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. 2023 Aug 31;2023(8):CD013074. doi: 10.1002/14651858.CD013074.pub2

Brass 2001.

Study characteristics
Methods Study design

  • Two parallel RCTs (study A + study B)


Study dates

  • Duration of follow‐up: 24 weeks

  • Time frame: not reported
Participants Study characteristics

  • Setting: multicentre (4 centres participated in study A and 12 centres participated in study B)

  • Country: USA

  • Inclusion criteria: ESKD; HD treatment 3 times/week for at least 6 months; > 18 years; medical suitability to undergo graded ergometer exercise testing; ratio of acylcarnitine to carnitine concentrations > 0.40; Kt/V > 1.2 with less than 20% of variation during the previous 3 months

  • Exclusion criteria: patients with claudication; medical condition that precluded safe performance of maximal exercise testing; inability to cooperate with exercise testing; the use of immunosuppressives, growth hormones, androgens, or anabolic steroids within the 3 months before study entry


Baseline characteristics

  • Number (analysed/randomised)

    • Study A: intervention group (22/30, the ITT population was 28 participants); control group (27/30, ITT population was 28 participants)

    • Study B: intervention group 1 (32/not reported); intervention group 2 (30/not reported); intervention group 3 (32/not reported); control group (33/33)

  • Mean age, range (years)

    • Study A (ITT population): intervention group (42, 19 to 76); control group (45, 23 to 64)

    • Study B: intervention group 1 (48, 27 to 76); intervention group 2 (48, 26 to 76); intervention group 3 (46, 25 to 79); control group (43, 24 to 67)

  • Sex (M/F)

    • Study A (ITT population): treatment group (16/12); control group (16/12)

    • Study B: intervention group 1 (21/11); intervention group 2 (24/6); intervention group 3 (21/11); control group (20/13)

  • Dialysis type: HD

  • Mean dialysis vintage, range (years)

    • Study A (ITT population): intervention group (4.1, 0.6 to 23.1); control group (3.8, 0.8 to 23.6)

    • Study B: intervention group 1 (4.8, 0.7 to 16.0); intervention group 2 (7.2, 0.7 to 23.6); intervention group 3 (4.6, 0.8 to 17.5); control group (4.9, 0.6 to 20.4)

  • Comorbidities

    • Study A

      • CVD: not reported

      • Diabetes: intervention group (3/28); control group (6/28)

      • Hypertension: not reported

      • Depression (clinician diagnosis): not reported

    • Study B

      • CVD: not reported

      • Diabetes: intervention group 1 (8/32); intervention group 2 (7/30); intervention group 3 (7/32); control group (4/33)

      • Hypertension: not reported

      • Depression (clinician diagnosis): not reported
Interventions Intervention classification

  • Pharmacological intervention

  • Indication: study targeting fatigue


Study A
Intervention group

  • L‐carnitine (IV): 20 mg/kg at the conclusion of each thrice‐weekly dialysis session for 24 weeks


Control group

  • Placebo


Study B
Intervention group 1

  • L‐carnitine (IV): 10 mg/kg at the conclusion of each thrice‐weekly dialysis session for 24 weeks


Intervention group 2

  • L‐carnitine (IV): 20 mg/kg at the conclusion of each thrice‐weekly dialysis session for 24 weeks


Intervention group 3

  • L‐carnitine (IV): 40 mg/kg at the conclusion of each thrice‐weekly dialysis session for 24 weeks


Control group

  • Placebo


Co‐interventions

  • Not reported
Outcomes Outcomes reported

  • Fatigue outcome measures used: validation data available

  • Change in exercise capacity

    • Maximal rate of oxygen consumption (VO2max) using cycle ergometry: assessed at 12 and 24 weeks

    • ECG: assessed at 12 and 24 weeks

  • Change in QoL

    • KDQ (Appendix 3): assessed at 12 and 24 weeks

      • Physical symptoms

      • Fatigue

      • Depression

      • Relationships with others

      • Frustration

  • Adverse events: assessed until the end of treatment

  • Serious adverse events: assessed until the end of treatment

  • Change in laboratory values (HCT, Hb, lipid profile, liver function, predialysis chemistry, total carnitine, free carnitine, acylcarnitine concentrations, BUN, phosphate, creatinine): assessed every 4 weeks

  • A/F ratio: assessed at baseline and after 24 weeks

  • Kt/V: assessed at baseline and after 24 weeks

  • Dry body weight: assessed at baseline and after 24 weeks

  • Death: assessed until the end of treatment
Notes Additional information

  • Funding: Sigma Tau Pharmaceuticals, Inc, Gaithersburg, MD

  • Conflicts of interest/disclosures: not reported

  • Trial registration identification number: not applicable

  • A priori published protocol: not reported
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Quote: "Two placebo‐controlled, double‐blinded, randomised studies of carnitine supplementation were performed."
Comment: Sequence generation methods were not reported in sufficient detail to permit judgement
Allocation concealment (selection bias) Unclear risk Method of allocation concealment was not reported in sufficient detail to permit judgement
Blinding of participants and personnel (performance bias)
All outcomes Unclear risk Quote: "Two placebo‐controlled, double‐blinded, randomised studies of carnitine supplementation were performed."
Comment: Although author reported that the study used a double‐blind design, information about blinding of participants and investigators were not clearly stated
Blinding of outcome assessment (detection bias)
All outcomes High risk Quote: "The Kidney Disease Questionnaire (KDQ) is a validated questionnaire for measuring quality of life in patients with ESRD. It was administered in English or Spanish by trained interviewers on non dialysis days. [...] A standardized chemistry panel was assessed during screening, at baseline, and after 12 and 24 weeks of treatment."
Comment: The outcomes were assessed with an appropriate measure, without differences between groups. However, subjective measures were used, it was not stated whether outcomes were assessed without knowledge of treatment allocation, and knowledge of treatment assignment may have influenced reporting. Participant beliefs about the superiority/inferiority of either intervention could have influenced their assessment of the outcome, but there was no evidence that this was likely. However, objective and subjective outcomes were assessed
Incomplete outcome data (attrition bias)
All outcomes High risk Quote: "Study A randomised 60 patients, 30 patients on each study arm. Four patients (2 patients from each group) were excluded from the intention‐to‐treat population because they withdrew before and post baseline exercise tests (2 patients received renal transplants, 1 patient relocated, and 1 patient withdrew after developing elevated serum transaminase levels). Within the intention‐to‐treat population (n = 56), 7 patients (1 patient, placebo; 6 patients, L‐carnitine) withdrew before completing the 24‐week protocol. Three patients received renal transplants, 1 patient withdrew consent, 1 patient became pregnant, 1 patient was unable to perform the exercise test, and 1 patient withdrew from the study after a serious adverse event unrelated to study drug. Study B randomised 133 patients. Six patients (all administered carnitine) did not have post baseline exercise assessments and were thus excluded from the intention‐to‐treat population (2 patients received renal transplants, 1 patient withdrew from the study, 1 patient experienced worsening of arthralgia, 1 patient died, and 1 patient withdrew because of ECG changes). Within the intention‐to‐treat population (n = 127), 9 patients (2 patients, placebo; 3 patients, 10 mg/kg of L‐carnitine; 2 patients, 20 mg/kg of L‐carnitine; 2 patients, 40 mg/kg of L‐carnitine) failed to complete the full 24‐week study. One patient had exercise‐related problems, 1 patient was unable to exercise because of carpal tunnel syndrome, 4 patients received renal transplants, 1 patient withdrew because of back spasms, I patient refused the study drug because of abdominal pain, and 1 patient withdrew because of ECG changes."
Comment: 11/60 in the study A did not complete the study (> 5% lost to follow‐up, with differences between groups). Reasons for discontinuations seemed to be not related to the treatment allocation. 15/133 in the study B did not complete the study (>5% lost to follow‐up, with differences between groups). Reasons for discontinuations seemed to be not related to the treatment allocation
Selective reporting (reporting bias) High risk Information about the protocol and the statistical analysis plan were not reported. It was not reported if multiple eligible outcome measurements (scales and time points) were pre‐specified. It was unclear if the reported approach to analysing this outcome was pre‐specified or influenced by the results. Fatigue data were cumulated for 2 RCTs, all time points were not reported. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were not reported
Other bias High risk There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups. Funding (pharmaceutical company) could influenced the data analysis and conflicts of interest were not reported