Clinical Nutrition ESPEN 50 (2022) 41e48

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Clinical Nutrition ESPEN

journal homepage: http://www.clinicalnutritionespen.com

Randomized Controlled Trial

Randomized controlled phase I trial for a novel peripheral parenteral

nutrition formula containing dextrose, amino acids, fat emulsion,
electrolytes, and FDA2000 recommendation-based vitamins
Kazuhiko Fukatsu a, *, Ryuzaburo Shineha b, Satoshi Katayose c, Yoshiyuki Kawauchi c,
Mitsuo Nakayama c
a
Surgical Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan
b
Soma Central Hospital, Fukushima 976-0016, Japan
c
Research and Development Center, Otsuka Pharmaceutical Factory Inc., Tokyo 101-0052, Japan

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: We developed the world's first all-in-one type peripheral parenteral nutrition
Received 28 April 2022 product containing dextrose, amino acids, fat emulsion, electrolytes and vitamins, according to the FDA
Accepted 8 May 2022 2000 recommendation. This phase I trial examined the safety and changes in nutritional parameters in
healthy participants.
Keywords: Methods: A single-center, randomized, open-label, active-controlled trial was performed in single
Peripheral parenteral nutrition
ascending dose (SAD: Step 1e3) and multiple dose (Step 4) studies.
Fat
Participants were administered a single dose of OPF-105 (test solution: 150 g of dextrose, 60 g of amino
Vitamin
acids, 40 g of fat, 1240 kcal of total energy per 2200 mL, and 106 NPC/N ratio, with multivitamins, n ¼ 17)
or BFI (control solution: 150 g of dextrose, 60 g of amino acids, 840 kcal of total energy per 2000 mL, and
64 NPC/N ratio, with vitamin B1, n ¼ 18) with three ascending doses (Step 1: 550 mL, Step 2: 1100 mL,
and Step 3: 2200 mL) in the SAD study, or received multiple doses with Step 3 amount of OPF-105 (n ¼ 5)
or BFI (n ¼ 6) for 3 days (Step 4) via peripherally inserted venous catheters. The safety and nutritional
parameters were assessed.
Results: There were no serious adverse events or events requiring discontinuation of the solution
administration in either group.
Blood urea nitrogen (BUN) levels remained within the normal range in both groups (Step 1e4). However, they
gradually increased during the time course of the study in the BFI group but not in the OPF group (Step 4),
suggesting the prevention of body protein breakdown. Blood triglyceride (TG) levels increased after
administration in the OPF group but promptly returned to the pre-administration level (Step 1e4). Blood total
ketone body levels increased the day after administration in both groups, which may imply a lower degree of
starvation (Step 1e3), but the increase in the OPF group was milder than that in the BFI group (Step 4).
Blood vitamin B6 and folic acid levels were maintained within the normal ranges in the OPF group but were
near the lower limit in the BFI group (Step 1e4). Blood vitamin C levels showed almost lower limit in the
two groups (Step 1e3), but increased only in the OPF group (Step 4). Blood vitamin K levels in the BFI group
remained near the lower limit of the normal range, but those in the OPF group were higher than the upper
limit at the end of administration and quickly returned to the pre-administration level (Step 1e4).
Conclusions: This trial suggests that the newly developed formula (OPF-105) improves fat metabolism,
maintains vitamin profiles, and may prevent body protein and fat breakdown and can be safely
administered to healthy participants.
Registration number of Clinical Trial: UMIN000046915; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/
ctr_view.cgi?recptno¼R000053479.
© 2022 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and
Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

* Corresponding author. Surgical Center, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
E-mail addresses: fukatsu-1su@h.u-tokyo.ac.jp, kazfukatsu@yahoo.co.jp (K. Fukatsu), shineha@tachiya.or.jp (R. Shineha), Katayose.Satoshi@otsuka.jp (S. Katayose),
Kawauchi.Yoshiyuki@otsuka.jp (Y. Kawauchi), nakayamami@otsuka.jp (M. Nakayama).

https://doi.org/10.1016/j.clnesp.2022.05.001
2405-4577/© 2022 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
K. Fukatsu, R. Shineha, S. Katayose et al. Clinical Nutrition ESPEN 50 (2022) 41e48

1. Introduction 2.2. Parenteral nutrition solutions

Peripheral parenteral nutrition (PPN) is a simpler, safer, less The composition of the test solution and control solution are
expensive, and more convenient alternative to total parenteral summarized in Table 1.
nutrition (TPN). However, depending on the osmolality and pH of
the PPN solution administered, infusion phlebitis may occur. 2.2.1. Test solution (OPF-105)
Therefore, nutrients and doses that can be administered by PPN are OPF-105 is a double-chamber bag preparation containing
limited, and they are not suitable for long-term parenteral nutrition dextrose, amino acids, fat, electrolytes, vitamin B1, vitamin B2,
management. In the parenteral nutrition guidelines of each country vitamin B6, vitamin B12, nicotinic acid, folic acid, biotin, vitamin C,
[1e3], TPN should be selected when the duration of parenteral pantothenic acid, vitamin A, vitamin D, vitamin E, and vitamin K. Its
nutrition is more than two weeks and when it is necessary for fluid appearance is a clear yellow upper chamber (amino acid/electro-
restriction. PPN is recommended when the duration of parenteral lyte/vitamin solution) and a white to pale yellow lower chamber
nutrition is within two weeks. Currently, in Japan, a preparation
containing dextrose, amino acids, and electrolytes is widely used as
a PPN formulation, but when a daily dose (2000 mL) is adminis- Table 1
Compositions of the test and control solutions.
tered, only 840 kcal of energy can be supplied. Therefore, when a
fat-free PPN formulation (dextrose and amino acids) is adminis- Ingredients Test solution Control solution Daily FDA
tered within 2 weeks, the physician must use another route or requirements
OPF-105 BFI
select a side-injection to administer fat emulsion. In addition, vi- 550 mL 500 mL
tamins need to be mixed into the PPN formulation. Carbohydrate
The novel PPN formulation (OPF-105) has a double-chamber bag Dextrose, g 37.5 37.50 e
system in which fat emulsions and multivitamins are kitted in Dextrose concentration, 6.8 7.5 e
addition to dextrose, amino acids, and electrolytes and has a total w/v%
Amino acids
energy of 1240 kcal per 2200 mL of daily dose. NPC/N was set to
Total free amino acids, g 15 15.00 e
106, the pH at the time of use was near neutral, and the osmotic Total nitrogen, g 2.35 2.35 e
pressure ratio was set to <3. OPF-105 may be helpful for patients Essential/nonessential 1.44 1.44 e
who are not able to have sufficient oral or enteral feeding and must amino acids
rely on parenteral nutrition for 1e2 weeks, especially when TPN Branched-chain amino 30 30 e
acids, w/w%
does not need to be performed immediately. Moreover, as OPF-105 Fat
can be prepared in a sterile and simple way by opening the septum Purified soybean oil, g 10 e e
between the upper and lower chambers, it is possible to skip the Fat concentration, w/v% 1.8 e e
process of mixing vitamins or the procedure in the combined use of Electrolytes
Naþ, mEq 17.5 17.5 e
fat emulsion. It also contributes to the prevention of dispensing
Kþ, mEq 10 10 e
errors, needlestick injuries in mixed preparations, as well as bac- Mg2þ, mEq 2.5 2.5 e
terial contamination. Ca2þ, mEq 2.5 2.5 e
In this study, we conducted a step-up trial in healthy adults to Cl, mEq 17.5 17.5 e
assess safety and nutritional parameters. Steps 1e3 were single SO24 , mEq 2.5 2.5 e
Acetate, mEq 7 8 e
ascending dose (SAD) studies with three ascending doses (550 mL, Gluconate, mEq 2.5 e e
1100 mL, and 2200 mL), while Step 4 was a multiple-dose study -
L-Lactate , mEq 10.5 10 e
with a dose of Step 3 (2200 mL/day) for 3 days. The control solution Citrate3, mEq 3 3 e
was a fat-free, commercially available PPN solution containing P, mmol 5 5 e
Zn, mmol 2.5 2.5 e
dextrose, amino acids, electrolytes, and vitamin B1.
Vitamins
Thiamine chloride 1.91 (1.5) 0.96 (0.75) 6.0
2. Materials & methods hydrochloride
(Thiamine equivalent),
This phase I trial was a single-center, randomized, open-label, mg
Riboflavin sodium 1.15 (0.9) e 3.6
active-controlled, SAD, and multiple-dose study. It was initiated phosphate (Riboflavin
by the trial sponsor Otsuka Pharmaceutical Factory, Inc. This trial equivalent), mg
was conducted in accordance with the Good Clinical Practice Pyridoxine hydrochloride 1.83 (1.5) e 6.0
guidelines in Japan. The trial site was Bio-Iatoric Center, Research (Pyridoxine
equivalent), mg
Center for Clinical Pharmacology, Kitasato University, currently
Cyanocobalamin, mg 1.25 e 5
known as Kitasato University Kitasato Institute Hospital. The pro- Nicotinamide, mg 10 e 40
tocol and informed consent forms were approved by the institu- Panthenol (Pantothenic 3.52 (3.8) e 15.0
tional review board at the trial site (Reference No.: 12638). acid equivalent), mg
Folic acid, mg 150 e 600
Biotin, mg 15 e 60
2.1. Participants Ascorbic acid, mg 50 e 200
Vitamin A oil, IU 825 e 3300
In this trial, all participants were healthy adult males aged Cholecarciferol, mg 1.25 e 5
over 20 and under 40 years at the time of obtaining consent, Tocopherol acetate, mg 2.5 e 10
Phytonadione, mg 37.5 e 150
no abnormalities were observed in both arms, and the body mass
pH Approx. 6.6 Approx. 6.7 e
index (BMI) was 18.5 or more and less than 30.0. The exclusion Osmotic pressure ratio Approx. 2.6 Approx. 3 e
criteria are summarized in Supplemental Table 1 (Supplemental (relative to saline
Tables are available at https://doi.org/10.1016/j.clnesp.2022.05. solution)
001). Investigators obtained written informed consent from all Total calories, kcal 310 210 e

participants who agreed to be enrolled in the trial. IU, international unit; FDA, U.S. Food and Drug Administration.

42
K. Fukatsu, R. Shineha, S. Katayose et al.
(dextrose/fat emulsion/vitamin solution). The formulation design
was based on the combination of 500 mL of BFI (BFUID® Injection,
Otsuka Pharmaceutical Factory, Inc., control solution) and 50 mL of
fat emulsion (Intralipos® Injection 20%, Otsuka Pharmaceutical
Factory, Inc.) with vitamins. The volume was 550 mL per bag, 50 mL
larger than that of the control solution. Immediately before use, the
center seal between the two chambers was broken, and the two
solutions were mixed thoroughly. By administering four bags
(2200 mL) of this solution, the daily maintenance requirements of
dextrose, amino acids, electrolytes, and 13 vitamins and 1240 kcal
of energy can be supplied. The amount of vitamins was determined
according to the FDA2000 recommendation published in the fed-
eral register [4]. In this trial, the infusion volume was different
because the doses of nutrients (dextrose, amino acids, and elec-
trolytes) other than fats and vitamins were set the same between
the two groups.
2.2.2. Control solution (BFI)
BFI (BFLUID® Injection, Otsuka Pharmaceutical Factory, Inc.) is
a double-chamber bag containing dextrose, amino acids, elec-
trolytes, and vitamin B1. Its appearance is a clear and colorless
upper chamber (amino acid/electrolyte solution) and a lower
chamber (dextrose/electrolyte/vitamin B1 solution). The volume
was 500 mL per bag, and immediately before use, the center seal
between the two chambers was broken, and the two solutions
were mixed thoroughly. By administering four bags (2000 mL) of
this solution, the daily maintenance requirements of dextrose,
amino acids, electrolytes, and vitamin B1 and 840 kcal of energy
can be supplied. The formulated amounts of dextrose, amino
acids, and electrolytes were the same as those used for OPF-105.
The amount of vitamin B1 was determined according to the
AMA1975 recommendation issued in the American Medical As-
sociation guidelines [5].
2.3. Procedure
A total of 48 healthy adult males were included in the study. The
participants were randomized (6:6) to OPF-105 or BFI in each step
according to the participant allocation table using the envelope
method by investigators. Each participant was included in one step
only. Participant allocation tables were prepared at the case registry
center of the EPS Corporation. (Tokyo, Japan). The participant
allocation tables were concealed until the time of allocation.
The test or control solutions were infused intravenously into
the peripheral vein of the forearm using peripheral vascular
catheters (PVCs). The amounts and periods of administration in
each step are summarized in Supplemental Table 2, the
Fig. 1. Time schedule of Step 4.
* Each day of multiple doses for 3 days.
43
Clinical Nutrition ESPEN 50 (2022) 41e48
administration rate of each compounded active ingredient is lis-
ted in Supplemental Table 3, and the criteria for step-up are
presented in Supplemental Table 4.
The use of therapeutic drugs, including over-the-counter drugs,
was prohibited from two weeks before participant enrollment to
the end of observation and examination at discharge. Restrictions
of food and drink intake from the day before hospitalization to the
day after administration (day of discharge) are summarized in
Supplemental Table 5.
Blood or urine sampling was performed for safety evaluations
(Supplemental Table 6) and assessments related to the ingredients
(Supplemental Table 7). The time schedules are shown in
Supplemental Fig. 1 (Step 1e3) and Fig. 1 (Step 4). Among the
clinical laboratory tests, all 1a and part of 1b and 2 items (sodium,
potassium, chloride, magnesium, calcium, phosphorus, glucose,
non-esterified fatty acids, and urinary volume) were measured at
the trial site, and other parameters were measured by SRL, Inc.
(Tokyo, Japan).
Adverse events were coded using the Japanese version of the
Medical Dictionary for Regulatory Activities (MedDRA/J Ver. 15.1).
2.4. Endpoints
In this trial, the safety and nutritional parameters of the test
solution were evaluated. Adverse events, clinical laboratory tests 1a
results, vital signs, body weight, and 12-lead electrocardiogram
reports were evaluated in order to understand the condition of the
participants and ensure safety. In addition, clinical laboratory tests
1b and 2 results were evaluated in order to confirm the urinary
volume and blood concentrations related to the ingredients of the
test solution.
Because the composition of dextrose, amino acids, and elec-
trolytes of OPF-105 are the same as those of BFI, it is considered that
they can be evaluated based on the clinical trial results of BFI [6].
Among the ingredients, electrolytes and water with the same
formulation as that of BFI were confirmed in the measurement
items and measurement time of clinical laboratory tests 1b, and
vitamins and fat with different formulations were confirmed in the
measurement items and measurement time of clinical laboratory
tests 2. As for the vitamins, B1, B6, folic acid, C, and K which had
their composition changed from the AMA1975 formulation in the
FDA2000 formulation, were set.
2.5. Statistical methods
Six participants per group in each step were selected as the
number of participants who could be assessed for safety and
K. Fukatsu, R. Shineha, S. Katayose et al. Clinical Nutrition ESPEN 50 (2022) 41e48

Table 2 Table 2 (continued )

Blood levels of BUN, GLU, TG, VLDL-TG, PL, linoleic acid, a-linolenic acid, total ketone
bodies, and NEFA (Step 4). OPF4 (n ¼ 5) BFI4 (n ¼ 6) p value

Discharge 16.70 ± 3.13 11.15 ± 2.30 0.008

OPF4 (n ¼ 5) BFI4 (n ¼ 6) p value
Total ketone bodies, mmol/L
BUN, mg/dL Day 1 prior to admin. 189.6 ± 194.9 55.8 ± 16.6 0.125
Day 1 prior to admin. 12.0 ± 1.9 11.2 ± 1.2 0.389 Day 1 end of admin. 67.0 ± 15.7 54.5 ± 11.0 0.156
Day 1 end of admin. 11.4 ± 1.1 12.0 ± 0.9 0.353 Day 1 3 h after admin. 302.0 ± 138.4 477.3 ± 305.6 0.269
Day 2 prior to admin. 12.0 ± 1.6 14.5 ± 1.4 0.021 Day 2 prior to admin. 386.0 ± 172.6 319.2 ± 129.3 0.481
Day 2 end of admin. 13.0 ± 1.9 16.0 ± 0.9 0.007 Day 2 end of admin. 69.6 ± 15.7 57.3 ± 16.4 0.239
Day 3 prior to admin. 13.2 ± 1.8 16.5 ± 1.8 0.013 Day 2 3 h after admin. 317.6 ± 47.5 532.0 ± 199.8 0.045
Day 3 end of admin. 13.2 ± 1.8 16.2 ± 1.5 0.014 Day 3 prior to admin. 252.4 ± 95.4 323.3 ± 207.7 0.502
Discharge 13.4 ± 1.9 16.5 ± 2.3 0.043 Day 3 end of admin. 63.8 ± 9.4 60.8 ± 10.7 0.641
GLU, mg/dL Day 3 3 h after admin. 269.8 ± 90.0 550.8 ± 305.0 0.08
Day 1 prior to admin. 94.4 ± 6.0 96.0 ± 3.2 0.582 Discharge 255.6 ± 101.7 360.2 ± 162.9 0.246
Day 1 end of admin. 79.8 ± 16.6 92.0 ± 13.4 0.209 NEFA, mEq/L
Day 1 3 h after admin. 91.8 ± 3.2 91.5 ± 4.4 0.901 Day 1 prior to admin. 0.460 ± 0.213 0.350 ± 0.060 0.254
Day 2 prior to admin. 87.8 ± 5.2 89.0 ± 1.8 0.605 Day 1 end of admin. 0.206 ± 0.032 0.095 ± 0.021 0
Day 2 end of admin. 96.4 ± 12.4 96.0 ± 26.2 0.976 Day 1 3 h after admin. 0.928 ± 0.183 1.103 ± 0.227 0.198
Day 2 3 h after admin. 92.0 ± 4.3 89.0 ± 4.0 0.262 Day 2 prior to admin. 0.630 ± 0.104 0.538 ± 0.133 0.242
Day 3 prior to admin. 87.4 ± 5.0 88.8 ± 3.3 0.584 Day 2 end of admin. 0.224 ± 0.023 0.123 ± 0.046 0.002
Day 3 end of admin. 97.6 ± 19.4 96.2 ± 11.9 0.884 Day 2 3 h after admin. 1.044 ± 0.135 1.017 ± 0.162 0.772
Day 3 3 h after admin. 92.6 ± 3.6 90.2 ± 4.2 0.338 Day 3 prior to admin. 0.640 ± 0.139 0.612 ± 0.122 0.727
Discharge 88.2 ± 4.8 89.0 ± 1.5 0.705 Day 3 end of admin. 0.212 ± 0.033 0.082 ± 0.019 0
TG, mg/dL Day 3 3 h after admin. 0.990 ± 0.226 1.100 ± 0.234 0.452
Day 1 prior to admin. 79.0 ± 29.8 97.3 ± 41.3 0.43 Discharge 0.656 ± 0.132 0.725 ± 0.098 0.345
Day 1 end of admin. 149.6 ± 122.9 76.7 ± 55.2 0.222
Data are means ± SD. BUN, blood urea nitrogen; GLU, glucose; TG, triglycerides;
Day 1 3 h after admin. 64.0 ± 19.8 96.7 ± 40.5 0.136
VLDL-TG: very low-density lipoprotein triglycerides; PL, phospholipids; NEFA, non-
Day 2 prior to admin. 90.4 ± 24.9 94.8 ± 42.1 0.841
esterified fatty acid.
Day 2 end of admin. 121.6 ± 53.8 56.8 ± 35.9 0.041
Day 2 3 h after admin. 59.6 ± 16.2 72.3 ± 26.2 0.371
Day 3 prior to admin. 91.6 ± 15.9 78.5 ± 25.4 0.344 nutritional parameters. Tabulations and descriptive statistics were
Day 3 end of admin. 121.8 ± 39.8 46.5 ± 25.9 0.004
obtained for each parameter, group, and assessment time point.
Day 3 3 h after admin. 54.8 ± 10.4 59.7 ± 20.4 0.642
Discharge 92.6 ± 21.1 71.0 ± 20.9 0.124 Statistical tests were performed using Fisher's exact test for
VLDL-TG, mg/dL participant characteristics and adverse events and Student's t-test
Day 1 prior to admin. 47.80 ± 28.57 60.93 ± 40.15 0.556 for laboratory data.
Day 1 end of admin. 103.76 ± 117.19 45.47 ± 52.14 0.299
Day 1 3 h after admin. 31.60 ± 18.82 64.47 ± 40.28 0.13
Day 2 prior to admin. 55.84 ± 24.60 58.03 ± 40.30 0.918 3. Results
Day 2 end of admin. 75.28 ± 51.24 28.03 ± 33.41 0.098
Day 2 3 h after admin. 25.52 ± 12.81 39.73 ± 24.14 0.269 3.1. Participant characteristics
Day 3 prior to admin. 53.68 ± 15.61 42.10 ± 24.17 0.382
Day 3 end of admin. 73.56 ± 37.22 18.30 ± 21.60 0.013
Day 3 3 h after admin. 20.00 ± 6.18 29.67 ± 18.19 0.289 A total of 48 participants underwent randomization (OPF group,
Discharge 52.76 ± 18.11 35.20 ± 19.39 0.158 n ¼ 24; BFI group, n ¼ 24). Two participants (one in the OPF3 group
PL, mg/dL and one in the OPF4 group) were withdrawn prior to administra-
Day 1 prior to admin. 157.2 ± 9.3 177.2 ± 13.5 0.021 tion. Therefore, a total of 46 participants (OPF groups: n ¼ 22, BFI
Day 1 end of admin. 199.8 ± 12.1 166.0 ± 19.4 0.008
Day 1 3 h after admin. 183.8 ± 10.4 171.7 ± 18.3 0.223
groups: n ¼ 24) with 12 participants in Step 1 (6 in the OPF1 group,
Day 2 prior to admin. 166.2 ± 13.2 177.8 ± 17.8 0.258 6 in the BFI1 group), 12 participants in Step 2 (6 in the OPF2 group, 6
Day 2 end of admin. 198.6 ± 9.2 151.2 ± 12.9 0 in the BFI2 group), 11 participants in Step 3 (5 in the OPF3 group, 6
Day 2 3 h after admin. 184.6 ± 11.0 163.2 ± 14.4 0.023 in the BFI3 group), and 11 participants in Step 4 (5 in the OPF4
Day 3 prior to admin. 171.8 ± 10.5 168.5 ± 16.1 0.704
group, 6 in the BFI4 group) were included in the statistical analyses.
Day 3 end of admin. 203.2 ± 13.2 143.0 ± 12.9 0
Day 3 3 h after admin. 186.4 ± 10.0 154.5 ± 12.7 0.001 The flow diagrams (Steps 1e4) are shown in Supplemental
Discharge 175.0 ± 8.2 163.5 ± 12.8 0.117 Figs. 2e5. The registration of the first participant was on
Linoleic acid, mg/mL December 18, 2012 and the observation and examination of the
Day 1 prior to admin. 684.44 ± 163.21 764.98 ± 119.21 0.368 final participant was completed on February 21, 2013. Participant
Day 1 end of admin. 1159.90 ± 633.07 688.85 ± 118.84 0.105
characteristics are presented in Supplemental Table 8. There were
Day 1 3 h after admin. 838.98 ± 157.25 781.78 ± 81.59 0.456
Day 2 prior to admin. 751.52 ± 170.66 711.63 ± 91.22 0.631 no notable differences between the two groups.
Day 2 end of admin. 925.58 ± 309.76 510.13 ± 70.29 0.01
Day 2 3 h after admin. 722.38 ± 106.98 614.77 ± 42.97 0.049
3.2. Safety monitoring results
Day 3 prior to admin. 725.14 ± 72.55 599.48 ± 38.46 0.005
Day 3 end of admin. 1097.32 ± 252.43 546.75 ± 73.80 0.001
Day 3 3 h after admin. 804.10 ± 120.77 624.52 ± 60.36 0.011 The incidence rate of adverse events was 13.6% (3 of 22 partic-
Discharge 746.52 ± 113.64 626.73 ± 53.64 0.046 ipants) in the test solution group and 4.2% (1 of 24 participants) in
a-Linolenic acid, mg/mL the control solution group, with no significant differences between
Day 1 prior to admin. 14.64 ± 4.71 18.12 ± 7.96 0.415
Day 1 end of admin. 59.70 ± 56.17 11.22 ± 6.99 0.063
the two groups (Supplemental Table 8). There were no serious
Day 1 3 h after admin. 21.84 ± 7.84 17.58 ± 5.48 0.317 adverse events or events requiring discontinuation of the solution
Day 2 prior to admin. 14.70 ± 3.64 12.95 ± 4.93 0.528 administration in either group. Adverse events included vascul-
Day 2 end of admin. 40.38 ± 22.15 5.90 ± 2.93 0.004 opathy (n ¼ 1) and headaches (n ¼ 1) in the OPF2 group, erythema
Day 2 3 h after admin. 17.38 ± 3.89 11.38 ± 2.79 0.016
(n ¼ 1) in the OPF3 group, and vasculopathy (n ¼ 1) and hepatic
Day 3 prior to admin. 14.58 ± 1.97 10.07 ± 1.85 0.004
Day 3 end of admin. 48.24 ± 18.13 5.57 ± 2.33 0 dysfunction (n ¼ 1) in the BFI4 group. All events were mild and
Day 3 3 h after admin. 19.54 ± 3.36 11.57 ± 2.82 0.002 resolved without worsening. There was no dose-related increase in
the number of incidences and severity.
44
K. Fukatsu, R. Shineha, S. Katayose et al. Clinical Nutrition ESPEN 50 (2022) 41e48

The step-up criteria were fulfilled in each step, and all the steps Table 3
were completed. Blood levels of vitamin B1, B6, folic acid, C, and K (Step 4).

OPF4 (n ¼ 5) BFI4 (n ¼ 6) p value

3.3. Changes in nutritional parameters Vitamin B1, ng/mL
Day 1 prior to admin. 28.8 ± 6.4 30.3 ± 2.4 0.597
The results of blood urea nitrogen (BUN), blood levels of glucose Day 1 end of admin. 36.2 ± 5.9 37.0 ± 4.6 0.806
(GLU), triglyceride (TG), very low-density lipoprotein triglyceride Day 1 3 h after admin. 41.8 ± 4.9 38.2 ± 3.7 0.193
Day 2 prior to admin. 34.0 ± 4.9 35.3 ± 4.2 0.639
(VLDL-TG), phospholipid (PL), linoleic acid, a-linolenic acid, total
Day 2 end of admin. 45.2 ± 6.4 39.3 ± 3.7 0.088
ketone bodies, and non-esterified fatty acid (NEFA) are summarized Day 2 3 h after admin. 46.8 ± 7.1 44.0 ± 5.6 0.484
in Table 2 and Supplemental Tables 9e11, while the blood levels of Day 3 prior to admin. 39.8 ± 6.6 38.3 ± 4.2 0.665
vitamins B1, B6, folic acid, C, and K are listed in Table 3 and Day 3 end of admin. 44.6 ± 4.2 39.7 ± 5.3 0.126
Day 3 3 h after admin. 44.2 ± 8.4 39.5 ± 4.4 0.262
Supplemental Tables 12e14.
Discharge 32.8 ± 6.3 31.7 ± 2.1 0.684
Vitamin B6, ng/mL
3.3.1. Step 1 Day 1 prior to admin. 10.94 ± 7.71 12.50 ± 14.92 0.838
BUN and GLU levels almost remained within the normal range Day 1 end of admin. 35.38 ± 15.71 12.65 ± 15.83 0.041
(BUN: 7e21 mg/dL, GLU: 79e106 mg/dL) in both the OPF1 and BFI1 Day 1 3 h after admin. 27.58 ± 12.97 11.78 ± 14.09 0.087
Day 2 prior to admin. 20.56 ± 9.50 11.45 ± 13.95 0.248
groups without marked differences. In response to the adminis-
Day 2 end of admin. 46.40 ± 17.08 11.78 ± 14.05 0.005
tration of lipids, blood TG and VLDL-TG levels were the highest at Day 2 3 h after admin. 37.48 ± 15.41 11.93 ± 14.55 0.02
the end of administration in the OPF1 group but promptly Day 3 prior to admin. 28.12 ± 10.99 10.70 ± 12.80 0.04
returned to pre-administration levels and those in the BFI1 group Day 3 end of admin. 58.34 ± 21.69 11.25 ± 12.74 0.001
did not change throughout the study period and remained within Day 3 3 h after admin. 46.60 ± 17.21 10.18 ± 11.54 0.002
Discharge 31.24 ± 11.60 9.32 ± 10.34 0.009
the normal range (TG: 30e147 mg/dL, VLDL-TG: 2.0e93.0 mg/dL). Folic acid, ng/mL
Blood PL levels were maintained within the normal range Day 1 prior to admin. 6.54 ± 2.17 6.32 ± 1.34 0.839
(166e294 mg/dL) in the two groups but were close to the lower Day 1 end of admin. 11.80 ± 4.92 3.80 ± 0.79 0.003
limit in the BFI1 group. Blood linoleic acid and a-linolenic acid Day 1 3 h after admin. 8.00 ± 2.28 5.02 ± 1.29 0.023
Day 2 prior to admin. 8.78 ± 3.14 7.45 ± 1.56 0.383
levels in the OPF1 group were increased at the end of adminis-
Day 2 end of admin. 23.84 ± 5.67 4.20 ± 0.87 0
tration and returned to the middle levels of the normal range Day 2 3 h after admin. 11.48 ± 3.12 5.55 ± 1.31 0.002
(linoleic acid: 708.1e1286.0 mg/mL, a-linolenic acid: 11.5e45.8 mg/ Day 3 prior to admin. 9.34 ± 2.46 7.82 ± 2.11 0.297
mL), whereas those in the BFI1 group showed lower limit levels. Day 3 end of admin. 26.90 ± 5.71 4.18 ± 0.92 0
Blood total ketone body levels were markedly increased at Day 3 3 h after admin. 12.40 ± 3.20 5.13 ± 1.35 0.001
Discharge 9.76 ± 2.55 7.87 ± 1.97 0.197
discharge in both groups, reflecting a shortage of energy supply Vitamin C, mg/mL
during the trial protocol. Blood NEFA levels were increased almost Day 1 prior to admin. 7.50 ± 1.80 7.90 ± 1.54 0.7
to the upper limit of the normal range (0.10e0.80 mEq/L) at 3 h Day 1 end of admin. 8.68 ± 1.76 5.35 ± 0.96 0.003
after administration in both groups, but the increase was blunted Day 1 3 h after admin. 8.38 ± 1.69 5.33 ± 0.85 0.004
Day 2 prior to admin. 6.32 ± 1.30 5.38 ± 1.20 0.247
in the OPF1 group. Blood vitamin B1 levels remained within the
Day 2 end of admin. 7.94 ± 1.56 4.10 ± 0.90 0.001
normal range (24e66 ng/mL) in both groups, though OPF1 group Day 2 3 h after admin. 8.60 ± 1.96 4.75 ± 1.02 0.002
significantly increased the levels at 1 h after administration as Day 3 prior to admin. 6.66 ± 1.53 5.03 ± 1.37 0.096
compared to those in the BFI1 group. Blood vitamin B6 and folic Day 3 end of admin. 10.08 ± 3.15 4.93 ± 1.42 0.006
acid levels were maintained within the normal ranges (vitamin B6: Day 3 3 h after admin. 11.54 ± 1.81 6.18 ± 1.37 0
Discharge 10.42 ± 1.94 6.43 ± 1.49 0.004
6.0e40.0 ng/mL, folic acid:  4.0 ng/mL) in the OPF1 group, while Vitamin K, ng/mL
the BFI1 group showed lower limit levels. With regard to vitamin C, Day 1 prior to admin. 0.4040 ± 0.2485 0.6350 ± 0.4977 0.372
the levels were near the lower limit of the normal range Day 1 end of admin. 3.3080 ± 2.8774 0.1250 ± 0.1489 0.023
(5.5e16.8 mg/mL) both in the OPF1 and BFI1 groups. Blood vitamin Day 1 3 h after admin. 0.9380 ± 0.4779 0.0867 ± 0.0796 0.002
Day 2 prior to admin. 0.2480 ± 0.0327 0.0392 ± 0.0347 0
K levels in the BFI1 group remained near the lower limit of the
Day 2 end of admin. 3.2440 ± 2.0854 0.0250 ± 0.0000 0.004
normal range (0.15e1.25 ng/mL). In the OPF1 group, they increased Day 2 3 h after admin. 0.8660 ± 0.3088 0.0250 ± 0.0000 0
over the upper limit at the end of administration but promptly Day 3 prior to admin. 0.2600 ± 0.0255 0.0250 ± 0.0000 0
returned to pre-administration levels. Day 3 end of admin. 3.6160 ± 1.9681 0.0250 ± 0.0000 0.001
Day 3 3 h after admin. 0.9440 ± 0.3582 0.0250 ± 0.0000 0
Discharge 0.2700 ± 0.0339 0.0250 ± 0.0000 0
3.3.2. Steps 2 and 3
The results of Step 2 (OPF2 and BFI2 groups) and 3 (OPF3 and Data are means ± SD.
BFI3 groups) were similar to the results of Step 1. However, in terms
of blood total ketone body levels, the increases at the discharge
were blunted in Steps 2 and 3 owing to the increased energy supply normal ranges in the OPF4 group, but those in the BFI4 group
as compared to that of Step 1. showed a temporal reduction. Blood total ketone body levels were
increased over the upper limit in both groups, but the increase was
3.3.3. Step 4 relatively mild in the OPF4 group (Fig. 4). Blood NEFA levels were
BUN levels were within the normal range in both the groups. increased at 3 h after administration in the two groups, but the
However, they gradually increased during the time course of Step 4 increase was blunted in the OPF4 group. Blood vitamin B1 levels
in the BFI4 group but not in the OPF4 group (Fig. 2). Blood GLU remained within the normal range in both groups, with no signif-
levels almost remained within the normal range in both groups, icant differences between the two groups. Blood vitamin B6 and
with no marked differences. Blood TG and VLDL-TG levels were the folic acid levels were increased in the OPF4 group, but the levels of
highest at the end of administration in the OPF4 group but the BFI4 group consistently stayed at the lower limit of the normal
promptly returned to pre-administration levels (TG: Fig. 3). They ranges (Figs. 5 and 6). Blood vitamin C levels were within the
were stable within the normal range in the BFI4 group. Blood PL, normal range in the OPF4 group, but these levels were lower in the
linoleic acid, and a-linolenic acid levels were maintained within the BFI4 group (Fig. 7). Blood vitamin K levels in the BFI4 group were

45
K. Fukatsu, R. Shineha, S. Katayose et al.
Fig. 2. Blood urea nitrogen level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
Fig. 3. Blood triglycerides level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
near the lower limit of the normal range throughout the trial
period. In the OPF4 group, they increased over the upper limit at
the end of administration but promptly returned to pre-
administration levels (Fig. 8).
4. Discussion
This phase I trial with step-up studies was completed without
unexpected adverse events and revealed some benefits of the
newly developed PPN formula (OPF-105) over the conventional
formula (BFI).
Regarding the safety evaluation, incidence rates in the OPF
group were higher than those in the BFI group, but the difference
was not statistically significant. All the incidences were not specific
to this trial but looked like those observed during the clinical course
46
Clinical Nutrition ESPEN 50 (2022) 41e48
Fig. 4. Blood total ketone bodies level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
Fig. 5. Blood vitamin B6 level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
of PPN administration. Moreover, none of the participants required
discontinuation of the test or control solution administration. These
data suggest the safety of OPF-105, at least in the setting of this
phase I trial.
The most interesting findings in this trial may be the kinetics of
BUN (Step 4) and blood total ketone bodies (Step 1e4) levels. An
increase in BUN levels generally reflects the breakdown of body
proteins or overdosing of amino acids and proteins [7]. The present
trial did not allow participants to consume extra food except for
the PPN solution, which only delivered 1240 kcal/day in the OPF4
group and 840 kcal/day in the BFI4 group. Thus, neither of the PPNs
fully met the energy requirements of the participants. However,
the presence of fat emulsion in the OPF formula increased energy
delivery and blunted marked increase in BUN levels in Step 4,
suggesting prevention of body protein breakdown, as compared to
those by the BFI formula. Because nutrition therapy solely with
K. Fukatsu, R. Shineha, S. Katayose et al.
Fig. 6. Blood folic acid level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
Fig. 7. Blood vitamin C level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
PPN cannot fulfill the demand for energy in patients, long-term
parenteral nutrition (PN) therapy needs central venous access.
However, modern nutrition therapy guidelines recommend PPN
for relatively short-period nutritional management [1e3]. Various
conditions increase metabolism and catabolism, resulting in body
protein loss. Therefore, OPF-105 containing fat emulsion may be
expected to reduce protein loss, thereby possibly maintaining
muscle mass and supporting early recovery from diseases and
injuries. Total blood ketone body levels are increased during
starvation. Step 1e3 studies only gave 310e1240 kcal/day, which
did not meet the energy requirements of the participants. Conse-
quently, an increase in the total blood ketone body levels appears
to be reasonable [8]. OPF-105 administration blunted the increase
compared to that by BFI, possibly reflecting the prevention of body
fat breakdown.
47
Clinical Nutrition ESPEN 50 (2022) 41e48
Fig. 8. Blood vitamin K level (Step 4).
Data are means ± SD.
* p < 0.05 versus BFI4 at each time point.
Taken together, the addition of fat emulsion to PPN has advan-
tages over conventional BFI formula in terms of maintenance of
body muscle and fat during the short course of PN therapy.
Blood levels of fat-associated parameters (TG, VLDL-TG, PL,
linoleic acid, and a-linolenic acid) showed a temporal increase but
returned to baseline levels in the OPF group. Thus, OPF-105
administration likely does not cause hyperlipidemia in the clinical
setting. With regard to blood NEFA levels, OPF-105 appeared to
delay the increase after administration, compared to that by BFI.
OPF-105 may reduce breakdown of body fats.
The benefits of the new PPN formula were also demonstrated in
the time course of blood vitamin levels. Vitamin B6, folic acid, and K
levels were near the lower limits of the normal ranges in the BFI
group throughout the study period (Step 1e4), while those in the
OPF group were preserved within the normal ranges after the
temporal spike increase (Step 4). As BFI also contains vitamin B1,
the benefit of OPF-105 was not clear in terms of vitamin B1 kinetics
regardless of the increased vitamin B1 dose. The participants in the
current study were healthy and had no significant insults. Vitamin
B1 demand in patients with severe diseases or injuries reportedly
increases [9]. Increased vitamin B1 content in OPF-105 may help in
metabolism in such patients. Blood vitamin C levels appeared to be
maintained within the normal range in the OPF group but remained
near the lower limit in the BFI group in the Step 4 study. These
findings might support the usefulness of OPF-105, particularly in
patients with marked stress, because such patients generally need
more vitamin C to overcome increased oxidative stress [10].
When we consider the advantages of OPF-105 in terms of
preparation for clinical use, prevention of pathogen and foreign
material contamination is expected. Administration of fat emulsion
through the side port of the infusion line may cause bacterial
contamination. Mixing vitamins from glass ampules to the solution
bag may cause glass piece contamination. Moreover, OPF-105 does
not require such manipulations and reduces the burden on medical
staff. OPF-105 may prevent metabolic disorders related to the rapid
administration of fat emulsion because fat emulsion is supplied
continuously and slowly with other constituents.
Although the present study is phase I, we have already
completed an unpublished phase III trial and obtained similar
benefits in patients undergoing gastrointestinal tract surgery.
K. Fukatsu, R. Shineha, S. Katayose et al.
In conclusion, the newly developed PPN solution, OPF-105, may
be used safely with advantages in nutritional management over a
relatively short period.
5. Conclusions
OPF-105 is a novel PPN formulation in which fat emulsion and
water-soluble/fat-soluble vitamins are contained in a double bag in
addition to dextrose, electrolyte, and amino acid solutions. OPF-105
can be safely administered via PVCs placed in peripheral vessels at
2200 mL/day. It is expected that the catabolism of body proteins is
suppressed by supplying fat as an energy source. It also leads to the
reduction of various risks associated with lateral injection of fat
emulsion, can administer all necessary vitamins, and is expected to
be useful in clinical use.
Funding statement
This trial was planned at Otsuka Pharmaceutical Factory, Inc.,
which is also a trial sponsor.
Author contributions
Kazuhiko Fukatsu: Conceptualization, Writing - Original Draft,
Writing - Review and Editing, Supervision.
Ryuzaburo Shineha: Conceptualization, Writing - Review and
Editing, Supervision.
Mitsuo Nakayama: Conceptualization, Methodology, Writing -
Review and Editing, Project administration.
Yoshiyuki Kawauchi: Conceptualization, Methodology, Writing -
Review and Editing, Project administration.
Satoshi Katayose: Conceptualization, Methodology, Writing -
Review and Editing, Project administration.
Declaration of competing interest
Kazuhiko Fukatsu and Ryuzaburo Shineha received payments
from Otsuka Pharmaceutical Factory, Inc., for conducting this trial
and writing the manuscript. Mitsuo Nakayama, Yoshiyuki Kawau-
chi, and Satoshi Katayose are employees of the Otsuka Pharma-
ceutical Factory, Inc.
Acknowledgements
The principal investigator (trial site) of this trial was Masako Aso
(Bio-Iatoric Center, Research Center for Clinical Pharmacology,
48
Clinical Nutrition ESPEN 50 (2022) 41e48
Kitasato University, currently known as Kitasato University, Kita-
sato Institute Hospital).
Employees of Otsuka Pharmaceutical Factory, Inc., contributing
to this trial and/or manuscript preparation, are as follows:
Susumu Aoki and Asumi Kubo contributed to the concept and
design, data interpretation. Daisuke Harada contributed to the
concept and design, data interpretation, writing assistance, and
reviewing the manuscript. Tatsukuni Kawakami contributed to data
acquisition. Yoshihiro Kume and Koji Mochinaga contributed to
data management. Yoshikazu Kawarabayashi and Motoki Oe
contributed to the concept and design, data interpretation, and data
analysis. Shigehiro Yoneda contributed to data analysis. Ayaka
Konishi contributed to writing assistance and manuscript review.
EPS Corporation prepared participant allocation tables and
supported data acquisition, management, and analysis. Honyaku
Center Inc. (Tokyo, Japan) contributed to the proofreading of the
manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnesp.2022.05.001.
References
[1] Japanese Society for Parenteral and Enteral Nutrition. Types and selection of
nutritional therapy. In: Guidelines on parenteral and enteral nutrition. 3rd ed.
Tokyo: Shorinsha; 2013. p. 13e23 [in Japanese].
[2] A.S.P.E.N Board of Directors and the Clinical Guidelines Task Force. Guidelines
for the use of parenteral and enteral nutrition in adult and pediatric patients.
JPEN - J Parenter Enter Nutr 2002;26(1 Suppl):1SAe138SA.
[3] Braga M, Ljungqvist O, Soeters P, Fearon K, Weimann A, Bozzetti F. ESPEN
guidelines on parenteral nutrition: surgery. Clin Nutr 2009;28(4):378e86.
[4] Food and Drug Administration. Parenteral multivitamin products; drugs for
human use; drug efficacy study implementation; amendment. Fed Regist
2000;65(77):21200e1.
[5] Department of Foods and Nutrition, American Medical Association. Guidelines
for multivitamin preparations for parenteral use. Chicago: American Medical
Association; 1975.
[6] Shineha R, Tsuchiya T, Yamasaki S, Yabata E, Goseki N, Nishi Y, et al.
Comparative phase III trial of AFV-03, an intravenous glucose, electrolytes,
amino acids solution containing vitamin B1; Multicenter trial in patients after
gastrointestinal surgery. J New Rem & Clin. 2006;55(3):305e38 [in Japanese].
[7] Yamashita Y, Kagawa Y, Takashima I, Ohtagaki S, Toge T. Non-protein calories
to nitrogen ratio (NPC/N ratio) in parenteral nutrition. Jpn J Surg Metab Nutr
2003;37(2):149e55 [in Japanese with English abstract].
[8] Cahill GF, Aoki TT. Starvation and body nitrogen. Trans Am Clin Climatol Assoc
1971;82:43e51.
[9] Frank LL. Thiamin in clinical practice. JPEN - J Parenter Enter Nutr 2015;39(5):
503e20.
[10] Spoelstra-de Man AME, Elbers PWG, Oudemans-Van Straaten HM. Vitamin C:
should we supplement. Curr Opin Crit Care 2018;24(4):248e55.