Pregabalin bone trial

ISRCTN	ISRCTN66947249
DOI	https://doi.org/10.1186/ISRCTN66947249
Protocol serial number	PBT 2007-3/10
Sponsors	Lothian Health Board (LHB) (UK), University of Edinburgh (UK), NHS Lothian
Funder	Cancer Research UK (CRUK) (UK) - Clinical Trials Advisory and Awards Committee (CTAAC) (ref: C17598/A7250)

Submission date: 18/04/2008
Registration date: 24/04/2008
Last edited: 16/06/2016

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-pregabalin-and-radiotherapy-for-pain-caused-by-secondary-cancer-in-the-bones

Contact information

Prof Marie Fallon
Scientific

Edinburgh Cancer Research Centre (CRUK)
Western General Hospital
Edinburgh
EH4 2XR
United Kingdom

Phone	+44 (0)131 777 3518
Email	Marie.Fallon@ed.ac.uk

Study information

Primary study design	Interventional
Study design	Double-blind randomised placebo-controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Double-blind randomised controlled trial of pregabalin versus placebo in conjunction with palliative radiotherapy for malignant bone pain
Study objectives	Although cancer-induced bone pain (CIBP) can be very difficult to treat, we are now in the fortunate position of understanding more about its pathophysiology because of the new animal model of CIBP. It is now possible to employ a rat model of CIBP to investigate the underlying neuronal responses. Electrophysiological studies reveal that animals with this pain state have a significantly more excitable spinal cord compared to control animals. While evidence points to a unique pain state distinct from neuropathic or inflammatory pain, there is a state of ongoing central sensitisation with major changes at the level of the spinal cord. Work from animal models indicates that glutamate is one of the key neurotransmitters involved. There is considerable evidence for involvement of the ionotropic glutamate receptor, the N-methyl D-aspartate (NMDA) receptor. We have treated malignant bone pain in the clinic with ketamine, an NMDA receptor antagonist, with encouraging results. Unfortunately, side effects can limit use of this drug. Additionally, there is increasing evidence that other glutamate receptor subtypes may have significant roles in sensitised pain states (such as metabotropic glutamate receptors). These are not blocked by ketamine or other NMDA receptor antagonists. Agents that have presynaptic activity to reduce glutamate release may be more effective as the net overall effect of glutamate will be reduced to a greater extent than with receptor specific agents. We are interested in the pre-clinical data which seems to support a role for gabapentin in malignant bone pain. There is clearly a clinical and scientific need to establish if pregabalin can improve on the analgesic effect of radiotherapy alone. This double-blind randomised placebo controlled trial of radiotherapy and pregabalin and best standard care for CIBP is intended to answer this question. On 15/02/2011 the overall trial end date was changed from 31/10/2010 to 31/05/2011. On 08/05/2012 the overall trial end date was changed from 31/05/2011 to 30/04/2012.
Ethics approval(s)	Multi-centre Research Ethics Committee (MREC), 16/08/2007, ref: 07/MRE00/59
Health condition(s) or problem(s) studied	Bone metastasis
Intervention	This study will be a double-blind randomised controlled trial. Patients who are due to receive palliative radiotherapy to cancer induced bone pain will be assessed, if agreeable, for inclusion in the study. The study will be divided into two stages: Stage 1: run in - This will last until the patient starts radiotherapy treatment. During the "run-in" period the opioid analgesic regimen in particular will be optimised to ensure optimum analgesia with minimal side-effects - using a defined schedule. The "run-in" period will last days to approximately 2 weeks, depending on the waiting time for palliative radiotherapy. At the point of receiving radiotherapy, patients who have a bone pain score of greater than or equal to 4 on a 0 - 10 Visual Analogue Scale (VAS) will be invited to take part in the next stage of the study, the "assessment phase". Stage 2: assessment - It is at this point that randomisation to receive active drug or placebo will take place. This will be day 1 of the titration of the study drug. Patients will be randomised to receive either pregabalin or placebo twice a day, approximately 12 hours apart. Patients will complete dose titration as per a predetermined protocol, with dose increases after each week in the study to reach a maximum dose by the beginning of week 4. The "assessment" period is from day 1 of the drug (baseline) to 4 weeks after first fraction of radiotherapy (trial endpoint). Treatment and follow-up will continue for 4 weeks after first fraction of radiotherapy. Study treatment dose titration will stop if effective analgesia or side-effects occur. Discontinuation of study medication: Due to the slight risk of adverse effects occurring with abrupt withdrawal of pregabalin (dizziness and somnolence), at study endpoint, patients will be instructed to reduce pregabalin gradually over one week. Patients will be advised to decrease dose by 50% every 48 hours to a dose of 75 mg daily and should continue at this dose until the end of the one-week period.
Intervention type	Mixed
Primary outcome measure(s)	To establish if radiotherapy and pregabalin gives superior analgesia in CIBP than radiotherapy alone. Primary and secondary outcomes will be measured at study baseline (date of first fraction of radiotherapy) and study endpoint (four weeks from study baseline).
Key secondary outcome measure(s)	1. Background, spontaneous and movement-related pain 2. Total opioid requirements, i.e. background and breakthrough doses 3. Tolerability of pregabalin 4. Global quality of life scores (European Quality of Life [EuroQoL] thermometer) 5. Hospital Anxiety and Depression (HAD) scores 6. Changes in sensory responses as assessed by Quantitative Sensory Testing (QST). Modified short version for those patients who want to complete this (20 minutes). 7. Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) only to be done in conjunction with QST 8. Opioid side-effects 9. Withdrawal from study 10. Serious adverse events - pregabalin Primary and secondary outcomes will be measured at study baseline (date of first fraction of radiotherapy) and study endpoint (four weeks from study baseline).
Completion date	30/04/2012

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	206
Key inclusion criteria	1. Clearly identifiable bone pain 2. Index bone pain greater than or equal to 4/10 3. Written informed consent 4. Aged greater than or equal to 18 years, either sex 5. Able to complete necessary assessments required as part of the trial 6. Life expectancy greater than two months 7. Due to receive palliative radiotherapy for bone pain
Key exclusion criteria	1. Aged less than 18 years 2. Current gabapentin/pregabalin use 3. Significant renal impairment (plasma creatinine greater than 1.5 mg/ml, creatinine clearance less than 60 mmls/hr) 4. Change in any tumoricidal therapy before entering the study which may be expected to have an analgesic benefit during the study period 5. Patients receiving bisphosphonates purely as an analgesic regimen which may be expected to have effects during the study period (patients on regular bisphosphonates pre-occurrence of current bone pain allowed) 6. Bed-bound patients 7. Patients who are having palliative radiotherapy to vertebral metastases 8. Patients receiving wide-field irradiation
Date of first enrolment	15/01/2008
Date of final enrolment	30/04/2012

Locations

Countries of recruitment

United Kingdom
Scotland

Study participating centre

Edinburgh Cancer Research Centre (CRUK)

Edinburgh
EH4 2XR
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	20/02/2016		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

29/02/2016: Cancer Help UK lay summary link added.