Trial of the University of Rochester Cancer Center 
Clinical Community Oncology Program Research Base. J Clin Oncol  2012; 
30:1974-1979.  
4. Kubista E, Glaspy J, Holmes FA et al. Bone Pain Associated with Once-Per-
Cycle Pegfilgrastim Is Similar to Daily Filgrastim in Patients with Breast 
Cancer.  Clin Breast Cancer. 2003 Feb;3(6):391-8. 
5. Tassone DM, Boyce E, Guyer J et al. Pregabalin: A Novel 7-Aminobutyric 
Acid Analogue in the Treatment of Neuropathic Pain, Partial-Onset Seizures, 
and Anxiety Disorders. Clin Ther. 2007; 29:26--48) 
6. Abraham JL. Management of Pain and Spinal Cord Compression in Patients 
with Advanced Cancer. Ann Intern Med. 1999;131(1):37-46. 
7. Reyes-Gibby C, Morrow PK, Bennett et al, Neuropathic Pain in Breast Cancer 
Survivors: Using the ID Pain as a Screening Tool. J Pain Symptom Manage. 
2010 May; 39(5): 882–889. 
8. Gregory SA, Schwartzberg LS, Mo M et al. Evaluation of reported bone pain 
in cancer patients receiving chemotherapy in pegfilgrastim clinical trials: a 
retrospective analysis. 2010;7(7):297-308. 
9. Schweizerhof M, Stösser S, Kurejova M et al. Hematopoietic colony–
stimulating factors mediate tumor-nerve interactions and bone cancer pain.  
Nat Med. 2009 Jul;15(7):802-807. 
 
 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
34 
 
 
11.0 APPENDICES 
11.1 
Appendix 1: Numerical Scale for Pain6: 
 
 
If “0” is “no pain” and “10” is the worst pain you can imagine, what was your 
worst pain today? 
 
 
11.2 
Appendix 2: Neuropathic Pain Scale (ID Pain)7: 
 
The ID Pain is a 6-item, patient-completed screening tool designed to help differentiate 
nociceptive and neuropathic pain. The items include: 
 
1. Did the pain feel like pins and needles?  
2. Did the pain feel hot/burning? 
3. Did the pain feel numb?  
4. Did the pain feel like electrical shocks? 
5. Is the pain made worse with the touch of clothing or bed sheets? 
6. Is the pain limited to your joints? 
 
These questions will be asked of each patient by research staff via telephone twice during 
study medication administration after pegfilgrastim administration.  A “yes” response to 
questions 1–5 are scored as 1.  A “yes” response to question 6 is scored as−1.  
 
Higher scores suggest a neuropathic component to the pain.  
 
 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
35 
11.3 
Appendix 3:  Model Patient Pain Monitoring Log  
 
Note: Patient will be instructed to begin log starting the day of pegfilgrastim 
administration.  This form will also be used to record their pre-cycle 2 baseline score on 
the first pre-cycle 2 day of study medication dosing. 
 
Date 
What is your worst 
pain score today on a 
scale of 0 to 10? 
 
Remember that “0” is 
no pain and “10” is the 
worst pain you can 
imagine. 
What is your worst 
bone/joint pain score 
today on a scale of 0 
to 10? 
 
Remember that “0” is 
no bone/joint pain and 
“10” is the worst 
bone/joint  pain you can 
imagine. 
Please list all pain 
medication and the 
doses of each on 
each day that you 
take your study 
medication. 
Pain medication is any 
prescription or over-
the-counter medicine 
you take for pain 
Why did you take the 
pain medication, to treat 
bone/joint pain or other 
type of pain? (check 
both if applicable) 
 
 
 
 
Bone/joint pain _______ 
 
Other pain ______ 
 
 
 
 
 
Bone/joint pain _______ 
 
Other pain ______ 
 
 
 
 
 
Bone/joint pain _______ 
 
Other pain ______ 
 
 
 
 
 
Bone/joint pain _______ 
 
Other pain ______ 
 
 
 
 
 
Bone joint pain _______ 
 
Other pain ______ 
 
 
 
 
 
Bone/joint  pain _______ 
 
Other pain ______ 
 
 
 
 
 
Bone/joint  pain _______ 
 
Other pain ______ 
 
Pre-
cycle 2 
 
 
 
Bone/joint pain _______ 
 
Other pain ______ 
 


LCCC 1314 
 
CONFIDENTIAL 
PI: B. Muluneh  
 
 
 
 
UNIVERSITY OF NORTH CAROLINA 
Version: January 15, 2014 
 
36 
11.4 
Appendix 4:  Model Pregabalin/Placebo Medication Compliance Diary 
Patient ID: ________    
#tablets per dose: ___________         Signature and date: ________________________________ 
While you are on this study, please record the date and time you take your pregablin/placebo for each dose, and the number of tablets taken at each 
dose.   Take your first daily dose of study medication at approximately the same time each day, and the second approximately 12 hours later.  If a 
dose is vomited or if a dose is missed for any reason, the dose should not be made up. Please make a note on the diary when a dose was missed.   
Study medication may be taken with or without a meal; tablets should be swallowed whole with a glass of water, and should not be chewed or 
crushed.  Please bring this diary to each appointment with your study doctor.   You will be taking your study medication for 11 days in cycles 1 
and 2, starting on the day you are instructed to begin.  Please sign and date when completed.  
 
Sunday  
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Date: 
Time (AM): 
_______  
 
Time (PM): 
 
_______ 
Date: 
Time (AM): 
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Time (PM): 
 
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Date: 
Time (AM): 
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Time (PM): 
 
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Time (PM): 
 
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Time (PM): 
 
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Time (PM): 
 
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