Utilizing the Crosstalk Among Chicoric Acid, 13-Cis Retinoic Acid(Aerosolized), Minocycline and Vitamin D as a Potent Quadrate Therapy for Treating Patients With Multidrug-resistant TB and Patient With Both Multidrug-resistant TB and COVID-19

NCT05077813 | Unknown Phase 2 DMC

• 1 other identifier: How to kill Tuberculosis
• Study Type: interventional
• Target: 250
• Locations: 2 countries
• Sites: 2

Brief Summary

Utilizing the Crosstalk Among Chicoric Acid, 13-Cis Retinoic Acid(Aerosolized), Minocycline and Vitamin D as a Potent Quadrate Therapy for treating patients with Multidrug-resistant TB and patient with both Multidrug-resistant TB and COVID-19 . A double-edged sword Clinical Study I)Part of Tuberculosis Tuberculosis (TB) is a major infectious disease killer globally. It affected 10 million and killed 1.4 million people in 2019 alone. The predicted impact of the COVID-19 pandemic is an additional 190,000 TB deaths in 2020, and it is expected in the next 5 y that there will be up to a 20% increase in the global TB disease burden , stressing the critical need for new safe and effective drugs against Mycobacterium tuberculosis (Mtb). In addition, controlling multidrug-resistant TB (MDR-TB) presents a huge public health challenge . New drug discovery could require several years with no guarantee but repurposing established may be useful to treat patients with tuberculosis . Here we demonstrate that we could utilize the crosstalk among Chicoric Acid, 13-Cis Retinoic Acid, Minocycline , and vitamin D as a novel quadrate therapy against TB.Drug-resistant tuberculosis represents a global emergency, requiring new drugs. Recently Minocycline was found to be highly potent in laboratory strains of Mycobacterium TB, and 30 drug-sensitive and multidrug/extensively drug-resistant clinical strains were susceptible to clinically attainable dosages. The lung concentration-time profiles of a 7 mg/kg/day human-equivalent minocycline dosage yielded bacterial kill rates comparable to first-line antituberculosis drugs. Extracellular bacilli were destroyed directly by minocycline. Minocycline also killed intracellular bacilli indirectly through granzyme A-driven apoptosis. Furthermore, minocycline showed dose-dependent antiinflammatory effect, suggesting that it may protect tuberculosis patients against immunopathology. A study showed that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing . A recent study showed that Minocycline-induced significantly inhibition of IDO expression. But Minocycline-induced inhibition of IDO expression is retinoid-dependent. The combined treatment with minocycline and retinol, however, resulted in a striking, statistically significant decrease in IDO. Co-treatment with minocycline and retinol again resulted in decreased TNF-α and IL-6 levels. A study showed that IL-6 inhibits IFN-γ induced autophagy in Mycobacterium (TB) H37Rv infected macrophages. As well as neutralization of endogenous IL-6 by anti-IL-6 antibody significantly enhances the IFN-γ mediated killing of the intracellular bacteria. Minocycline's anti-inflammatory effects are mediated through RAR signaling. Therefore, The combined treatment with minocycline and retinol is expected to effectively inhibit (TB) and its inflammatory complication, Fortunately, Retinoic Acid significantly inhibits the in vivo growth of M. tuberculosis and the development of tuberculosis. In addition to, 13-Cis RA and Chicoric Acid ( CA ) enhanced the cell surface expression of HLA-DR and CD14 molecules on U937 macrophages and prevented the growth of Mtb within macrophages. Moreover, 13-cis RA and CA, have increased NO generation compared to untreated control macrophages, significantly . Both drugs have a significant inhibitory effect on Mtb growth but CA at the highest concentration was more potent than 13-cis RA . Therefore we will use retinoic acid to induce the effect of Minocycline as well as its ability to inhibit tuberculosis in combination with CA .Recent data showed that Vitamin D support innate immune responses to Mycobacterium TB and Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis. Deficiency of vitamin D has long been implicated in activation of (TB) . Serum vitamin D in TB patients are lower than in healthy controls . Vitamin D has been found to speed up the clearance of (TB) bacteria from the lungs of people with multi-drug resistant TB, according to a study of 1,850 patients. It was showed that Vitamin D receptor (VDR) must form a heterodimer complex with retinoid X receptor (RXR) to regulate gene transcription. Retinol plays a crucial role in lung development and signaling the vitamin D pathway. 9-cis-retinoic acid, an active vitamin A metabolite and the ligand of RXR, assists VDR signaling and suppresses the degradation of circulating vitamin D.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Time to first negative SARS-CoV-2 PCR in NP swap and Mycobacterium tuberculosis sputum culture

  within 4 weeks

Secondary Outcomes (10)

• Sputum culture result (positive or negative)& COVID-19 PCR (positive or negative)

  2 weeks after therapy start date

• Serum levels of CRP and ESR

  one month

• All cause mortality rate

  one month

• Absolute lymphocyte counts (CD4,CD8 and CD25+FOXP3+ Regulatory T)

  one month

• Measurement of cytokine (IFN-gamma and alpha , IL-6, IL-10, TNF-alpha, TGF-beta) levels produced in response to M. tb.

  one month

Study Arms (6)

13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D for (MDR-TB)

ACTIVE COMPARATOR

50 Subjects will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Combination Product: 13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D for (MDR-TB)

9 cis retinoic acid , Minocycline,Chicroic Acid and Vitamin D for (MDR-TB)

ACTIVE COMPARATOR

50 Subjects will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized 9 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Combination Product: 9 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D for (MDR-TB)

All trans retinoic acid , Minocycline,Chicroic Acid and Vitamin D for (MDR-TB)

ACTIVE COMPARATOR

50 Subjects will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized All trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Combination Product: All trans retinoic acid , Minocycline,Chicroic Acid and Vitamin D for (MDR-TB)

13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB)

ACTIVE COMPARATOR

50 Subjects with confection of COVID-19 and multidrug-resistant tuberculosis (MDR-TB) will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Combination Product: 13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB)

All trans retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB)

ACTIVE COMPARATOR

50 Subjects with confection of COVID-19 and multidrug-resistant tuberculosis (MDR-TB) will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized All trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

Combination Product: All trans retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB)

The standard therapy

PLACEBO COMPARATOR

The standard therapy 100 infected patients with confection of COVID-19 and MDR-TB will receive the standard therapy for tuberculosis for 30 days 50- 50-

Other: The standard therapy

Interventions

13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D for (MDR-TB) COMBINATION_PRODUCT

A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D for (MDR-TB)

9 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D for (MDR-TB) COMBINATION_PRODUCT

A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized 9 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

9 cis retinoic acid , Minocycline,Chicroic Acid and Vitamin D for (MDR-TB)

All trans retinoic acid , Minocycline,Chicroic Acid and Vitamin D for (MDR-TB) COMBINATION_PRODUCT

Active Comparator: All trans retinoic acid , Minocycline,Chicroic Acid and Vitamin D 50 Subjects will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized All trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

All trans retinoic acid , Minocycline,Chicroic Acid and Vitamin D for (MDR-TB)

All trans retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB) COMBINATION_PRODUCT

50 Subjects with confection of COVID-19 and multidrug-resistant tuberculosis (MDR-TB) will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized All trans retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

All trans retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB)

13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB) COMBINATION_PRODUCT

50 Subjects with confection of COVID-19 and multidrug-resistant tuberculosis (MDR-TB) will be randomly assigned to receive A) Minocycline i.v. 4,5 mg/kg gradual in 2 divided doses increases from 4,5 mg/kg from the first week to 7.5 and 10 mg/kg to the last week. In addition to Aerosolized 13 cis retinoic acid in gradual 2 divided doses increases from 0.2 mg/kg/day to 4 mg/kg/day as inhaled retinoic acid therapy for 30 days. Moreover, the patients will receive Echinacea Purpurea Extract Capsules Polyphenols Chicoric Acid. Echinacea phytochemical profile Each tablet is comprised of the equivalent of 1275 mg of echinacea root, as follows: A) Echinacea purpurea - 675 mg root yields 112.5 mg dried extract, standardized to contain 2.1mg alkamides. Each batch of tablets contain choric acid = 3.4 to 8.5 mg/tablet. Furthermore, the patients will receive Cholecalciferol(Vitamin D) Intramuscular injection of 600,000 units of Cholecalciferol for 2 doses given at week 0 and week 4

13 cis retinoic acid, Minocycline, Chicroic Acid and Vitamin D For (COVID-19 and MDR-TB)

The standard therapy OTHER

The standard therapy 100 infected patients with confection of COVID-19 and MDR-TB will receive the standard therapy for tuberculosis for 30 days

The standard therapy

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age above 18 up to 65 years
• Microbiologically or histologically confirmed active tuberculosis as well as confirmed positive with COVID-19
• Clinically confirmed latent tuberculosis
• Drug resistant MTb
• Negative pregnancy test for 18-40 year-old females
• Able to sign consent

You may not qualify if:

• HIV positive
• Known intolerance of vitamin D
• Sarcoidosis
• Hyperparathyroidism or nephrolithiasis
• Taking vitamin D or A supplementation in the two months preceding enrolment
• Baseline serum corrected calcium \>2.65 mmol/L
• Current haemodialysis
• Children, pregnant or breastfeeding individuals
• Concomitant benzothiadiazine derivative, cardiac glycoside, carbamazepine, phenobarbital, phenytoin, primidone or long-term immunosuppressant therap
• Extra-pulmonary or smear negative tuberculosis
• Patients receiving steroids, cytotoxic drugs, post transplant or metastatic malignancy, or not expected to survive for the duration of ATT
• Pregnant or lactating women
• Active diarrhoea, indicating possible fat-soluble vitamin malabsorption.
• Baseline Hypercalcemia \>10.5 mg/dl
• Concurrent use of cyclosporin, cisplatin, amfotericin B, cephalosporins, polymyxins and vancomycin.

Sponsors & Collaborators

• Kafrelsheikh University: lead
• Ministry of Health, Saudi Arabia: collaborator

Study Sites (2)

Kafr El-sheikh University

Cairo, Kafr el-Sheikh Governorate, 33561, Egypt

Location

Ministry of health. First health cluster

Riyadh, Riaydh, 12221, Saudi Arabia

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

Isotretinoin; Minocycline; Vitamin D; Alitretinoin; Tretinoin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Tetracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Secosteroids; Steroids; Fused-Ring Compounds; Vitamin A; Diterpenes

Study Officials

• Dr Mahmoud R Elkazzaz, M.Sc of Biochemistry

  Faculty of Science , Damietta University

  PRINCIPAL INVESTIGATOR

• Amr K Ahmed

  Ministry of Health

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dr Mahmoud R Elkazzaz, M.Sc of Biochemistry

CONTACT

00201090302015; mahmoudramadan2051@yahoo.com

Amr K Ahmed

CONTACT

00966597310032; drmedahmed@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participant
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Scientist

Study Record Dates

• First Submitted: October 10, 2021
• First Posted: October 14, 2021
• Study Start: December 1, 2021
• Primary Completion: February 1, 2022
• Study Completion: February 1, 2022
• Last Updated: October 14, 2021

Record last verified: 2021-10

Locations

SA (1); EG (1)