IV sodium chlorite in COVID-19 1

PHASE II STUDY: EVALUATING THE EFFICACY AND SAFETY FOR IV

SODIUM CHLORITE IN COVID-19 RESPIRATORY FAILURE

1. RATIONALE FOR THE STUDY

In the context of the COVID-19 pandemic, there is a global emergency situation and a great need to
support patients with severe Acute Respiratory Distress Syndrome (ARDS). There is a real danger
of having the medical system overwhelmed. This is a grave and exceptional situation.

The possible role of Sodium Chlorite:

According to the European Medicines Agency, sodium chlorite, when given by injection into a vein,
modulates the function of macrophages and can reduce their production of cytokines.1 In
COVID-19 induced ARDS, high levels of circulating cytokines can lead to multi-organ failure. As a
consequence of its immunomodulatory activity, sodium chlorite could help reduce the mortality in
advanced cases of COVID-19 pneumonia. 2

- In 2007, the FAO/WHO established the acceptable daily intake (ADI) for oral acidified sodium
chlorite to be 0 - 0,03 mg/kg bw 3

- Neuraltus Pharmaceuticals conducted in 2016-18 a multicenter phase II trial in the United States
on safety and efficacy of IV sodium chlorite (NP001, a pH-adjusted IV formulation of purified
sodium chlorite) in patients with ALS (amyotrophic lateral sclerosis) and systemic inflammation.
The trial included 138 participants. The treatment group received sodium chlorite at the dose of 2
mg/kg by IV administration for 5 consecutive days in month 1 and for 3 consecutive days in
months 2 through 6. The expected efficacy was not proved, but no adverse side effects were
reported. Massachusetts General Hospital, Mayo Clinic and Columbia University were among
the 22 recruiting medical centers.4 In 2015, Miller et al. had already published the results of a
phase 2 randomized, double-blind, placebo-controlled trial of sodium chlorite (NP001) in 136
patients with ALS. Participants received NP001 2mg/kg, NP001 1mg/kg, or placebo for 6
months. Only adverse effect that was statistically significant between the treatment group and the
placebo group was infusion site pain. The study provided Class I evidence that for patients with
ALS, sodium chlorite is safe. 5

1European Medicines Agency (EMA). Sodium chlorite for the treatment of amyotrophic lateral sclerosis.
EMA/COMP/317798/2013 Corr. approval of sodium chlorite — also called NP001 — as orphan medication.
September 9, 2013.
2 Kühne, L. Regulierung humaner Natürlicher Killer Zellen durch den redox-aktiven Immunmodulator WF10
(2011). Doctoral dissertation, Heidelberg University.

3 68th Joint FAO/WHO Expert Comittee on Food Additives (68th JECFA).

4 US National Library of Medicine, clinicaltrials.gov (identificator of the study NCT02794857).

5 Miller RG, Block G, Katz JS, Barohn RJ, Gopalakrishnan V, Cudkowicz M, Zhang JR, McGrath MS,
Ludington E, Appel SH, Azhir A. Randomized phase 2 trial of NP001, a novel immune regulator. Safety and
efficacy in ALS. Neurol Neuroimmunol Neuroinflamm, 2015 (American Academy of Neurology).
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 IV sodium chlorite in COVID-19 2
In summary, safety of intravenous (IV) administration of sodium chlorit in humans has been
established and published results of multicenter phase II trial of sodium chlorite in patients with
ALS indicate that there were no adverse events observed (ref. 5).

Tetrachlorodecaoxide (TCDO) as chemical equivalent of Sodium Chlorite:

In 1989, Habermann and Müller demonstrated that tetrachlorodecaoxide (TCDO) is a chemical

equivalent for sodium chlorite. 6 Patented names of TCDO are WF10®, Oxoferin®, Immunokine®,
Makrokine®.

- WF 10 is a 1:10 dilution of TCDO formulated for IV delivery. It was developed by Oxo Chemie
in Switzerland as an adjunctive therapy to combination antiretroviral and opportunistic infection
prophylaxis regimens in AIDS patients. WF 10 specifically targets macrophages. Oxo completed
a trial in 72 cervical cancer patients undergoing radiation therapy in 1989. Results from this trial
demonstrated complete remission in 75% of patients receiving WF 10. A follow-up placebo
controlled trial in 1996 produced similar results. WF 10 received regulatory approval in Thailand
for postradiation cystitis following a trial completed in 1998 in 20 patients following radiation
treatment for cervical carcinoma. Oxo Chemie completed a controlled randomised, crossover
study in France in 1991 that examined the effects of 103 patients with acute radiation dermatitis
and radiation- or chemotherapy-induced mucositis. Results demonstrated that WF 10
significantly improved lesions and accelerated recovery without side effects. Patent claims cover
potential treatment for autoimmune disease, organ transplant or graft rejection, lymphoma and
inflammation manifested as hepatitis or chronic obstructive pulmonary disease. 7

- Topical TCDO in a less concentrated formulation (1:55) is marketed as Oxoferin for wound
healing. WF 10 is approved for use in Thailand under the name IMMUNOKINE in patients with
postradiation chronic inflammatory disease including cystitis, proctitis and mucositis. 8

- In 2016, Wabnitz and Samstag from the University of Heidelberg 9 , demonstrated that WF10
inhibits CTL-mediated (CTLs are human cytotoxic T-cells) target cell killing in a dose-
dependent manner, 10 providing a potential explanation of why graft survival in a concordant
xenograft model was significantly prolonged in the presence of WF10, 11 and why WF10
improves the clinical outcome of diabetic foot ulcer. 12

6 Habermann E, Müller B. Oxoferin® und Natriumchlorit- Ein Vergleich. Klin Wochenschr (1989) 67:20 25 .

7 Drugs R D. 2004;5(4):242-4.
8 Drugs R D. 2004;5(4):242-4.

9Wabnitz GH, Samstag Y. Oxidative downmodulation of T cell-mediated cytotoxicity. Cell Death and
Disease (2016) 7, e2373; doi:10.1038/cddis.2016.273; published online 22 September 2016.

10 Wabnitz GH et al. Cell Death Discov 2016(2), 16057.

11 Kemp K et al. Pharmacol Toxicol 2002; 90: 346–348.

12 Yingsakmongkol N et al. J Foot Ankle Surg 2011; 50: 635–640.

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 IV sodium chlorite in COVID-19 3
Figure 1 (Wabnitz and Samstag, 2016) Cellular and molecular regulation of serial killing and its
inhibition by WF10. (a) Cellular level. Cytotoxic T cells (CTLs) migrate as solitaire cells during the
immune surveillance into inflammed tissues in order to find target cells. After encountering a target
cells, CTLs firmly adhere to these cells and induce their apoptosis (first kill, upper row). To kill a
second target cell, CTLs need to detach from the dying target cell and attach to a second target cell,
perform the second kill and so on. One CTL can kill more than 6 target cells in a row. WF10
interferes with detachment of the CTL from their initial target cell (lower row). This leads to a strong
decrease in the killing frequency of CTLs. (b) Molecular level. The attachment/detachment cycle
during serial killing is dependent on an LFA-1 avidity up- and down regulation circle (upper row).
The molecular motor regulating the LFA-1 avidity is the actin bundling protein L-plastin (LPL). L-
plastin is transiently phosphorylated upon target cell encounter. Only the dephosphorylation of L-
plastin enables the downregulation of LFA-1 avidity and the detachment of CTLs from the target cell.
WF10 shifts the balance toward phosphorylated L-plastin by an as yet unknown mechanism and,
thereby, prevents serial killing (lower row)

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 IV sodium chlorite in COVID-19 4
2. AIM OF THE STUDY

Primary objective: To evaluate the efficacy of IV sodium chlorite in patients with COVID-19 who
need mechanical assisted ventilation.

Secondary objective: To evaluate the safety of IV sodium chlorite in patients with COVID-19 who
need mechanical assisted ventilation.

3. STUDY DESIGN

Randomized double blind placebo-controlled phase II clinical study.

Primary Endpoint:

1. Overall survival rate in patients with COVID-19 who are on mechanical assisted ventilation.

Secondary Endpoint:

1. To evaluate adverse events related to study treatment intervention IV sodium chlorite in

patients with COVID-19 who need mechanical assisted ventilation.

Randomization: Eligible COVID-19 patients with mechanical assisted ventilation will be

randomized to either the study intervention group or to the placebo group.

Sample size: 116 patients with 1:1 randomization

Statistical considerations for sample size:

Our study hypothesis is that survival is increased by 50 % with the intervention. Current data in
Spain indicate approximately 50% mortality in COVID-19 patients who require mechanical
assisted ventilation With two independent study groups (intervention vs. placebo) and a
dichotomous primary endpoint (dead / not dead) and assuming a 50% survival for the placebo and a
75% survival for the intervention group, we would need a total of 116 patients to prove the
hypothesis that survival is increased by 50 % with the study intervention.

4. EFFICACY EVALUATIONS

30 days-survival: Overall survival status on Day 30.

Time to death: Number of days from day 1 of study intervention.

Reason for stopping ventilatory support: Death or recovery from COVID-19 induced respiratory
failure or other (specify).

Duration (Number of days) on ventilatory support from Day 1 of the study

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Duration (Number of days) on oxygen therapy after weaning from ventilatory support

Discharged with need for oxygen therapy: yes/no

Data collection: Following data will be collected.

Age, sex, ethnicity, co-morbid conditions, concomittant medications, concomittant treatment for
COVID-19, type and date of COVID-test, laboratory parameters and radiologic data at study entry
as well as during study treatment, date for first day of mechnical assisteted ventilation, date of first
day of study treatment, dates of study treatment, doses of study treatment, reasons for stopping
study treatment, status of mortality at 5-days, 10-days, 15-days and 30-days starting from day 1 of
study treatment, Grade 3-5 (moderate, severe and life threatening) adverse events attributed to study
drug, date of death, cause of death, COVID testing results performed before study entry and any
time during the study up to 60-days from day of 1 study treatment.

5. STUDY PHASES

SCREENING (day 0) / STUDY INTERVENTION (days 1-10) / FOLLOW UP (in 1 month)

SCREENING STUDY INTERVENTION FOLLOW UP

(DAYS 1-10) VISIT
Study Days 0 1 2 … 10 days 5/10 in 1 month

Informed Consent/Assent X

Review Inclusion/Exclusion X
Criteria
Demographics/Medical History X X

Physical Examination X X X X X
Vital Signs: BP, HR, RR X X X X X
Assisted Ventilation parameters X X X X

Days on assisted ventilation X

Pregnancy Test (in childbearing X

women)
Prior/Concomitant Medications X X X X X
Clinical Laboratory Evaluation X X X

Adverse Event Assessment X X X X

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 IV sodium chlorite in COVID-19 6
6. INCLUSION/EXCLUSION CRITERIA

Inclusion criteria:

- Patients aged from 18 to 80 years.

- Established diagnosis of COVID-19 (test positive for COVID-19) or suspected diagnosis of
COVID-19 based on clinical judgement of treating physician that is supported by either typical
radiologic or laboratory findings of low lymphocytes.

- On the first or the second day of having initiated mechanical assisted ventilation.
Exclusion criteria:

- Pregnancy
- Concurrent investigational therapy for COVID-19

7. STUDY INTERVENTION (DRUG ADMINISTRATION)

The randomization will be 1:1 and doubled blinded.

Intervention Group (Arm A): 2 mg/kg/day sodium chlorite by intravenous administration for 5
consecutive days, diluted in 500cc of 0.9% normal saline and administered as a 24 h drip.

Placebo Group (Arm B): 500cc of plain 0.9% normal saline will be administered as a 24h IV drip.

On Day 5, all patients will be assessed:

- If the patient’s condition has improved to the point of not needing ventilatory support, the dose
will be 1 mg/kg/day (so reduced by half compared to doses given on days 1-5) and administered for
days 6-10 in the same way (diluted in 500cc of a 24h 0.9% saline IV drip)

- If the patient’s condition has not improved and has ongoing need of ventilatory support, the
initial dose will be continued for 5 more days

In all cases, if the condition of the patient deteriorates on days 6-10, the study treatment will be
stopped.

On Day 10, the study treatment will be terminated for all patients.

8. ADVERSE EVENT MANAGEMENT

Clinical adverse events will be monitored throughout the study. Life-threatening adverse events and
all adverse events that are notable and could involve risks to subjects will be summarized in
narrative or other format and submitted promptly to the Institutional Review Board.
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 IV sodium chlorite in COVID-19 7
An adverse event (AE) is any untoward medical occurrence in a subject who has undergone the
study intervention. The occurrence does not necessarily have to have a causal relationship with the
treatment. An AE can therefore be any unfavorable or unintended sign (including an abnormal
laboratory finding, for example), symptom, or disease temporally associated with the study
intervention, whether or not considered related to the study intervention.

All adverse events will be noted in the study records and on the case report form with a full
description including the nature, date and time of onset, determination of non-serious versus
serious, intensity (mild, moderate, severe), duration, causality, and outcome of the event.

A serious adverse event (SAE) is any adverse drug experience occurring at any dose that results in
any of the following outcomes:

• death,
• a life-threatening event (at risk of death at the time of the event),
• requires inpatient hospitalization or prolongation of existing hospitalization,
• a persistent or significant disability/incapacity, or
• a congenital anomaly/birth defect in the offspring of a subject.
Important medical events that may not result in death, be life-threatening, or require hospitalization
may be considered a serious adverse drug event when, based upon appropriate medical judgment,
they may jeopardize the subject and may require medical or surgical intervention to prevent one of
the outcomes listed in this definition.

A distinction should be drawn between serious and severe adverse events. A severe adverse event is
a major event of its type. A severe adverse event does not necessarily need to be considered
serious. For example, nausea which persists for several hours may be considered severe nausea, but
would not be a severe adverse event (SAE). On the other hand, a stroke that results in only a limited
degree of disability may be considered a mild stroke, but would be an SAE.

The relationship of each SAE to the study intervention should be characterized using one of the
following terms: definitely, probably, possibly, unlikely or unrelated.

TYPE OF UNANTICIPATED INITIAL NOTIFICATION 
 WRITTEN REPORT

PROBLEM (PHONE, EMAIL …)

Internal (on-site) SAEs
 24 hours Within 2 calendar days

Death or Life Threatening

Internal (on-site) SAEs
 7 days Within 7 business days

All other SAEs
Unanticipated Problems Related 7 days Within 7 business days
to Research

All other AEs N/A Brief Summary of important AEs

may be reported at time of
continuing review

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If an SAE has not resolved at the time of the initial report and new information arises that changes
the investigator’s assessment of the event, a follow-up report including all relevant new or
reassessed information (e.g., concomitant medication, medical history) should be submitted to the
IRB. The investigator is responsible for ensuring that all SAE are followed until either resolved or
stable.

9. ETHICAL CONSIDERATIONS

All patients are to be treated according to the best standard of care: the study treatment with sodium
chlorite will be an added intervention, not an alternative one.

All enrolled patients or their legally acceptable representative (LAR) will need to give their
informed consent.

In obtaining and documenting informed consent, the investigator should comply with the applicable
regulatory requirement(s), and should adhere to good clinical practice (GCP) and to the ethical
principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the
investigator should have the institutional review board (IRB)’s approval.

Prior to a subject’s participation in the trial, the written informed consent form should be signed and
personally dated by the subject or by the subject’s legally acceptable representative, and by the
person who conducted the informed consent discussion.

If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial

witness should be present during the entire informed consent discussion. After the written informed
consent form and any other written information to be provided to subjects, is read and explained to
the subject or the subject’s legally acceptable representative, and after the subject or the subject’s
legally acceptable representative has orally consented to the subject’s participation in the trial and,
if capable of doing so, has signed and personally dated the informed consent form, the witness
should sign and personally date the consent form. By signing the consent form, the witness attests
that the information in the consent form and any other written information was accurately explained
to, and apparently understood by, the subject or the subject’s legally acceptable representative, and
that informed consent was freely given by the subject or the subject’s legally acceptable
representative.

_____________________________

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