Khan et al. (2017): Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial

Reference ↗
Title	Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial
Topic	Vitamin D
Author	Khan, QJ, Kimler, BF, Reddy, PS, Sharma, P, Klemp, JR, Nydegger, JL, Yeh, H-W, Fabian, CJ
Year	2017
Journal	Breast Cancer Research and Treatment
DOI	https://doi.org/10.1007/s10549-017-4429-8

Brief summary

This study investigated the efficacy of vitamin D3 in breast cancer patients with regard to typical aromatase inhibitor-associated side effects (musculoskeletal disorders, abbreviation AIMSS) compared to a placebo. There were virtually no significant differences between the vitamin D3 and placebo arms in the number of patients with worsening AIMSS symptoms and fatigue symptoms. The vitamin D3 arm also did not report a higher quality of life. A positive aspect of this study was that the authors examined and reported the development of vitamin D levels. However, on the negative side, the sample size was too small to detect potential differences in the calculations well.

In dieser Studie wurde die Wirksamkeit von Vitamin D3 bei Brustkrebspatientinnen hinsichtlich typischer Aromatasehemmer assoziierter Nebenwirkungen (Muskel-Skelett-Erkrankungen, Abkürzung AIMSS) im Vergleich zu einem Placebo untersucht. Es gab so gut wie keine bedeutsamen Unterschiede zwischen dem Vitamin D3- und Placebo-Arm bezüglich der Anzahl an Patienten mit einer Verschlechterung der AIMSS-Symptome und Erschöpfungssymptomen. Der Vitamin D3 Arm berichtete auch keine höhere Lebensqualität. Positiv an dieser Studie war, dass die Autoren die Entwicklung des Vitamin D Spiegels untersucht und berichtet haben. Negativ war jedoch, dass die Stichprobe zu klein war, um potentielle Unterschiede in den Berechnungen gut aufdecken.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Single
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	Postmenopausal women with stage I–III hormone receptor positive breast cancer scheduled to start treatment with an adjuvant aromatase inhibitors and with a 25(OH)D level B40 ng/ml
Exclusion criteria	History of renal stones, hypercalcemia, or hyper- parathyroidism
N randomized	160
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	NI
Countries of data collection	United States
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1: at week 12 T2: at week 24

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Curative, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage
Specifications on cancer stages	Stage I–III hormone receptor positive breast cancer
Comorbidities	NI
Current cancer therapies	Chemotherapy
Specifications on cancer therapies	NI
Previous cancer therapies	Surgery
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Intervention arm: median and interquartile ranges of age at diagnosis: 60.5 (55-71) Placebo arm: median and interquartile ranges of age at diagnosis: 62 (54-69)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	80
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	10
Drop-out reasons	n=2 protocol violations, n=7 withdrew for reasons other than study agent related adverse events
Intervention	Vitamin D3
Dosage and regime	Three capsules of 10,000 IU Vitamin D3 weekly + all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	168
Side effects / Interactions	No adverse events attributed to vitamin D3

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	80
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	Withdrew for reasons other than study agent related adverse events
Intervention	Placebo
Dosage and regime	Three capsules of placebo weekly + all patients: 1200 mg of calcium plus 600 IU of vitamin D daily (‘‘standard supplementation’’) and Letrozole 2.5 mg PO daily
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	168
Side effects / Interactions	Mild hypercalcemia at 12 week assessment

Outcomes

Musculoskeletal symptoms

Outcome type As specificed by the authors	Primary
Outcome specification	Evidenced by any of the following three events: an increase in the HAQ-II score of 0.25 or more; an increase in CPIS score; or discontinuation of letrozole specifically due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS)
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	high risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	high risk
Other sources of bias	NA
Overall RoB judgment	high risk

Vitamin D level

Outcome type As specificed by the authors	Others
Outcome specification	NI
Type of measurement	Blood Test
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Placebo arm: median increase in 25(OH)D was 7.1 ng/ml between week 0 and 12, and then no further increase from 12 to 24 weeks; 9 subjects achieved a level >40 ng/ml; Intervention arm: increased 25(OH)D levels by a median of 32 ng/ml between week 0 and 12, with a slight further increase between weeks 12 and 24 (median 3.0 ng/ml); 91% achieved a level >40 ng/ml by 24 weeks; maximum value measured was 87 ng/ml
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	NA
Bias due to deviation from intended intervention (assignment to intervention)	NA
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	NA
Bias in measurement of the outcome	NA
Bias in selection of the reported result	NA
Other sources of bias	NA
Overall RoB judgment	NA

Hand grip strength

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	Dynamometer
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	high risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Fatigue

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	BFI (Brief Fatigue Inventory)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	high risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	FACT (Functional Assessment of Cancer Therapy), MENQOL (Menopause-Specific Quality of Life)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	high risk
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	low risk
Bias in selection of the reported result	low risk
Other sources of bias	NA
Overall RoB judgment	high risk

Funding and Conflicts of Interest

Funding	Funding for support of research and clinical trials from the following companies: AstraZeneca; Bristol-Myers Squibb; Celgene, Inc.; Novartis Pharmaceutical Company, Inc.; Genentech-Roche, GlaxoSmithKline, and Pfizer. Study agent but no funding has been provided by DSM and Pfizer for trials conducted by Dr. Fabian.
Conflicts of Interest	Within the past three years, Dr. Khan has served as a consultant to Novartis Pharmaceutical Company, Inc. and Pfizer. Drs. Khan and Sharma have received during the past three years, via their institution

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	Yes
- Reasons for insufficient sample size based on power analysis	NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	NA
Ethnicity mentioned	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention	No
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	NA

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	Yes
Correction for multiple testing	No
Measurement of compliance	No
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	Yes
Side effects considered in result interpretation	No
Ethics votum	Yes

Additional Notes

PRO:

• Ethics vote
• Study protocol
• Information on the development of vitamin D levels

CONTRA:

• Fewer patients evaluated than according to power analysis (arm B < 72)
• Possible baseline differences e.g. descriptive Arm B higher baseline vitamin D level (25.1 (95% CI: 18.0, 30.5) A:22.5 (95% CI: 15.9, 29.7))
• Baseline differences with regard to QoL
• High dropout, but week 12 (A: 8/80, B: 10/80) and 24 (A: 15/80, B: 7/80) no significant difference in the amount of dropout between arms (p = 0.80 and p = 0.11)
• Poor report quality (e.g. no information on QoL figures)