Clinical trial NCT04847791: Lactoferrin in Covid-19 Hospitalized Patients
Official title: Lactoferrin for Treatment of Acute COVID-19 Infection in Hospitalized Patients: a Double-blind Multicenter Placebo-controlled Randomized Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Covid19
Lead sponsor: Paolo Manzoni
Sponsor class: OTHER
First posted: 2021-04-19
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective randomized double-blind placebo- controlled designed trial
Primary purpose: TREATMENT

Brief summary: TRIAL LAC is a randomized double-blind non profit multicenter study with a nutritional product: bovine lactoferrin - Mosiac 200 mg.

the hypothesis to be confirmed is that bovine LF, administered daily orally in addition to standard therapies for 1 month to hospitalized patients with Covid-19 infection, can be useful to limit the severity, progression of the disease, shorten the time of swabs negativization (i.e. time required to eliminate the virus) and to reduce the morbidity load associated with it.

Patient recruitment will involve 2 centers in Italy: Ospedale degli Infermi (Ponderano, Biella) and AOU Maggiore della Carità (Novara).

The subjects enrolled will be randomized to two Groups:

Group A (experimental arm) - Standard Anti-Covid-19 Therapy + Oral Administration of Bovine Lactoferrin (fixed dose 800 mg / day) for 30 days Group B (control arm) - Standard anti-Covid-19 therapy + Placebo administration (identical capsule with the same amount as an inert compound, starch of corn powder), according to the same pattern of use.

It should be specified that the study treatment and placebo will be administered in addition to the standard care in place, and therefore in addition to all the pharmacological treatments currently used in clinical hospital practice against Covid-19.

Detailed description: It has been shown with 'in vitro' studies that LF is able to prevent the entry of SARS-CoV-2 into the of the host cells.

Overall, the available evidence suggests that LF may be a therapeutic option that can be used to counteract and reduce the severity of Covid 19 infection. The study hase been designed in order to demonstrate efficacy of Lactoferrin in vivo.

Patients who will be admitted by Participating Centers for Covid-19 Infection will be screened for eligibility for study . If considered eligible, they will be offered participation in the Study, and it will be proposed and informed consent will be explained. Eligible patients will be registered in a centralized database at the IT systems of the University of Piedmont Orientale (UPO)/Hospital-University Company "Maggiore della Carità" of Novara. The pseudo-anonymized patient data will be recorded by the clinical centre in an 'ad hoc' Clinical Report Form with web-based access.

After obtaining informed consent, patients will then be randomised to LF or placebo group allocation using previous randomization lists Prepared. Randomization will take place on a competitive and balanced basis per clinical center participant. Permuted block randomization of size 4 will be implemented with an allocation ratio of 1:1 to ensure the balance between the groups of treatment. The randomization list will be managed through a REDCap randomization module.

The Hospital Pharmacy of the Participating Center, not involved in the enlistment of patients, will prepare a numbered sequence of sealed envelopes containing the code of allocation, and will keep its list that will remain inaccessible to the professionals involved in recruitment.These sealed envelopes will be opened sequentially, at the time of randomization.

The maintenance of the blind person will be guaranteed by keeping the staff randomization lists, i.e. the staff of the Hospital Pharmacy, on the one hand (staff who will also manage and deliver to the investigators the products being studied, which will look the same), and the randomizing and experimenting medical staff, on the other.

The logistical location of the two staff will also be completely separated, in sectors of the Hospital different and distant from each other, and not communicating in any way.

It should be pointed out that the patient enrolled by the clinical centers on the basis of the selection criteria can start standard-of-care therapy, in any case, before the randomization procedure being the identical basic therapeutic regimen in the two study arms.

For the calculation of the sample size required to demonstrate the primary endpoint, it was used a model built on historical data regarding the same endpoint. Pre-trial data from the two Participating Centres estimate the need for ICU admission at 25%; the need for mechanical ventilation in 30%; hospital mortality in 15%; the average duration hospitalization in 16 days.

The sample size was determined considering a two-sided t-test for two independent samples according to the following parameters:

1. A correct alpha level of 0.025 for two Bonferroni-method endpoints (Alpha total=0.025x2=0.05)
2. A total power of 0.8
3. A Cohen h effect size of 0.44 (corresponding to an effect standardized medium/small \[Cohen 1977\]), i.e. with a 14-day resignation rate of 60% for controls and 80% for treaties.

In this scenario, the size of the study achieved consists of 97 patients per arm of study. Calculations were performed using the R 3.6.1 software \[Core Team 2015\] and the pwr package \[Champely 2018\]. references:

* Cohen, J. Statistical power analysis for the behavioral sciences (rev.ed.1977).
* Core Team R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing: Vienna, Austria, 2015;
* Champely, S.; Ekstrom, C.; Dalgaard, P.; Gill, J.; Weibelzahl, S.; Anandkumar, A.;Ford, C.; Volcic, R.; De Rosario, H.; De Rosario, M.H. Package 'pwr.' R package version 2018, 1-2.

Eligibility criteria: Inclusion Criteria:

1. Hospitalization in non-ICU ward for Covid-19 infection, with virological diagnosis SARS-CoV2 confirmed via RT-PCR (or quick test)
2. Age\>18 aa
3. Covid symptomatology story from no more than 12 days

Exclusion Criteria:

1. Refusal of consent
2. Need for immediate admission to intensive care
3. Severe neoplasms (in advanced stage)
4. Allergies or intolerances known to Lactoferrin

4. Already being treated with Lactoferrin at the entrance to the Hospital 5. Patients with end-stage renal failure (stage 5) 6. Extremely serious general conditions to suggest an imminent exitus 7. Clinical conditions of absolute impossibility of tolerating ingestion of drugs/capsules due to conditions contraining the initiation of therapy for os.

Primary outcomes:
measure: intensive care unit hospitalization rate
timeFrame: 1 year
measure: death
timeFrame: 1 year
measure: proportion of discharged patients
timeFrame: 1 year
measure: National Early Warning Score (NEWS)
timeFrame: during hospitalization
Secondary outcomes:
measure: daily clinical severity score
timeFrame: during hospitalization
measure: oxygen
timeFrame: during hospitalization
measure: ferritin
timeFrame: during hospitalization
measure: IL 6
timeFrame: during hospitalization
measure: D dimers
timeFrame: during hospitalization
measure: hepcidine
timeFrame: during hospitalization
measure: ventilation
timeFrame: during hospitalization
measure: adverse events
timeFrame: during hospitalization
measure: pO2/FiO2
timeFrame: during hospitalization
Other outcomes:
Locations:
city: Ponderano
country: Italy
facility: ASL BI Ospedale degli Infermi
state: Biella
city: Novara
country: Italy
facility: AOU Ospedale Maggiore della Carità
Study officials:
affiliation: ASL BI
name: Paolo Manzoni, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S, Glaser A, Elsayegh D. COVID-19 presenting as stroke. Brain Behav Immun. 2020 Jul;87:115-119. doi: 10.1016/j.bbi.2020.04.077. Epub 2020 Apr 28.
citation: Yang Z, Jiang R, Chen Q, Wang J, Duan Y, Pang X, Jiang S, Bi Y, Zhang H, Lonnerdal B, Lai J, Yin S. Concentration of Lactoferrin in Human Milk and Its Variation during Lactation in Different Chinese Populations. Nutrients. 2018 Sep 5;10(9):1235. doi: 10.3390/nu10091235.
citation: Wang Y, Wang P, Wang H, Luo Y, Wan L, Jiang M, Chu Y. Lactoferrin for the treatment of COVID-19 (Review). Exp Ther Med. 2020 Dec;20(6):272. doi: 10.3892/etm.2020.9402. Epub 2020 Oct 27.
citation: Wakabayashi H, Oda H, Yamauchi K, Abe F. Lactoferrin for prevention of common viral infections. J Infect Chemother. 2014 Nov;20(11):666-71. doi: 10.1016/j.jiac.2014.08.003. Epub 2014 Aug 30.