Concussion, BrainPhase 1/2MEDICNCT05434130
Modulating Exercise Dosage to Improve Concussion Recovery
A Phase 1/2 study testing High Dose Exercise in people with Concussion, Brain and Treatment, run by University of Colorado, Denver at 3 sites in United States.
Trial summary
Aerobic exercise has emerged as an effective treatment to reduce sport-related concussion symptom severity, yet existing work lacks rigor regarding the precise exercise volume and intensity required to elicit therapeutic effects, how exercise can alter concussion-related pathophysiology, and whether exercise can… Read more about this study
- Who is it for?
- Ages 13 to 18 years
- Conditions the study is for
- Concussion, Brain, Treatment, Aerobic Exercise
- What is being tested?
- High Dose Exercise
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 178 participants
- Where
- 3 sitesUnited States
- Study dates
- 5 Aug 2022to 1 Feb 2027
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 13-18 years of age
- Post-Concussion Symptom Scale (PCSS) score >10 to ensure participants are not recovered by enrollment
- Concussion diagnosis by a sports medicine physician
Who cannot join
- Pre-existing neurological disorders
- Exercise contraindications
- Concussion <6 months before enrollment (excluding the current injury)
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States3 sites, 3 recruiting
- Recruiting
University of Colorado Denver
Aurora, Colorado, 80045
David R Howell, PhD, 7207771502, ConcussionResearch@cuanschutz.edu
Kelsie Richardson, MS, 7207771502, ConcussionResearch@cuanschutz.edu
- Recruiting
Boston Children's Hospital
Boston, Massachusetts, 02115
Danielle Hunt, MS
William P Meehan III, MD
- Recruiting
Spaulding Rehabilitation Hospital
Cambridge, Massachusetts, 02138
Andrew Taylor, PhD
J Andrew Taylor, PhD
About this study
Official title: Modulating Exercise Dosage to Improve Concussion Recovery: A Randomized Clinical Trial
Aerobic exercise has emerged as an effective treatment to reduce sport-related concussion symptom severity, yet existing work lacks rigor regarding the precise exercise volume and intensity required to elicit therapeutic effects, how exercise can alter concussion-related pathophysiology, and whether exercise can prevent the development of secondary sequelae. Our objective is to examine if a high dose exercise program (higher volume than currently prescribed at an individualized, safe intensity level) initiated within 21 days of concussion results in faster symptom resolution, altered physiological function, or reduced secondary sequalae. Findings from this research will lead to more rigorous and precise rehabilitation guidelines and improved understanding about how exercise affects neurophysiological function among adolescents with concussion.
Read the detailed description
Concussions are defined as a mild form of traumatic brain injury that result in acute neurological dysfunction. Recent work suggests post-concussion aerobic exercise at an intensity level below symptom exacerbation is safe. Yet, clinical benefits from existing randomized controlled trials indicate substantial room for improvement. Also, there is currently an incomplete understanding of the neurophysiology underlying changes in response to exercise treatment. Identifying the precise exercise dose (volume/intensity) required to elicit a therapeutic response following concussion will lead to enhanced and more precise post-concussion rehabilitation strategies. Published and pilot data by the investigators indicate light post-concussion exercise was associated with faster symptom resolution time and less severe symptoms, yet this relied on self-reported data and observational designs. Furthermore, the investigators have identified that the optimal exercise volume to differentiate those with/without concussion symptoms after one month was >160 minutes/week, which is higher than standard exercise volumes prescribed (>100 minutes/week), and in line with existing recommendations for cardiovascular health (>150 minutes/week). Beyond this, given the positive effects of regular moderate exercise to reduce inflammation (e.g., interleukin 6) and restore cerebrovascular regulation, these physiological functions represent viable and feasible rehabilitation targets. Thus, using a prospective randomized clinical trial design, the investigators aim to identify if high dose exercise >(150 minutes/week at an individualized intensity level), relative to standard-of-care, results in: faster/slower symptom resolution, altered physiological function, or reduced secondary sequalae. Our multidisciplinary investigative team has expertise investigating concussion, exercise physiology, fluid biomarkers, cerebrovascular physiology, and psychosocial outcomes. Thus, the investigators will enroll, initially test, and randomize adolescents ages 13-18 years old ≤21 days post-concussion to high dose aerobic exercise or standard-of-care (symptom limited, self-guided physical activity), and reassess upon symptom resolution and 8-weeks post symptom resolution. The investigators will obtain cerebrovascular function and serum biomarker data at each visit, and quantify exercise, symptoms, and secondary sequalae continuously. First, The investigators aim to examine how the dose (intensity, duration, and frequency) of an aerobic exercise program initiated within 21 days of concussion affects time to symptom resolution, relative to standard-of-care, among adolescents. Second, the investigators aim to assess the mechanistic relationship between aerobic exercise, biomarkers of neuroinflammation, and cerebrovascular function. Third, the investigators aim to elucidate how high dose exercise after concussion affects persistent secondary sequalae development (anxiety, depression, kinesiophobia, peer relationships, academic concerns). By challenging the currently accepted, exercise recommendations for sport-related concussion, the investigators will break new ground toward improving rehabilitation strategies.
- Being tested
- High Dose Exercise
- Keywords
- intervention, mild traumatic brain injury
- Medical subject headings
- Brain Concussion, Inflammation, Depression, Anxiety Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High Dose ExerciseBehavioural
The investigators will initially test and randomize adolescents ages 13-18 years old ≤21 days post-concussion to high dose aerobic exercise (>150 min/week, individualized intensity level) or standard-of-care (symptom limited, self-guided physical activity), and re-test upon symptom resolution and 8-weeks post symptom resolution
| Study group | Role | What they receive |
|---|---|---|
| High Dose Exercise | Experimental | The investigators will provide exercise dose recommendations for initial visit until symptom resolution, and revise upon symptom resolution (to use for the subsequent 8 weeks). These include intensity (target HR) and volume (frequency/duration). Intensity is calculated as 90% of the HR at the end of the exercise test. The volume recommendation is 150 mins/week (~30 min/day; 5 days/week). The mode of exercise is another consideration. This will be left to participant preference, so that the investigators do not exclude potential participants due to lack of access to specific exercise equipment. Receives: Behavioral: High Dose Exercise |
| Standard-of-care | No intervention | Participants are instructed to perform activity in line with physician recommendations. This consists of a general recommendation (no specific HR/volume) or symptom limited physical activity. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time from injury to symptom resolution
The PCSS is a standard form that records the presence and severity of 22 concussion symptoms at the time of testing. Participants rate their concussion symptoms from 0-6 where 0 equates to "no symptoms," and 6 to "severe symptoms."
Measured: From time of injury until defined symptom resolution observed, about 30 days
Serum biomarker concentration: GFAP change
Concentrations of GFAP will be simultaneously assayed along with other biomarkers using multi-plex digital array technology, which allows for single molecule immunoarrays while minimizing the amount of sample required
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Anxiety and depression severity change
Participants will report anxiety using the Hospital Anxiety and Depression Scale (HADS).The HADS addresses questions related to depression and anxiety symptoms. Responses range from 0 to 3, where 3=experiencing symptoms a great deal of the time, on 14 questions. Seven items are specific to depression symptoms, and 7 to anxiety symptoms. For each sub-scale (HADS-anxiety and HADS-depression) scores range from 0 (no symptoms) to 21 (maximum symptom severity).
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Secondary outcomes (10)
Serum biomarker concentration: IL-6 change
Concentrations of IL-6 will be simultaneously assayed along with other biomarkers using multi-plex digital array technology, which allows for single molecule immunoarrays while minimizing the amount of sample required
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Serum biomarker concentration: TNF-alpha change
Concentrations of TNF-alpha will be simultaneously assayed along with other biomarkers using multi-plex digital array technology, which allows for single molecule immunoarrays while minimizing the amount of sample required
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Serum biomarker concentration: IL1-RA change
Concentrations of IL1-RA will be simultaneously assayed along with other biomarkers using multi-plex digital array technology, which allows for single molecule immunoarrays while minimizing the amount of sample required
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Serum biomarker concentration: VEGF change
Serum biomarkers will be obtained via venipuncture at the initial visit, after symptom resolution, and 8 weeks after symptom resolution.
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Serum biomarker concentration: MMP-9 change
Concentrations of MMP-9 will be simultaneously assayed along with other biomarkers using multi-plex digital array technology, which allows for single molecule immunoarrays while minimizing the amount of sample required
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Cerebral autoregulation
The investigators will examine the ability to buffer against pressure changes during exercise. Autoregulation will be assessed by deriving the relationship between arterial pressure and cerebral blood flow fluctuations elicited using low resistance breathing.
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Cerebral vasoreactivity change
The investigators will examine the ability to increase blood flow in response to increases in blood CO2. This is assessed by measuring the progressive increase in cerebral blood flow in response to progressive increases in inspired CO2.
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Kinesiophobia severity change
The Tampa Scale of Kinesiophobia (TSK) is a 17-item self-report, 4-point Likert scale questionnaire designed to assess fear of pain with movement (kinesiophobia). The questionnaire was originally designed to measure fear of pain during movement among patients with low back pain, and is reliable.
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Peer relationship attitudes change
Using the Patient Reported Outcomes Measurement Information System (PROMIS), The investigators will obtain data regarding participant attitudes toward peer relationships (friends and other acquaintances).
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Academic concerns change
The Concussion Learning Assessment and School Survey (CLASS) aims to assess concern for the effect of concussion on school learning, new or exacerbated post-concussion academic problems, and perceived impact on academic performance.
Measured: Baseline, Visit 2 (scheduled after symptoms resolve, about 35 days post-baseline)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jun 2022
- Study start5 Aug 2022
- Primary completion1 Feb 2027 (estimated)
- Study completion1 Feb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Concussion, BrainStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The study will use a block stratified RCT design. Our stratum factors are the biological variable of sex and recruitment location
- Masking
- Double blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 178 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- Boston Children's Hospital, Spaulding Rehabilitation Hospital, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- David R Howell, PhD, Principal investigator, University of Colorado Denver | Anschutz
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05434130
- Sponsor's protocol ID
- 21-4932
- Other IDs
- R01HD108133
- Acronym
- MEDIC
- Status last verified
- May 2026
- First submitted
- 26 May 2022
- Last updated
- 31 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Donahue CC, Smulligan KL, Wingerson MJ, Brna ML, Simon SL, Wilson JC, Howell DR. Clinical Cut Point for the Pittsburgh Sleep Quality Index After Adolescent Concussion. Orthop J Sports Med. 2025 Apr 18;13(4):23259671251330571. doi: 10.1177/23259671251330571. eCollection 2025 Apr.
PubMed 40297050Iverson H, Smulligan K, Donahue C, Kniss J, Wingerson M, Wilson J, Howell D. Comparing peer relationship ratings among adolescents with sport and non-sport related concussions. Phys Sportsmed. 2025 Jun;53(3):249-255. doi: 10.1080/00913847.2025.2450216. Epub 2025 Jan 6.
PubMed 39760650Smulligan KL, Armento AM, Brna ML, Meehan WP 3rd, Wilson JC, Howell DR. Low-Energy Availability Indicators Among Female Adolescents After Concussion: A Comparison With Uninjured Controls. Orthop J Sports Med. 2025 Sep 26;13(9):23259671251380877. doi: 10.1177/23259671251380877. eCollection 2025 Sep.
PubMed 41019467Moseley R, Carry PM, Donahue CC, Hicks SD, Simon SL, Wilson J, Meehan WP 3rd, Howell DR. The Dynamic Interaction Between Psychological Health and Sleep Symptoms Following Adolescent Concussion. J Pediatr. 2026 Jan;288:114800. doi: 10.1016/j.jpeds.2025.114800. Epub 2025 Aug 29.
PubMed 40887012Wiegman A, Wingerson M, Smulligan K, Kniss J, Donahue C, Wilson J, Howell D. Clinical predictors of post-concussion kinesiophobia severity among adolescents. Brain Inj. 2026;40(1):1-8. doi: 10.1080/02699052.2025.2565632. Epub 2025 Sep 24.
PubMed 40990413Hurlburt KD, Richardson KL, Wingerson MJ, Kniss JR, Smulligan KL, Wilson JC, Howell DR. NSAID Use Is Not Associated With Persisting Symptoms in Adolescent Concussion. Clin J Sport Med. 2026 Jul 1;36(4):437-443. doi: 10.1097/JSM.0000000000001420. Epub 2026 Feb 2.
PubMed 41622533Donahue CC, Smulligan KL, Wingerson MJ, Kniss JR, Wilson JC, Howell DR. Clinical Cut Point for the Postconcussion Symptom Inventory Following Adolescent Concussion. Med Sci Sports Exerc. 2026 Jun 1;58(6):1140-1148. doi: 10.1249/MSS.0000000000003949. Epub 2026 Jan 26.
PubMed 41593831Salfi ZP, Wingerson MJ, Donahue CC, Smulligan KL, Simon SL, Wilson JC, Howell DR. The Integrated Effect of Physical Activity and Sleep Problems on Concussion Symptom Resolution. J Sport Rehabil. 2026 Apr 9:1-9. doi: 10.1123/jsr.2025-0385. Online ahead of print.
PubMed 41956449Moseley R, Wingerson MJ, Hurlburt KD, Richardson KL, Nagle SM, Wilson JC, Meehan WP 3rd, Howell DR. Concussion Symptom Resolution Expectations and Subsequent Development of Persisting Symptoms After Adolescent Concussion. J Athl Train. 2026 Jun 3;61(6):416-423. doi: 10.4085/1062-6050-0489.25. eCollection 2026 Jun.
PubMed 42245142Moseley RR, Wingerson MJ, Richardson KL, Hurlburt KD, Warren K, Wilson JC, Meehan WP 3rd, Mannix R, Howell DR. Postconcussion physical activity frequency and plasma biomarker associations among adolescents. J Neurosurg Pediatr. 2026 Jun 12:1-8. doi: 10.3171/2026.2.PEDS25624. Online ahead of print.
PubMed 42284615