Safety, Tolerability and Symptom Outcomes Associated with l-Carnitine Supplementation in Patients with Cancer, Fatigue, and Carnitine Deficiency: A Phase I/II Study

Abstract: Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer. Administration of exogenous l-carnitine may hold promise as a treatment for this common symptom. Little is known about l-carnitine safety, tolerability, and dose-response in patients with cancer. We conducted a Phase I/II open-label trial to assess the safety and tolerability of exogenous l-carnitine and clarify the safe dose range associated with symptom effects for future controlled trials. Adult patients with advanced cancer, carnitine deficiency (free carnitine <35 for males or <25μM/L for females, or acyl/free carnitine ratio >0.4), moderate to severe fatigue, and a Karnofsky Performance Status (KPS) score ≥50 were entered by groups of at least three into a standard maximum tolerated dose design. Each successive group received a higher dose of l-carnitine (250, 750, 1250, 1750, 2250, 2750, 3000mg/day, respectively), administered in two daily doses for 7 days. To compare symptom outcomes before and after supplementation, patients completed validated measures of fatigue (Brief Fatigue Inventory [BFI]), depressed mood (Center for Epidemiologic Studies Depression Scale [CES-D]), quality of sleep (Epworth Sleeplessness Scale [ESS]), and KPS at baseline and 1 week later. Of the 38 patients screened for carnitine levels, 29 were deficient (76%). Twenty-seven patients participated (“intention to treat, ITT”) (17 males, 10 females), and 21 completed the study (“completers”); 17 of these patients (“responders,” mean±[SD] age=57.9±15) had increased carnitine levels at the end of the supplementation period. The highest dose achieved was 3000mg/day. No patient experienced significant side effects and no toxicities were noted. Analysis of all the patients accrued (ITT, n =27) showed a total carnitine increase from 32.8±10 to 54.3±23μM/L (P <0.001) and free carnitine increase from 26.8±8 to 44.1±17μM/L (P <0.001). BFI decreased significantly, from 66±12 to 39.7±26 (P <0.001); ESS decreased from 12.9±12 to 9±6 (P =0.001); and CES-D decreased from 29.2±12 to 19±12 (P <0.001). A separate analysis of the 17 “responders” showed a dose-response relationship for total- (r =0.54, P =0.03), free-carnitine (r =0.56, P =0.02) levels, and fatigue (BFI) scores (r =−0.61, P =0.01). These findings suggest that l-carnitine may be safely administered at doses up to 3000mg/day and that positive effects may be more likely at relatively higher doses in this range. This study provides the basis for the design of future placebo-controlled studies of l-carnitine supplementation for cancer-related fatigue. [Copyright &y& Elsevier]