Trial of Pregabalin for Granulocyte Colony-stimulating Factor (GCSF)-Induced Bone Pain
| Status: | Terminated |
|---|---|
| Conditions: | Breast Cancer, Cancer, Chronic Pain, Lymphoma |
| Therapuetic Areas: | Musculoskeletal, Oncology |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 6/27/2018 |
| Start Date: | January 27, 2016 |
| End Date: | July 20, 2017 |
A Phase II, Placebo-controlled, Double-blind, Randomized Crossover Trial of Pregabalin for the Prophylaxis of Pegfilgrastim-induced Bone Pain
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.
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.
**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.
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.
Inclusion Criteria:
- Age ≥18 years
- 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.
- Schedule of chemotherapy and pegfilgrastim initiation can accommodate initiation of
pregabalin 4 days prior to pegfilgrastim dose.
- 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.
Exclusion Criteria:
- A history of (within one month) or current pregabalin use.
- Baseline pain scores ≥7 as measured via 10-point numerical scale for pain (see section
11.1).
- Unwilling to discontinue use of antihistamines from 7 days prior to D1 of study
medication.
- Creatinine clearance (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
- 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).
- Patient is unable or unwilling to abide by the study protocol or cooperate fully with
the investigator.
- Eligible and agrees to enroll into therapeutic trial ongoing at the Lineberger
Comprehensive Cancer Center (LCCC) (i.e., the treatment trial will take precedence
over LCCC1314).
- Currently receiving therapeutic doses of anticoagulants (ie, prophylactic use of
anticoagulants is allowed) due to possibility of dizziness and falls while on
pregabalin.
- Currently receiving aromatase inhibitors or agents targeted against Ph+ leukemias
(i.e., imatinib, dasatinib, nilotinib, and ponatinib) or scheduled to start these
drugs during cycle 1 of scheduled chemotherapy.
- Presence of bone metastases.
- History of angioedema.
- History of a seizure disorder.
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