Prospective, randomized, controlled, double-blinded pilot trial evaluating the feasibility in relation to recruitment, retention, and acceptability of a single perineural PRP injection compared to that of steroid/anesthetic injection or injection with normal saline to the greater occipital nerve as a treatment for GON in patients following TBI. Flow through the study is portrayed in Figure 1.
The trial protocol is registered on ClinicalTrials.gov (NCT04051203). This study was registered at ClinicalTrials.gov on August 9, 2019; the study was open for enrollment at this time. This study protocol was prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines for reporting clinical trials (38).
Study setting and recruitment
Participants will be recruited primarily from the Calgary Brain Injury Program at the Foothills Medical Centre. Recruitment in this study will also be advertised at other Calgary-area neurology and sports medicine clinics. Once a participant is referred and has provided consent to contact, they will be contacted by a member of our research team. If they meet inclusion criteria at that time, an initial assessment will be scheduled and participants will complete a digital informed consent.
Eligible participants will be males or females at least 18 years of age who suffer from post-traumatic headaches secondary to GON. Patients must fulfill the ICHD-3 criteria (6) for post-traumatic headache (Table 1) and for GON (Table 2) in establishing a diagnosis of post-traumatic GON. This diagnosis will be established by an experienced Physiatrist and/or Neurologist with extensive experience in headache and related disorders. To meet this criteria, participants must have experienced previous successful temporary relief with local anesthetic/steroid injection surrounding the greater occipital nerve in the past, but have not received local injection within the past 3 months. Pre-treatment numerical pain rating scale (NPRS) for daily headache intensity must be ≥4/10, with a headache frequency ≥10 days/month. Possible secondary causes of headache must be ruled out with a reasonable level of investigation prior to enrollment.
Inability to provide informed consent; history of surgery in the occipital region; unstable psychiatric or medical condition; uncontrolled rheumatologic or inflammatory disorders; widespread neurologic disorders (eg. MS); fibromyalgia/chronic fatigue syndrome; coagulopathy; immunosuppression; active cancer; herpes zoster infection in last 6 months; pregnancy; steroid injection to the greater or lesser occipital nerve infiltration in past 3 months.
Blinding and randomization
Each participant will be randomized following screening and enrollment in the study. Participants will be randomized (via sealed envelope) by a blinded research assistant in a 1:1 fashion to one of three treatment arms: 1) autologous PRP injection 2) steroid/anesthetic injection (standard care) or 3) placebo injection with normal saline. All patients will undergo 60mL blood draw on their scheduled day of injection. Whole blood samples will be prepared in the PRP group only, otherwise, they will be discarded appropriately. Syringes (3mL each) will be prepared by a research assistant and will be covered in an opaque tape so the physician providing the injection is blinded to the type of injectate. The physician will fill out a questionnaire at the time of injection indicating their best guess of the syringe contents, which will be evaluated afterwards, to ensure adequate blinding. Unblinding will occur only in extraordinary circumstances if knowledge of the actual treatment received is deemed essential to providing further patient care.
Injections will be prepared as stated below. Patients will be asked to complete a numeric pain rating scale (NPRS) immediately pre- and post-injection. Patients will be asked to refrain from use of anti-inflammatory medications for 2 weeks prior to the injection and for 2 weeks following the injection due to the possible inhibitory effect on the action of PRP. Two 3mL syringes with 2mL of injectate (PRP, steroid/anesthetic, or normal saline) will be prepared for each participant. Patients will be assessed at the time of injection and will receive a single injection, if experiencing unilateral symptoms only, or two injections to each greater occipital nerve, if symptoms are bilateral. Patients will be monitored for 30 minutes following injection for any immediate adverse reactions, such as local reaction, increased pain intensity, anaphylaxis, nausea or dizziness.
Platelet rich plasma
PRP will be prepared using the “Arthrex Angel System”, which is a fully automated PRP preparation machine. 60 mL of blood will be drawn from the antecubital vein and processed via centrifugation. Five mL of sodium citrate will be added to the syringe prior to blood draw to prevent coagulation. Samples will be centrifuged as per manufacturer instructions, yielding 5mL of PRP. For quality testing, 1mL of PRP will be sent to the lab for analysis of platelet and leukocyte count, as compared to the patients’ whole blood. The remaining 4mL of PRP will be divided into two syringes and 2mL will be injected per symptomatic side.
Steroid injections will be prepared to include 20mg Depo-Medrol and 2mL 2% lidocaine.
Placebo injections will be with 2mL normal saline.
Given that ultrasound (US) guided greater occipital nerve blockade demonstrated superiority over conventional blind technique in one study (39), participants will receive perineural injections under ultrasound guidance. Injections will be performed bilaterally if participants’ symptoms are bilateral, otherwise they will be performed unilaterally. Where the greater occipital nerve is not visible under US, injection will be performed in accordance with conventional blind technique (40).
Demographic information will be collected two weeks prior to starting the study including age, sex, weight/height, education, family history, past medical history, and medication use. Headache history will be collected including headache frequency, severity, as needed medication-use, type of headache, associated symptoms (i.e. paresthesia, fronto-orbital pain, nausea, vomiting) and headache triggers.
Questionnaires will be completed 2 weeks prior to injections, 1 week, 1 month, and 3 months post-injection. A daily headache diary provided via mobile application (Secure RedCap) available in iPhone or android device will be provided to record daily records of NPRS, headache frequency, and medication-use. Patients will complete daily headache diaries beginning at two weeks pre-injection and ending 3 months post-injection. See Figure 1 in appendix for a schematic of the study design.
The primary outcomes of this trial will assess the feasibility of a double-blinded randomized control trial for the treatment of GON in patients with post-traumatic headaches. This pilot trial is a smaller version and will aim to inform a more extensive and larger version of this randomized control trial. Specific outcomes for evaluation will include:
- Recruitment: Ability to recruit at least 30% of those patients screened for participation.
- Intervention attendance: At least 70% of those patients recruited for the study will attend and participate in the primary intervention.
- Retention: At least 70% of those receiving the primary intervention will complete the 3 month follow-up.
- Adverse events: Adverse events will be minimal. No more than 1 individual will have an adverse event. Any adverse event will be minor and reversible (ie. nausea, light headedness, temporary pain at site of injection).
The primary exploratory outcome will be a reduction in the numeric pain rating scale (NPRS) at 3 months in the PRP group, as compared to the steroid and placebo groups. The suggested minimal clinical important difference (MCID) at the time of writing is 2 points (41) or ≥50% compared to placebo. Secondary outcomes will include headache frequency based on daily diaries and NPRS. Additional questionnaires completed at 2 weeks prior to injection, 1 week, 1 month, and 3 months post-injection will be the Headache Impact Test-6 (HIT-6; a valid and reliable 6-item questionnaire for assessment of the impact of headaches across different diagnostic groups of headaches (42, 43)) and the quality of life in following brain injury questionnaire (QOILIBRI). As well, participants will complete daily medication diaries tracking prn analgesic use.
Attrition and adherence
Participants will be withdrawn from the study if there is a change in routine medications during the study period or if they do not complete study questionnaires. Daily headache diaries will be completed by all participants for the duration of the study submitted on their mobile device. In the event that daily diaries are not completed, reminders will be sent out by the study team.
Data management and monitoring
Participants will be assigned a study ID at the time of study enrolment. All identifying information will be removed once study participant numbers have been assigned and data is collected. Study data will be entered into a highly secure electronic REDCap database (REDCap 7.6.9 2020 @ Vanderbilt University). Only research team members will have access to this database. Paper copies of any data or participant information will be stored in a secure fashion. All data will be retained for five years following project completion in accordance with the University of Calgary Conjoint Health Research Ethics Board.
There will not be a formal data monitoring committee; a research assistant will periodically evaluate participant data for completeness and inform investigators of any issues. Adverse events will be reported via telephone or email, a research assistant will contact participants for further details at the time of reporting. A study physician will be alerted of any serious adverse events that require immediate attention.
The primary outcomes for this pilot trial requires descriptive statistics for recruitment, completion of primary assessment, retention, and adverse effect profiles. The exploratory outcomes: change in NPRS, HIT-6, and QOLIBRI at 1 and 3 months following intervention for patients receiving PRP compared to steroid/anesthetic and normal saline will be analyzed. A two-way mixed ANOVA test will be completed to evaluate the change in NRPS between groups. Chi-square testing will be performed to determine the relationship between basic characteristics in the three groups. For secondary outcomes, Kruskal-wallis non-parametric analysis based on ranks will be completed correcting for multiple comparisons with Bonferroni correction.
At the time of submission we are recruiting and enrolling participants in the study.
Any modifications to the study protocol will be submitted and approved through the University of Calgary Conjoint Health Research Ethics Board. The ClinicalTrials.gov registry will be updated as required and trial participants will be notified of relevant study modifications.
Access to data
The principal investigator, research assistants, students, and statistician colleagues who are directly involved in the study will have access to the final data set.
Trial results will be disseminated through presentations at conferences, invited presentations and published manuscripts by study authors and contributors. The study is registered on clinicaltrials.gov. There will be no use of professional writers.