Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

72 participants (44% women), aged 18 to 65 years, mean age 47 years, with chronic HCV genotype 1.

Inclusion criteria: aged 18 to 65 years; chronic HCV genotype 1 infection; no previous treatment for HCV; seronegative for HBV, HDV, and HIV infections; absolute neutrophil count > 1500/mm³; platelet count > 90,000/mm³; and normal haemoglobin level

Exclusion criteria: decompensated liver disease (cirrhosis with a Child‐Pugh score > 9), another cause of clinically significant liver disease, or presence of hepatocellular carcinoma

Interventions

Intervention: PEG‐IFN‐α‐2b (1.5 μg/kg body weight) + oral ribavirin 1000 mg/day (for body weight < 75 kg) or 1200 mg/day (for body weight > 75 kg) and vitamin D₃ 2000 IU/day (n = 36)

Control: PEG‐IFN‐α‐2b (1.5 μg/kg body weight) + oral ribavirin 1000 mg/day (for body weight < 75 kg) or 1200 mg/day (for body weight > 75 kg) (n = 36)

For 48 weeks. All participants had ≥ 1 follow‐up visit at 24 weeks after completion of treatment.

Outcomes

Outcomes reported in abstract of publication

Primary outcome: SVR defined as undetectable HCV‐RNA at 24 weeks' post‐treatment

Secondary outcomes: treatment efficacy at weeks 4 (RVR), and 12 (EVR) during therapy, and 24 weeks after cessation of therapy (SVR)

Stated aim of study

To determine whether adding vitamin D improves HCV response to antiviral therapy

Notes

All participants completed the trial. Vitamin D₃ (Vitamidyne D, Fischer Pharmaceuticals, Israel) given by oral drops for 4 weeks before initiation of antiviral treatment and after serum levels had reached > 32 ng/mL in all participants in the treatment group.

Registered at ClinicalTrials.gov NCT00804752

Additional information received through personal communication with authors on 8 February 2017.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generation performed using computer random number generation.

Allocation concealment (selection bias)

Low risk

Participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation sequence hidden in sequentially numbered, opaque, and sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and the outcome is likely to have been influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

All predefined outcomes reported in full.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Open‐label randomised clinical trial with parallel‐group design (2 groups)

Participants

Number of participants randomised: 115 participants (50% women), aged 31 to 82 years, mean age 64 years, with chronic hepatitis C

Inclusion criteria: HCV genotype 1b as determined by the conventional PCR‐based method; IL28B SNP rs8099917 genotype TG or GG (designated as non‐TT); HCV RNA persistently detectable in serum by the real‐time PCR technique; white blood cell count of more than 2000 μL; platelet count of more than 50,000 μL; and haemoglobin levels of more than 9.0 g/dL at the time of enrolment. Patients could participate in the study regardless of whether they had received prior IFN‐based therapy. Patients who had not received PEG IFN/ribavirin combination therapy were considered naive patients.

Exclusion criteria: decompensated liver cirrhosis, evidence of other forms of liver disease, presence of malignancy and other serious medical illness, evidence of hypercalcaemia or hyperparathyroidism, positive hepatitis B surface antigen and antibody to HIV type 1, medication with Chinese herbal medicine or other type of vitamin D, past medical history of interstitial pneumonia, pregnancy or possibility of pregnancy, lactating, and past medical history of allergy to biological preparations or antiviral agents

Interventions

Intervention: lead‐in treatment with oral native vitamin D₃ (Healthy Natural Products, Florence, KY, USA) at a dose of 2000 IU once daily for 4 weeks, followed by the addition of the vitamin D₃ to the 12‐week triple therapy (PEG IFN‐α‐2a (Roche Group‐Chugai, Tokyo, Japan), ribavirin (Chugai), and simeprevir (Janssen, Tokyo, Japan)), followed by 12 weeks of PEG IFN‐α‐2a and ribavirin (n = 57)

Control: 12‐week triple therapy (PEG IFN‐α‐2a (Roche Group‐Chugai, Tokyo, Japan), ribavirin (Chugai), and simeprevir (Janssen, Tokyo, Japan)) for 12 weeks, followed by 12 weeks of PEG IFN‐α‐2a and ribavirin (n = 58)

PEG IFN‐α‐2a was administered subcutaneously at a dose of 180 μg once weekly. Ribavirin was administered orally twice daily, with doses adjusted according to body weight (600 mg daily for < 60 kg, 800 mg daily for 60 to 80 kg, and 1000 mg daily for > 80 kg). Simeprevir was administered orally once daily at a dose of 100 mg.

Because of the low likelihood of achieving an SVR and high likelihood of developing antiviral resistance, treatment was stopped for participants with serum HCV RNA decline from baseline of less than 3 log IU/mL at 4 weeks of treatment, detectable HCV RNA at 12 weeks of treatment, or more than 2 log IU/mL increase in HCV RNA levels from the lowest levels during treatment (defined as viral breakthrough).

Outcomes

Primary outcome: sustainability of undetectable viraemia 24 weeks after the end of treatment

Stated aim of study

To clarify whether native vitamin D₃ supplementation could improve SVR rate in PEG‐IFN/ribavirin therapy with simeprevir for people with treatment‐refractory genotype 1b HCV with the IL28B SNP rs8099917 non‐TT

Notes

Study authors did not report any deaths. "No patient complained of vitamin D‐related symptoms or developed signs of a vitamin D‐related adverse reaction".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Used computer‐generated random number table

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and outcome is likely to have been influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding, and outcome measurement is likely to have been influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to assess whether missing data in combination with method used to handle missing data was likely to induce bias

Selective reporting (reporting bias)

Unclear risk

Unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

65 participants (35% women), mean age 59 years, with NAFLD

Inclusion criteria: men or women aged 25 to 70 years; diagnosis of type 2 diabetes according to American Diabetes Association 2009 criteria; presence of fatty liver detected by upper US and confirmed by MRI in people with clinical suspicion of NAFLD (increased serum transaminase levels in absence of known hepatic chronic disease, ALT > AST, presence of multiple components of metabolic syndrome); negative tests for hepatitis B surface antigen and antibody to HCV

Exclusion criteria: history of alcohol abuse (defined by mean daily consumption of alcohol > 30 g/day in men and > 20 g/day in women), cirrhosis, autoimmune hepatitis and other causes of liver disease (haemochromatosis, Wilson's disease), chronic enteropathies, advanced renal failure, cancer, hyper/hypoparathyroidism, known hypersensitivity to cholecalciferol or any other excipients, hypercalcaemia, hypercalciuria, nephrolithiasis, nephrocalcinosis; ongoing/recent (previous 6 months) supplementation with vitamin D, calcium, multivitamin products; treatment with agents affecting bone and calcium/vitamin D metabolism (anticonvulsants, glucocorticoids, antacids containing aluminium, cholestyramine); ultraviolet radiation exposure; pregnancy and lactation; or severe psychiatric illnesses

Interventions

Intervention: vitamin D₃ 2000 IU/day (n = 29)

Control: placebo (n = 36)

For 24 weeks

Outcomes

Primary outcomes: reduction of hepatic fat fraction measured by MRI, changes in serum transaminases, CK18‐M30, N‐terminal procollagen III propeptide levels, and Fatty Liver Index

Secondary outcomes: metabolic (fasting glycaemia, glycated haemoglobin, lipids, homeostasis model assessment ‐ insulin resistance, homeostasis model assessment ‐ beta cell function, adipose tissue insulin resistance, body fat distribution) and cardiovascular (ankle‐brachial index, intima‐media thickness, flow‐mediated dilatation) parameters

Stated aim of study

To assess the efficacy and safety of 24‐week oral high‐dose vitamin D supplementation in people with type 2 diabetes and NAFLD

Notes

Registered at www.clinicaltrialsregister.eu (number 2011‐003010‐17). Funded by research grants from the Sapienza University Ateneo Scientific Research (authors MGC and IB) and the Italian Minister of University and Research (authors MGC and MGB).

Study authors did not report any deaths. Authors were not contacted, as information on our outcomes of interest was found in the publication: “As per the safety profile, no major adverse events occurred during the study”.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation performed by statistician using computer‐generated and centrally administered procedure

Allocation concealment (selection bias)

Low risk

Participant allocations could not have been foreseen in advance of, or during, enrolment. Used central and independent randomisation unit‐controlled allocation

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, investigators, clinical site staff, laboratory staff, and radiologists were all masked to treatment assignment throughout study. Treatment and placebo provided in identical vials by an experienced independent pharmacist.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment ensured, and it is unlikely that blinding could have been broken.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to assess whether missing data in combination with method used to handle missing data was likely to introduce bias on the results

Selective reporting (reporting bias)

Low risk

Study authors reported all predefined outcomes in full.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

Country: India

60 participants (40% women), mean age 41 years

Inclusion criteria: age 18 to 65 years, chronic HCV genotype 1/4, infection with detectable HCV RNA for 6 months, and no previous treatment for hepatitis C

Exclusion criteria: advanced cirrhosis (Child‐Pugh B or C), presence of HCC, HIV and hepatitis B co‐infection, autoimmune liver disease, Wilson disease, haemochromatosis, α1‐antitrypsin deficiency, concomitant use of medications known to affect serum vitamin D metabolism, and patients with active intravenous drug addiction

Interventions

Intervention: PEG‐IFN alfa‐2a 180 μg per week, and RBV (1000 mg/day for participants weighing < 75 kg, 1200 mg/day for participants weighing > 75 kg) and vitamin D₃ 2000 IU/day (n = 28)

Control: PEG‐IFN alfa‐2a 180 μg per week, and RBV (1000 mg/day for participants weighing < 75 kg, 1200 mg/day for participants weighing > 75 kg) (n = 32)

For 48 weeks

Outcomes

Primary outcomes: rapid, early and sustained viral response

Stated aim of study

To assess the effect of vitamin D supplementation on treatment outcome in patients with genotype 1/4 chronic hepatitis C (CHC) infection

Notes

All participants completed the trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The computer‐generated block randomization schedule was prepared using random number generator to create a list of random numbers. Stat Trek programme (https://stattrek.com) was used to derive the randomization list."

Allocation concealment (selection bias)

Unclear risk

Study authors did not describe the method used to conceal the allocation, so the intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and the outcome is likely to have been influenced by lack of blinding.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

The study was registered in Clinical Trials Registry‐India (CTRI/2015/07/005992).

Other bias

Unclear risk

Trial may or may not have been free of other factors that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised placebo‐controlled clinical trial with parallel‐group design (2 groups)

Participants

Country: Thailand

Number of participants randomised: 60 participants

Inclusion criteria: NAFLD patients who have ALT elevation with vitamin D insufficiency

Exclusion criteria: none stated

Interventions

Intervention: vitamin D (n = 30)

Control: placebo (n = 30)

For 20 weeks

Outcomes

Primary outcomes: serum ALT, inflammatory markers, and homeostasis model assessment and Fibroscan

Secondary outcomes: none stated

Stated aim of study

To demonstrate the effect of vitamin D replacement on liver enzymes and inflammatory markers in NAFLD patients

Notes

Results were presented as an abstract. We were unable to find the address of the authors to contact them for the missing information. Study authors did not report any deaths. No information provided about adverse events.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study authors did not specify the method of sequence generation.

Allocation concealment (selection bias)

Unclear risk

Study authors did not describe the method used to conceal the allocation, so the intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Information was insufficient to assess whether missing data in combination with the method used to handle missing data was likely to induce bias on the results.

Selective reporting (reporting bias)

Unclear risk

The protocol was not available.

Other bias

Unclear risk

Trial may or may not have been free of other factors that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised double‐blind placebo‐controlled clinical trial with parallel‐group design (3 groups)

Participants

Country: Iran

Number of participants randomised: 106 participants (59% women), mean age 45 years

Inclusion criteria: men and women aged between 20 and 75 years with presence of hepatic steatosis diagnosed by ultrasound

Exclusion criteria: liver cirrhosis, with positive results for hepatitis B virus surface antigen or hepatitis C virus antibody, patients with alcohol consumption (> 10 g/day), patients with autoimmune hepatitis or other causes of chronic liver diseases such as Wilson’s disease and haemochromatosis, known cancer, nephrolithiasis, nephrocalcinosis, chronic renal failure, hypercalcaemia, hypercalciuria, pregnancy, lactation, hypersensitivity to vitamin D₃, patients receiving oestrogen, tamoxifen, methotrexate, amiodarone, or tetracycline, and receiving vitamin D and calcium supplementations in previous 6 months

Interventions

Intervention group 1: vitamin D₃ (cholecalciferol) 50,000 IU pearl per week (n = 35)

Intervention group 2: calcitriol 0.25 mg (1,25 dihydroxycholecalciferol) pearl per day (n = 35)

Control: placebo (n = 36)

For 12 weeks

Outcomes

Primary outcomes: reduction of serum ALT, AST, GGT from baseline to 12 weeks

Secondary outcomes: improvement of metabolic component of participants including fasting plasma glucose, LDL, HDL, triglyceride, and total cholesterol

Stated aim of study

To investigate the role of vitamin D therapy in the amelioration of hepatic steatosis in people with NAFLD

Notes

Study authors did not report any deaths. No information provided about adverse events.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Block randomisation with a block size of 5 was used through a computer‐based procedure.

Allocation concealment (selection bias)

Unclear risk

Study authors did not describe the method used to conceal the allocation, so the intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken. Quote: "Treatments and placebo were provided in identical packages and were given to the participants by an educated person who was blinded to the drug and patients."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment ensured, and it is unlikely that the blinding could have been broken.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

The protocol was not available.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

101 participants (25% women) aged 18 to 60 years, mean age 40 years, with chronic HCV genotype 4

Inclusion criteria: aged 18 to 60 years, chronic HCV infection genotype 4 for > 6 months by detectable serum quantitative HCV‐RNA, naive to treatment, compensated liver disease with the following minimum haematological and biochemical criteria: haemoglobin ≥ 12 g/dL for men and ≥ 11 g/dL for women, WBC > 3500/mm³, granulocyte count > 1500/mm³, platelet count > 75,000/mm³, albumin and thyroid function tests within normal limit, and antinuclear antibody ≤ 1:80. US‐guided liver biopsy within 12 months prior to study entry, using a semiautomatic true‐cut needle (16G)

Exclusion criteria: other liver diseases, decompensated liver cirrhosis, hepatocellular carcinoma, liver biopsy contraindication, unsuitable for combined IFN and ribavirin treatment due to persistent haematological abnormalities, receiving medications known to affect vitamin D₃ level or metabolism (calcium, vitamin D supplementation, oestrogen, alendronate, isoniazid, thiazide diuretics, long‐term antacids, calcium channel blockers, cholestyramine, anticonvulsants, and orlistat), clinically evident osteomalacia (waddling gait, bone pain, and pathological fractures), renal diseases or parathyroid diseases, and BMI > 35

Interventions

Intervention: vitamin D₃ 15,000 IU/week + PEG‐IFN‐α‐2b + ribavirin (n = 50)

Control: placebo + PEG‐IFN‐α‐2b + ribavirin (n = 51)

PEG‐IFN‐α‐2b (PegIntron, MSD) at 1.5 mg/kg subcutaneous injection once/week. Ribavirin (Rebetol, MSD) dose determined by body weight (< 75 kg 1000 mg/day; ≥ 75 kg 1200 mg/day in 2 separate oral doses after meals morning and night) for 48 weeks. Vitamin D₃ given as oral solution with juice once weekly for 48 weeks.

Outcomes

Primary outcome: SVR

Secondary outcome: stage of hepatic fibrosis

Stated aim of study

To assess the role of vitamin D supplementation on response to treatment in people with chronic HCV 4 and its possible relation to stage of hepatic fibrosis

Notes

Study authors did not report any deaths. “None of the missed patients had stopped the treatment due to adverse events”. Additional information received through personal communication with authors on 23 January 2017.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not specified.

Allocation concealment (selection bias)

Low risk

Allocation sequence hidden in sequentially numbered, opaque, and sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

No blinding, but we judged that outcomes were not likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

No blinding of outcome assessment, but we judged that outcome measurements were not likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to assess whether missing data in combination with the method used to handle missing data was likely to induce bias

Selective reporting (reporting bias)

Unclear risk

Unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

60 participants (52% women), aged 30 to 70 years, mean age 48.5 years with NAFLD

Inclusion criteria: NAFLD confirmed by US and normal range of ALT and AST (< 31 IU/L)

Exclusion criteria: acute illnesses, chronic kidney disease, hyperparathyroidism, hypoparathyroidism, chronic heart failure, HCV or HBV, Wilson's syndrome, history of chronic liver diseases or disorders that affect gallbladder and bile ducts, pregnancy, history of taking any drugs affecting levels of ALT (e.g. valproic acid, tamoxifen, 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors, metformin, angiotensin‐converting enzyme 1 and angiotensin‐converting enzyme‐related 1). Furthermore, participants should not have followed any special diet, and should not take oral vitamin D, calcium, or multivitamin supplements.

Interventions

Intervention: vitamin D₃ 50,000 IU (n = 30)

Control: placebo (n = 30)

Weekly for 10 weeks

Outcomes

Primary outcomes: inflammatory markers, liver function, lipid profile, body composition, and liver steatosis

Secondary outcomes: none stated

Stated aim of study

To investigate the effect of vitamin D supplementation on inflammation, liver function, and liver steatosis in people with NAFLD

Notes

All participants completed the trial. Clinical trial registered at Iranian Registry of Clinical Trials (IRCT2013060411763N8). Funded by Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Used computer‐generated random numbers

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

All predefined outcomes reported in full.

Other bias

Unclear risk

Trial may or may not have been free of other factors that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised double‐blind placebo‐controlled clinical trial with parallel‐group design (3 groups)

Participants

Country: Switzerland

Number of participants randomised: 20 participants, mean age 45 years

Inclusion criteria: increased alanine aminotransferase level (1.2‐fold ULN), histological diagnosis of NASH diagnosed according to the SAF score obtained within 18 months preceding entry and decreased 25‐OH vitamin D level (< 30 ng/L). The definition of NASH included non‐excessive alcohol consumption as fewer than 21 standard drinks on average per week in males and fewer than 14 standard drinks on average per week in females.

Exclusion criteria: cirrhosis, HCV RNA positivity, HBs antigen positivity, other liver disease including autoimmune hepatitis, hereditary haemochromatosis, alpha‐1‐antitrypsin deficiency, Wilson’s disease, drug‐induced fatty liver disease, serious diseases limiting life expectancy, pregnancy or breastfeeding, intention to become pregnant during the course of the study, or childbearing potential in women who were not using safe contraception

Interventions

Intervention: 2100 IU vitamin D₃ (cholecalciferol) (n = 10)

Control: placebo (n = 10)

Orally daily for 48 weeks

Outcomes

Primary outcomes: change in ALT from baseline to end of treatment

Secondary outcomes: absolute reduction of hepatic steatosis by at least 20% or by at least 1 point in NASH, serious adverse events, safety laboratory assessments, physical examination findings and vital signs

Stated aim of study

To investigate the efficacy and safety of 48‐week treatment with vitamin D₃ in NASH patients

Notes

Study authors did not report any deaths. 2 serious adverse events were recorded: circular haemorrhoidal prolapse and bronchopneumonia. The study medication (vitamin D₃ 2100 IU daily) and placebo were produced and provided by Antistress AG, Rapperswil‐Jona, Switzerland.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study authors did not specify the method of sequence generation.

Allocation concealment (selection bias)

Low risk

A central and independent randomisation unit controlled the allocation. Quote: "Randomisation (stratified for the presence of diabetes, block size 10, not stratified by center) was performed by the Cantonal Pharmacy Zurich."

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

The trial was registered (NCT01571063; KEK‐ZH‐Nr. 2011‐420).

Other bias

Unclear risk

Trial may or may not have been free of other factors that could have put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

Country: Iran

Number of participants randomised: 82 women, aged 18 to 50 years, mean age 34 years

Inclusion criteria: BMI between 25 and 40 kg/m² with NAFLD confirmed by single ultrasonographist, vitamin D insufficiency (serum 25‐hydroxyvitamin D < 30 ng/mL), not taking dietary supplements including calcium and vitamin D over the last 6 months

Exclusion criteria: renal, hepatic, other endocrine disorders, malignancies, pregnancy and lactation, alcohol consumption, menopause condition, receiving medications influencing vitamin D metabolism or insulin

Interventions

Intervention: vitamin D₃ (cholecalciferol) 600,000 IU single intramuscular injection (n = 41)

Control: no intervention (n = 41)

All participants received pearl of vitamin E 400 IU/day for 1 month. Participants were followed up for 1 month.

Outcomes

Primary outcomes: changes in serum 25‐hydroxyvitamin D, serum adiponectin, HOMA‐IR, liver enzymes, and change in grade of NAFLD

Secondary outcomes: change in anthropometric variables

Stated aim of study

To examine the effect of single intramuscular injection of 600,000 IU of cholecalciferol on serum levels of vitamin D, adiponectin, insulin resistance, and liver function status of women with NAFLD

Notes

Study authors did not report any deaths. No information provided about adverse events.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The patients were randomly assigned in the random blocks of four subjects using a computer Random Allocation Software, version 1, with stratification by age."

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

The trial was registered in the Iranian Registry of Clinical Trials with code number of IRCT201503163320N10.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised double‐blind placebo‐controlled clinical trial with parallel‐group design (2 groups)

Participants

Country: Pakistan

Number of participants randomised: 109 (36% women), mean age 28 years

Inclusion criteria: randomised selection based on age, sex, BMI > 28, fatty liver on sonographic findings, moderate increase in hepatic enzymes with altered serum lipid profile

Exclusion criteria: pregnant and lactating women, smokers, type 2 diabetes, hypertension, chronic hepatitis B and C infection, alcoholic liver disease, chronic liver disease, decompensated liver disease and hepatocellular carcinoma, any history of cardiac, renal, and thyroid disorders, extremely abnormal ultrasound and liver enzymes that can indicate hereditary and autoimmune diseases of the liver

Interventions

Intervention: vitamin D₃ (cholecalciferol) 50,000 IU (n = 54)

Control: placebo (n = 55)

Orally, weekly for 12 weeks

Outcomes

Primary outcomes: body weight, BMI, insulin resistance, dyslipidaemia, hepatic enzymes, CRP, and adiponectin

Stated aim of study

To investigate the effects of oral vitamin D supplementation on body weight, BMI, insulin resistance, dyslipidaemia, hepatic enzymes, CRP, and adiponectin in NAFLD patients

Notes

Study authors did not report any deaths. No information provided about adverse events.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A computed generated number was given to each patients based upon randomization."

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to assess whether missing data in combination with the method used to handle missing data was likely to induce bias

Selective reporting (reporting bias)

Unclear risk

The trial was not registered. Unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

Country: Republic of Korea

Number of participants randomised: 148 (49% women), aged 20 to 75 years, mean age 52 years

Inclusion criteria: age 20 to 75 years, positive in hepatitis C virus‐RNA PCR screening, normal serum calcium level before treatment, and HCV genotypes 1, 2, and 3

Exclusion criteria: HCC at enrolment or past history of HCC within last 1 year, decompensated cirrhosis (Child‐Pugh class B or C), absolute neutrophil count < 1000/mm³ or platelet count < 70,000/mm³, serum creatinine level above 1.5 times to upper normal limit, present or past history of severe psychiatric diseases, parathyroid disease, uncontrolled thyroid disease, co‐infection with other hepatitis virus or HIV, history of malignant diseases besides HCC within last 2 years, patients who were considered unfit to perform clinical trial, and pregnancy

Interventions

Intervention: PEG‐IFN‐α‐2a 180 μg weekly plus RBV daily plus vitamin D 800 IU daily (n = 77)

Control: PEG‐IFN‐α plus RBV (n = 71)

Ribavirin was given orally daily in a dose of 1000 mg (body weight < 75 kg) or 1200 mg (body weight ≥ 75 kg) daily in genotype 1, or 800 mg in genotype 2 and 3.

All participants were followed up 24 weeks after the completion of treatment.

Outcomes

Primary outcomes: rate of SVR

Secondary outcomes: change in risk factors for SVR

Stated aim of study

To assess the role of vitamin D supplementation in response to PEG‐IFN‐α plus RBV treatment in naive patients with chronic hepatitis C

Notes

Study authors did not report any deaths. “Serious adverse events occurred in 10 patients, but all recovered.”

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study authors did not specify the method of sequence generation.

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

High risk

24 participants (33.8%) in the control group and 19 participants (24.7%) in the vitamin D group dropped out during the treatment period.

Selective reporting (reporting bias)

High risk

The study was registered at ClinicalTrials.gov (NCT01439776). No data about the early and rapid virological response

Other bias

Unclear risk

Trial may or may not have been free of other factors that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

Country: India

Number of participants randomised: 101 (24% women), aged 18 to 70 years, mean age 45 years

Inclusion criteria: decompensated cirrhosis of liver, Child Turcott Pugh (CTP) score ≥ 10, age between 18 years to 70 years

Exclusion criteria: septicaemia, infection with HIV, episodes of variceal bleeding within 6 weeks, hepatocellular carcinoma or any malignancy, hepatorenal syndrome at the time of enrolment, significant cardiac and respiratory disease, pregnancy, patients being taken up for transplant, and refusal to participate in the study

Interventions

Intervention: vitamin D (cholecalciferol 300,000 IU) intramuscularly, single dose plus 800 IU and calcium 1000 mg daily (n = 51)

Control: no intervention (n = 50)

For 6 months

Outcomes

Primary outcomes: all‐cause mortality

Secondary outcomes: clinical parameters, vitamin D level

Stated aim of study

To assess vitamin D levels in a cohort of patients with decompensated liver cirrhosis and the effect of vitamin D level replenishment on all‐cause mortality in patients with vitamin D deficient decompensated cirrhosis

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Study authors did not specify the method of sequence generation.

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and the outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

The protocol was not available.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised double‐blind, placebo‐controlled clinical trial with parallel‐group design (2 groups)

Participants

Country: Thailand

Number of participants randomised: 80 (46% women), aged 18 to 70 years, mean age 52 years

Inclusion criteria: patients with CHC

Exclusion criteria: none stated

Interventions

Intervention: vitamin D₂ (ergocalciferol 60,000 to 100,000 IU (depending on vitamin D status)) (n = 40)

Control: placebo (n = 40)

Orally, weekly for 6 weeks

The dose of vitamin D₂ was based on the ranges of vitamin D deficiency, as follows: mild deficiency (20 to ≤ 30 ng/mL) 60,000 IU/week; moderate deficiency (10 to ≤ 20 ng/mL) 80,000 IU/week; and severe deficiency (≤ 10 ng/mL) 100,000 IU/week. Each vitamin D₂ capsule contained 20,000 units. The total dosage was divided into 2 separate doses given on Monday and Friday.

Outcomes

Primary outcomes: T‐helper 1/2 cytokines, IP‐10 and DPP‐IV levels

Secondary outcomes: vitamin D level

Stated aim of study

To assess the changes in serum levels T‐helper cells associated cytokines, IP‐10 and DPP‐IV, without influences driven by interferon treatment, after a short‐term period for correction of vitamin D deficiency in chronic hepatitis C patients

Notes

All participants completed the trial. The trial was conducted between April 2012 and April 2013.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The randomization sequence was stratified with a 1:1 allocation using random block sizes of 4 based on computer generated method based (www.randomisation.com)."

Allocation concealment (selection bias)

Low risk

Quote: "The randomization was performed by a research assistant without involvement in clinical trial. Details of the allocated group were given in sequentially numbered, opaque, sealed envelopes. After patient enrollment, the research assistant will open the envelope and inform stratified groups (A or B) to the investigators."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "The vitamin D₂ (Ergocalciferol) and placebo were prepared by a pharmacist in a capsule form and identical in appearance. They were prepacked in a bottle for six‐week supplement and consecutively numbered for each CHC patient according to the randomised results."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment ensured, and it is unlikely that the blinding could have been broken.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values. All participants completed the trial.

Selective reporting (reporting bias)

Low risk

The trial was registered in the Thai Clinical Trials Registry, which was based on World Health Organization criteria under registration number TCTR20160429001.

Other bias

Unclear risk

Trial may or may not have been free of other factors that could have put it at risk of bias, such as academic bias.

Study characteristics

Methods

Randomised double‐blind, placebo‐controlled clinical trial with parallel‐group design (2 groups)

Participants

Country: Thailand

Number of participants randomised: 58 (38% women), aged 18 to 70 years, mean age 50 years

Inclusion criteria: patients with CHC, naive cases or non‐responder cases of CHC without decompensated cirrhosis, and serum 25‐hydroxyvitamin D levels less than 30 ng/mL

Exclusion criteria: decompensated cirrhosis, HIV infection, autoimmune diseases, active infections from other pathogens, a history of steroid or immunosuppressive therapy, or a history of interferon treatment within 12 months

Interventions

Intervention: vitamin D₂ (ergocalciferol 20,000 IU orally, weekly) (n = 29)

Control: placebo (n = 29)

For 6 weeks

The dose of vitamin D₂ was based on the ranges of vitamin D deficiency, as follows: mild deficiency (20 to ≤ 30 ng/mL) 60,000 IU/week; moderate deficiency (10 to ≤ 20 ng/mL) 80,000 IU/week; and severe deficiency (≤ 10 ng/mL) 100,000 IU/week. Each vitamin D₂ capsule contained 20,000 units. The total dosage was divided into 2 separate doses given on Monday and Friday.

Outcomes

Primary outcomes: serum fibrotic markers

Secondary outcomes: vitamin D level

Stated aim of study

To assess the dynamic changes in serum fibrogenic cytokines/enzymes in CHC patients with vitamin D deficiency after short‐term supplementation with vitamin D

Notes

All participants completed the trial. The trial was conducted between February and December 2014.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "The enrolled patients were randomized into two groups with a 1:1 allocation using a random block size of 4, which was generated by computer software based on www.randomisation.com."

Allocation concealment (selection bias)

Low risk

Quote: "The randomization was performed by a research assistant who was not involved in the clinical trial. Upon enrollment, the patients were stratified into two groups (A and B) with the details of the drugs placed in sealed envelopes."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "Vitamin D₂ and a placebo were prepared in identical capsules of the same weight by the Department of Pharmacy at King Chulalongkorn Memorial Hospital. All investigators and patients were blinded to the type of medication used until the end of the study."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment ensured, and it is unlikely that the blinding could have been broken.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

The clinical trial was retrospectively registered with the Thai Clinical Trials Registry, based on World Health Organization criteria on 2 November 2016 (TCTR20161103003).

Other bias

Unclear risk

Trial may or may not have been free of other factors that could have put it at risk of bias, such as academic bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (3 groups)

Participants

120 participants (38% women), aged 18 to 65 years, mean age 41 years, with NAFLD

Inclusion criteria: BMI 25 kg/m² to 35 kg/m², serum 25‐hydroxyvitamin D₃ level < 15 ng/mL, reporting a daily calcium intake 700 mg/day to 800 mg/day, and willingness to introduce a dietary change to lose weight

Exclusion criteria: calcium intake < 700 mg/day or > 800 mg/day (in diet or as a supplement); drugs for blood glucose or lipid control; pregnancy or having given birth in the past year or planning a pregnancy in the next 6 months; lactation; weight loss ≥ 10% of body weight within the 6 months before enrolment; participation in competitive sport; abnormal thyroid hormone concentration; intake of medications that could affect body weight or energy expenditure (or both); allergy; smoking; diagnosis of chronic diseases including inflammatory diseases; heart, liver, and renal failure; cancer; acute myocardial infarction; diabetes; stroke; or serious injuries and any other conditions that were not suitable for the trial as evaluated by the physician

Interventions

Intervention 1: vitamin D 25 μg/day as cholecalciferol (Jalinus Arya Co, Iran) + calcium carbonate placebo (25 mg/day as lactose; Jalinus Arya Co, Iran) (n = 40)

Intervention 2: vitamin D 25 μg/day as cholecalciferol (Jalinus Arya Co, Iran) + calcium (500 mg/day as calcium carbonate; Jalinus Arya Co, Iran) (n = 40)

Control: placebo of calcitriol + placebo of calcium (25 mg/day as lactose; Jalinus Arya Co, Iran) (n = 40)

After lunch with a glass of water for 12 weeks

Outcomes

Primary outcomes: weight loss, body fat, fasting plasma glucose, serum insulin concentrations, lipid profiles, and liver function tests

Secondary outcomes: carbohydrate and lipid metabolism

Stated aim of study

To compare the effect of vitamin D supplementation with and without calcium on anthropometric measures and biochemical parameters in people with NAFLD during a weight‐loss programme

Notes

Study authors did not report any deaths. No information provided about adverse events. Clinical trial registered at Iranian Registry of Clinical Trials (IRCT201408312709N29). Trial did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. Additional information received through personal communication with authors on 20 January 2017.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants randomly assigned using computer‐generated random‐numbers method by project co‐ordinator.

Allocation concealment (selection bias)

Low risk

Participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation controlled by a central and independent randomisation unit.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Products administered by blinded research assistant to blinded participants. Shape, colour, and packaging of placebo similar to supplements in the intervention group.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

All predefined outcomes reported in full.

Other bias

Unclear risk

Trial may or may not have been free of other factors that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (3 groups)

Participants

18 men, aged 32 to 61 years, mean age 52 years, with alcoholic cirrhosis

Inclusion criteria: men with advanced biopsy‐confirmed alcoholic cirrhosis with low levels of serum 25‐hydroxyvitamin D (< 20 ng/mL) and decreased bone density (i.e. > 1.5 standard deviations below mean of healthy Baltimore men of same ages)

Exclusion criteria: history of corticosteroid, anticonvulsant, or vitamin D intake; renal disease

Interventions

Intervention 1: vitamin D₂ 50,000 IU 2 or 3 times weekly (n = 6)

Intervention 2: 25‐hydroxyvitamin D₃ 800 IU/day to 2000 IU/day (prepared and supplied as identical soft elastic capsules (20 or 50 μg) by Upjohn Co) (n = 6)

Control: no intervention (n = 6)

For 1 year

Outcomes

Outcomes reported in abstract of publication

Primary outcomes: bone mineral density

Secondary outcomes: none stated

Stated aim of study

To compare the efficacy of 25‐hydroxyvitamin D₃ or vitamin D₂ in correcting the bone disease of people with alcoholic cirrhosis

Notes

This study was supported by grants from Upjohn Co and the Veterans Administration.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of sequence generation was not specified.

Allocation concealment (selection bias)

Unclear risk

The method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and the outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

All clinically relevant and reasonably expected outcomes were reported.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

50 participants (58% women), mean age 47 years, with chronic HCV genotype 2 or 3

Inclusion criteria: aged 18 to 65 years; chronic genotype 2 or 3 HCV infection; no previous treatment for HCV; seronegative for HBV, hepatitis A virus, and HIV infection; absolute neutrophil count > 1500/mm³; platelet count > 90,000/mm³; and normal haemoglobin level. Liver biopsies not required prior to study entrance.

Exclusion criteria: decompensated liver disease (cirrhosis with Child‐Pugh score > 9), another cause of clinically significant liver disease, or presence of hepatocellular carcinoma

Interventions

Intervention: PEG‐IFN‐α‐2a 180 μg weekly + oral ribavirin 800 mg/day + oral vitamin D₃ 2000 IU/day (Vitamidyne D, Fischer Pharmaceuticals, Israel), given by oral drops (n = 20)

Control: PEG‐IFN‐α‐2a 180 μg weekly + oral ribavirin 800 mg/day (n = 30)

For 24 weeks

Outcomes

Outcomes reported in abstract of publication

Primary outcome: SVR defined as undetectable HCV‐RNA at 24 weeks' post‐treatment

Secondary outcomes: treatment efficacy at weeks 4 (RVR) and 12 (EVR) during therapy, and 24 weeks after cessation of therapy (SVR)

Stated aim of study

To assess prospectively the influence of vitamin D supplementation on SVR in the treatment of people with chronic HCV with HCV genotype 2‐3

Notes

All participants completed the trial. Additional information received through personal communication with authors on 8 February 2017.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generation performed using computer random number generation.

Allocation concealment (selection bias)

Low risk

Participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation sequence hidden in sequentially numbered, opaque, and sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and outcomes are likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding, and outcome measurements are likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

Unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

36 participants (25% women), aged 18 to 75 years, mean age 61 years, with liver cirrhosis

Inclusion criteria: compensated cirrhosis, 25‐hydroxyvitamin D < 30 ng/mL, aged 18 to 75 years, and a negative pregnancy test in women of childbearing potential

Exclusion criteria: presence of hepatocellular carcinoma, hypercalcaemia (plasma calcium concentrations > 2.65 mmol/L), pregnant or lactating women, drug intake as part of another clinical study, estimated glomerular filtration rate according to Modification of Diet in Renal Disease formula < 15 mL/min/1.73 m², any clinically significant acute disease requiring drug treatment, regular intake (in addition to study medication) of vitamin D > 800 IU daily during the last 4 weeks before study entry

Interventions

Intervention: vitamin D₃ 2800 IU/day (Oleovit D3, Fresenius Kabi, Austria) (n = 18)

Control: placebo daily (n = 18)

For 8 weeks

Outcomes

Primary outcome: vitamin D status

Secondary outcomes: liver function tests (i.e. AST, ALT, gamma glutamyl transpeptidase, and alkaline phosphatase), albumin, international normalised ratio, bilirubin, and hyaluronic acid; and parameters of mineral metabolism (i.e. parathyroid hormone, total plasma calcium, free plasma calcium, urinary midstream calcium to creatinine ratio, and plasma phosphate)

Stated aim of study

To evaluate the effects of vitamin D supplementation on 25‐hydroxyvitamin D, parameters of liver function and synthesis, and hyaluronic acid as a marker of liver fibrosis

Notes

“No patient died during the study and there was no excess of adverse events in the vitamin D group.”

Study sponsored by the Medical University of Graz, Austria.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sequence generation performed using computer random number generation.

Allocation concealment (selection bias)

Low risk

Participant allocations could not have been foreseen in advance of, or during, enrolment. Central and independent randomisation unit controlled allocation. Investigators were unaware of allocation sequence.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of participants and key study personnel ensured, and it is unlikely that blinding could have been broken.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment ensured, and it is unlikely that blinding could have been broken.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

All predefined outcomes reported.

Other bias

Unclear risk

Trial may or may not have been free of other factors that could put it at risk of bias, such as small‐trial bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

Country: India

81 participants (32% women), aged > 12 years, mean age 38 years with NAFLD

Inclusion criteria: patients with NAFLD aged > 12 years, non‐alcoholic individuals defined as either total abstainers or individuals who consumed less than 20 g of alcohol per day, ultrasound showing features of steatosis, with or without raised ALT (> 40 IU/L), and negative viral markers (hepatitis B surface antigen and anti‐hepatitis C virus), patients with raised ALT who had negative autoimmune markers (antinuclear antibody, anti‐smooth muscle antibody, anti‐liver kidney microsomal antibody, and antimitochondrial antibody) and normal ceruloplasmin/negative Kayser–Fleischer ring with normal iron workup (serum iron, total iron‐binding capacity, ferritin, and transferrin saturation)

Exclusion criteria: pregnant females, patients with a history of drug intake likely to cause NAFLD, patients with jejunoileal bypass or extensive small bowel resection or total parenteral nutrition at the time of liver biopsy, and those with clinical, laboratory, and imaging features of cirrhosis of liver and patients with renal, hepatic, respiratory, or congestive cardiac failure

Interventions

Intervention: vitamin D single intramuscular injection 600,000 IU with lifestyle modifications (n = 51)

Control: lifestyle modifications (n = 30)

Participants were treated and followed up for 6 months.

Lifestyle modifications in both groups included moderate‐to‐vigorous exercise in the form of brisk walking, jogging, swimming, cycling, etc. for 45 to 60 min at least 5 days per week in all participants, and calorie reduction (1000 to 1200 kcal/day for overweight women and 1200 to 1600 kcal/day for overweight men and heavier or more active women) in overweight and obese subjects.

Outcomes

Primary outcomes: insulin resistance and serum ALT

Secondary outcomes: serum levels of adiponectin and tumour necrosis factor‐α

Stated aim of study

To evaluate the effect of vitamin D supplementation in patients with NAFLD

Notes

All participants completed the trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of sequence generation was not specified.

Allocation concealment (selection bias)

Unclear risk

The method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and the outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

Trial protocol was not available.

Other bias

Unclear risk

Trial may or may not have been free of other factors that could have put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

60 (51% women), aged 18 to 70 years, mean age 42 years, with NAFLD

Inclusion criteria: diagnosis of NAFLD by US and increased serum levels of ALT (> 19 units/L for women and 30 units/L for men)

Exclusion criteria: alcohol consumption > 20 g/day; pregnant and lactating women; hereditary haemochromatosis; Wilson's disease; α1‐antitrypsin deficiency; history of jejunoileal bypass surgery or gastroplasty; using total parenteral nutrition in the past 6 months; taking hepatotoxic drugs such as calcium channel blocker, high doses of synthetic oestrogens, methotrexate, amiodarone, and chloroquine; history of hypothyroidism, Cushing's syndrome, renal failure, and kidney stones; serum calcium levels > 10.6 mg/dL; and intake of vitamin D, vitamin E, and calcium supplements during the last 6 months

Interventions

Intervention: vitamin D₃ 50,000 IU (D‐Vitin Zahravi Pharm Co, Tabriz, Iran) (n = 30)

Control: placebo (Zahravi Pharm Co) (n = 30)

Every 14 days for 4 months

Outcomes

Primary outcomes: changes in serum ALT and changes in insulin resistance index

Secondary outcomes: other liver enzymes, oxidative stress, and inflammatory biomarkers

Stated aim of study

To determine the effect of vitamin D supplementation on serum liver enzymes, insulin resistance, oxidative stress, and inflammatory biomarkers in people with NAFLD

Notes

Study authors did not report any deaths. “Participants did not report any adverse or side effects such as hypercalcemia.”

Study financially supported by grant (No. RDC‐9105) from Vice‐Chancellor for Research Affairs of Jundishapur University of Medical Sciences and approved by the Research Institute for Infectious Diseases of the Digestive System, Jundishapur University of Medical Sciences, Ahvaz, Iran.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The study authors performed sequence generation using computer random number generation.

Allocation concealment (selection bias)

Low risk

An investigator with no clinical involvement in the trial packed the supplements and placebos in numbered bottles based on the random list. Another person, who was not involved in the trial and not aware of random sequences, assigned the participants to the numbered bottles of pearls.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinding of outcome assessment ensured, and it is unlikely that the blinding could have been broken.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

It was unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported.

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

76 participants (66% women), aged 38 to 84 years, mean age 61 years, with cirrhosis and an underlying infection of liver (HBV and HCV)

Inclusion criteria: liver cirrhosis and an underlying infection of the liver (HBV and HCV)

Exclusion criteria: none stated

Interventions

Intervention: calcitriol 0.5 μg twice daily (n = 38)

Control: no intervention (n = 38)

For 1 year

Outcomes

Outcomes reported in abstract of publication

Primary outcome: bone mineral density of the lumbar vertebrae

Secondary outcomes: none stated

Stated aim of study

To evaluate the efficacy of calcitriol (1,25‐dihydroxyvitamin D) in the treatment of bone disease associated with cirrhosis and an underlying hepatitis viral infection

Notes

All participants completed the trial. Additional information received through personal communication with the authors on 12 February 2014.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not specified.

Allocation concealment (selection bias)

Low risk

Allocation sequence hidden in sequentially numbered, opaque, and sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

High risk

Not all predefined outcomes were reported in full.

Other bias

Unclear risk

Trial may or may not have been free of other components that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

34 women, aged 36 to 72 years, mean age 56 years, with primary biliary cirrhosis

Inclusion criteria: primary biliary cirrhosis

Exclusion criteria: none stated

Interventions

Intervention: calcitriol 0.5 μg twice a day (n = 17)

Control: no intervention (n = 17)

For 1 year

Outcomes

Outcomes reported in abstract of publication

Primary outcome: bone mineral density

Secondary outcomes: none stated

Stated aim of study

To evaluate the efficacy of calcitriol (1,25‐dihydroxyvitamin D) in the treatment of bone disease associated with primary biliary cirrhosis

Notes

All participants completed the trial. Additional information received through personal communication with authors on 12 February 2014.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not specified.

Allocation concealment (selection bias)

Unclear risk

Method used to conceal allocation not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

High risk

Not all predefined outcomes reported in full.

Other bias

Unclear risk

Trial may or may not have been free of other components that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

40 participants (50% women), aged between 30 to 70 years, mean age 42 years with NAFLD

Inclusion criteria: age above 18 years, increased levels of alanine aminotransferase level (more than 30 in women and 40 in men), a diagnosis of NAFLD and ruling out other causes of increased liver enzymes, and vitamin D level less than 30 ng/mL

Exclusion criteria: the presence of liver cirrhosis, pregnancy and lactation, alcohol consumption, drug abuse, administration of vitamins in the last 6 months and during the study, weight loss more than 5% over a year before entering the study, diabetes mellitus, weight‐lowering medications, hypercalcaemia, chronic kidney disease, end‐stage heart and lung disease, history of hyperlipidaemia which required treatment, history of medical therapies with impact on liver enzymes such as acetaminophen, statins, azathioprine, antibiotics such as sulfonamide and penicillin, amiodarone, methotrexate, anticonvulsants, isoniazid, steroids, and herbal medicines

Interventions

Intervention: vitamin D₃ 50,000 IU weekly plus lifestyle modification (n = 20)

Control: lifestyle modification (n = 20)

For 12 weeks. Participants were followed up for 6 months.

Outcomes

Primary outcomes: biochemical indices (ALT, AST, alkaline phosphatase, fasting blood sugar, triglycerides, cholesterol, LDL, creatinine, calcium, vitamin D) and level of liver steatosis on the basis of CAP score and fibrosis

Secondary outcomes: none stated

Stated aim of study

"Investigating the effects of vitamin D on NAFLD."

Notes

All participants completed the trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Random allocation of the patients in each group was performed using a random number table."

Allocation concealment (selection bias)

Unclear risk

Method used to conceal allocation not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Quote: "Subjects and all study staffs were blinded to treatment group assignments."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

The research was also registered in Iranian Registry of Clinical Trials (2015102624725n1).

Other bias

Unclear risk

Trial may or may not have been free of other components that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

68 participants (13% women), mean age 42 years, with chronic HCV genotype 1, 2, 3, 4

Inclusion criteria: adult patients with chronic HCV infection (> 6 months) and detectable serum levels of HCV RNA (genotype 1, 2, 3, or 4) with compensated liver disease fulfilling the following criteria: absolute neutrophil count above 1500/mm³, platelet count above 90,000/mm³, and normal haemoglobin level

Exclusion criteria: co‐infection with hepatitis B virus or HIV, decompensated liver disease (Child‐Pugh classification B or C), autoimmune or metabolic liver disease, hepatocellular carcinoma, a history of anti‐HCV therapy or use of medications which alter vitamin D₃ levels or metabolism (calcium, vitamin D supplementation, oestrogen, alendronate, isoniazid, anticonvulsants, and orlistat), a history of diarrhoea or malabsorption syndromes such as coeliac and chronic pancreatitis, or those with renal or parathyroid diseases

Interventions

Intervention: PEG‐IFN‐α‐2a (180 μg) + oral ribavirin (Rebetol, MSD), at dosage determined based on participant’s weight and genotype, was administered for 48 weeks in participants with genotypes 1 and 4 and for 24 weeks in those with genotypes 2 and 3, and vitamin D₃ 1600 IU/day (n = 34)

Control: PEG‐IFN‐α‐2a (180 μg) + oral ribavirin (Rebetol, MSD), at dosage determined based on participant’s weight and genotype

PEG‐IFN‐α‐2a was administered for 48 weeks in participants with genotypes 1 and 4 and for 24 weeks in those with genotypes 2 and 3 (n = 34).

Vitamin D₃ was administered for 12 weeks.

Outcomes

Primary outcome: EVR defined as undetectable HCV‐RNA at 12 weeks' post‐treatment

Stated aim of study

To assess the influence of vitamin D supplementation on viral response to PEG‐IFN/RBV therapy

Notes

The research council of Mashhad University of Medical Sciences, Mashhad, Iran financially supported this study.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not specified.

Allocation concealment (selection bias)

Low risk

Participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation sequence hidden in sequentially numbered, opaque, and sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and the outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and the outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Low risk

Registered under Iranian Registry of Clinical Trials Identifier no. IRCT201408312709N29. All predefined outcomes reported in full.

Other bias

Unclear risk

Trial may or may not have been free of other components that could put it at risk of bias, such as competing interest bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (3 groups)

Participants

75 participants (17% women), aged 28 to 65 years, mean age 48 years, undergoing liver transplantation

Inclusion criteria: primary liver transplant recipients

Exclusion criteria: history of corticosteroid, anticonvulsant, or vitamin D intake; renal disease

Interventions

Intervention 1: calcitriol 0.25 μg/day + calcium gluconate (n = 25)

Intervention 2: calcium gluconate (n = 25)

Control: placebo (n = 25)

For 1 month

Outcomes

Outcomes reported in abstract of publication

Primary outcomes: acute cellular rejection rate at 1 month post‐transplant

Secondary outcomes: none stated

Stated aim of study

To investigate the effects of calcitriol on acute cellular rejection rate of liver transplant recipients

Notes

All participants completed the trial. Study sponsored by grants from Shanghai Nature Science Fund project and Science and Technology Department of Shanghai. Additional information received through personal communication with the authors on 13 February 2014.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not specified.

Allocation concealment (selection bias)

Unclear risk

Method used to conceal allocation not described, so that intervention allocations may have been foreseen in advance of, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to permit judgement of 'low risk' or 'high risk'

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

Unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.

Study characteristics

Methods

Randomised clinical trial with parallel‐group design (2 groups)

Participants

84 participants (49% women), aged 30 to 78 years, mean age 59 years, with HCV genotype 1b

Inclusion criteria: aged ≥ 20 years, chronically infected with HCV genotype 1 and plasma HCV RNA concentrations ≥ 100 log IU/mL

Exclusion criteria: decompensated cirrhosis, liver cancer, HBV or HIV infection, renal insufficiency, history of heart disease or cerebral infarction, pregnancy or breastfeeding

Interventions

Intervention: subcutaneous injections of PEG‐IFN‐α‐2b (1.5 μg/kg body weight) once weekly, along with weight‐based oral ribavirin (600 mg/day to 1200 mg/day) + vitamin D₃ 1000 IU (n = 42)

Control: subcutaneous injections of PEG‐IFN‐α‐2b (1.5 μg/kg body weight) once weekly, along with weight‐based oral ribavirin (600 mg/day to 1200 mg/day) (n = 42)

For 16 weeks

Outcomes

Primary outcome: undetectable HCV RNA at week 24

Secondary outcomes: none stated

Stated aim of study

To rigorously evaluate the antiviral effects of vitamin D supplementation in people with HCV genotype‐1 infection being treated with PEG‐IFN + ribavirin

Notes

No serious side effects were observed.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of sequence generation not specified.

Allocation concealment (selection bias)

Unclear risk

Method used to conceal the allocation not described, so intervention allocations may have been foreseen before, or during, enrolment.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, and outcome is likely to have been influenced by lack of blinding

Blinding of outcome assessment (detection bias)
All outcomes

High risk

No blinding of outcome assessment, and outcome measurement is likely to have been influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Missing data were unlikely to make treatment effects depart from plausible values.

Selective reporting (reporting bias)

Unclear risk

Unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported

Other bias

Low risk

Trial appeared to be free of other factors that could put it at risk of bias.