Trial of Pregabalin for Granulocyte Colony-stimulating Factor (GCSF)-Induced Bone Pain

**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.