Arginine supplementation increases mitochondrial activity and decreases oxidative stress in children with sickle cell disease and vaso-occlusive pain episodes (SCD-VOE), according to study results presented at the 2022 ASH Annual Meeting.

The phase 2, prospective, single-center, double-blind, randomized controlled trial (RCT; Identifier: NCT02536170) evaluated the role of intravenous (IV) arginine (3 times per day, up to 7 days) as adjuvant therapy for children with SCD-VOE. The patients with SCD were aged 3 to 21 years and hospitalized with VOE and required IV opioids. The children who had significant liver or renal dysfunction or were previously enrolled were excluded from the study.

The participants were randomly assigned into 1 of 3 arms: standard dose (SD) 100 mg/kg/dose arginine; loading dose: 200 mg/kg followed by SD; or placebo. The study authors obtained data regarding demographics, total parenteral opioid (TPO) use, time to crisis resolution (time of study drug delivery to last IV opioid), pain scores, patient-reported outcomes (PROMIS), and mitochondrial function before treatment and at discharge.

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TPO use among the study arms was the primary outcome measure. Cross-sectional and longitudinal outcomes within and among the treatment groups were compared with use of hypothesis tests and unadjusted and covariate-adjusted fixed and mixed effects generalized linear regression models.

A total of 1548 patients were screened, and 108 were randomly assigned as follows: arginine group (n = 36; mean age, 13.1 ± 3.7 years; 47% male); loading dose arginine group (n = 36; mean age, 13.1 ± 3.7 years; 53% male); and placebo group (n = 36; mean age, 11.8 ± 4.0 years; 44% male).

A clinically relevant decrease was observed in TPO and time to crisis resolution in both arginine treatment arms compared with the placebo group. Participants in the placebo arm required 45% higher TPO and had >15 hours longer mean time to crisis resolution vs the combined arginine treatment groups after adjustment for hydroxyurea use, continuous age, and sex.

The mean adjusted rate of total IV opioids (mg/kg IV morphine equivalents) was 1.55 (95% CI, 0.96-2.15) in the arginine group, 1.75 (95% CI, 1.06-2.45) in the loading dose arginine group, and 2.40 (95% CI, 1.32-3.48) in the placebo group (P =.203). The mean adjusted time to crisis resolution was 51.8 (95% CI, 35.3-8.3) hours in the arginine group, 49.6 (95% CI, 35.1-64.0) hours in the loading dose arginine group, and 66.3 (95% CI, 39.1-93.4) hours in the placebo group (P =.294).

In children aged <17 years, the placebo group (n = 33) required 80% more TPO compared with the combined arginine groups (n = 57; P =.075). No differences occurred in emergency department vs discharge pain scores or patient/parent PROMIS reports among the treatment groups. For patients who used hydroxyurea, mitochondrial complex V activity was greater (P =.02) and protein carbonyl levels were lower (P =.003) at the emergency department visit.

The 2 arginine groups had a significant increase in mitochondrial complex IV and V activity, and no change was observed in the placebo group (P <.001). Protein carbonyl levels in platelet-rich plasma decreased in the 2 arginine arms (P <.001), which suggests a decrease in oxidative stress that increased in the placebo group (P =.02). The highest level of mitochondrial improvement occurred among participants in the arginine loading dose group.

The rates of serious adverse events and adverse events were similar among the study groups, with no unexpected drug-related events occurring. Study limitations include the single-center design and small sample size.

“This is the first report to suggest a hydroxyurea-related impact on mitochondrial activity in SCD,” stated the researchers, who noted that arginine therapy also improves symptoms associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.

“Given emerging data supporting a link between mitochondrial function and pain, improved mitochondrial activity may mechanistically contribute to decreased pain and ultimately less opioid requirement with IV arginine treatment, as well as have further implications for improved metabolism and oxidative signaling in SCD,” the investigators commented in their presentation. “In this RCT, arginine therapy also demonstrated clinically relevant opioid-sparing and a decreased time to crisis resolution that was statistically insignificant. A larger sample size may elucidate potential differences.”

The researchers are enrolling 360 children in the Sickle Cell Disease Treatment with Arginine Therapy (STArT) study, an ongoing, multicenter, phase 3 RCT ( Identifier: NCT04839354).

Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures.

Morris CR, Bakshi N, Leake D, et al. Impact of arginine therapy on clinical outcomes, mitochondrial function and oxidative stress in children with sickle cell disease hospitalized with vasoocclusive pain episodes: a randomized controlled trial. Presented at ASH 2022. December 10-13, 2022. Abstract 7.