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Study of Standardized Withaferin-A for the Treatment of Steroid Refractory Acute Graft Versus Host Disease. (Withaferin_A)

11 juli 2026 bijgewerkt door: Akanksha Chichra, Tata Memorial Centre

A Phase II Clinical Trial of Standardized Withaferin-A for the Treatment of Steroid Refractory Acute Graft Versus Host Disease

Study Design Prospective, single center, single arm, Phase II study.

Research aims and objectives Aim:

To evaluate the efficacy and safety of standardized Withaferin A in steroid refractory acute GvHD in patients post allogeneic stem cell transplantation

Primary Objective:

To evaluate the objective Response Rate (ORR) at Day 28 from the start of SWA defined as the proportion of patients achieving Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR).

Methodology

Treatment plan and Interventions Administration of study treatment Name of the intervention: Standardized WA (standardized root extract of Withania somnifera. This will be provided free of cost to the trial patients.

Formulation: The standardized root extract of W. somnifera contains 5% of WA w/w. SWA is available as a 500 mg capsule (AshwaMAX) that contains 25 mg of WA.

Route of administration: Per-oral (P/O) Dose schedule: The dose of SWA is 1500mg/day. It will be administered as 3 capsules of 500 mg once a day.

Duration of treatment:

  • Every patient will receive treatment for at least 12 weeks followed by a taper as per physician's discretion. WA can be tapered after 12 weeks if the patient has achieved CR or VGPR and has discontinued corticosteroids for at least 4 weeks.
  • Dose adjustments/modifications: If the patient experiences any grade ≥3 toxicities related to SWA, further administration of SWA will be withheld immediately. Once the severity of the adverse event reduces to grade ≤1, the study agent will be rechallenged with 25% dose reduction. The same strategy will be adopted for successive grade ≥3 toxicities. If the drug is not tolerated at 25% of original dose (100 mg), no further rechallenge will be attempted.
  • Corticosteroid tapering will be done as per the treating physician's discretion and clinical condition of the patient.

Studie Overzicht

Toestand

Werving

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

Secondary Objectives:

  1. To evaluate the ORR at other defined time points (Day 14 and Day 56) from initiation of SWA
  2. To study the Non relapse Mortality (NRM) at 1 year post transplant
  3. To study the Relapse rate at 1 year post transplant
  4. To study the Overall Survival (OS) at 1 year post transplant
  5. To study the incidence of chronic GvHD at 1 year post transplant
  6. To study the incidence of adverse effects attributed to SWA

Exploratory Objectives:

  1. Reduction of steroid dose by ≥30% from baseline will be calculated for all patients on day 28 after start of SWA.
  2. To measure the JAK2-STAT3 levels, JAK2-STAT3 receptor kinetics at baseline (pre- conditioning) and post initiation of WA.
  3. Immune cell phenotype, cytokine profile and pharmacokinetics of WA in patients post treatment with SWA at baseline, Day +7, Day +14, Day +28, Day+56, Day+90 and Day +180 post HSCT.

What is acute Graft versus host disease (GvHD)? GvHD is a complication that can occur after an allogeneic stem cell transplant resulting in damage to internal organs. Patients with GvHD have a mortality rate of 15-40%. In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow harm the body. Acute GvHD usually develops in the skin, liver or gastrointestinal tract, and symptoms might appear within weeks after transplant. Symptoms of acute GvHD are skin rash or reddened areas on the skin, yellow discoloration of the skin and/or eyes, and abnormal blood test results, nausea, vomiting, diarrhea, or abdominal cramping.

What is steroid refractory acute GvHD (SR GvHD)? Most of patients who develop acute GvHD are successfully treated with corticosteroids, a type of medicine that suppress the donor cells from attacking the recipient's organs. If steroids are unsuccessful, it is termed as acute SR GvHD. Acute SR GvHD is a condition with poor outcomes as effective treatments are not available.

What is the current treatment for SR GvHD? The only treatment that is US-FDA approved for the treatment of SR GvHD is ruxolitinib. Ruxolitinib is expensive and hence not affordable for most patients. It also has its own set of side effects which include low blood counts. Although, there are other medicines that have shown to be effective in this condition, none of them have been approved by the regulatory authorities.

What is standardized Withaferin-A (SWA)? Withaferin-A (WA) is the principal active component of Withania somnifera (Ashwagandha). It has been shown in many studies to have properties of healing and immune-modulation (improving the immune system). Studies have been done in our Clinical Pharmacology Laboratory that have shown a significant beneficial effect on reducing the risk of acute GvHD. The drug has also been tested and proven to be very safe in humans.

What is the rationale of this trial? As has been described earlier, SR GvHD is a difficult complication of allogeneic stem cell transplant which can lead to increased hospital stay and deaths post-transplant. The only approved drug for steroid refractory GvHD (Ruxolitinib) is expensive and out of reach for most patients. It also has side effects which can lead to its discontinuation. SWA is an oral formulation of WA which seems to be beneficial in the early studies done in the Clinical Pharmacology Laboratory. SWA has also been found to be safe at very high doses. Whether SWA will actually patients undergoing allogeneic stem cell transplant who develop SR GvHD has not been proven as this can only be done by conducting a systematic trial. This trial is being conducted to see if SWA is beneficial in SR GvHD which will give us a drug which is easily available, oral and inexpensive to treat SR GvHD.

How will SWA be given? Patients who agree to participate in this trial and are found to be eligible will be given SWA as a capsule at a dose of 1500 mg/day orally. The drug will be given for a total duration of 12 weeks after which the dose will be reduced and stopped. All other standard treatments which are part of a transplant procedure will be carried out without any change.

Participants will be monitored clinically for any adverse events and followed up as per standard protocols post-transplant.

What additional tests will be carried out? Additional blood sampling to study the levels of the drug WA, checking immune cell profile and cytokines (which are markers of your immunity levels) will be done at baseline, Day+7, Day +14, Day+28, Day+56, Day+90, Day +180 from the start of SWA

. What are the risks involved in participation? According to available literature and information, SWA is a safe and well tolerated drug. There is a possibility that rifaximin can have interaction with cyclosporine (immunosuppressant) and antifungal (Azole) drugs which are used in BMT, although studies done in bone marrow transplant (BMT) with rifaximin have not documented such an interaction. Drug levels of azole antifungals and cyclosporine in the blood are monitored as a standard of care (i.e. these will be done irrespective of the decision to take part in this study) in BMT which will help to take corrective action in case there is such an interaction, which will mitigate any potential risk due to this.

What is the possible impact of this trial? If indeed SWA works and treats SR GvHD effectively then this could be a major breakthrough in treatment. It would help many patients who develop SR GvHD post allogeneic stem cell transplant and would be a safe, easily available, inexpensive and oral drug for the same. This possibly could benefit and help future patients who undergo bone marrow transplant (BMT) to have better chances of survival and reduce their financial burden.

Studietype

Ingrijpend

Inschrijving (Geschat)

34

Fase

  • Fase 2

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Studie Locaties

  • Indië
    • Maharashtra
      • Navi Mumbai, Maharashtra, Indië, 410210
        • Werving
        • Advanced Centre for Treatment, Research and Education in Cancer
        • Contact:
        • Contact:
        • Hoofdonderzoeker:
          • Dr Akanksha Chichra, FNB DNB Pediatric oncology

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Kind
  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Beschrijving

Inclusion Criteria:

  • Patients age ≥ 12 years with a hematological malignancy who have undergone allogeneic stem cell transplant with matched related donor (MRD), Haploidentical (Haplo) donor or matched unrelated donor (MUD)
  • Evidence of myeloid engraftment (eg, absolute neutrophil count ≥0.5 × 109 /L for 3 consecutive days)
  • ECOG performance score of 0 or 1
  • Patients with steroid-refractory aGvHD, defined as any of the following:
  • Patients with progressive GvHD (ie, increase in stage in any organ system or any new organ involvement) after 3 days of primary treatment with methylprednisolone ≥2 mg/kg/d (or equivalent)
  • Patients with GvHD that has not improved (ie, decrease in stage in at least 1 involved organ system) after 7 days of primary treatment with methylprednisolone ≥2 mg/kg/d (or equivalent)
  • Patients who previously began corticosteroid therapy at a lower dose (≥1 mg/kg/d methylprednisolone) for treatment of skin GvHD or skin GvHD accompanied by upper gut GvHD but develop new GvHD in another organ system
  • Patients who cannot tolerate a corticosteroid taper, that is, begin corticosteroids at 2.0 mg/kg/d, demonstrate response, but progress before a 50% decrease from the initial starting dose of corticosteroids is achieved

Exclusion Criteria:

  • Known hypersensitivity or contraindications against Withaferin-A.
  • Presence of an active uncontrolled infection defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection.
  • Any medical or psychiatric illness which precludes the participant from giving informed consent.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: NVT
  • Interventioneel model: Opdracht voor een enkele groep
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Standardized Withaferin A (SWA)

Withaferin-A Standardized WA (standardized root extract of Withania somnifera Dose schedule: The dose of SWA is 1500mg/day. It will be administered as 3 capsules of 500 mg once a day.

Route :Oral Duration: Every patient will receive treatment for at least 12 weeks followed by a taper as per physician's discretion. WA can be tapered after 12 weeks if the patient has achieved CR or VGPR and has discontinued corticosteroids for at least 4 weeks.
Geneesmiddel: Standardized Withaferin A (SWA)

Withaferin-A (standardized root extract of Withania somnifera ) Route of administration: Per-oral (P/O) Dose schedule: The dose of SWA is 1500mg/day. It will be administered as 3 capsules of 500 mg once a day.

Duration of treatment Every patient will receive treatment for at least 12 weeks followed by a taper as per physician's discretion. WA can be tapered after 12 weeks if the patient has achieved CR or VGPR and has discontinued corticosteroids for at least 4 weeks.

Andere namen:
  • root extract of Withania somnifera

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
OBJECTIVE RESPONSE RATE (ORR)
Tijdsspanne: Day 28 after initiation of standardized Withaferin A (SWA)
OBJECTIVE RESPONSE RATE (ORR)
Day 28 after initiation of standardized Withaferin A (SWA)

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Overall response rate
Tijdsspanne: Day 14 and Day 56 after initiation of standardized Withaferin A
Overall response rate at Day 14 and Day 56
Day 14 and Day 56 after initiation of standardized Withaferin A
Non-relapse mortality (NRM)
Tijdsspanne: Up to 1 year post-transplant
The non-relapse mortality (NRM) at 1 year post transplant.
Up to 1 year post-transplant
Overall survival (OS)
Tijdsspanne: Up to 1 year post-transplant
The overall survival (OS) at 1 year post transplant
Up to 1 year post-transplant
Incidence of chronic graft versus host disease
Tijdsspanne: Up to 1 year post-transplant
The incidence of chronic graft versus host disease (GVHD) at 1 year post transplant.
Up to 1 year post-transplant
Incidence of adverse effects
Tijdsspanne: until 12 weeks after last dose of Investigational product
The incidence of adverse effects attributed to standardized Withaferin A (SWA).
until 12 weeks after last dose of Investigational product
Relapse rate
Tijdsspanne: upto 1 year post transplant
Relapse rate 1 year post transplant
upto 1 year post transplant

Andere uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Number of participants with a ≥30% reduction in corticosteroid dose from baseline
Tijdsspanne: Day 28 after initiation of standardized Withaferin A(SWA).
Number of participants achieving a reduction of ≥30% in corticosteroid dose from baseline after initiation of standardized Withaferin A (SWA).
Day 28 after initiation of standardized Withaferin A(SWA).
Change in JAK2 and STAT3 biomarker levels from baseline
Tijdsspanne: Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
Change in JAK2 and STAT3 biomarker levels from baseline (before initiation of standardized Withaferin A [SWA])
Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
Change in JAK2-STAT3 receptor kinetics from baseline
Tijdsspanne: Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
Change in JAK2-STAT3 receptor kinetics from baseline (before initiation of standardized Withaferin A [SWA])
Baseline (before initiation of SWA), Day +7 and Day +28 after initiation of SWA.
Change in immune cell subset frequencies from baseline
Tijdsspanne: Baseline, Day +7 , Day +14 ,Day +28 , and Day +100 post hematopoietic stem cell transplantation (HSCT)
Change in the frequency of predefined immune cell subsets
Baseline, Day +7 , Day +14 ,Day +28 , and Day +100 post hematopoietic stem cell transplantation (HSCT)
Change in serum cytokine concentrations from baseline
Tijdsspanne: Baseline, Day +7 , Day +14 , Day +28, and Day +100 post transplant
Change in the concentrations of the predefined cytokines from baseline
Baseline, Day +7 , Day +14 , Day +28, and Day +100 post transplant
Maximum plasma concentration (Cmax) of Withaferin A
Tijdsspanne: Pharmacokinetic sampling time points from baseline through Day +100 , post transplant
Maximum observed plasma concentration (Cmax) of Withaferin A following administration of standardized Withaferin A (SWA).
Pharmacokinetic sampling time points from baseline through Day +100 , post transplant

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Tata Memorial Centre

Onderzoekers

  • Hoofdonderzoeker: Dr.Akanksha Chichra, DNB, Advanced Centre for Treatment, Research and Education in Cancer

Publicaties en nuttige links

De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.

Algemene publicaties

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Werkelijk)

23 september 2023

Primaire voltooiing (Geschat)

9 januari 2028

Studie voltooiing (Geschat)

25 september 2028

Studieregistratiedata

Eerst ingediend

15 september 2023

Eerst ingediend dat voldeed aan de QC-criteria

11 juli 2026

Eerst geplaatst (Werkelijk)

16 juli 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

16 juli 2026

Laatste update ingediend die voldeed aan QC-criteria

11 juli 2026

Laatst geverifieerd

1 juli 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • 900937

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Beschrijving IPD-plan

IP details not shared

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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