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Research
Mega-dose vitamin C in treatment of the common cold: a randomised
controlled trial
Carmen Audera, Roger V Patulny, Beate H Sander and Robert M Douglas
MJA 2001; 175: 359-362
Abstract -
Methods -
Results -
Discussion -
Acknowledgements -
Competing interests -
Reference -
Authors' details -
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Objective: To determine the effect of large doses of
vitamin C in the treatment of the common cold.
Study design: Double-blind, randomised clinical trial
with four intervention arms: vitamin C at daily doses of 0.03 g
("placebo"), 1 g, 3 g, or 3 g with additives ("Bio-C") taken at onset of a
cold and for the following two days.
Participants and setting: 400 healthy volunteers were
recruited from staff and students of the Australian National
University, Canberra, ACT, between May 1998 and November
1999. The trial continued for 18 months.
Interventions: Participants were instructed to
commence medication when they had experienced early symptoms of a
cold for four hours, and to record daily their symptoms, severity,
doctor visits and use of other medications.
Main outcome measures: Duration of symptoms and cold
episodes; cumulative symptom severity scores after 7, 14 and 28 days;
doctor visits; and whether participants guessed which medication
they were taking.
Results: 149 participants returned records for 184 cold
episodes. No significant differences were observed in any measure of
cold duration or severity between the four medication groups.
Although differences were not significant, the placebo group had the
shortest duration of nasal, systemic and overall symptoms, and the
lowest mean severity score at 14 days, and the second lowest at 7 and 28
days.
Conclusions: Doses of vitamin C in excess of 1g daily
taken shortly after onset of a cold did not reduce the duration or
severity of cold symptoms in healthy adult volunteers when compared
with a vitamin C dose less than the minimum recommended daily intake.
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A recent Cochrane systematic review of the effects of vitamin C on the
common cold concluded that large maintenance doses of vitamin C do not
lower the incidence of colds in well-nourished subjects in Western
countries.1 Nevertheless, the
meta-analysis of 17 trials found that prophylactic doses of at least
1g per day were associated with a statistically significant weighted
mean reduction in symptom days of about 0.45 days per cold (9% of
symptom days).1 However, the authors of the Cochrane review could not draw
conclusions about the therapeutic effects of vitamin C (ie, effects
when taken at onset of a cold).1 Findings of four
well-conducted trials of the effects of treating colds with a loading
dose of vitamin C were inconclusive2-5(Box 1). This
prompted us to design a study to answer the question "Would vitamin C,
when used exclusively as a therapeutic agent in doses that greatly
exceed the required daily intake, reduce the duration or severity of
symptoms of the common cold in healthy Australian adults?".
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Our study was a double-blind, randomised trial comparing the effects
of different doses and formulations of vitamin C. We chose as
"placebo" a dose of 0.03g per day of vitamin C (about half the
recommended minimum daily intake), recognising that all
participants would have some nutritional vitamin C intake. Ethics
approval was obtained from the Human Ethics Committee of the
Australian National University, Canberra.
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Participants |
Staff and students of the Australian National University, Canberra,
ACT, were recruited between May 1998 and November 1999 through
personal letters and emails, announcements at student gatherings
and direct approach in university common areas. Volunteers were
eligible for the study if they were aged over 18 years, not pregnant or
planning to become pregnant, in good general health, and did not take
vitamin supplements regularly or take vitamin C, echinacea, zinc or
Chinese herbal preparations regularly at the onset of a cold.
Volunteers were clearly informed about the objectives of the study
and signed an informed consent form. They also completed a
questionnaire about their current health and medication status,
including respiratory infections in the previous year. An
information letter was provided for their general
practitioners. Participants who returned information on one
respiratory event were eligible to re-enrol in the study.
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Interventions |
Participants were randomised to receive one of four interventions:
vitamin C in a daily dose of 0.03 g, 1 g or 3 g, or "Bio-C" (containing
vitamin C [3 g daily] plus bioflavenoids [75 mg], rutin [150 mg],
hisperidin [150 mg], rose hip extract [750 mg] and acerola [150 mg]).
They were to take the medication at onset of cold symptoms and on the
following two days.
The medications were prepared by Blackmores Ltd (Sydney, NSW) as
compressed tablets with identical appearance and packaging. Dosage
was confirmed by chemical analysis of unused tablets at the end of the
study.
A random number table was constructed to order the medications
sequentially so that each sequence of four numbers comprised all four
types of medication. The medications were issued to investigators in
400 sequentially numbered sets of three bottles, each bottle
containing the daily dose in three tablets. As volunteers joined the
study they were given a set of three bottles and a correspondingly
numbered "respiratory event card" to record outcome. The code was
retained by the manufacturer until we were ready to analyse the
results.
Participants were instructed that they must have at least two of the
following symptoms for a minimum of four hours before commencing
medication: sore or scratchy throat, nasal congestion or discharge,
headache or stinging eyes, muscle aches, fever, or "four hours of
certainty that a cold is coming on". On the first day of illness, they
were to take the contents of one bottle (three tablets) as soon as
possible. For the next two days, they were to take three tablets a day at
intervals of at least four hours.
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Outcome measures | |
The respiratory event card was designed to be carried in a wallet or
purse. When a cold began, participants were instructed to score
symptoms daily, noting presence and severity (1, mild; 2, moderate;
or 3, severe) of cough, nasal, throat, and systemic symptoms,
including fever, headache, aches, feeling unwell and "other
symptoms". Recording was to cease either when all symptoms
disappeared or 28 days after onset of the cold.
Participants were also instructed to record hours between onset of
symptoms and first dose of medication, use of other medication and
whether they sought medical attention. They were also invited to
guess to which medication group they had been assigned.
Duration of the cold was measured from day of symptom onset to the last
day of any symptom. Cold severity scores were the sum of daily
individual symptom scores throughout the duration of the cold.
Symptom days and severity scores for cough, nasal, throat and
systemic symptoms were considered separately, and cumulative
scores were considered at 7, 14, and 28 days. For any one day of
symptoms, the maximum severity score was 12. Participants who did not
return a respiratory event card were sent reminder letters after nine
months and 15 months. The initial 12-month study period was extended
by six months in an effort to increase the response rate.
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Statistical analysis | |
We aimed to study 75 individuals in each intervention arm, in the
expectation that the study would have an 80% power to detect a 30%
difference between groups in duration or severity, which we
considered clinically significant. Desired sample size was
calculated assuming a mean duration of seven days and a standard
deviation of four days.
Statistical comparisons were carried out using the software package
SPSS.6 Distribution, mean and
median of duration and severity scores for each symptom were compared
between the four groups by t-tests, analysis of variance and
box plots.
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Study population | |
Four hundred sets of medication were distributed to 323 volunteers.
By November 1999, when the study was terminated, 149 people had
returned completed respiratory event cards for 184 cold episodes.
These 149 were significantly older than those who did not return cards
(45.1 versus 40.9 years; P < 0.05), but the two groups did
not differ significantly in sex distribution or previous cold
history.
Personal characteristics and previous cold history of those who
returned cards are shown in Box 2, along with time from symptom onset to
beginning medication. Participants in the four medication groups
were comparable in sex distribution and time to beginning
medication, but those who took Bio C were significantly older and had
fewer colds in the previous year than those in the other three groups
(P < 0.05).
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Cold duration and severity | |
Duration and severity of symptoms are compared between the four
medication groups in Box 2. There were no significant differences
between the groups in either mean duration of symptoms or mean
severity scores at Days 7, 14 or 28, although the placebo group (30 mg
vitamin C daily) had the shortest duration of nasal, systemic
and overall symptoms, and the lowest mean severity score at 14 days,
and the second lowest at 7 and 28 days.
A box plot of cumulative severity scores at Day 28 (Box 3) revealed that
the distribution of values was more dispersed in the 1 g and 3 g
vitamin C groups, with the lowest median values occurring in the
placebo and Bio C groups. A box plot of cold duration showed a
similar pattern (Box 3).
Only 31 participants (17%) recorded a guess about the dose of vitamin C
they had taken, and 14 guessed correctly that they had taken a high
dose. Seventeen gussed incorrectly that they had taken either a high
or low dose.
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Actual power of the study | |
Because the mean cold duration for the whole group was 9.8 days with a
standard deviation of 6.6 days, the number of completed cold episodes
returned per group provided 80% power to detect a 40% difference in
cold duration with a 95% level of confidence. Similarly, given that
the mean severity score at Day 28 was 32 with a standard deviation of
32.3, the number of completed cold episodes provided 80% power to
detect a 50% difference in severity at the 95% level of confidence.
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Our study found no significant differences in severity or duration of
cold symptoms between groups who took low-dose (placebo) and
high-dose vitamin C as treatment for the common cold. The lack of
benefit from high-dose therapeutic vitamin C is consistent with the
findings of four other randomised controlled trials2-5 (Box 1).
The Cochrane and other reviews of the published evidence on high-dose
vitamin C and the common cold have drawn attention to the relatively
consistent trend for those taking prophylactic doses in
excess of 1 g daily to experience some reduction in duration or
severity of colds.1,7-9 Although high-dose
prophylactic vitamin C was also found not to reduce the
incidence of colds in well-nourished adult
populations,1,7 Hemila has proposed that
it may have an effect in groups who are physically stressed or have low
nutritional intake.8-10
The main weakness of our study is that it necessarily relied on study
participants to decide when the criteria for commencing medication
were met and to provide all outcome data. In such a study,
double-blindness must be rigorously preserved, and allocation to
intervention arms must avoid selection bias. We are confident that
our study met these requirements and that the few participants who
correctly guessed their medication dose did so by chance.
The focus on the university community meant a potential bias in
socioeconomic and educational status of participants. The
observed spectrum of cold experience may not have been
representative of the cold experience of the rest of the Canberra
community. Many potential volunteers in our study were ruled
ineligible because of their regular use of vitamin C and other,
non-traditional approaches for cold therapy and prophylaxis. A
recent US study found that 67% of patients seeking medical care for
cold episodes believed that vitamin C reduces cold
symptoms.11
Our target of 75 colds in each treatment group was not reached, despite
extension of the study and repeated reminder letters to
participants. Fewer than half those enrolled returned a completed
respiratory event card. As we expected most to suffer at least one cold
during the 18 months of the study, based on their previous history, we
assume that many did not use the medication as instructed. Although
those who completed a respiratory event card were older than those who
did not, both groups had similar previous cold experience. The
double-blind nature of the study makes it unlikely that greater
compliance would have changed the result.
Our study had medication groups of comparable size, and for each
medication group colds were found to have occurred across the entire
study period. The Bio-C group was slightly older than the other groups
and, probably in consequence, experienced fewer colds in the
previous year, as the incidence of colds tends to decrease with age.
However, these differences were not associated with significant
differences in outcomes.
The average time between symptom onset and medication use was 13
hours, although we encouraged participants to begin medication as
soon as four hours after they were certain that a cold was developing.
However, the time to beginning medication did not differ
significantly between groups.
The power of our study to detect a possible significant difference in
symptom severity and duration after high-dose vitamin C treatment
was limited by the smaller than expected participation rate.
However, the non-significant trend that was observed was the
reverse: symptoms tended to be less severe and of shorter duration in
the placebo group. The lack of observed benefit in this trial
is fully consistent with the observations from the four previous
randomised controlled trials that have sought to evaluate this
issue.2-5
It is time to question again the wisdom and utility of the wide practice
of well nourished adults taking mega-doses of vitamin C to treat the
common cold, a practice which has become prevalent worldwide since
the advocacy of Linus Pauling in the early 1970s.12,13
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The project was supported by a grant from Blackmores Ltd, who also
provided the study medications. We thank all those who participated
in the study for their patience and compliance.
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Blackmores Ltd were not involved in conduct or analysis of the trial or
preparation of this article.
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- Douglas RM, Chalker EB, Treacy B. Vitamin C for preventing and
treating the common cold (Cochrane Review). In: The Cochrane
Library, 3, 2001. Oxford: Update Software.
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Anderson TN, Suranyi B, Beaton GW. The effect on winter illness of
large doses of vitamin C. Can Med Assoc J 1974; 111: 31-38.
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Karlowski TR, Chalmers TC, Frenkel LD, et al. Ascorbic acid for the
common cold. A prophylactic and therapeutic trial. JAMA
1975; 231: 1038-1042.
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Elwood PC, Hughes SJ, St Leger AS. A randomized controlled trial of
the therapeutic effect of vitamin C in the common cold.
Practitioner 1977; 218: 133-137.
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Tyrrell DA, Craig JW, Meada TW, White T. A trial of ascorbic acid in
the treatment of the common cold. Br J Prev Soc Med 1977; 31:
189-191.
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SPSS [computer program]. Version 10.0 for Windows. Chicago, Ill:
SPSS Inc, 1999.
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Hemila H. Vitamin C and the common cold. Br J Nutr 1992; 31:
3-16.
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Hemila H. Vitamin C supplementation and the common cold: was Linus
Pauling right or wrong? Int J Vitam Nutr Res 1997; 67: 329-325.
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Hemila H. Vitamin C and common cold incidence: A review of studies
with subjects under heavy physical stress. Int J Sports Med
1996; 17: 379-383.
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Hemila H, Douglas RM. Vitamin C and acute respiratory infections.
Int J Tuberc Lung Dis 1999; 3: 756-761.
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Braun BL, Fowles JB, Solberg L, et al. Patient beliefs about the
characteristics, causes, and care of the common cold: an update. J
Fam Pract 2000; 49: 153-156.
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Pauling L. The significance of the evidence about ascorbic acid
and the common cold. Proc Natl Acad Sci USA 1971; 68:
2678-2681.
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Pauling L. Vitamin C, the common cold, and the flu. San Francisco:
Freeman, 1976.
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National Centre for Epidemiology and Population Health, Australian National
University, Canberra, ACT.
Carmen Audera, MD, MPH, Lecturer;
Roger V Patulny, BEc, BA (Hons), Research Assistant;
Beate H Sander, BAppSc (Nursing), MEcDev, Research Assistant;
Robert M Douglas, MD, FRACP, FAFPHM, Visiting Fellow.
Reprints will not be available from the authors. Correspondence: Emeritus Professor R M Douglas,
National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT 0200.
Bob.DouglasATanu.edu.au
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| 1: Previous randomised controlled
trials of the therapeutic effect of high-dose vitamin C on cold symptoms |
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| Study |
Participants and setting |
Interventions |
Outcomes |
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| Anderson et al2 (1974) |
Toronto, Canada Hospital and business employees (>275
per arm) |
4 arms: 2 placebo, 2 therapeutic (4g or 8g vitamin C taken
on day of symptom onset) |
The two placebo arms unfortunately differed in outcome.
Mean days of respiratory symptoms over 3 months: placebo, 5.4 and 4.16 days
(combined placebo mean, 4.77 days); intervention, 4.82 days (4g dose) and
4.52 days (8g) |
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| Karlowski et al3 (1975) |
Bethesda, USA National Institutes of Health employees
(46 placebo, 43 therapy) |
3g vitamin C daily or placebo for the first 5 days of
a cold |
Problem in blinding, as over half the participants correctly
guessed their medication through taste. Although mean duration of colds
was longer in the placebo than therapy group (7.1 v 6.5 days), difference
was confined to those who guessed their medication ("unblinded"). Unblinded
group: 8.6 (placebo) v 4.7 days (therapy); blinded group: 6.3 (placebo)
versus 6.7 days (therapy). |
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| Elwood et al,4 (1977) |
South Wales, UK Community volunteers (119 placebo, 145
therapy) |
3g vitamin C daily or placebo for 3 days |
Vitamin C significantly reduced duration of "simple" colds
in men (5.7 days [placebo] v 3.97 days [therapy]), but had no benefit in
women (4.97 days [placebo] v 6.05 [therapy]), or in "chest" colds in either
sex. |
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| Tyrrell et al5 (1977) |
Salisbury, UK 482 volunteers |
4g of vitamin C or an identical-tasting placebo daily
for 2.5 days |
No evidence that vitamin C alleviated or shortened upper
respiratory or general constitutional symptoms. |
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| 2: Characteristics of
participants and outcomes of a study of the effect of therapeutic vitamin
C on the common cold |
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Vitamin
C formulation (daily dose) |
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0.03g (n=42)* |
1g (n=47)* |
3g (n=50)* |
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| Participant characteristics |
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| Mean age in years (95% CI) |
38.6 (34.2-43.0) |
40.1 (35.8-44.4) |
39.9 (36.2-43.6) |
| Male sex (95% CI) |
45% (30%-61%) |
38% (26%-54%) |
50% (36%-65%) |
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| Cold history in previous year
Mean number of colds (95% CI)
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2.2 (1.7-2.7) (n=40) |
2.25 (1.9-2.6) (n=46) |
2.2 (1.8-2.7) (n=49) |
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| Mean number of days unwell from
colds (95% CI) |
8.0 (3.4-12.5) (n=39) |
7.7 (6.2-9.3) (n=46) |
7.7 (6.5-9.2) (n=49) |
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| Mean hours from symptom onset
to medication (95% CI) |
13.3 (9.4-17.2) (n=39) |
11.6 (8.7-14.7) (n=44) |
10.2 (8.2-12.3) (n=48) |
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| Outcome measures |
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| Mean days of symptom (95% CI)
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8.5 (6.6-10.5) |
10.1 (8.1-12.1) |
10.4 (8.5-12.2) |
| Cough |
5.3 (3.0-7.6) |
6.4 (4.1-8.6) |
6.3 (4.4-8.3) |
| Nasal symptoms |
7.3 (5.4-9.1) |
8.4 (6.7-10.1)
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9.2 (7.4-11.1)
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| Throat symptoms |
5.4 (3.6-7.2) |
6.1 (4.3-7.9) |
6.3 (4.6-7.9) |
| Systemic symptoms |
3.5 (2.1-4.9) |
3.7 (2.3-5.2) |
3.8 (2.7-4.8) |
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| Mean severity score (95% CI) |
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| Day 7 |
20.2 (16.5-24.0) |
22.1 (18.1-26.0) |
23.0 (19.3-26.6) |
| Day 14 |
25.6 (19.0-32.1) |
31.1 (23.5-38.8) |
30.8 (24.9-36.6) |
| Day 28 |
29.0 (19.5-38.6) |
35.4 (23.4-47.5) |
34.3 (26.6-42.1) |
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| Doctor visit (95% CI) |
7% (2%-20%) |
19% (8%-31%) |
4% (0.5%-14%) |
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| Other medication taken for symptoms
(95% CI) |
57% (41%-72%) |
55% (40%-70%) |
55% (39%-68%) |
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Vitamin C formulation (daily dose) |
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"Bio C" (3g plus additives) (n=45)* |
Total (n=184)* |
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| Participant characteristics |
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| Mean age in years (95%
CI) |
45.1 (40.6-49.5) |
40.9 (38.8-43.0) |
| Male sex (95% CI) |
51% (36%-66%) |
46% (39%-54%) |
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| Cold history in previous
year
Mean number of colds (95% CI)
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1.5 (1.3-1.8)
(n=44) |
2.1 (1.9-2.3)
(n=179) |
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| Mean number of days unwell
from colds (95% CI) |
6.8 (5.4-8.2)
(n=43) |
7.5 (6.4-8.9)
(n=177) |
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| Mean hours from symptom
onset to medication (95% CI) |
18.6 (11.2-26)
(n=44) |
13.4 (11.1-15.8)
(n=175) |
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| Outcome measures |
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| Mean days of symptom (95%
CI) |
9.9 (7.9-11.9)
|
9.8 (8.8-10.7) |
| Cough |
4.4 (2.2-6.5)
|
5.6 (4.6-6.7) |
| Nasal symptoms |
8.1
(6.1-10.1) |
8.3
(7.4-9.2) |
| Throat symptoms |
5.4 (3.8-6.9) |
5.8 (5.0-6.7) |
| Systemic symptoms |
4.4 (3.2-5.6)
|
3.9 (3.2-4.5) |
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| Mean severity score (95%
CI) |
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| Day 7 |
19.2 (15.4-23.0)
|
21.2 (19.3-23.0) |
| Day 14 |
25.9 (19.1-32.6)
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28.5 (25.2-32.8) |
| Day 28 |
28.6 (20.0-37.3)
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32.0 (27.3-36.7) |
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| Doctor visit (95% CI) |
9% (3%-21%) |
9% (6%-14%) |
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| Other medication taken
for symptoms (95% CI) |
53% (38%-68%)
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55% (47%-62%) |
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| *Number of completed cold episodes;
35 participants were counted twice, as they reported two medicated colds.
For variables with missing data, numbers of participants who provided information
are shown in parentheses. P |
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