01 January 2017 - Vitamin D Council - Pilot RCT assesses the benefit of high dose versus low dose vitamin D for Crohn’s disease

A pilot randomized controlled trial (RCT) found that Crohn’s disease (CD) patients given high dose vitamin D supplementation have fewer relapses than those given low dose; however, this difference was insignificant.

Crohn’s disease is an inflammatory bowel disease caused by inflammation of the digestive tract lining. The symptoms often include abdominal pain, severe diarrhea, fatigue, weight loss and malnutrition.

Researchers have found that vitamin D helps Crohn’s patients relieve their painful, and at times, debilitating symptoms. A randomized controlled trial discovered that CD patients who supplemented with 2000 IU daily for three months were more likely to maintain their intestinal permeability compared to those who received placebo. Intestinal permeability measures “gut leakiness,” a known predictor for clinical relapse in CD. Furthermore, the same RCT discovered the maintenance of intestinal permeability was likely attributed to the reduction of inflammation and strengthened immune system (measured by C-reactive protein and antimicrobial peptides, respectively) in those who received vitamin D supplementation. The difference in antimicrobial peptide levels was most pronounced when patients’ vitamin D levels reached 40 ng/ml or greater.

In a new pilot RCT, researchers aimed to determine the most effective vitamin D dosage for the treatment of Crohn’s disease. They compared the effects of high dose vitamin D supplementation at 10,000 IU daily to 1000 IU daily for 12 months among 34 patients with CD in remission.

Here is what the researchers found:

• Patients who received 10,000 IU (n=18) daily improved their vitamin D levels from an average of 29.4 ng/ml to 64.3 ng/ml (p = 0.02).
• Patients who received 1,000 IU daily slightly increased their vitamin D status from an average of 28.5 ng/ml to 33.1 ng/ml; however, this change was insignificant (p = 0.63).
• Nearly half of the patients (44%) from both groups were already supplementing with vitamin D prior to enrollment into the study.
• On an intention to treat basis, the rates of relapse were 33.3% in the high dose group and 68.8% in the low dose group (p = 0.0844). This difference did not reach a statistical significance.
• In per protocol analysis, the clinical relapse was significantly less frequent in those receiving a high dose with 0% experiencing relapse (0/12) compared to the 37.5% (3/8) frequency of relapse among the low dose group (p = 0.049).
• Clinically significant improvements in anxiety and depression scores were observed in both groups treated with vitamin D. Although, the difference between both groups was not statistically significant (p = 0.55).

When reviewing the findings of the study, it’s important to acknowledge the differences in statistical analyses between per protocol analysis and intention to treat. Intention to treat limits bias involved in the study by including all patients initially enrolled in the statistical analysis, even those who dropped out of the study. This means that those who dropped out were considered to have shown no improvement.

Intention to treat strengthens findings by including the patient who drop out for a reason, like a side effect. For example, if the high dose vitamin D group had a high dropout rate, this may be caused by unwanted side effects of treatment, making the patients no longer capable of tolerating the treatment being tested. The downside of intention to treat is that it limits the study’s ability to show the beneficial effects of a treatment, especially for a study with a small sample size.

Per protocol analysis only assesses the patients who remained in the study until completion. This technique can potentially lead to bias as it can disregard the study participants who dropped out due to unwanted side effects.

In this study, half (8/16) of the enrolled patients dropped out of the low dose group and one third (6/18) of the enrolled patients dropped out of the high dose group. This dismisses the idea that the high dose supplementation elicited more side effects than the low dose. In fact, only two people dropped out due to side effects; one participant from each group. The participant from the low dose group reported heartburn and nausea as side effects; whereas the participant from the high dose group reported acne. None of the participants experienced toxicity symptoms. In fact, the researchers stated that the supplementation was well tolerated.

The low attrition rate was largely attributed to lost contact, which likely meant that one year was too large of a commitment for some. Other reasoning for such a high dropout rate include a new diagnosis of breast cancer and relocation out of the country.

Since the pilot study consisted of such a small initial sample size, the researchers did not possess sufficient numbers to prove significance when using intention to treat. Thus, per protocol analysis produced stronger results.

Finally, the study results confirmed previous findings that vitamin D supplementation offers benefits to CD patients, especially when using doses that achieve vitamin D levels of 40 ng/ml or higher.