N-Acetylcysteine in Patients with Sickle Cell Disease: A Randomized Controlled Trial

Patients with sickle cell disease (SCD) suffer from frequent and severe episodes of pain that are associated with hospitalizations, impaired quality of life and increased mortality. Current treatment options are scarce. Oxidative stress appears to play a pivotal role in the pathophysiology of SCD. Pilot studies have demonstrated that administration of the antioxidant N-acetylcysteine (NAC) effectively reduces markers of oxidative stress in SCD and may decrease the hospitalization rate for painful crises. NAC is a safe, inexpensive and well-tolerated drug that has been used for years for various indications. The primary aim of this study was to evaluate the effect of NAC on the frequency of daily pain in patients with SCD.

We conducted a randomized (1:1), double-blind, placebo-controlled, parallel-group trial at 11 sites across The Netherlands, Belgium and the United Kingdom. Patients were eligible for participation if they were ≥12 years of age, had either HbSS, HbSC, HbSβ⁰- or HbSβ⁺-thalassemia with a history of at least 1 painful crisis per year over the 3 years prior to enrolment. At randomization patients were assigned to receive either oral NAC 600 mg twice daily or placebo for a total duration of 6 months. Patients had monthly checkups during the study. The primary endpoint was the rate of SCD related pain days per patient year, assessed daily with the use of pain diaries. Secondary endpoints included the rate of days with painful crises, admission days, hospitalizations and days with home analgesic use, the severity of pain, the time to first painful crisis and hospitalization, the number of adverse events and the effect on quality of life and various blood markers. The primary intention-to-treat analysis of this study was limited to patients with a minimal completed diary observation time of 110 days. Sensitivity analyses were done in both all randomized patients as well as a subset with ≥80 days of observation time. Lastly, an additional per protocol analysis was performed on patients with adequate adherence (≥80% of tablets used) and ≥110 days of completed diary observation time.

A total of 96 patients were randomized of which 67 patients met the minimum observation time of 110 days (27 in the NAC and 40 in the placebo arm). Inclusions were stopped before reaching the estimated sample size of 116 patients due to imposed time restrictions by the main funder of this study. Groups were well balanced for baseline characteristics. The proportion of patients adherent to the assigned study medication regimen was low in both treatment groups (53% in the NAC and 50% in the placebo arm). The rate of SCD related pain days per patient year was 61.4 in the placebo group and 61.6 in the NAC group (rate ratio 0.98; 95% confidence interval [CI] 0.54-1.78; P=.98). Moreover, there were no significant differences in the secondary endpoints between groups. These findings were consistent in the sensitivity analyses. In the total study population, more patients reported gastro-intestinal events in the NAC group (42%) as compared to the placebo group (15%, P<0.01). In addition, we performed a per protocol analysis in the patients with adequate adherence (n=27), demonstrating a significantly lower rate of painful crisis days in the NAC group as compared to the placebo group, respectively 20.5 versus 40.1 events per patient year (rate ratio 0.50; CI 0.27-0.94; P=.03). Event rates of pain days (rate ratio 0.85; CI 0.33-2.20), admission days (rate ratio 0.33; CI 0.08-1.34) and hospitalizations per patient year (rate ratio 0.65; CI 0.19-2.15) appeared to be lower in the NAC group, but did not reach statistical significance. Moreover, NAC seemed to decrease the risk of a first hospitalization for painful crisis (hazard ratio 0.56; CI 0.23-1.39).

In conclusion, treatment with oral NAC did not provide any clinical benefit over placebo in this phase 3 study, possibly due to low compliance rates. Therefore, a potential effect of NAC in SCD cannot fully be excluded based on these results. In an adherent subset of patients we did observe a reduction of days with painful crises and a trend to reduction in other pain related endpoints in the NAC treatment arm. To corroborate these findings additional blood sample analysis of pathophysiological markers is currently being performed. This may further elucidate on the dose-effect relation of NAC in SCD.