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Clinical Trial
. 2022 Nov 8;6(21):5711-5715.
doi: 10.1182/bloodadvances.2022007977.

First-in-human phase 1 trial of hemoglobin vesicles as artificial red blood cells developed for use as a transfusion alternative

Hiroshi Azuma  1 , Toraji Amano  2 , Naoya Kamiyama  3 , Naofumi Takehara  3 , Maki Jingu  2 , Harumi Takagi  2 , Osamu Sugita  2 , Naoko Kobayashi  4 , Tomoko Kure  4 , Taro Shimizu  5 , Tatsuhiro Ishida  5 , Masanori Matsumoto  6   7 , Hiromi Sakai  4
Affiliations
Clinical Trial

First-in-human phase 1 trial of hemoglobin vesicles as artificial red blood cells developed for use as a transfusion alternative

Hiroshi Azuma et al. Blood Adv. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: H.S. is a holder of patents related to the production and utilization of HbV. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Production of HbV, phase 1 study design, adverse event and change of systemic blood pressure. (A) Outline of production scheme of HbV: carbonylhemoglobin (HbCO) solution was purified from nucleic acid amplification test (NAT)-inspected human red blood cell concentrate. The lipids for Hb encapsulation in liposomes comprised 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), cholesterol, 1,5-O-dihexadecyl-N-succinyl- l-glutamate (DHSG), and 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-poly(ethylene glycol) (DSPE-PEG). The HbCO encapsulation and particle size control were performed using the kneading method. The entire procedure was performed under Good Manufacturing Practice (GMP) controls (supplemental Methods). (B) Phase 1 study design: (a) Twelve healthy volunteers were scheduled to receive single doses of HbV with no premedication in 2 consecutive dosing cohorts 1 and 2 (10 mL and 50 mL). In each cohort (n = 4), HbV suspension was administered to 1 subject in week 1 and to 3 subjects in week 2. (b) For a subsequent cohort 3 (n = 4), administration was made of a single dose of 100 mL of HbV suspension to 1 subject per week with premedication. After completion of administration, subjects were housed for 4 days and were monitored as ambulatory on days 5, 8, and 15. In some cases, an additional follow-up study was conducted to confirm recovery from the deviated laboratory variable. ∗Review of safety and tolerability by the Data and Safety Monitoring Committee. (C) Summary of adverse events associated with the infusion of HbV: these adverse events were resolved without medication. Premedication: dexamethasone 6.6 mg (IV), famotidine 20 mg (PO), and acetaminophen 500 mg (PO) were premedicated 1 hour before infusion of the HbV suspension. ∗Same subject. (D) Change of systemic systolic blood pressure: the systemic systolic pressure was measured sequentially. No significant change was found among blood pressure measurements of the respective cohorts. P values (2-tailed) of cohorts 1, 2, and 3 were, respectively, 0.996, 0.866, and 0.073; post, immediately after the start of infusion (in cohorts 2 and 3, only saline was being infused at this time point); closed small circle, blood pressure of each subject; open large circle, mean blood pressure.
Figure 2.
Figure 2.
Biochemical, immunological, and pharmacological parameters. (A) List of deviated laboratory data. Arrows indicate the values of analytes which were ±20% or more of the corrected preload value. §Preload values were corrected using a correction coefficient (supplemental Table 3; supplemental Methods). ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase; n.t., not tested. ∗Only approximately 10 mL was infused because of the manifestation of rash with wheal. (B) C-reactive protein (CRP) and complement system parameters of the subjects in cohort 3. Slightly increased CRP was found in 3 subjects regardless of the infusion volume of HbV suspension. No significant change in complement system parameters was found. CH50, 50% hemolytic complement activity. (C) Plasma Hb concentration profile of subjects in cohort 3 (100-mL dosing). In cohort 3, 2 subjects completed a 100-mL infusion of HbV suspension: (a) sequential change of plasma color and transparency; (b) plasma Hb concentrations; and (c) pharmacokinetic parameters. AUC∞, area under the plasma concentration – time curve from time zero until infinity; AUCt, area under the plasma concentration – time curve from time zero until t; CL/F, apparent total body clearance; Cmax, maximum plasma concentration; MRTt, mean residence time from time zero until t; Kel, elimination rate constant; T1/2, elimination half-life; Tmax, time of maximum plasma concentration.
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