Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Stroehlein, 2021

Study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to march 2021.

A: Murai, 2021

B: Entrenas Castillo, 2020

C: Rastogi, 2020

Study design:

A: RCT, placebo controlled

B: RCT, open-label

C: RCT, placebo controlled

Setting and Country:

A: inpatient, Brazil

B: inpatient, Spain

C: outpatient, India

Source of funding and conflicts of interest:

A: non-commercial

B: non-commercial

C: non-commercial

Inclusion criteria SR:

• RCTs;
• studies in adults with confirmed COVID-19;
• any type of vitamin D supplementation, given alone or + individual care.

Exclusion criteria SR:

• controlled non-randomised studies of intervention and observational studies;
• studies on vitamin D for other coronavirus diseases/other viral diseases;
• treatment (other than vitamin D) differed between control group and treatment group.

3 studies included

Important patient characteristics at baseline:

N, age mean (SD)/median (IQR)

A: 240 patients

I: 56.8 (14.2) yrs

C: 55.8 (15.0) yrs

B: 76 patients

I: 53.14 (10.77)

C: 52.77 (9.35)

C: 40 patients

I: 50 (36 to 51)

C: 47.5 (39.3 to 49.2)

Sex (% Male)

A: I: 58.3 C:54.2

B: I: 54 C: 69

C: I: 37.5 C: 58.3

Groups comparable at baseline?

Gender was not equally distributed in Entrenas Castillo (2020) and Rastogi (2020). Not all relevant factors are reported in the SR (see ET for separate studies).

Describe intervention:

A: 25(OH)-vitamin D 200,000 IU, single dose, orally, and standard of care

B: Calcifediol 0.532 mg orally on day 1, calcifediol 0.266 mg on days 3 and 7, and then weekly until discharge or ICU admission

C: 25 (OH)-vitamin D 60,000 IU daily for 7 days followed by:

- daily supplementation until day-14, if 25(OH)Vitamin D3 level at day 7 < 50 ng/mL.

- weekly supplementation of 60, 000 IU if 25(OH)Vitamin D3 level at day 7 > 50 ng/mL

Describe control:

A: placebo

B: standard of care

C: placebo

End-point of follow-up:

A: until hospital discharge or death

B: until admission to ICU, hospital discharge or death

C: NR

For how many participants were no complete outcome data available?

(intervention/control)

A: NR

B: NR

C: NR

All cause mortality

Defined as mortality until hospital discharge

Effect measure: RR [95% CI]:

A: 1.49 (0.55 to 4.05)

B: 0.11 (0.01 to 2.13)

C: NR

Pooled effect: NA

Respiratory support (NIV)

Effect measure: RR [95% CI]:

A: 0.52 (0.24 to 1.13)

B: NR

C: NR

Pooled effect: NA

Duration of hospitalisation

Effect measure: MD [95% CI]:

A: 1.07 (0.81 to 1.41)

B: NR

C: NR

Pooled effect: NA

Admission to the ICU

Effect measure: RR [95% CI]:

A: 0.75 (0.44 to 1.29)

B: 0.04 (0.01 to 0.29)

C: NR

Pooled effect: NA

Adverse events

Effect measure: RR [95% CI]:

A: 2.98 (0.12 to 72.30)

B: NR

C: no events of hypercalcaemia were observed during the study period

Pooled effect: NA

Facultative:

This is a living systematic review on vitamin D and COVID-19.

Authors conclusion

Based on the current evidence, we are very uncertain about the

effectiveness of vitamin D supplementation for participants with COVID-19. Moreover, inconsistency in the reporting of adverse and

serious adverse events impeded evaluation of safety of vitamin D supplementation. Therefore, we cannot draw conclusions about vitamin D supplementation as a treatment for individuals with

COVID-19. With respect to the identified studies in trial registries, our results are subject to change in the future.

Remarks

Rastogi (2020) did not report on prioritised outcomes. Therefore Stroehlein (2021) did not formally assess risk of bias by RoB 2.0.

GRADE

Assessed by Stroehlein (2021)

Mortality: very low GRADE

Respiratory support: low GRADE

Admission to ICU: not assessed with GRADE

Duration of hospitalization: not assessed with GRADE

Adverse events: very low GRADE

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Hospitalized patients

Entrenas Castillo, 2020

Type of study:

RCT, pilot, double-masked (?)

Setting and country:

University hospital, Spain

Funding and conflicts of interest:

Source of funding is not reported, might be FIBICO in Spain, COI not reported.

COVID-19 patients, (hospitalized, moderate to severe disease)

Inclusion criteria:

Hospitalized patients with COVID-19 infection clinical picture of acute respiratory infection, confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale

Exclusion criteria:

• Patients <18 years
• Pregnant woman

N total at baseline: 76

Intervention: 50

Control: 26

Important prognostic factors²:

age ± SD:

I: 53.14y±10.77

C: 52.77±9.35

Sex:

I: 27/50 (54%) male

C: 18/26 (69%) male

Disease severity:

I: NR

C: NR

At least one prognostic bad risk factor, n/N (%)*

I: 24/50 (48)

C: 16/26 (61.5)

C-reactive protein mg/l±SD)

I: 82.93±62.74

C: 94.71±63.64

Pao2/FiO2 mean±SD

I: 346.57±73.38

C: 334.62±66.33

*Patients with at least one of the following risk factors (age >60, previous lung disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular

disease or Immunosuppressed and transplanted patients).

Groups comparable at baseline?

No, differences with regard to e.g. hypertension an diabetes

Calcifediol + standard of care

Oral Calcifediol (Faes-

Farma, Lejona, Spain), in soft capsules (0.532 mg) on the day of admission. Treatment was continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission.

Standard of care: see control group.

Standard of care

Per hospital protocol, a combination of hydroxychloroquine

(400 mg every 12 h on the first day, and 200 mg every 12 h

for the following 5 days), azithromycin (500 mg orally for 5 days) and for patients with pneumonia and NEWS score≥5, a broad spectrum

antibiotic (ceftriaxone2 g intravenously every 24 h for 5 days) was

added.

Length of follow-up:

Until admission to ICU, hospital discharge or death.

Loss-to-follow-up:

Intervention:

0 (0%)

Reasons NA

Control:

0 (0%)

Reasons NA

Incomplete outcome data:

Intervention:

NR

Reasons NA

Control:

NR

Reasons NA

Mortality (28-30 day) - crucial

Not reported

Mortality (in-hospital ?), n/N (%)

I: 0/50 (0)

C: 2/26 (7.7)

Effect (95%CI): NR

P=NR

Respiratory support - mechanical respiratory support, optiflow ) - crucial

Not reported

Duration of hospitalization - important

Not reported

ICU admission, n/N (%)

I: 1/50 (2)

C: 13/26 (50)

Effect (95%CI): 0.03 (0.003 to 0.25).*

P=NR

*Adjusted for hypertension and DM.

Time to symptom resolution - important

Not reported

Respiratory support - non-invasive respiratory support - important

Not reported

Adverse events - important

Not reported

Viral clearance - important

Not reported

Definitions:

NR

Remarks:

• This is a pilot study.
• BMI was not investigated: there might be an overlap between risk factors for severe COVID-19 and vitamin D deficiency.
• Serum 25OHD concentrations at baseline or during treatment are not available

Authors conclusion:

Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin

D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.

Murai, 2021

Type of study:

RCT; multicentre, double-blind, randomized, placebo-controlled

Setting and country:

2 sites in Sao Paulo, Brazil; enrollment from June 2, 2020, to Aug 27, 2020; final follow-up on Oct 7, 2020.

Country:

Brazil

Source of funding:

This study was supported by

FAPESP

and Conselho Nacional de

Desenvolvimento Científico e Tecnológico. The funders had no role in the design and conduct of the study; collection, management, analysis, and

interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Hospitalized patients with moderate to severe COVID-19

Inclusion criteria:

• age ≥18 years;
• diagnosis of COVID-19 via PCR testing for SARS-CoV-2 from nasopharyngeal swabs or CT scan findings compatible with the disease (bilateral multifocal ground-glass opacities ≥50%);
• diagnosis of flu syndrome with institutional criteria for hospitalization on hospital admission: respiratory rate > 24/min, saturation < 93% while breathing room air, or risk factors for complications (eg, heart disease, diabetes, systemic arterial hypertension, neoplasms, immunosuppression, pulmonary tuberculosis, obesity) followed by COVID-19 confirmation.

Exclusion criteria:

• unable to read and sign the written consent form,
• already admitted + receiving invasive mech. ventilation,
• previous vitamin D3 supplementation (>1000 IU/d),
• kidney failure requiring dialysis or creatinine of at least 2.0 mg/dL,
• hypercalcemia (total calcium >10.5 mg/dL),
• pregnant or lactating,
• expected hospital discharge < 24 hours

N total at baseline:

N = 237 (randomized 240)

Intervention: 119 (random. 120)

Control: 118 (random. 120)

Important prognostic factors²:

Age (SD):

I: 56.5 (13.8)

C: 56.0 (15.0)

Sex, n/N (%) male:

I: 70 (58.8)

C: 63 (53.4)

Disease severity:

I: NR

C: NR

25-hydroxyvitamin D ng/ml (SD):

I: 21.2 (10.1)

C: 20.6 (8.1)

Total calcium, ng/ml (SD):

I: 8.7 (0.5)

C: 8.7 (0.5)

C-reactive protein, median (IQR)

I: 57.9 (23.3 to 100.5)

C: 68.4 (31.5 to 111.5)

Oxygen supplementation, n (%)

No

I: 16 (13.4)

C: 9 (7.6)

Oxygen therapy

I: 86 (72.3)

C: 95 (80.5)

NIV

I: 17 (14.3)

C: 14 (11.9)

*Also available: coexisting diseases, acute COVID-19 symptoms and concomitant medications.

Groups comparable at baseline?

Yes

Vitamin D3

Single, oral dose of 200 000 IU of vitamin D3 dissolved in a 10-mL peanut oil solution.

Placebo

10 mL of a peanut oil solution. The solutions were identical in colour, taste, smell, consistency, and container.

Length of follow-up:

Until hospital discharge

Loss-to-follow-up:

Intervention:

1/120 (0.8%)

Reasons: withdrew consent

Control:

2/120 (1.7%)

Reasons: withdrew consent

Incomplete outcome data:

Intervention:

NR

Reasons: NA

Control:

NR

Reasons: NA

Mortality (28-30 day) – crucial

Not reported

In-hospital mortality (% (95%CI))

I: 7.6 (3.5 to 13.9)

C: 5.1 (1.9 to 10.7)

Difference (95%CI): 2.5 (–4.1 to 9.2)

P=0.43

Subgroup: Patients with 25-hydroxyvitamin D deficiency (<20 ng/mL) n = 57 n = 58

I: 7.0 (1.9 to 17.0)

C: 1.7 (0.04 to 9.2)

Difference (95%CI): 5.3 (–3.3 to 15.1)

P=0.21

Respiratory support - mechanical respiratory support, optiflow ) - crucial

Need for mechanical ventilation, % (95%CI)

I: 7.6 (3.5 to 13.9)

C: 14.4 (8.6 to 22.1)

Difference (95%CI): –6.8 (–15.1 to 1.2)

P=0.09

Duration of mechanical ventilation, mean:

I: 15.0

C: 12.8 days

Difference (95%CI): 2.2 (–8.4 to 12.8)

P=0.69

Subgroup: Patients with 25-hydroxyvitamin D deficiency (<20 ng/mL) n = 57 n = 58

I: 7.0 (1.9 to 17.0)

C: 8.6 (2.9 to 19.0)

Difference –1.6% (–12.5 to 9.2)

P=>0.99

Duration of hospitalization - important

Hospital length of stay; median days (IQR)

I: 7.0 (4.0-10.0)

C: 7.0 (5.0-13.0)

Unadj. HR (95%CI): 1.07 (0.82 to 1.39)

P=0.62

Adj. HR (95%CI): 0.99 (0.71 to 1.37)

P=0.94

Admission to the intensive care unit, % (95%CI);

I: 16.0 (9.9 to 22.5)

C: 21.2 (14.2 to 29.7)

Difference (95%CI): –5.2 (–15.1 to 4.7)

Subgroup: Patients with 25-hydroxyvitamin D deficiency (<20 ng/mL) n = 57 n = 58

I: 19.3 (10.0 to 31.9)

C: 15.5 (7.4 to 27.4)

Difference (95%CI): 3.8 (–10.3 to 17.8)

Time to symptom resolution - important

Not reported

Respiratory support - non-invasive respiratory support - important

Not reported

Adverse events - important

Serious adverse events

I: 0

C: 0

Adverse events

I: 1 (vomiting after vitamin d3 administration)

C: 0

Viral clearance - important

Not reported

Definitions:

Hospital length of stay: defined as the total number of days that patients remained hospitalized from the date of randomization until the date of hospital discharge;

The criteria used for patient discharge were no need for supplemental oxygen in the past 48 hours, no fever in the past 72 hours, and oxygen saturation greater than 93% without supplemental oxygen and without respiratory distress.

Remarks:

• Predefined length of follow-up unclear
• Patients were given a dose of vitamin D3 after a relatively long time from symptom onset to randomization (ie, mean of 10.3 days).
• The % patients with 25-hydroxy vitamin D deficiency enrolled in this study was considerably lower than those reported in other cohorts.

Authors conclusion:

Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of vitamin D3 for treatment of moderate to severe COVID-19.

Elamir, 2021

Type of study:

RCT, open-label

Setting and country:

Mount Sinai Beth Israel, Mount Sinai Morningside, and

Mount Sinai West Hospitals, enrolment between

September 2020 and December 2020

Funding and conflicts of interest:

No funding. The authors declare no competing interests.

COVID-19 patients, (hospitalized, moderate disease)

Inclusion criteria:

• adult patients;
• hospitalized with COVID-19

Exclusion criteria:

• admitted directly to the intensive care unit (ICU);
• hypercalcemia and/or hyperphosphatemia on admission blood tests;
• untreated disorders of calcium metabolism including hyperparathyroidism, hypoparathyroidism, chronic renal insufficiency with glomerular filtration rate < 30 ml/min;
• prescribed calcitriol for any reason outside of the study;
• declined to participate prior to enrollment.

N total at baseline:

Intervention: = 25

Control: N = 25

Important characteristics:

Age, mean (SD):

I: 69 y (18.0)

C: 64 y (16)

Sex, n/N (%) male:

I: 12/25 (48.0%)

C: 13/25 (52%)

Groups comparable at baseline?

No differences between the groups with regard to age and prognostic factors.

Vitamin D + standard of care

Calcitriol 0.5 μg daily for 14 days or until

hospital discharge

Standard of care: see control group.

Standard of care

‘Standard of care’ may include treatment with remdesivir (200 mg for one day followed by 100 mg for 4 days), examethasone (6 mg daily for 10 days), or

convalescent plasma, as well as supplemental O2.

Length of follow-up:

At least 14 days

Loss-to-follow-up:

Intervention: 0

Reasons: NA

Control: 0

Reasons: NA

Incomplete outcome data:

Intervention:

NR

Reasons: NA

Control:

NR

Reasons: NA

Mortality - crucial

Mortality, n/N (%)

I: 0/25 (0.0%)

C: 3/25 (12.0%)

P= 0.23

Respiratory support - mechanical respiratory support, optiflow ) - crucial

Not reported

Duration of hospitalization – important

Hospital stay, mean days±SD

Days, mean (SD)

I: 5.5 (3.9%)

C: 9.2 (9.4%)

P=0.14

ICU admission - important

ICU admission, n/N (%)

I: 5/25 (20.0 %)

C: 8/25 (32.0%)

P=0.33

Time to symptom resolution - important

Not reported

Respiratory support - non-invasive respiratory support - important

Not reported

Adverse events - important

Reduction in glomerular filtration rate by >10%

I: 0/25 (8.0 %)

C: 4/25 (16.0%)

P=0.1

No adverse effects were observed, including no hypercalcemia or hyperphosphatemia.

Viral clearance - important

Not reported

Definitions:

-

Remarks:

• 25-hydroxyvitamin D levels were not measured;
• It is a pilot study.

Authors conclusion:

This pilot study illustrates improvement in oxygenation among hospitalized patients with COVID-19 treated

with calcitriol and suggests the need for a larger randomized trial.

Non-hospitalized patients

Rastogi, 2020

(SHADE study)

Type of study:

RCT, placebo controlled

Setting and country:

Tertiary care hospital, India

Funding and conflicts of interest:

The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. No competing interests were declared.

COVID-19 patients, hospitalized, mild or moderate disease

Inclusion criteria:

Patients with vitamin D deficiency defined as 25 (OH)D level<20 ng/ml

Exclusion criteria:

Patients requiring invasive ventilation and patients with significant comorbidities like uncontrolled hyperglycaemia or hypertension.

N total at baseline:

N = 40

Intervention: N = 16

Control: N = 24

Important characteristics:

Age, median (IQR):

I: 50.0 y (36 to 51)

C: 47.5 y (39.3 to 49.2)

Sex, n/N (%) male:

I: 6/16 (37.5%)

C: 14/24 (58.3%)

Disease severity: not reported

25 (OH) D3 (ng/ml)(median;IQR)

I: 8.6 (7.1 to 13.1)

C: 9.54 (8.1 to 12.5)

P=0.730

Procalcitonin (nl/ml) (median;IQR)

I: 0.02 (0.02 to 0.03)

C: 0.03 (0.02 to 0.09)

P=0.411

C reactive protein( mg/L) (median;IQR)

I: 2.1 (0.8 to 20.4)

C: 2.6 (0.7 to 14)

P=0.295

Calcium (mg/dl) (median;IQR)

I: 9.4 (9.2 to 9.7)

C: 8.8 (8.0 to 9.2)

P=0.042

Groups comparable at baseline?

Unclear, since important factors like disease severity were not reported.

Cholecalciferol + standard of care

60000 IU of

cholecalciferol (5 ml oral solution in nano droplet form) daily, for 7 days with the aim to achieve 25 (OH)D level>50 ng/ml. When 25 (OH)D levels >50 ng/ml at day 7, patients received weekly supplementation of 60000IU. In case of lower 25 (OH)D levels, daily supplementation of 60000 IU was continued.

Placebo + standard of care

5 ml distilled water for 7 days

Standard of care: per institute protocol.

Length of follow-up:

Until day 21 or virus negativity

Loss-to-follow-up:

Intervention:

0 (0%)

Reasons NA

Control:

0 (0%)

Reasons NA

Incomplete outcome data:

Intervention:

NR

Reasons NA

Control:

NR

Reasons NA

Mortality (28-30 day) - crucial

Not reported

Respiratory support - mechanical respiratory support, optiflow ) - crucial

Not reported

Duration of hospitalization - important

Not reported

Time to symptom resolution - important

Not reported

Respiratory support - non-invasive respiratory support - important

Not reported

Adverse events - important

No episodes of hypercalcaemia were observed in either group.

Viral clearance - important

SARS-CoV-2 negativity (n/N)

I: 10/16 (62.5%)

C: 5/24 (20.8%)

P=0.018

Mean duration to SARS-CoV-2 negativity, mean±SD

I: 17.6±6.1

C: 17.6±6.4

Definitions:

NA

Remarks:

• Method of randomisation and allocation concealment, nor blinding are reported.
• Placebo was not exactly matched with the intervention.

Authors conclusion:

In conclusion, a high dose, oral vitamin D supplementation to

augment 25(OH)D >50 ng/ml helped to achieve SARS-CoV-2 RNA negativity in greater proportion of asymptomatic vitamin D-deficient individuals with SARS-CoV-2 infection along with a significant decrease in inflammatory marker. SARS-CoV-2 RNA negativity by cholecalciferol supplementation may help in reducing transmission rates of the highly contagious SARS-CoV-2 infection. A reassurance for public health workers regarding greater likelihood of SARS CoV-2 RNA negativity in individuals receiving therapeutic cholecalciferol supplementation will be

encouraging.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Hospitalized patients

Entrenas Castillo, 2020

Definitely yes

Reason: An electronically generated randomization 2:1 list was prepared by independent statisticians.

Probably no

Reason: Randomization list was only accessible to non-masked specialists.

Probably no

Reason: Blinding of participants is not described. Randomization list was only accessible to non-masked specialists. Technical data collectors and data analysts were blinded.

Definitely yes

Reason: None of the participants was lost to follow-up.

Probably no

Reason: Outcome measures described in the method section are also reported. However, definition of mortality differed between trial registry and publication (unclear FU of patients and definition of mortality in the protocol)

Definitely no

Reason: ITT analysis was performed, the study was not placebo-controlled.

HIGH

Mortality

Unclear concealment process;

Risk of selective reporting.

Other outcomes

Unclear concealment process;

No blinding of participants (might not induce high risk of bias in objective outcomes).

Murai, 2021

Definitely yes

Reason: Patients were assigned in a 1:1 ratio to the vitamin D3 group or the placebo group. The randomization list was created using a computer-generated code with block sizes of 20.

Probably yes

Reason: A staff member who had no role in the study managed the randomization. Unclear whether the randomization list was accessible before patient enrolment and whether allocation was concealed.

Definitely yes

Reason: Patients and investigators remained blinded to randomization until the final analysis.

Definitely yes

Reason: Resp. 1 and 2 patients dropped out; withdrew consent

Probably yes

Reason: Relevant outcomes reported; described in publication why some outcomes are to follow and some were not possible.

Probably yes

Reason: No ITT protocol, but low dropout rates.

Some concerns

All outcomes

Unclear allocation concealment

Elamir, 2021

Definitely yes

Reason: Eligible patients were allocated at a 1:1 ratio

through electronic randomization on the day of admission.

Probably yes

Reason: Unclear whether the randomization list was accessible before patient enrolment and whether allocation was concealed.

Definitely no

Reason: It is an open label study.

Definitely yes

Reason: None of the participants was lost to follow-up.

Probably yes

Reason: the outcome measure adverse effects is not mentioned in the methods.

Probably no

Reason: baseline differences between the groups (e.g. with regard to age and prognostic factors), follow-up is not clear

HIGH

Mortality

Baseline differences, follow-up was not clear.

Other outcomes

Open label study, baseline differences, follow-up was not clear.

Non-hospitalized patients

Rastogi, 2020

No information

Method of randomisation not reported.

No information

Method of randomisation and concealment not reported.

No information

Blinding is not described.

Definitely yes

None of the participants was lost to follow-up.

Definitely yes

Outcome measures described in the method section are also reported.

Probably yes

ITT analysis was performed, disease severity at baseline is not reported. Placebo

was not exactly matched with regards to the taste and

consistency with the intervention.

HIGH

Mortality

Unclear randomization and allocation concealment

Other outcomes

Unclear randomization and allocation concealment;

unclear blinding (might not induce high risk of bias in objective outcomes); placebo and intervention were not matched.