Niravath et al. (2019): Randomized controlled trial of high‐dose versus standard‐dose vitamin D3 for prevention of aromatase inhibitor‐induced arthralgia

Reference ↗
Title	Randomized controlled trial of high‐dose versus standard‐dose vitamin D3 for prevention of aromatase inhibitor‐induced arthralgia
Topic	Vitamin D
Author	Niravath, P, Hilsenbeck, SG, Wang, T, Jiralerspong, S, Nangia, J, Pavlick, A, Ademuyiwa, F, Frith, A, Ma, C, Park, H, Rigden, C, Suresh, R, Ellis, M, Osborne, CK, Rimawi, MF
Year	2019
Journal	Breast Cancer Research and Treatment
DOI	https://doi.org/10.1007/s10549-019-05319-4

Brief summary

The study included 93 patients with breast cancer who were undergoing aromatase inhibitor therapy. Randomly divided into 2 arms, about half of the patients received high doses of vitamin D3, while the other arm received a standard dose. Symptoms of arthralgia syndrome (mainly joint pain) were recorded. There were no differences between the arms after 12 and 52 weeks. Due to the lack of effect after 12 weeks, no further patients were recruited, which is too small a sample size in view of previous studies in this area. The study also has a lot of missing data from patients, as they did not complete the questionnaires at all times.

In der Studie wurden 93 Patienten mit Brustkrebs eingeschlossen, die einer Aromatasehemmer-Therapie unterzogen wurden. Zufällig in 2 Gruppen eingeteilt erhielt etwa die Hälfte der Patientinnen hochdosiert Vitamin D3, während der andere Arm eine Standarddosis erhielt. Erhoben wurden Symptome eines Arthralgiesyndroms (vorwiegend Gelenkschmerzen). Nach 12 und 52 Wochen zeigten sich keine Unterschiede zwischen den Armen. Aufgrund des Fehlen des Effektes nach 12 Wochen wurden keine weiteren Patienten rekrutiert, was in Anbetracht vorheriger Studien in dem Bereich zu einer zu kleinen Stichprobe führt. Die Studie hat zudem viele fehlende Daten von Patienten, da diese nicht zu jedem Zeitpunkt die Fragebögen ausgefüllt haben.

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	Multicentric
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	No
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	≥ 21 years old, with stage I-III hormone receptor-positive breast cancer, who were beginning adjuvant aromatase inhibitor therapy; post-menopausal, defined as any of the following: age ≥ 60 years old; history of bilateral oophorectomy; or serum estradiol and FSH concentrations in the post-menopausal range, along with either amenorrhea for 12 months or previous hysterectomy; if the patient was < 60 years old at the time of study enrollment and had completed chemo- therapy, post-menopausal status had to have been confirmed prior to chemotherapy
Exclusion criteria	Aromatase inhibitor therapy in the last 6 weeks, history of kidney stones, hypercalcemia at baseline, history of symptomatic hypercalcemia or hyperparathyroidism, baseline 25-OH Vitamin D level >50 ng/mL, currently taking phenytoin or phenobarbital, currently taking cholestyramine or orlistat, malabsorption syndrome, or chronic granulomata forming disorders, such as sarcoidosis or tuberculosis
N randomized	93
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, ITT Analysis
Specifications on analyses	93 patients were evaluable for efficacy analysis; because six patients did not start treatment with vitamin D, only 87 patients were evaluable for safety
Countries of data collection	United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline T1: week 12 T2: week 52

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, Advanced Stage
Specifications on cancer stages	Stage I-III
Comorbidities	NI
Current cancer therapies	Hormone therapy
Specifications on cancer therapies	Aromatase inhibitor therapy
Previous cancer therapies	Chemotherapy, Hormone therapy
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Median (range): 64 (44-82)

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	46
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	n=4 not start treatment (n=3 withdrew consent, n=1 ineligible); n=1 not complete 12 weeks, found ineligible
Intervention	High-dose vitamin D
Dosage and regime	50,000 International Units (IU) oral vitamin D3 per week for 12 weeks followed by 2000 IU daily for 40 weeks + all patients: calcium carbonate 600 mg 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.	364
Side effects / Interactions	No grade 4 or grade 5 adverse events, n=1 renal stones, 4 grade 3 events (deemed to be unrelated to the study drugs)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	47
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	n=2 not start treatment (withdrew consent); n=3 not complete 12 weeks (n=2 withdrew consent, n=1 non-compliant)
Intervention	Standard-dose vitamin D
Dosage and regime	800 IU Vitamin D3 daily for 52 weeks + all patients: calcium carbonate 600 mg 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.	364
Side effects / Interactions	No grade 4 or grade 5 adverse events, n=1 hypercalcemia, 8 grade 3 events (deemed to be unrelated to the study drugs)

Outcomes

Pain

Outcome type As specificed by the authors	Primary
Outcome specification	Aromatase inhibitor-induced arthralgia
Type of measurement	HAQ-DI (Health Assessment Questionnaire-Disability Index), VAS (Visual Analogue Scale)
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".	At 12 weeks: no significant differences; At 52 weeks: 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	some concerns
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	some concerns

Interaction with cancer treatment

Outcome type As specificed by the authors	Secondary
Outcome specification	Compliance with aromatase inhibitor therapy, measured by pill counts
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 statistical tests because of low numbers of patients (control arm: 96.5% vs. intervention arm: 98.1%)
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

Vitamin D level

Outcome type As specificed by the authors	Secondary
Outcome specification	Correlation of low- baseline vitamin D levels with development of aromatase inhibitor-induced arthralgia
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".	At 12 weeks: mean vitamin D level in control arm was 29.3 ng/mL, compared to 50 ng/mL in intervention arm, increase and the week 12 level were both significantly higher in the intervention arm (p<0.0001 for both comparisons); No correlation between vitamin D level and development of aromatase inhibitor-induced arthralgia
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	Others
Outcome specification	Explorative endpoint
Type of measurement	NI
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 difference between patients who did develop aromatase inhibitor-induced arthralgia and those patients who did not develop aromatase inhibitor-induced arthralgia
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	some concerns
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	some concerns

Funding and Conflicts of Interest

Funding

See conflicts of Interests

Conflicts of Interest

Dr. Nangia has had a consultant/advisory role with Puma, and she has received funding from Paxman Coolers. Dr. Ade- muyiwa has had a consultant/advisory role with Immunomedics, AstraZeneca, Jounce, Eisai, and Best Doctors; she has received funding from Pfizer, Abbvie, Seattle Genetics, Immunomedics, and Polyphor. Dr. Ellis has had a consultant/advisory role with NanoString, Novartis, AstraZeneca, Pfizer, Abbvie, Sermonix, and Puma; he has stock own- ership in Bioclassifier with Royalty income from Prosigna/NanoString. Dr. Osborne has had a consultant/advisory role with Puma, AstraZeneca, and Genentech; stock ownership in GENETEX; and funding from Puma. Dr. Rimawi has had a consultant/advisory role in MacroGenics, Daiichi, and Novartis; he has received funding from Novartis and Pfizer. Dr. Ma has had a consultant/advisory role with Pfizer, Novaris, and Lilly; she has received funding from Eisai, Puma, and Pfizer.

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	No
- Reasons for insufficient sample size based on power analysis	NI
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	Yes
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	?
Side effects considered in result interpretation	Yes
Ethics votum	No

Additional Notes

PRO:

• Ethics vote
• Intention to treat analysis
• Adherence controlled with pill counting
• Power analysis
• Comparability of the groups to the baseline

CONTRA:

• Sample too small in view of the power analysis (about half); early discontinuation of study recruitment as no effect could be found at T1
• No blinding
• Patients who did not complete HAQ-II after 12 weeks were interpreted as having developed AIA
• For compliance, too few complete data sets were available to perform analyses, so general compliance was also unclear