key: cord-0299869-dfjsf2ni
authors: Kankam, M.; Handley, S.; Galloway, C.; Clarke, D.
title: Evaluation of Trans-Sodium Crocetinate (TSC) on Peripheral Oxygenation in Healthy Individuals Using Transcutaneous Oximetry
date: 2022-01-17
journal: nan
DOI: 10.1101/2022.01.16.22269147
sha: 49697cf319a37c025281b5ee066e9fdbaf575a44
doc_id: 299869
cord_uid: dfjsf2ni

Introduction Trans sodium crocetinate (TSC) is a synthetic carotenoid with a unique mechanism of action that improves the diffusion of oxygen by reducing oxygen transfer resistance within plasma, and it is currently being developed to enhance oxygen delivery to hypoxic tissues in multiple conditions. The goals of this study were to evaluate safety, pharmacokinetics, and pharmacodynamic properties of escalating doses of TSC on peripheral oxygenation utilizing transcutaneous oxygen measurements, when administered to healthy subjects breathing supplemental oxygen. Methods This was a dose-escalation, single-center, randomized, phase 1 study aimed at assessing the safety, pharmacokinetic and pharmacodynamic properties of TSC at doses of 0.5, 1.0, 1.5, 2.0, or 2.5 mg/kg as an intravenous bolus. Thirty healthy adult subjects of 18 to 55 years of age were enrolled and allocated to one of the five dose groups or placebo. Venous blood samples were collected for pharmacokinetic evaluations of TSC at 1, 10, 30 minutes, and 1.5 hours after the start of injection of the study drug. Pharmacodynamic assessment of tissue oxygenation was performed while the subjects breathed supplemental oxygen at 6 L/minute for 70 minutes prior to study drug administration: the first 10 minutes was to allow for equilibration, and the subsequent 60 minutes served as a baseline period (Period 1), followed by a time-matched 60-minute intervention period (Period 2). Tissue oxygenation readings were obtained by transcutaneous oximetry (TcpO2) measurement using four TcpO2 sensors placed on the lower limbs of subjects lying in a supine or semi-recumbent position. TcpO2 values were recorded over a 2-hour time period: 60 minutes prior to study drug administration (Period 1) and 60 minutes post administration of the study drug (Period 2). Results TSC was safe and well tolerated at all doses tested. The pharmacokinetic analyses demonstrated that clearance decreased at escalating doses of TSC. The results of the primary pharmacodynamic analysis revealed high levels of variability in the 60-minute baseline TcpO2 levels, however despite such variability, time-matched TcpO2 measurements demonstrated observed increases in median TcpO2 values in subjects who received TSC, relative to those who received a placebo. The high variability observed across the four sensors suggested that the data could not be pooled across all four sensors, therefore, additional supplemental analyses were performed. The results of the supplemental analyses indicated that the TcpO2 intra-subject slopes of the TSC treatment groups were consistently positive during the study intervention period, and therefore suggestive of an increase in TcpO2 levels. This was not observed in the placebo group. Based on this analysis, all TSC dose groups had a greater increase in TcpO2 levels than the placebo group, with the 2.5 mg/kg dose demonstrating the most notable increase over the 1-hour intervention period (Period 2). Conclusions TSC administered as a single IV bolus dose ranging from 0.5 mg/kg to 2.5 mg/kg to healthy subjects breathing supplemental oxygen, was safe and well tolerated. Pharmacokinetic assessments demonstrated that TSC plasma concentrations increased with escalating dose and that increasing TSC dose was associated with a decrease in clearance. The high levels of variability in TcpO2 levels did not allow for pooling of sensor measurements for primary analysis; however, supplemental analysis of individual sensor measurements demonstrated an observed dose effect of TSC on peripheral tissue oxygenation relative to placebo.

Trans sodium crocetinate (TSC) is a synthetic carotenoid with a unique mechanism of action that improves the diffusion of oxygen by reducing oxygen transfer resistance within plasma, and it is currently being developed to enhance oxygen delivery to hypoxic tissues in multiple conditions. The goals of this study were to evaluate safety, pharmacokinetics, and pharmacodynamic properties of escalating doses of TSC on peripheral oxygenation utilizing transcutaneous oxygen measurements, when administered to healthy subjects breathing supplemental oxygen.

This was a dose-escalation, single-center, randomized, phase 1 study aimed at assessing the safety, pharmacokinetic and pharmacodynamic properties of TSC at doses of 0.5, 1.0, 1.5, 2.0, or 2.5 mg/kg as an intravenous bolus. Thirty healthy adult subjects of 18 to 55 years of age were enrolled and allocated to one of the five dose groups or placebo. Venous blood samples were collected for pharmacokinetic evaluations of TSC at 1, 10, 30 minutes, and 1.5 hours after the start of injection of the study drug. Pharmacodynamic assessment of tissue oxygenation was performed while the subjects breathed supplemental oxygen at 6 L/minute for 70 minutes prior to study drug administration: the first 10 minutes was to allow for equilibration, and the subsequent 60 minutes served as a baseline period (Period 1), followed by a time-matched 60-minute intervention period (Period 2). Tissue oxygenation readings were obtained by transcutaneous oximetry (TcpO 2 ) measurement using four TcpO 2 sensors placed on the lower limbs of subjects lying in a supine or semi-recumbent position. TcpO 2 values were recorded over a 2-hour time period: 60 minutes prior to study drug administration (Period 1) and 60 minutes post administration of the study drug (Period 2).

TSC was safe and well tolerated at all doses tested. The pharmacokinetic analyses demonstrated that clearance decreased at escalating doses of TSC. The results of the primary pharmacodynamic analysis revealed high levels of variability in the 60-minute baseline TcpO 2 levels, however despite such variability, time-matched TcpO 2 measurements demonstrated observed increases in median TcpO 2 values in subjects who received TSC, relative to those who received a placebo. The high variability observed across the four sensors suggested that the data could not be pooled across all four sensors, therefore, additional supplemental analyses were performed. The results of the supplemental analyses indicated that the TcpO 2 intra-subject slopes of the TSC treatment groups were consistently positive during the study intervention period, and therefore suggestive of an increase in TcpO 2 levels. This was not observed in the placebo group.

Based on this analysis, all TSC dose groups had a greater increase in TcpO 2 levels than the placebo group, with the 2.5 mg/kg dose demonstrating the most notable increase over the 1-hour intervention period (Period 2).

Conclusions TSC administered as a single IV bolus dose ranging from 0.5 mg/kg to 2.5 mg/kg to healthy subjects breathing supplemental oxygen, was safe and well tolerated. Pharmacokinetic assessments demonstrated that TSC plasma concentrations increased with escalating dose and that increasing TSC dose was associated with a decrease in clearance. The high levels of variability in TcpO 2 levels did not allow for pooling of sensor measurements for primary . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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Oxygen is essential in mammals for aerobic metabolism and therefore the proper delivery of oxygen to tissues is vital (1) . Delivery of oxygen to tissues is dependent on both convection and diffusion. Convective delivery of oxygen is primarily driven by cardiac output and arterial oxygen content, while the diffusive transport occurs at the microcirculatory level and is dependent on Fick's Law of diffusion, therefore representing a rate limiting step (2) . Gainer et al. demonstrated that crocetin, a natural carotenoid compound, was able to increase the diffusion of oxygen through plasma (3, 4) .

When local, regional, or generalized oxygen delivery to tissues is either inadequate or disrupted, cells become hypoxic; if not reversed, hypoxia can rapidly lead to tissue damage and cell death (1) . Stroke, myocardial infarction, COVID-19 are just some examples of conditions complicated by hypoxia, for which hypoxia directly contributes to short-and long-term morbidity and mortality. In addition, hypoxia can often complicate many sub-acute conditions, such as with many cancers (6) . Hypoxia is present in nearly all solid tumors and has been shown to contribute to resistance to radiotherapy, chemotherapy, and immunotherapy, as well as increase the potential for tumor invasion and metastasis (5) .

Diffusion Pharmaceuticals has developed trans sodium crocetinate (TSC), a fully synthetic transisomer salt of crocetin that has demonstrated the ability to increase the diffusion of oxygen by transiently increasing hydrogen bonds between water molecules within the plasma component of blood (4) . This enhances the organizational matrix within plasma, which facilitates the passive diffusion of oxygen from high to low concentration areas with less resistance (6, 7) .

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The copyright holder for this preprint this version posted January 17, 2022. ; https://doi.org/10.1101/2022.01. 16.22269147 doi: medRxiv preprint In-vitro studies have shown that TSC increases oxygen diffusion in water by up to 30% (8, 9) .

Following these in-vitro experiments, in-vivo studies were performed to assess the potential of TSC as a therapeutic intervention in animal models of hypoxia. Several studies were performed in various ischemic animal models where TSC was administered following ischemic shock, and these studies demonstrated significant improvement in survival rates of rats recovering from post ischemic shock (12-15). TSC was also shown to enhance radiosensitivity in a glioblastoma multiforme (GBM) model in rats (16) , and to improve survival in a rat model of hypoxemia (17) .

The safety and tolerability of TSC was first clinically evaluated in a placebo-controlled Phase 1 study enrolling 40 normal healthy subjects (15) . The results of this study demonstrated that TSC was safe and well tolerated with a maximum tolerated dose of 2.5 mg/kg. Safety, tolerability, and dose response were also evaluated in a placebo-controlled Phase 1/2 study of 48 patients with symptomatic peripheral artery disease (PAD) with claudication (16, 17) . Multiple doses of TSC were demonstrated to be safe and well tolerated, with improved scores observed at higher doses in a test of peak walking time and in-patient perceived walking distance. TSC has been evaluated for safety and dose tolerance in a placebo-controlled Phase 1/2 study of 59 patients with newly diagnosed GBM who also received chemotherapy and radiation therapy standard of care (18) .

The results of this study also demonstrated that TSC was safe and well tolerated. In 2020-2021, TSC was evaluated in a Phase 1/2 study of 24 patients with confirmed SARS-CoV-2 infection and hypoxemia who required hospitalization. The results of this study demonstrated that administration of TSC every six hours for up to 15 days was safe and well tolerated with clinical benefit observed on the WHO Ordinal Scale for Clinical Improvement and length of stay in the treatment of COVID-19-related hypoxemia at the highest doses tested in the trial (19) .

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The copyright holder for this preprint this version posted January 17, 2022. ; https://doi.org/10.1101/2022.01. 16.22269147 doi: medRxiv preprint Along with safety, the objectives of this study were to evaluate pharmacokinetic and pharmacodynamic responses after administration of TSC or placebo in a randomized and blinded trial in the peripheral tissues of healthy subjects breathing supplemental oxygen, as measured by transcutaneous oximetry (TcpO 2 ). Transcutaneous oximetry is a non-invasive test which measures the partial pressure of oxygen diffusing through the skin and provides insight into local tissue oxygenation (20) . The intent was to further characterize the objective dose-response relationship of TSC and tissue oxygenation to provide data for further studies.

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This was a single center randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of TSC in 30 subjects. Healthy, non-smoking male and non-pregnant female volunteers aged 18 to 55 years with a body mass index ranging from 18.0 to 30.0 kg/m 2 and a minimum body weight of 50.0 kg were eligible for study inclusion. A screening visit occurred within 21 days of drug administration. Health status was determined by medical history, physical examination, oxygen saturation, electrocardiogram, laboratory tests and urine drug screen. A negative serum pregnancy test was required for women. Subjects were instructed to refrain from exercise, caffeine, alcohol, and a heavy meal prior to study drug administration. On the treatment day, the inclusion and exclusion criteria were reassessed and a pregnancy test, drug screen, and alcohol screen were performed. Mean (±SD) age was 33 (±9) years ( Table 1 ). The subject population included non-smokers, different ethnicities, and a balanced ratio of males and females. One subject in the 2.5 mg/kg dose cohort experienced inadvertent subcutaneous infiltration of TSC due to IV cannula migration and was excluded from the analysis. Study results reflect the pharmacokinetic and pharmacodynamic analyses of 24 and 29 subjects, respectively.

The study was conducted in a temperature-controlled room (22.0-25.0˚C). Subjects maintained a supine or semi-recumbent position and were asked to lie quietly and minimize body movement for the entire study procedure.

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The copyright holder for this preprint this version posted January 17, 2022. Period 2 transcutaneous oximetry readings included observations at 1-, 3-, and 5-minute intervals after TSC dosing, then every 5 minutes thereafter. Vital signs (heart rate, blood pressure, respiratory rate) were measured at clinic arrival, baseline, and at 10, 30, and 60-minutes post study drug dosing. Subjects were monitored for adverse events for the study duration, remaining in the research unit overnight, and were contacted by telephone 48 hours after injection of study drug or placebo to assess adverse events and any new medication use.

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Venous blood samples were drawn within 10 minutes before study drug injection and at 1, 10, 30 minutes (±1 minute), and 90 (± 2) minutes after the injection to determine the concentration of TSC.

Plasma was assayed for TSC using a validated liquid-chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Sample pre-treatment involved a protein precipitation extraction procedure. The LC-MS/MS method utilized electrospray ionization in the negative ionization mode, with prednisone as an internal standard. The lower limit of quantitation (LLOQ) was 10 ng/mL. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 1 matched differences between values obtained during Period 1 and Period 2 represented the least biased estimate of the effect of the study drug versus placebo.

The raw data recordings of the individual TcpO 2 sensor measurements demonstrated high variability among sensors, suggesting that the data should not be pooled across all four sensors.

Therefore, a supplementary pharmacodynamic analysis on the intra-subject slopes from each period and sensor was performed. For Period 1, on an intra-subject basis, the median value from each of the 12 intervals was used to construct the slope using orthogonal spacing with respect to time. For Period 2, the slope was constructed using the median value from each of the 13 intervals-of note, Period 2 observations included 1-and 2-minute values-in addition to the 5minute measurements for comparison to the 12 corresponding intervals of Period 1. An additional set of analyses were conducted using the Period 2 intra-subject slopes as the dependent variable. The active dose groups were pooled and the least square means were compared to placebo. This procedure was repeated iteratively, each time removing the next lowest dose group to determine the separation of each cohort's least square means relative to placebo.

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For 19 of the 24 subjects included in the analysis, TSC concentration in the 1-minute sample was smaller (often many-fold) compared to the 10-minute sample (Figure 1 Table 2 . The concentration profile for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The high range of variability observed in the 60-minute baseline portion (Period 1) among the four sensors suggested that the data was not able to be pooled across all four sensors. Therefore, additional supplemental analyses were performed as described in the Methods section. The supplemental analyses demonstrated that the subjects of the TSC groups had consistently positive intra-subject slopes across multiple sensors observed during Period 2 that were not observed for the placebo group (Table 3 ). In addition, pooling the TSC groups and comparing their least square means to those of the placebo arm within Period 2 revealed a significant separation across all four sensors (Tables 4-7) . The greatest least square mean difference occurred with 2.5 mg/kg dose versus to placebo.

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The copyright holder for this preprint this version posted January 17, 2022. ; https://doi.org/10.1101/2022.01.16.22269147 doi: medRxiv preprint Differences were observed in sensor 1 which had a greater number of positive intra-subject slopes and increased least square means compared to the other three sensors (Tables 3 and 4 ).

However, the results of sensor 1 were similar to those of the other sensors, in which the TSC treated groups displayed increases in TcpO 2 slopes which were not observed in the placebo group. Furthermore, sensor 1 was the most distal sensor in all subjects (placed on the middorsum of the foot) which may in part explain the larger observed change in the TcpO 2 levels at this sensor's anatomic location. Augmentation in peripheral oxygenation would potentially be most notable when starting from a lower baseline level of tissue oxygenation which can occur in the most distal parts of the body, and it is conceivable that more significant increases in TcpO 2 values would be observed in patient populations who are hypoxic at baseline.

Overall, the supplemental analysis was suggestive of an effect across all sensors in which the TSC groups had a greater increase in TcpO 2 than placebo. Of note, the 2.5 mg/kg dose resulted in the greatest difference from placebo over the 1-hour treatment period (Period 2). There was no correction for multiplicity across the analyses, given the probability values were calculated for informational purposes.

TSC was safe and well tolerated, with a total of nine treatment-emergent adverse events reported overall among seven of the 30 subjects (23.3%). Of the nine treatment-emergent adverse events experienced by five subjects (16.7%), five were determined to be drug-related and all were deemed mild in intensity. The most frequent treatment-emergent adverse event was post procedural erythema experienced by two subjects; others included transient chromaturia (a known effect of TSC), post procedural pruritus, headache, taste disorder, injection site pain, and . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 17, 2022. ; 1 5 injection site streaking. No subjects experienced a serious adverse event or withdrew from the study for any reason.

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This study was designed to evaluate the dose-response effect of escalating doses of TSC on peripheral tissue oxygenation, evaluated using transcutaneous oximetry measurements in healthy subjects breathing supplemental oxygen. Overall, TSC administered as a single IV bolus dose ranging from 0.5 mg/kg to 2.5 mg/kg to healthy subjects breathing supplemental oxygen at 6 L/min was safe and well tolerated. TSC demonstrated decreasing drug clearance with increasing doses which is consistent with previous clinical studies (19) . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 17, 2022. ; 1 7 calculations demonstrated consistent positive increases in TcpO 2 readings across multiple individual sensors in Period 2 for all TSC groups when compared to the placebo group. The greatest TcpO 2 difference was observed when the 2.5 mg/kg TSC group was compared to the placebo group, suggesting that the effect of TSC is greatest at higher doses. The safety profile of TSC in this study is consistent with previous clinical experience as well as the pharmacokinetic profile between clearance and intravenous dosing of TSC.

In conclusion, TSC is a safe and novel oxygenation enhancing compound that has the potential to be a valuable adjunct to standards of care across a wide range of acute and chronic conditions complicated by hypoxia, agnostic of causation, where improving oxygen delivery is pivotal to improving patient outcomes.

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The study was conducted according to the principles of good clinical practice (GCP), along with the Declaration of Helsinki (1996) , and in accordance with local regulations and the International Conference on Harmonization (ICH) guidelines. All study-related documents were approved by an independent institutional review board (IRB; MidLands Independent Review Board, Overland Park, Kansas). Written informed consent was obtained from all study subjects at screening prior to initiation of any study related procedures.

We thank the study participants, the investigational team, laboratories, and reviewers; and our CRO partner Altasciences and their medical writing team.

Chris Galloway, MD, is the Chief Medical Officer at Diffusion Pharmaceuticals Inc.

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The copyright holder for this preprint this version posted January 17, 2022. ; https://doi.org/10.1101/2022.01.16.22269147 doi: medRxiv preprint The subtraction of the placebo TcpO 2 levels from the TSC treated groups in Period 2 illustrates an increase in TcpO 2 values post TSC administration relative to placebo in the higher TSC dose groups (≥2mg/kg). For Period 2, the median value was used from each of the 13 intervals of 1, 3and 5-minute duration.

-0. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 17, 2022. ; 2 6 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 17, 2022. Abbreviations: Max = maximum; Min = minimum. SD = standard deviation Thirty subjects were included in this study with a mean age of 33 and included non-smokers, distinct ethnicities/race, and a balanced ratio of males and females.

.

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The copyright holder for this preprint this version posted January 17, 2022. In all sensors TSC treated subjects display positive slopes which is not the case in the placebo treated subjects (with the exception of one subject in sensor 1). Sensor 1 differed from the others with respect to the number of subjects that had a significant slope during Period 2, independent of the treatment assignment. One subject (assigned 2.5 mg/kg) received an inadvertent subcutaneous injection of TSC due to IV cannula malposition and was excluded from both the Pharmacokinetic and Pharmacodynamic analysis. As a result, the pharmacodynamic analyses included 29 subjects.

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The copyright holder for this preprint this version posted January 17, 2022. Differences between the least square means of the placebo group and the TSC dose groups reveal that TSC groups have a greater trajectory than the placebo group. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 17, 2022. Differences between the least square means of the placebo group and the TSC dose groups reveal that TSC groups have a greater trajectory than the placebo group. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 17, 2022. ; https://doi.org/10.1101/2022.01.16.22269147 doi: medRxiv preprint Differences between the least square means of the placebo group and the TSC dose groups reveals that TSC groups have a greater trajectory than the placebo group. These differences are significant (p value ≤ 0.05) in all groups.

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