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Methoxsalen and Extracorporeal Photopheresis (ECP) for the Treatment of Pediatric Participants With Steroid Refractory Acute Graft Versus Host Disease

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ClinicalTrials.gov Identifier: NCT02524847
Recruitment Status : Terminated (Slow enrollment)
First Posted : August 17, 2015
Results First Posted : September 11, 2020
Last Update Posted : September 11, 2020
Sponsor:
Information provided by (Responsible Party):
Mallinckrodt ( Therakos, Inc., a Mallinckrodt Company )

Tracking Information
First Submitted Date  ICMJE August 13, 2015
First Posted Date  ICMJE August 17, 2015
Results First Submitted Date  ICMJE July 16, 2020
Results First Posted Date  ICMJE September 11, 2020
Last Update Posted Date September 11, 2020
Actual Study Start Date  ICMJE January 20, 2016
Actual Primary Completion Date July 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
Number of Participants Achieving Overall Response (OR) Using the Modified International Bone Marrow Transplant Registry (IBMTR) Severity Index at Week 4 [ Time Frame: 4 weeks ]
OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows:
  • CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment
  • PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment
Original Primary Outcome Measures  ICMJE
 (submitted: August 14, 2015)
Complete response plus partial response (CR+PR) [ Time Frame: 4 weeks ]
The proportion of patient who achieve an overall response (CR+PR) after 4 weeks of ECP treatment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2020)
  • Number of Participants With Adverse Events [ Time Frame: 16 weeks ]
    Clinically significant changes in vital signs, laboratory values and investigations are reported as adverse events. Summary data are provided below, with details listed in the adverse events module.
  • Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 8 [ Time Frame: 8 weeks ]
    OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows:
    • CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment
    • PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment
  • Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 12 [ Time Frame: 12 weeks ]
    OR using the modified IBMTR Severity Index is defined as complete response (CR) + partial response (PR) as follows:
    • CR: complete resolution of all signs and symptoms of aGvHD in all evaluable organs without addition of next-line systemic treatment
    • PR: improvement of 1 stage in 1 or more aGvHD target organs without progression in others and without addition of next-line systemic treatment
  • Duration of Response (Days) Within 16 Weeks Using Modified IBMTR Severity Index [ Time Frame: 16 weeks ]
    Duration of first response is presented for patients whose disease progressed. Duration of response is defined in the following way: Patients whose response failed: Date at which 1st disease progression occurs - date of 1st response +1. Patients whose response did not relapse: Date of 16 week follow-up or final assessment prior to week 16 (if patient withdrew early) - date of 1st response.
  • Overall Response Rate (ORR) According to the Modified Glucksberg Criteria [ Time Frame: 4 weeks, 8 weeks, and 12 weeks ]
    ORR is defined as the percentage of patients who achieve an overall response after 4 weeks, 8 weeks, and 12 weeks of ECP treatment according to a scoring algorithm applied to calculate the grade of aGvHD using the modified Glucksberg Criteria.
  • Cumulative Dose of Daily Steroids [ Time Frame: From diagnosis of aGvHD to 12 Weeks ]
    Steroids administered from diagnosis of aGvHD to 12 Weeks after initiation of ECP treatment
  • Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria [ Time Frame: at 4, 8 and 12 weeks ]
    Number of patients whose skin was rated as Stage 0 - 4 using the modified Glucksberg criteria based on the Graft versus Host Disease (GvHD) rash - Stages are defined as 0=No GvHD rash, 1=Maculopapular rash on <25% body surface area (BSA), 2=Maculopapular rash on 25-50% BSA, 3=Maculopapular rash on >50% BSA, and 4=Generalized erythroderma plus bullous formation, which are blisters bigger than 5 mm across
  • Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria [ Time Frame: at 4, 8 and 12 weeks ]
    Number of patients whose liver was rated as Stage 0 - 4 on the modified Glucksberg criteria - Stages are based on level of bilirubin, defined as: Stage 0 = Bilirubin < 2.0 mg/dL, Stage 1 = Bilirubin 2.0-3.0 mg/dL, Stage 2 = Bilirubin 3.1-6.0 mg/dL, Stage 3 = Bilirubin 6.1-15.0 mg/dL, and Stage 4 = Bilirubin > 15.0 mg/dL
Original Secondary Outcome Measures  ICMJE
 (submitted: August 14, 2015)
  • Safety parameters (vital signs, laboratory tests, and spontaneously reported AEs and SAEs) [ Time Frame: 12 weeks ]
    Safety parameters including vital signs, laboratory tests, and spontaneously reported AEs and SAEs
  • Overall response [ Time Frame: 8 weeks ]
    Proportion of patients who achieve an overall response 8 weeks after initiation of ECP treatment
  • Duration of response [ Time Frame: 16 weeks ]
    Duration of response, defined as the length of time a patient maintains a response through Week 16 of the follow-up period
  • Overall response of Glucksberg criteria [ Time Frame: 4 weeks and 8 weeks ]
    Proportion of patients who achieve an overall response after 4 weeks and 8 weeks of ECP treatment according to the modified Glucksberg Criteria
  • Steroid sparing effect [ Time Frame: 12 weeks ]
    Cumulative dose of daily steroids administered from diagnosis of aGvHD to 12 weeks after initiation of ECP treatment
  • Organ specific CR+PR rates [ Time Frame: 4 weeks and 8 weeks ]
    Organ specific CR+PR rates at 4 weeks and 8 weeks after initiation of ECP treatment
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: August 14, 2015)
  • Very good partial response (VGPR) [ Time Frame: 4 weeks and 8 weeks ]
    Proportion of patients who achieve a VGPR 4 weeks and 8 weeks after initiation of ECP treatment
  • Additional immunosuppressive therapy [ Time Frame: 12 weeks ]
    Addition of use of alternative immunosuppressive therapies throughout the 12 week Treatment Period
  • Nonrelapse mortality [ Time Frame: 12 weeks ]
    Nonrelapse mortality 12 weeks after initiation of ECP treatment
  • Performance status [ Time Frame: 4 weeks and 8 weeks ]
    Performance status (Karnofsky/Lansky score) 4 weeks and 8 weeks after initiation of ECP treatment
  • Biomarkers [ Time Frame: 4 weeks, 8 weeks and 12 weeks ]
    Assessment of regulatory T cells (Tregs)
 
Descriptive Information
Brief Title  ICMJE Methoxsalen and Extracorporeal Photopheresis (ECP) for the Treatment of Pediatric Participants With Steroid Refractory Acute Graft Versus Host Disease
Official Title  ICMJE Single-Arm Study to Assess the Efficacy of UVADEX® (Methoxsalen) Sterile Solution in Conjunction With the THERAKOS® CELLEX® Photopheresis System in Pediatric Patients With Steroid-Refractory Acute Graft-vs-Host Disease (aGvHD)
Brief Summary This is a single-arm, open-label, multicenter study of the efficacy of UVADEX® (methoxsalen) Sterile Solution in conjunction with THERAKOS® CELLEX® Photopheresis Systems (ECP) in pediatric participants with steroid-refractory aGvHD. The study is composed of Screening, Treatment, and Follow-up Periods.
Detailed Description

Screening:

After the informed consent/assent form (ICF) is signed, the screening assessments will be performed in a single visit to establish the eligibility of the participant, based on inclusion and exclusion criteria, as well as aGvHD grading. Scheduling of the first week of ECP treatments and the arrangements for availability of typed and cross-matched donor packed red blood cells (PRBCs) for transfusion, if required, will be made in advance of participants entering the Treatment Period.

Treatment Period:

Once eligibility is established, participants will enter the 12-week ECP Treatment Period. The availability of typed and cross-matched donor PRBCs for transfusion during treatment, if needed, should be established prior to the scheduling of ECP treatments.

Participants will be allowed to continue standard aGvHD prophylaxis regimens (e.g., cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil) without the addition of new therapies. Participants will be allowed to discontinue prophylaxis regimens for reasons of toxicity, and will also be allowed to switch to another prophylaxis medication within the same class (e.g., the calcineurin inhibitors cyclosporine and tacrolimus) for reasons of toxicity.

All participants enrolled in this trial will have received corticosteroids for the treatment of aGvHD. After entering the treatment period on study, tapering of steroids by total weekly decrements of 12.5% to 25% of the steroid dose at initiation of ECP therapy is permitted after a sustained response of aGvHD has been observed for at least 3 consecutive days, with the suggested goal to decrease the starting steroid dose by at least 50% 4 weeks after initiation of ECP.

Follow-Up Period:

After completion of the 12-week Treatment Period, participants may continue ECP treatment on commercial product at the Principal Investigator's discretion. Acute GvHD status will be assessed 4 weeks after completion of the Treatment Period. Participant survival will be assessed by passive follow-up (chart review) 26 weeks after initiation of ECP treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Steroid Refractory Acute Graft Versus Host Disease
Intervention  ICMJE
  • Drug: Methoxsalen
    Sterile solution used in conjunction with photopheresis procedure.
    Other Name: UVADEX®
  • Procedure: Extracorporeal Photopheresis (ECP)
    Other Name: THERAKOS® CELLEX® Photopheresis System
Study Arms  ICMJE Experimental: Methoxsalen with ECP
Participants receive methoxsalen 20 µg/ml in conjunction with ECP procedure three times per week for Weeks 1 to 4, and two times per week for Weeks 5 to 12.
Interventions:
  • Drug: Methoxsalen
  • Procedure: Extracorporeal Photopheresis (ECP)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 10, 2020)
29
Original Estimated Enrollment  ICMJE
 (submitted: August 14, 2015)
48
Actual Study Completion Date  ICMJE July 16, 2019
Actual Primary Completion Date July 16, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion:

  1. Male or female 1 to 21 years of age at the time of consent
  2. Steroid-refractory grade B-D aGvHD.

    • Steroid-refractory is defined as a failure to respond to steroid treatment, with failure to respond defined as any grade B-D (IBMTR grading) aGvHD that shows progression ≥ 3 days, or no improvement by 5 days of treatment with 2 mg/kg/day methylprednisolone or equivalent in participants with lower gastrointestinal (GI) or liver disease, or skin disease associated with bullae. Grade D organ involvement will be limited to skin and liver.
    • Steroid refractory may also be defined as a failure to respond to 1 mg/kg/day of methylprednisolone or equivalent in participants with disease confined to upper GI disease or lesser degrees of skin GvHD
    • Participants with lack of complete response after 2 weeks of steroid treatment
  3. A Lansky scale Performance Status score ≥ 30
  4. Laboratory values are within the following limits, assessed within 3 days of the first study treatment:

    • Absolute neutrophil count > 0.5 × 10^9/liter (L)
    • Creatinine level < 2 times the upper limit of normal
  5. For participants with isolated upper GI symptoms, pre-Screening biopsy results to confirm diagnosis of aGvHD
  6. Female participants of childbearing potential and nonsterilized males who are sexually active with a female partner must be practicing highly effective, reliable, and medically approved contraceptive regimen throughout their participation in the study and for 3 months following the last ECP treatment. Or, for the US only, abstinence may be used in place of an approved contraceptive regimen. Females of childbearing potential are those who have reached the onset of menarche, or 8 years of age, whichever comes first. Approved contraceptive methods for female participants of childbearing potential or nonsterilized males who are sexually active with a female partner are as follows:

    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
    • Established use of oral, injectable, or implanted hormonal methods of contraception.
    • Placement of an intrauterine device or intrauterine system
  7. Signed informed consent/assent is obtained before conducting any study procedures; the parent, legal guardian, or legally authorized representative of a minor must also provide written informed consent

Exclusion:

  1. Currently enrolled in another clinical trial for the treatment of aGvHD
  2. Use of any experimental regimens or medication(s) for aGvHD treatment
  3. Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within 30 days prior to the first study treatment
  4. Overt signs of relapse of the underlying condition
  5. Uncontrolled viral, fungal, or bacterial infection
  6. Platelet count < 20.0 × 10^9/L, despite platelet transfusion
  7. Inability to tolerate the extracorporeal volume shifts associated with ECP treatment
  8. Uncontrolled GI bleeding
  9. Veno-occlusive liver disease
  10. Life expectancy < 4 weeks
  11. Participant requires invasive ventilation or vasopressor support
  12. Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection (proof of seronegativity within 6 months of screening is required)
  13. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its excipients
  14. Known hypersensitivity and allergy to heparin and Anticoagulant Citrate Dextrose Formula-A (ACD-A)
  15. Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus, albinism) or aphakia
  16. Coagulation disorders that cannot be corrected with simple transfusion
  17. Co-existing melanoma, basal cell, or squamous cell skin carcinoma
  18. Previous splenectomy
  19. White blood cell count greater than 25,000 cubic millimeter (mm^3)
  20. Currently being treated with any systemic immunosuppressive or biologic therapy for the treatment of a medical condition other than aGvHD
  21. Female participant is breastfeeding or pregnant
  22. Any medical concerns that may pose risk to the participant
  23. Any psychological, familial, sociological, and/or geographical condition that may potentially hamper compliance with the study protocol and follow-up schedule
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   France,   Germany,   Hungary,   Italy,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02524847
Other Study ID Numbers  ICMJE TKS-2014-001
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description:

Because we work in the rare disease space, to eliminate risk of patient identification we do not share individual patient data.

We post summary aggregate results for applicable clinical trials in the registry, and statistical endpoints and discussion in publications; with each referencing the other.

Responsible Party Mallinckrodt ( Therakos, Inc., a Mallinckrodt Company )
Study Sponsor  ICMJE Therakos, Inc., a Mallinckrodt Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Team Leader Mallinckrodt
PRS Account Mallinckrodt
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP