Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03963128 |
| Other study ID # |
D_SAF |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 6, 2017 |
| Est. completion date |
December 2023 |
Study information
| Verified date |
May 2019 |
| Source |
University of Surrey |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The study will comprise of an original investigation that will take the form of a prospective
intervention (two matched groups) study. Condition-1 will be a vitamin D supplementation
group (50.000 IU every two months), and Condition-2 will be a placebo supplementation group.
The primary research aim of this project is to evaluate the effectiveness of vitamin D
supplementation to reduce stress fracture risk and susceptibility to skin, soft tissue
infection (SSTI) and respiratory infection in Royal Marine recruits undertaking arduous
physical training in a randomised control trial (RCT). The secondary research aims are:
1. To investigate whether supplementation of vitamin D3 at a dose of 50.000 IU every two
months (equivalent to 800 IU per day) is effective in reducing the risk of stress
fracture and susceptibility to skin, soft tissue and respiratory infection.
2. To examine changes in vitamin D status (relative to baseline serum 25(OH)D
concentration), serum PTH concentration, and markers of bone turnover in response to
vitamin D3 supplementation during the winter and summer months.
3. To identify interactions between dietary intakes, physical fitness, physical
characteristics (body mass, BMI, thigh girth), smoking habit, alcohol consumption, and
stress fracture prevalence with serum 25(OH)D status, serum PTH concentration and
markers of bone turnover in the vitamin D3 supplemented group vs. the placebo
supplemented group.
Description:
Study Overview:
Aim: The effect of vitamin D3 supplementation in (male) Royal Marine recruits during 32-weeks
of (arduous) initial military training on stress fracture and respiratory illness risk.
Volunteer recruits will initially complete a healthy history, smoking habit and alcohol
consumption questionnaire. Height, body mass (from which BMI will be calculated), and calf
girth/skinfold will be measured. A 20 ml blood sample will be drawn (gold and purple top
vacutainers) for determination of vitamin D status, calcium and albumin concentrations, PTH
concentration, markers of bone turnover, antibody responses against S. aureus or other
antigens and plasma cytokine levels. A (3-5 ml) saliva sample will be taken for S. aureus
culture, and for assessment of oral microbiota, cytokine and antibody levels in saliva. A dry
swab would be taken from both anterior nares for enumeration of S. aureus, and stored in
phosphate buffered saline. The study recruit cohort will be divided into two groups: (i) a
vitamin-D3 supplementation (50,000 IU administered orally every two months - equivalent to
800 IU per day); and (ii) a placebo supplementation (administered orally every two months)
control group. The vitamin D supplement and the placebo supplement will be manufactured by
Pharmaterials Ltd., Unit B, 5 Boulton Road, Reading, RG2 0NH, UK. The active and placebo
supplements will be presented as identical (size and appearance) tablets, indiscernible from
each other for the volunteer or the study team in situ at CTC. Both groups will receive one
tablet at each time point. Recruits will be randomly assigned to a study group, but the two
groups will be matched for age, height, body mass and aerobic fitness. The randomisation of
supplement/placebo administration to study volunteers will be undertaken by statisticians
from the University of Surrey. Study team staff will monitor supplement taking and will
further confirm supplement taking through exit interviews. Further 20 ml blood samples will
be drawn every two months (i.e. at weeks 8, 16 and 32 of RM training), saliva samples and
nasal swabs will also be taken, and the smoking habit and alcohol consumption questionnaire
will be re-administered. The study team will take into consideration prevailing data on
recruit attrition to inform this decision. Food Frequency Questionnaire (FFQ) will be
administered in week-6 of training; this will allow the recruits' habitual RM training diet
to be established following the civilian to military transition. Permission will be sought to
collate the outcome of the week-1 and week-9 Royal Marine Fitness Assessment (RMFA).
Permission will also be sought to prospectively collate data from the Defence Medical
Information Capability Programme (DMICP) system describing the prevalence of injury and
illness in study volunteers.
Study Procedures: All potential volunteer recruits to the study will have been initially
passed medically and physically fit to undertake RM training. Following an initial brief,
those recruits volitionally consenting to participate in the study will complete a Health
History Questionnaire and a Smoking Habit and Alcohol Consumption Questionnaire. The Royal
Marine Fitness Assessment (RMFA) is completed as part of the Recruit Syllabus (RS10) in weeks
1 and 9 of training; these data (i.e. Multi-Stage Fitness Test performance, number of
sit-ups, number of press-ups and number of pull-ups) are collected by the PT Branch at CTC,
and will be compiled by the study team to allow fitness comparisons to be made with the
recruit sample monitored during SGBHP. Height and body mass will be measured (from which BMI
will be calculated), and calf girth/skinfold will be measured, the Smoking Habit and Alcohol
Consumption Questionnaire completed, antibiotic exposure determined (i.e. antibiotics use not
prescribed by the Medical Centre will be ascertained, where the antibiotics prescribed by
Medical Centre will be collected from medical centre notes), occurrence of skin infections
treated outside the CTCRM Medical Centre determined (where skin infections diagnosed by
Medical Centre will be collected from medical centre notes), and a further blood sample will
be drawn every two months during training (i.e. at weeks 8, 16) and at the End of training
(week32). The precise timing of measurement sessions will be determined through discussions
between the study team and the Commando Training Wing (CTW). All measures will be undertaken
in appropriate venues at CTC, and will be accommodated in the recruits' programme where there
would be minimum impact upon other training/personal administration activities.
Vitamin D or Placebo Supplement Administration: The INM study team staff will undertake
vitamin D or placebo supplement administration during a programmed medical serial in the RM
recruit programme. The study team will observe and monitor recruits taking the supplement or
placebo tablet, and will further confirm supplement or placebo taking through exit
interviews. The pattern of randomisation of the supplement(s) and placebo for the study will
be determined and monitored independently by UoS study team members. There will be two study
groups - a vitamin D supplement group and a placebo supplement group. The two groups will be
matched for age, height, body mass and aerobic fitness. The study plan is to supplement at
the Start of Training, and every two months thereafter (i.e. at weeks 8, 16 and 24 of RM
training). Preliminary discussions with CTC indicate that - to schedule this within the RM
training programme and therefore ensure minimum impact on RM recruit time - supplementation
during training may need to take place at weeks 6, 15 and 24. During these programmed
serials, the study team will also collate information detailing if a study participant had
undertaken military exercises or leave, where they would be exposed to increased sunlight,
since the last measurement time point. This will be particularly pertinent where measurement
points span CTC block leave (i.e. Christmas, Easter and Summer).
Assessment of Injury/Illness Incidence: The incidence of injury/illness (including SF, SSTI
and respiratory infection) in recruits during training will be monitored in association with
colleagues from the Medical Centre.
Measurements:
1. Health History Questionnaire: Whilst attending for the blood sample, a Health History
Questionnaire will be completed.
2. Smoking and Alcohol Histories Questionnaire: Whilst attending for the blood sample, a
validated Smoking and Alcohol Histories Questionnaire will be completed.
3. Body Mass: Volunteers will be weighed in shorts and t-shirt to the nearest 0.1 kg (Seca,
Hamburg, Germany).
4. Height: Volunteers will remove their shoes/boots before standing on the stadiometer
(Invicta, England) with feet together. Feet, buttocks and scapulae will be in contact
with the back of the stadiometer, and personnel should look directly ahead. Height will
be measured to the nearest 0.1 cm.
5. Body Mass Index (BMI): Body mass index will be calculated according to the equation, BMI
= Body Mass รท (Height)2.
6. Calf Circumference: Each recruit will be measured to the nearest 0.1 cm at the site of
maximum girth using a Silverflex anatomical metal tape measure (Rabone Chesterman,
England).
7. Calf Skinfold: A calf skinfold will be measured to the nearest 0.2 mm at the site of
maximum girth for each recruit using Harpenden callipers (BodyCare UK).
8. Royal Marine Fitness Assessment (RMFA): The RMFA is a programmed serial of RM training,
and is administered in weeks 1 and 9 of training. It comprises four component parts
including: Multistage Fitness Test (MSFT); press-up test; sit-up test; and pull-up test.
The RMFA will be administered by the PT Branch in accordance with CTC PT Instructional
Specifications (ISPECs). The MSFT will be employed to estimate maximum oxygen uptake
(VO2max). Sit-ups, press-ups, and pull-ups will be performed in accordance with standard
RM techniques.
9. MOD Food Frequency Questionnaire (FFQ): A questionnaire examining nutrition and physical
activity levels during the childhood and teenage years, and validated for use in
military recruits, will be administered during a classroom serial in week-6 of training.
This questionnaire was originally developed to assess nutritional and lifestyle
influences on bone health in pre-menopausal women, and is based on a FFQ approach.
Output data provide an estimated dietary analysis of respondents (in terms of macroand
micro-nutrient intakes), and information on other lifestyle risk factors associated with
bone health including physical activity habits and smoking. The aim of the FFQ is to
classify research participants into low, medium and high consumers of dairy and
vegetables. Non-dietary questions based on previous physical activity levels are
calculated using James and Schofield equations. Questions regarding smoking are also
included. In order to make this questionnaire more appropriate for the MOD population,
certain regional food items were omitted, questions about convenience and takeaway food
consumption were included, and questions regarding alcohol intake were modified to
reflect the customary alcoholic beverages of the target age group in the present study
(e.g. Alco-pops). The James and Schofield Human Energy Requirement equation will be used
to calculate basal metabolic rate (BMR),31 from which the mean energy intake (EI) to BMR
ratio (EI:BMR) will be determined to assess reporting accuracy of dietary intake.
Goldberg et al.32 established a EI:BMR ratio of 1.35 as being indicative of food diary
under-reporting.
10. Saliva: A (3-5 ml) saliva sample will be taken for S. aureus culture, and for assessment
of oral microbiota, cytokine and antibody levels in saliva.
11. Nasal Swab: A dry swab will be taken from both anterior nares for enumeration of
S.aureus, and stored in phosphate buffered saline.
12. Measures of metabolic and/or biochemical status: A 20 ml blood sample will be drawn from
an antecubital vein by medical personnel - using gold and white capped vacutainers -
during routine medical serials at the Start and End of Training, and during scheduled
medical serials at weeks 8, 16 (or 6, 15) of training to match the weeks when the
supplement/placebo will be administered. The 15 ml gold vacutainer blood samples will be
left to clot for 1 h, after which it will be centrifuged for 15 min within 1 - 2 h, the
serum subsequently being aspirated and initially stored in plastic 0.5 ml aliquots in
plastic Eppendorf tubes at -80 C at CTC. The white vacutainer tubes contain EDTA, which
acts as a strong anticoagulant for whole blood samples. The blood will be centrifuged
for 15 min and the plasma supernatant will be extracted and initially stored in plastic
0.5 ml aliquots in plastic Eppendorf tubes at -80 C at CTC. The serum samples will be
assayed for: vitamin D status (relative to 25(OH)D); parathyroid hormone (PTH)
concentration; calcium (Ca) and albumin (as markers of vitamin D status and Ca
metabolism); serum collagen type I cross-linked C-telopeptide (CTx) as a marker of bone
resorption; carboxy-terminal propeptide of type I collagen (P1NP) as a marker of bone
formation (as markers of bone turnover); and ferritin (Fe) as a marker of iron status.
Immunological metrics will be measured in serum including: serum cytokine levels;
antibody responses against S. aureus or other antigens; full blood count; lymphocyte
phenotyping and measurement of T cell responses against S.aureus and S. pyogenes
antigens; and RNA profiling. At one sample point only, specific DNA would be extracted
from the cell pellet acquired from the (white top EDTA vacutainers) blood sample, which
has been centrifuged to acquire plasma. This DNA will be analysed ONLY to study the
genetic variation in the calcium / vitamin D axis in recruit volunteers. The specific
SNPs for analysis will include: rs12785878 - 11q12 near DHCR7 (7-dehydrocholesterol
reductase); rs10741657 - 11p15 near CYP2R1 (25hydroxylation); rs2282679 - 4p12 in GC
(vitamin D binding protein); rs1998199 - 20q13 near STX16/NPEPL1/GNAS (associated with
pseudo-hypoparathyoidism); rs6013897 - 20q13 near CYP24A1 (24 hydroxylation); and, Apa,
taq, Bsm, fok1 - vitamin D receptor gene polymorphism. Samples for DNA extraction and
analysis will initially be transferred to the University of Oxford, Oxford, for this
work to be completed.
13. Microbiological assessment of aetiology: If a purulent discharge is evident,
microbiological swabs will be obtained from infected lesions, swabs being either taken
on the surface (where no incision and drainage occurs) or from pus samples (where
Incision and drainage has occurred). These will be cultured for S. aureus as recommended
in the current UK Standards in Microbiological Investigation. Consent for collection of
any such samples from NHS laboratories to which they may have been sent will be obtained
at baseline. Additionally, serological diagnosis will be determined using anti-S. aureus
and anti-S. pyogenes antigen EIAs, including the methods described (Karppelin, 2015;
Toleman, 2015; Jeng, 2010).
14. Incidence of illness and injury relative to week of training: The incidence of
injury/illness (including SF, SSTI and respiratory infection) in recruits during
training will be monitored in association with colleagues from the Medical Centre.
Consent to prospectively access this medical information will be obtained from recruits
at the start of training, and their consent will be re-confirmed at the end of training
in the event of any circumstances having changed. Recruits participating in the study,
who report to the Medical Centre, will have the details of their complaint coded on the
DMICP system by the doctor, nurse or medical assistant according to current CTC
procedures. In addition the staff member will categorise the presenting complaint as
'Injury' or 'Illness or Disease' according to the DMICP read codes. The Week of Training
will also be coded on DMICP. To ensure data protection issues are addressed and to
ensure recruit confidentiality, all medical data relating to illness/injury will be
collated through a routine meeting with a single point of contact in the Medical Centre.
The DMICP database will be searched for recruits participating in the study who have
attended medical appointments; the categorisation of the presenting complaint and Week
of Training will be identified. As this study is concerned with the recruit outcomes to
training in itsentirety, recruits who enter Hunter Company due to the severity of their
illness/injury - or for professional reasons - will continue to participate in the study
(subject to their continued consent), and progress with their new Troop will be mapped
through to passout. As far as possible SSTI will be systematically categorised as
follows:
i. Impetigo: A skin infection that is common throughout the world, consists of discrete
purulent lesions caused by beta haemolytic Streptococcus or S. aureus.
ii. Cutaneous Abscesses: Collections of pus within the dermis and deeper skin tissues.
iii. Furuncles and Carbuncles: Furuncles "boils" are infections of the hair follicles caused
by S. aureus in which suppuration extends through the dermis into the subcutaneous tissue
where a small abscess forms. A carbuncle is a collection of infected hair follicles and can
occur anywhere on hairy skin.
iv. Folliculitis: Superficial inflammation and pus is present in the epidermis. v. Cellulitis
and Erysipelas: Diffuse spreading skin infections excluding infections associated with
underlying suppurative foci such as cutaneous abscesses, NF, septic arthritis and
osteomyelitis. Erysipelas affects the upper dermis and cellulitis the deeper dermis and
subcutaneous fat. Erysipelas and cellulitis are usually due to Streptococcus pyogenes.
vi. Necrotising SSTI: Rare subcutaneous infection that tracks along the fascial planes and
may involve the muscle, fat and deeper structures, with an associated mortality of up to 83%
if associated with toxic shock. The major pathogens are S. pyogenes and S. aureus.
vii. Other SSTI not classified.
