The Effect of Creatine Monohydrate on Persistent Post-concussive Symptoms

Mild Traumatic Brain Injury Clinical Trial

Official title:

The Effect of Creatine Monohydrate on Persistent Post-concussive Symptoms - a Pilot Study Protocol

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05562232
• Other study ID #: PRURegionZealand4
• Status: Not yet recruiting
• Phase: N/A
• Start date: October 1, 2022
• Est. completion date: January 31, 2023

Study information

• Verified date: September 2022
• Source: Psychiatric Research Unit, Region Zealand, Denmark
• Contact: Ronni Lykke Bødker, MSc
• Phone: +45 61710188
• Email: ronni[@]commotio.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study, is to investigate whether creatine monohydrate as a supplement reduces the number and severity of symptoms in patients with persistent post-concussive symptoms through self-reported post-concussion symptoms questionnaires.

Description:

Mild traumatic brain injury (mTBI), which throughout the literature is used interchangeably with concussion, is a problem the media is drawing more and more attention to, which have made it a public concern too. It is estimated that between 0.6 % and 1.2 % of the general population will suffer an mTBI each year. Out of these, an estimated 10-30 % of the patients, will suffer from persistent post-concussive symptoms (PPCS). These symptoms typically includes headache, poor concentration, memory problems, fatigue, sleep difficulties, dizziness, irritability, feeling nervous or anxious. At the moment no single treatment option is available with guaranteed success, and therefore nutritional supplements are a possibility.

The nutritional supplement Creatine Monohydrate (CrM) is one of the most popular ergogenic aids on the market among professional and amateur athletes. It is mostly used in the development of muscle mass, as creatine is primarily located skeletal muscle. Roughly five percent of the body's creatine is distributed in the brain and testicles. As mTBI's also see a change in the metabolism of the brain, creatine supplementation might be beneficial for patients with PPCS. This is further supported by a newly conducted study, that creatine supplementation may reduce the severity of mild concussion in animal models.

Furthermore, as the enzyme Creatine Kinease (CK), which is involved in ATP energy system, also has a brain specific isoform (BB-CK), creatine may be a relevant part of the energy system of the central nervous system (CNS). In addition evidence points towards creatine supplementation can increase cellular energy availability. It has been reported to increase brain phosphocreatine content by as much as 15 %, which in turn improves the metabolic processes of the brain.

CrM has been described to be a potent anti-inflammatory molecule. It has been shown to reduce the cytotoxic effects in oxidatively-injured cells without affecting antioxidant enzyme activities, and has been shown to inhibit reactive oxygen species-induced formation of mitochondrial permeability transition pores in the liver mitochondria of mice. At the same time, concussion seems to increase inflammation in the brain, and this inflammation has been hypothesized to correlate with the symptomatology and duration. And even though research in the area of recovery is still scarce, neuroinflammation seems to play a vital role in the pathophysiology of concussions. This warrants hopes of a decrease in post-concussive symptoms.

Other studies have indicated an improvement of cognitive functions, including fatigue, working memory and mood state. All symptoms related to PPCS. Additionally evidence points towards creatine supplementation can help with chronic fatigue, depression and anxiety. All this points towards CrM being helpful in the treatment of PPCS.

PPCS has proven to be not only a health problem, but also a socioeconomical problem. Data from Fallesen et al. showed that salary in Denmark five years after a concussion decreased 4.2 %, with an increased risk of losing ones job. Currently there is not viable treatment option for these patients, but if the intervention shows positive results, patients suffering from PPCS would be able to improve on their symptoms, relatively easy and cheap. They would have a go-to supplement, that would make it possible for them to get a normal day, without any of the symptoms connected to PPCS.

The study will be performed as a randomized controlled study. The study is expected to include a convenience sample of 45 patients. The patients will randomly be allocated to either a control group (CG), placebo group (PLA) or intervention group (INT), with 15 patients in each. The study will be double blinded, i.e., the participants not knowing which group they will be allocated to.

The study population consists of patients with persistent post-concussive symptoms between six and twelve months at start of participation. Participants will be recruited through social media and contact with neurological outpatient clinics throughout Denmark. At the start of the study, participants will have to be between 25 and 35 years of age. This will make the population a homogenous age group, and we will avoid physical and cognitive challenges related to early childhood and adolescents, as well as avoiding the degeneration in physical capacities that begin at approximately the age of 35 as well as the cognitive decline around the same time.

Their anthropometrics will consist of:

• Age (years)

• Gender (male/female)

• Height (cm)

• Weight (kg)

• Period with PPCS (months)

• Concussion history (yes/no)

• If yes - how many (number)

• Training status (hours/week)

Study procedure

• Baseline phase:

• Before inclusion in the study, participants have to sign a declaration of consent, to make them fully aware of what they agree to participate in, what risks there are and what they can gain from the study.

• When the declaration is signed, the participants have to have their height in cm and weight in kg measured, as well as answering how many concussions they previously suffered, along with their training status as hours/week.

• The baseline measurements concludes with participants answering the Rivermead Post-Concussion Symptom Questionnaire (RPQ).

• Study phase:

• The participants will randomly be allocated to either the CG, PLA or INT group. CG will not receive any treatment other than usual treatment. PLA and INT will both receive a powder, that has to be ingested. PLA will receive a powder similar in looks to CrM, but with no apparent nutritional value, while INT will receive CrM.

oAs both PLA and INT are the interventions, they will follow the same protocol for ingestion

• 5 grams per day in seven weeks. All 5 grams will be ingested at once.

• This protocol has been chosen instead of the more common 0.3 g/day for the first week, ingested over five times during the day. In other studies on CrM and the brain, this have been the chosen strategy also. But studies on CrM in the muscles show, that both protocols illicit the same response with 28 days, and the loading phase is not required. Furthermore, some studies have used this protocol with creatine supplementation, and found increased cognitive function.

• Our reason for choosing 5 g/day in seven weeks, is to increase the chances of compliance, and decrease the risks of discomfort with to high an intake of CrM. An intake five times a day for the first week, is demanding, and will most likely get some participants to quit the study.

• At the mid phase of the study, all baseline measurements will be done again.

• End of study protocol:

• The length of the intervention is seven weeks. After the seven weeks, all baseline measurements will be done again. And a week after last ingestion, the measurements will be done one last time.

• At the week eight appointment, every participant will have to answer whether they thought they were getting placebo or CrM. This is done in order to figure out how big an effect placebo have on the results.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 45
• Est. completion date: January 31, 2023
• Est. primary completion date: November 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 35 Years

Eligibility

Inclusion Criteria:

• Have had PPCS for a minimum of six months and a maximum of 12 months at the start of the study.

• Being between 25 and 35 years of age

Exclusion Criteria:

• Elite athletes, as well as people who in general is physical active for more than ten hours a week on average.

• Participation in other interventions/treatment than this study

• Have had PPCS in:

• <6 months

• >12 months

• Pregnant

• Other brain diseases or traumatic injuries

• Musculoskeletal diseases

Related Conditions & MeSH terms

• Brain Concussion
• Brain Injuries
• Brain Injuries, Traumatic
• Concussion, Brain
• Mild Traumatic Brain Injury
• Post-Concussion Syndrome

Intervention

Dietary Supplement:
• Creatine Monohydrate
Follows

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Psychiatric Research Unit, Region Zealand, Denmark	University of Southern Denmark

References & Publications (34)

Antonio J, Candow DG, Forbes SC, Gualano B, Jagim AR, Kreider RB, Rawson ES, Smith-Ryan AE, VanDusseldorp TA, Willoughby DS, Ziegenfuss TN. Common questions and misconceptions about creatine supplementation: what does the scientific evidence really show? J Int Soc Sports Nutr. 2021 Feb 8;18(1):13. doi: 10.1186/s12970-021-00412-w. Review. — View Citation

Avgerinos KI, Spyrou N, Bougioukas KI, Kapogiannis D. Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp Gerontol. 2018 Jul 15;108:166-173. doi: 10.1016/j.exger.2018.04.013. Epub 2018 Apr 25. — View Citation

Bakian AV, Huber RS, Scholl L, Renshaw PF, Kondo D. Dietary creatine intake and depression risk among U.S. adults. Transl Psychiatry. 2020 Feb 3;10(1):52. doi: 10.1038/s41398-020-0741-x. — View Citation

Balalla S, Krägeloh C, Medvedev O, Siegert R. Is the Rivermead Post-Concussion Symptoms Questionnaire a Reliable and Valid Measure to Assess Long-Term Symptoms in Traumatic Brain Injury and Orthopedic Injury Patients? A Novel Investigation Using Rasch Analysis. Neurotrauma Rep. 2020 Aug 11;1(1):63-72. doi: 10.1089/neur.2020.0017. eCollection 2020. — View Citation

Bélanger M, Allaman I, Magistretti PJ. Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes. J Neurochem. 2011 Feb;116(4):564-76. doi: 10.1111/j.1471-4159.2010.07135.x. Epub 2011 Jan 19. — View Citation

Bender A, Klopstock T. Creatine for neuroprotection in neurodegenerative disease: end of story? Amino Acids. 2016 Aug;48(8):1929-40. doi: 10.1007/s00726-015-2165-0. Epub 2016 Jan 9. Review. — View Citation

Cassidy JD, Carroll LJ, Peloso PM, Borg J, von Holst H, Holm L, Kraus J, Coronado VG; WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004 Feb;(43 Suppl):28-60. Review. — View Citation

Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol. 1999 Sep;277(3):R698-704. doi: 10.1152/ajpregu.1999.277.3.R698. — View Citation

Eyres S, Carey A, Gilworth G, Neumann V, Tennant A. Construct validity and reliability of the Rivermead Post-Concussion Symptoms Questionnaire. Clin Rehabil. 2005 Dec;19(8):878-87. — View Citation

Fallesen P, Campos B. Effect of concussion on salary and employment: a population-based event time study using a quasi-experimental design. BMJ Open. 2020 Oct 21;10(10):e038161. doi: 10.1136/bmjopen-2020-038161. — View Citation

Hanna-El-Daher L, Braissant O. Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models? Amino Acids. 2016 Aug;48(8):1877-95. doi: 10.1007/s00726-016-2189-0. Epub 2016 Feb 10. Review. — View Citation

Harmon KG, Clugston JR, Dec K, Hainline B, Herring S, Kane SF, Kontos AP, Leddy JJ, McCrea M, Poddar SK, Putukian M, Wilson JC, Roberts WO. American Medical Society for Sports Medicine position statement on concussion in sport. Br J Sports Med. 2019 Feb;53(4):213-225. doi: 10.1136/bjsports-2018-100338. — View Citation

Johnson SB, Blum RW, Giedd JN. Adolescent maturity and the brain: the promise and pitfalls of neuroscience research in adolescent health policy. J Adolesc Health. 2009 Sep;45(3):216-21. doi: 10.1016/j.jadohealth.2009.05.016. Review. — View Citation

King NS, Crawford S, Wenden FJ, Moss NE, Wade DT. The Rivermead Post Concussion Symptoms Questionnaire: a measure of symptoms commonly experienced after head injury and its reliability. J Neurol. 1995 Sep;242(9):587-92. — View Citation

Kreider RB, Kalman DS, Antonio J, Ziegenfuss TN, Wildman R, Collins R, Candow DG, Kleiner SM, Almada AL, Lopez HL. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017 Jun 13;14:18. doi: 10.1186/s12970-017-0173-z. eCollection 2017. Review. — View Citation

Kreider RB, Stout JR. Creatine in Health and Disease. Nutrients. 2021 Jan 29;13(2). pii: 447. doi: 10.3390/nu13020447. — View Citation

Langer L, Levy C, Bayley M. Increasing Incidence of Concussion: True Epidemic or Better Recognition? J Head Trauma Rehabil. 2020 Jan/Feb;35(1):E60-E66. doi: 10.1097/HTR.0000000000000503. — View Citation

Levin HS, Diaz-Arrastia RR. Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol. 2015 May;14(5):506-17. doi: 10.1016/S1474-4422(15)00002-2. Epub 2015 Mar 20. Review. — View Citation

Ling J, Kritikos M, Tiplady B. Cognitive effects of creatine ethyl ester supplementation. Behav Pharmacol. 2009 Dec;20(8):673-9. doi: 10.1097/FBP.0b013e3283323c2a. — View Citation

Lowe MT, Faull RL, Christie DL, Waldvogel HJ. Distribution of the creatine transporter throughout the human brain reveals a spectrum of creatine transporter immunoreactivity. J Comp Neurol. 2015 Apr 1;523(5):699-725. doi: 10.1002/cne.23667. Epub 2014 Sep 12. — View Citation

Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, Cohen BM, Renshaw PF. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res. 2003 Jun 30;123(2):87-100. — View Citation

Makdissi M, Schneider KJ, Feddermann-Demont N, Guskiewicz KM, Hinds S, Leddy JJ, McCrea M, Turner M, Johnston KM. Approach to investigation and treatment of persistent symptoms following sport-related concussion: a systematic review. Br J Sports Med. 2017 Jun;51(12):958-968. doi: 10.1136/bjsports-2016-097470. Epub 2017 May 8. Review. — View Citation

McCrory P, Meeuwisse W, Dvorák J, Aubry M, Bailes J, Broglio S, Cantu RC, Cassidy D, Echemendia RJ, Castellani RJ, Davis GA, Ellenbogen R, Emery C, Engebretsen L, Feddermann-Demont N, Giza CC, Guskiewicz KM, Herring S, Iverson GL, Johnston KM, Kissick J, Kutcher J, Leddy JJ, Maddocks D, Makdissi M, Manley GT, McCrea M, Meehan WP, Nagahiro S, Patricios J, Putukian M, Schneider KJ, Sills A, Tator CH, Turner M, Vos PE. Consensus statement on concussion in sport-the 5(th) international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med. 2017 Jun;51(11):838-847. doi: 10.1136/bjsports-2017-097699. Epub 2017 Apr 26. — View Citation

O'Gorman E, Beutner G, Dolder M, Koretsky AP, Brdiczka D, Wallimann T. The role of creatine kinase in inhibition of mitochondrial permeability transition. FEBS Lett. 1997 Sep 8;414(2):253-7. — View Citation

Peters R. Ageing and the brain. Postgrad Med J. 2006 Feb;82(964):84-8. Review. — View Citation

Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. 2003 Oct 22;270(1529):2147-50. — View Citation

Romeu-Mejia R, Giza CC, Goldman JT. Concussion Pathophysiology and Injury Biomechanics. Curr Rev Musculoskelet Med. 2019 Jun;12(2):105-116. doi: 10.1007/s12178-019-09536-8. Review. — View Citation

Roschel H, Gualano B, Ostojic SM, Rawson ES. Creatine Supplementation and Brain Health. Nutrients. 2021 Feb 10;13(2). pii: 586. doi: 10.3390/nu13020586. Review. — View Citation

Sestili P, Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, Falcieri E, Agostini D, Gioacchini AM, Stocchi V. Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med. 2006 Mar 1;40(5):837-49. Epub 2005 Nov 2. — View Citation

Smith RN, Agharkar AS, Gonzales EB. A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000Res. 2014 Sep 15;3:222. doi: 10.12688/f1000research.5218.1. eCollection 2014. Review. — View Citation

Sowell ER, Thompson PM, Holmes CJ, Jernigan TL, Toga AW. In vivo evidence for post-adolescent brain maturation in frontal and striatal regions. Nat Neurosci. 1999 Oct;2(10):859-61. — View Citation

Watanabe A, Kato N, Kato T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res. 2002 Apr;42(4):279-85. — View Citation

Westerståhl M, Jansson E, Barnekow-Bergkvist M, Aasa U. Longitudinal changes in physical capacity from adolescence to middle age in men and women. Sci Rep. 2018 Oct 3;8(1):14767. doi: 10.1038/s41598-018-33141-3. — View Citation

Whyte MP, Chines A, Silva DP Jr, Landt Y, Ladenson JH. Creatine kinase brain isoenzyme (BB-CK) presence in serum distinguishes osteopetroses among the sclerosing bone disorders. J Bone Miner Res. 1996 Oct;11(10):1438-43. — View Citation

* Note: There are 34 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Height	Descriptive measurement	Baseline
Other	Training status	To determine if the participants are at the same initial training status.	Baseline
Other	Period with PPCS	To assess persistent post-concussive symptoms	Baseline
Primary	Change from Baseline Post-Concussion Symptoms at 7 weeks	Rivermead Post-Concussion Symptom Questionnaire	Baseline, 3 weeks and 7 weeks (follow-up)
Secondary	Change from Baseline Body weight at 7 weeks	As we are using a dietary supplement as our intervention, following participants body weight in kg throughout the intervention is necessary in order to know if changes in body weight have any effect on our results.	Baseline, 3 weeks and 7 weeks (follow-up)