Plain English Summary
Background and study aims
Chronic pain affects 20-30% of Canadians, costs >$650 billion/year in North America and is recognized as a disease in its own right. Current therapies have limited efficacy and tolerability. Rational, carefully supervised, combination therapy with different treatments may provide improvements in pain relief and quality of life and potentially fewer anti-inflammatory drug-related and opioid-related mortalities. Over half of pain sufferers receive 2 or more analgesic drugs, but evidence for combination therapy is limited and more research is needed. Previous Canadian Institutes of Health Research (CIHR)-funded studies have shown improved patient outcomes with combination therapy and provided a framework for evaluating novel combination strategies to target pain and sleep impairment. This study aims to compare a pregabalin (PGB) + melatonin (MLT) combination therapy versus the monotherapies for chronic pain (fibromyalgia). The anticonvulsant, PGB, has been shown to reduce pain and improve sleep maintenance in multiple studies. The pineal gland hormone, MLT, regulates the body's daily (circadian) clock and has shown evidence of pain reduction in both laboratory and clinical settings. Multiple clinical trials have demonstrated efficacy for primary insomnia and delayed sleep phase syndrome. This study hypothesizes that a PGB+MLT combination therapy has superior effects versus monotherapy for chronic pain, because of: 1) favourable interactions between these agents; 2) evidence of superior efficacy of other PGB-containing, and MLT-containing combinations; and 3) compounded benefits of concurrently reducing both pain and sleep disturbance. The study will evaluate pain, sleep, function, mood, and adverse effects in patients taking these agents. Expected results will guide improvements in therapy by advancing knowledge about rational combination therapy for chronic pain.
Who can participate?
Patients ≥18 years old with fibromyalgia and daily moderate pain
What does the study involve?
Participants progress through three different 6-week treatment periods during which they take the following medications on an outpatient basis: melatonin alone, pregabalin alone, and a combination of melatonin and pregabalin. These three treatments will be given in a random order and the doses of each treatment will be gradually increased to a maximally tolerated level. Participants will rate their pain, side effects and other outcome measures throughout the study.
What are the possible benefits and risks of participating?
Given the known effects of pregabalin in patients with fibromyalgia, there is a possibility that participants will enjoy meaningful pain relief whenever they are receiving pregabalin during this study. There is, however, less evidence regarding the use of melatonin for fibromyalgia, which is one of the reasons for doing this study. Participants may gain no benefit from participating in the study. However, new knowledge gained from this study may help improve the quality of pain management for other patients.
Pregabalin side effects and participant safety:
Relatively common (>10%) adverse effects associated with pregabalin include dizziness, somnolence, weight gain, peripheral edema and visual symptoms such as double vision. These side effects are reversible upon stopping medication and most of these side effects gradually improve after continuing a given dose of pregabalin for several days. Although relatively uncommon, pregabalin abuse/addiction has been reported – particularly in individuals with other substance abuse issues such as opioid addiction.
Melatonin side effects and participant safety:
Current evidence suggests that oral administration of melatonin is generally safe. A recent review of 37 different studies of melatonin reported side effects of daytime sleepiness (in only 1.7% of participants), headache (in only 0.7%) and dizziness (0.7%).
Some side effects may occur more frequently during combination treatment as compared to either drug alone.
Where is the study run from?
Kingston General Hospital
When is the study starting and how long is it expected to run for?
January 2024 to August 2028
Who is funding the study?
Canadian Institutes of Health Research (CIHR)
Who is the main contact?
Dr Ian Gilron, gilroni@queensu.ca
Study website
Contact information
Type
Public, Scientific, Principal Investigator
Contact name
Dr Ian Gilron
ORCID ID
http://orcid.org/0000-0002-5293-8792
Contact details
Dept of Anesthesiology & Perioperative Medicine
Victory 2
Kingston General Hospital
76 Stuart St
Kingston
K7L2V7
Canada
+1 6135487827
gilroni@queensu.ca
Additional identifiers
EudraCT/CTIS number
Nil known
IRAS number
ClinicalTrials.gov number
Nil known
Protocol/serial number
Nil known
Study information
Scientific title
Clinical trial of a melatonin-pregabalin combination for fibromyalgia
Acronym
PRECISE
Study hypothesis
The combination of melatonin and pregabalin has superior analgesic efficacy versus either single agent for fibromyalgia.
Ethics approval(s)
Not yet submitted 11/03/2024, Queen's University Research Ethics Board (355 King Street West, 2nd floor, Kingston, K7L2X3, Canada; +1-613-533-2000; research@queensu.ca), ref: Pending
Study design
Single-centre double-blind randomized double-dummy 3-period crossover design
Primary study design
Interventional
Secondary study design
Randomised cross over trial
Study setting(s)
Home, Hospital
Study type
Treatment, Safety, Efficacy
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Fibromyalgia
Intervention
This study has a single-centre, double-blind, randomized, double-dummy, 3-period, crossover design (18 weeks/participant) to compare a melatonin-pregabalin combination to each monotherapy in participants with fibromyalgia. Participants will be randomly allocated to melatonin, pregabalin, and a melatonin-pregabalin combination.
Study participants will be randomized, in a double-blind fashion, to one of six possible sequences (e.g. sequence 1: combination>melatonin>pregabalin) such that each participant progresses through each of three 6-week treatment periods. Treatment periods will conclude with a 7-day dose taper and a 4-day complete washout. During each period, participants will receive two sets of capsules: 1) “melatonin” capsules - which may contain melatonin 3 mg or inert matching placebo and 2) “pregabalin” capsules - which may contain pregabalin 75 mg or inert matching placebo. During the “melatonin-pregabalin combination” period, set 1 will contain melatonin (3 mg capsules) and set 2 will contain pregabalin (75 mg capsules). During the “melatonin alone” period, set 1 will contain melatonin (3 mg capsules) and set 2 will contain an inert matching placebo. During the “pregabalin alone” period, set 1 will contain an inert placebo and set 2 will contain pregabalin (75 mg capsules). Melatonin (and melatonin placebo) study drug administration will occur only in the evenings, whereas pregabalin (and pregabalin placebo) study drug administration will occur according to twice daily dosing (morning and evening).
Outcome measures will be assessed as follows:
The primary outcome will be the mean of daily “average” pain intensity ratings from the last 7 days at MTD, of each treatment period. Pain intensity is self-rated each morning as “average pain over the last 24 hours” using a 0-10 Likert numerical rating scale with the anchors: 0 = “no pain”; 10 = “worst pain imaginable”. Following informed consent, participants receive study teaching on how to consistently rate their pain intensity, twice daily, as per the daily pain diary. The process of regular monitoring and encouragement of complete daily diary completion during weekly follow-up calls to participants has ensured excellent compliance and data completeness in our 7 previous and recent trials.
Secondary outcomes include change from treatment period baseline to MTD week, Fibromyalgia Impact Questionnaire, MOS-Sleep Scale, global pain relief, Brief Pain Inventory, Beck Depression Inventory-II, Beck Anxiety Inventory, the short-form McGill Pain Questionnaire, the SF-36 Quality of Life Survey, MTDs of melatonin and pregabalin, frequency/severity of other treatment-emergent AEs, blinding questionnaires, acetaminophen consumption, and study drug pill counts. Participant safety will be monitored through vigilant and judicious drug titration. Any occurrences of major adverse events will be tracked as secondary outcomes and also reported to the Queen’s University Research Ethics Board, and Health Canada.
Intervention type
Drug
Pharmaceutical study type(s)
Comparative efficacy trial
Phase
Phase III/IV
Drug/device/biological/vaccine name(s)
Melatonin, pregabalin, melatonin-pregabalin combination
Primary outcome measure
Mean of “average” pain intensity self-ratings at the maximally tolerated dose of each treatment period measured using a Likert numerical rating scale twice daily over the last 7 days
Secondary outcome measures
1. Review of adverse events and concurrent analgesic treatments measured by monitoring of study records throughout screening (pre-trial), baseline (pre-trial), during each treatment period (titration period, maximal tolerated dose and taper/washout), and 2 weeks and 3 months after the end of the trial
2. Pain intensity measured using pain diaries at baseline (pre-trial), during each treatment period (titration period, maximal tolerated dose and taper/washout), and 2 weeks after the end of the trial
3. Study medication dose levels and patient global impression of change during each treatment period (titration period, maximal tolerated dose and taper/washout)
4. Drug dispensing; Medical Outcomes Study (MOS); Brief Pain Inventory (BPI); Beck Anxiety Inventory (BAI); the MOS 36-item shortform health survey (SF-36) and the Fibromyalgia Impact Questionnaire (FIQ) at baseline (pre-trial) and the maximal tolerated dose during each treatment period
5. Vital signs, height, weight and Beck Depression Inventory - 2 (BDI-2) at screening (pre-trial) and the maximal tolerated dose during each treatment period
6. Pain (average and worst) measured using the Present Pain Intensity (PPI) (0-10 numerical scale), demographics, medical history and clinical laboratory assessments at screening (pre-trial)
7. Blinding questionnaire, drug compliance at the maximal tolerated dose during each treatment period
Overall study start date
31/01/2024
Overall study end date
31/08/2028
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Participants ≥18 years old and over meeting the 2016 American College of Rheumatology diagnostic criteria for fibromyalgia
2. Daily moderate pain (≥ 3/10) for at least 3 months
3. Liver function test, ALT, no greater than 20% above normal
4. Creatinine clearance >50 mL/min
5. Sufficient cognitive function and language comprehension skills – regardless of native language – for questionnaire completion and communication with trial personnel (and translator, if necessary)
6. Women of childbearing potential will be required to receive a highly effective form of contraception
Participant type(s)
Patient
Age group
Adult
Lower age limit
18 Years
Sex
Both
Target number of participants
54
Participant exclusion criteria
1. Participants with any major organ system disease, psychiatric, suicidal ideation or substance abuse disorder, which, in the opinion of the investigators, would interfere with trial participation
2. Hypersensitivity to any of the study medications
3. Other painful conditions as severe as fibromyalgia pain
4. Shift workers who work during typical sleeping hours
5. Any other abnormalities or conditions that, in the judgement of the investigators would interfere with the protocol
Recruitment start date
01/12/2024
Recruitment end date
30/11/2027
Locations
Countries of recruitment
Canada
Study participating centre
Research Clinic, Providence Care Hospital (Queen's University)
752 King St W
Kingston
K7L 4X3
Canada
Sponsor information
Organisation
Canadian Institutes of Health Research
Sponsor details
160 Elgin Street
10th Floor
Address Locator 4809A
Ottawa ON
K1A 0W9
Canada
+1 613-941-2672
support-soutien@cihr-irsc.gc.ca
Sponsor type
Government
Website
https://cihr-irsc.gc.ca/e/193.html
ROR
Funders
Funder type
Government
Funder name
Canadian Institutes of Health Research
Alternative name(s)
Instituts de Recherche en Santé du Canada, Canadian Institutes of Health Research (CIHR), CIHR_IRSC, Canadian Institutes of Health Research | Ottawa ON, CIHR, IRSC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
Canada
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal and presentation at several scientific conferences
Intention to publish date
01/09/2028
Individual participant data (IPD) sharing plan
The datasets generated during and/or analysed during the current study are not expected to be made available as the research unit does not yet have the policies and procedures in place for the public sharing of individual participant data. The data will be held in a non-publically available repository at Kingston Health Sciences Centre (Canada).
IPD sharing plan summary
Stored in non-publicly available repository, Not expected to be made available
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|