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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 )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Steroid Refractory Acute Graft Versus Host Disease
Interventions Drug: Methoxsalen
Procedure: Extracorporeal Photopheresis (ECP)
Enrollment 29
Recruitment Details  
Pre-assignment Details Participants were recruited by multiple treatment centers in the United States and Europe
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description Participants receive methoxsalen 20 µg/ml in conjunction with extracorporeal photopheresis (ECP) procedure three times per week for Weeks 1 to 4, and two times per week for Weeks 5 to 12.
Period Title: Overall Study
Started 29
Completed Treatment Up to Week 12 [1] 14
Started Second Line Treatment 5
Completed 15
Not Completed 14
Reason Not Completed
Adverse Event             4
Unsatisfactory Therapeutic Effect             4
Condition no Longer Requires Treatment             4
Death             1
Reason not Specified             1
[1]
Includes participants who received ECP treatments up to and including Week 12
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 29
Hide Baseline Analysis Population Description
Safety Analysis Set included all participants who receive any amount of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 29 participants
8.6  (5.02)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants
Female
12
  41.4%
Male
17
  58.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants
Hispanic or Latino
5
  17.2%
Not Hispanic or Latino
24
  82.8%
Unknown or Not Reported
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 29 participants
Asian
1
   3.4%
Black or African American
2
   6.9%
White
22
  75.9%
Other
4
  13.8%
1.Primary Outcome
Title Number of Participants Achieving Overall Response (OR) Using the Modified International Bone Marrow Transplant Registry (IBMTR) Severity Index at Week 4
Hide Description

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
Time Frame 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 29
Measure Type: Count of Participants
Unit of Measure: Participants
16
  55.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methoxsalen With ECP
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments [Not Specified]
Method t-test, 2 sided
Comments 2-sided p-value for testing the null hypothesis H0: Standard therapy has a CR+PR rate = 10% after 4 weeks, using the exact Binomial test.
Method of Estimation Estimation Parameter Overall response rate (%)
Estimated Value 55.2
Confidence Interval (2-Sided) 95%
35.7 to 73.6
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description 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.
Time Frame 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 29
Measure Type: Count of Participants
Unit of Measure: Participants
Any serious AE
12
  41.4%
Non-serious TEAE at 5% threshold
17
  58.6%
Death for any cause
3
  10.3%
3.Secondary Outcome
Title Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 8
Hide Description

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
Time Frame 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable Participants (Participants with appropriate efficacy data at the given time point)
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 19
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
73.7
(48.8 to 90.9)
4.Secondary Outcome
Title Percentage of Participants Achieving Overall Response (OR) Using Modified IBMTR Severity Index at Week 12
Hide Description

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
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Evaluable Participants (Participants with appropriate efficacy data at the given time point)
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 14
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
78.6
(49.2 to 95.3)
5.Secondary Outcome
Title Duration of Response (Days) Within 16 Weeks Using Modified IBMTR Severity Index
Hide Description

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.

Time Frame 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Population meeting the criterion
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 18
Median (Full Range)
Unit of Measure: days
13.5
(4 to 50)
6.Secondary Outcome
Title Overall Response Rate (ORR) According to the Modified Glucksberg Criteria
Hide Description 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.
Time Frame 4 weeks, 8 weeks, and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants with a score at the given time point
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 29
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Week 4 Number Analyzed 24 participants
50
(29.1 to 70.9)
Week 8 Number Analyzed 19 participants
63.2
(38.4 to 83.7)
Week 12 Number Analyzed 14 participants
78.6
(49.2 to 95.3)
7.Secondary Outcome
Title Cumulative Dose of Daily Steroids
Hide Description Steroids administered from diagnosis of aGvHD to 12 Weeks after initiation of ECP treatment
Time Frame From diagnosis of aGvHD to 12 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 29
Median (Full Range)
Unit of Measure: mg
1917
(192 to 6895)
8.Secondary Outcome
Title Number of Patients With Skin Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria
Hide Description 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
Time Frame at 4, 8 and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants with scores at the given time point
Arm/Group Title All Participants
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 29
Measure Type: Count of Participants
Unit of Measure: Participants
Week 4 Number Analyzed 23 participants
Stage 0
9
  39.1%
Stage 1
8
  34.8%
Stage 2
3
  13.0%
Stage 3
3
  13.0%
Stage 4
0
   0.0%
Week 8 Number Analyzed 18 participants
Stage 0
11
  61.1%
Stage 1
5
  27.8%
Stage 2
1
   5.6%
Stage 3
1
   5.6%
Stage 4
0
   0.0%
Week 12 Number Analyzed 14 participants
Stage 0
10
  71.4%
Stage 1
2
  14.3%
Stage 2
1
   7.1%
Stage 3
1
   7.1%
Stage 4
0
   0.0%
9.Secondary Outcome
Title Number of Patients With Liver Rated as Stage 0 - 4 Using the Modified Glucksberg Criteria
Hide Description 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
Time Frame at 4, 8 and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants with scores at the given time point
Arm/Group Title All Participants
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 29
Measure Type: Count of Participants
Unit of Measure: Participants
Week 4 Number Analyzed 21 participants
Stage 0
19
  90.5%
Stage 1
1
   4.8%
Stage 2
1
   4.8%
Stage 3
0
   0.0%
Stage 4
0
   0.0%
Week 8 Number Analyzed 13 participants
Stage 0
13
 100.0%
Stage 1
0
   0.0%
Stage 2
0
   0.0%
Stage 3
0
   0.0%
Stage 4
0
   0.0%
Week 12 Number Analyzed 12 participants
Stage 0
12
 100.0%
Stage 1
0
   0.0%
Stage 2
0
   0.0%
Stage 3
0
   0.0%
Stage 4
0
   0.0%
Time Frame Up to 16 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Methoxsalen With ECP
Hide Arm/Group Description 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.
All-Cause Mortality
Methoxsalen With ECP
Affected / at Risk (%)
Total   3/29 (10.34%) 
Hide Serious Adverse Events
Methoxsalen With ECP
Affected / at Risk (%)
Total   12/29 (41.38%) 
Blood and lymphatic system disorders   
Autoimmune haemolytic anaemia  1  1/29 (3.45%) 
Pancytopenia  1  1/29 (3.45%) 
General disorders   
Pyrexia  1  2/29 (6.90%) 
General physical health deterioration  1  1/29 (3.45%) 
Immune system disorders   
Acute graft versus host disease  1  2/29 (6.90%) 
Acute graft versus host disease in intestine  1  1/29 (3.45%) 
Acute graft versus host disease in liver  1  1/29 (3.45%) 
Graft versus host disease  1  1/29 (3.45%) 
Infections and infestations   
Aspergilloma  1  1/29 (3.45%) 
Bk virus infection  1  1/29 (3.45%) 
Cellulitis  1  1/29 (3.45%) 
Cystitis viral  1  1/29 (3.45%) 
Cytomegalovirus infection  1  1/29 (3.45%) 
Device related infection  1  1/29 (3.45%) 
Hepatitis E  1  1/29 (3.45%) 
Metabolism and nutrition disorders   
Hyperkalaemia  1  1/29 (3.45%) 
Hypokalaemia  1  1/29 (3.45%) 
Hypomagnesaemia  1  1/29 (3.45%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  1/29 (3.45%) 
Nervous system disorders   
Haemorrhage intracranial  1  1/29 (3.45%) 
Renal and urinary disorders   
Cystitis haemorrhagic  1  1/29 (3.45%) 
Renal failure  1  1/29 (3.45%) 
Respiratory, thoracic and mediastinal disorders   
Respiratory failure  1  1/29 (3.45%) 
Vascular disorders   
Hypertension  1  1/29 (3.45%) 
1
Term from vocabulary, MedDRA (21.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Methoxsalen With ECP
Affected / at Risk (%)
Total   17/29 (58.62%) 
Gastrointestinal disorders   
Abdominal pain  1  4/29 (13.79%) 
Nausea  1  4/29 (13.79%) 
General disorders   
Pyrexia  1  3/29 (10.34%) 
Immune system disorders   
Hypogammaglobulinaemia  1  3/29 (10.34%) 
Infections and infestations   
Clostridium difficile infection  1  2/29 (6.90%) 
Cytomegalovirus infection  1  2/29 (6.90%) 
Pneumonia  1  2/29 (6.90%) 
Investigations   
Immunoglobulins decreased  1  2/29 (6.90%) 
Metabolism and nutrition disorders   
Hyperglycaemia  1  3/29 (10.34%) 
Hypocalcaemia  1  3/29 (10.34%) 
Hyperkalaemia  1  2/29 (6.90%) 
Hypophosphataemia  1  2/29 (6.90%) 
Malnutrition  1  2/29 (6.90%) 
Psychiatric disorders   
Depression  1  2/29 (6.90%) 
Respiratory, thoracic and mediastinal disorders   
Cough  1  4/29 (13.79%) 
Vascular disorders   
Hypertension  1  4/29 (13.79%) 
Hypotension  1  3/29 (10.34%) 
1
Term from vocabulary, MedDRA (21.0)
Indicates events were collected by systematic assessment
This study did have a notable limitation in its single-group study design. This may limit a more robust assessment vs standard of care alone for primary endpoint of overall response and secondary endpoints steroid sparing and disease progression.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Information Call Center
Organization: Mallinckrodt Pharmaceuticals
Phone: 800-844-2830 ext 5
EMail: clinicaltrials@mnk.com
Layout table for additonal information
Responsible Party: Mallinckrodt ( Therakos, Inc., a Mallinckrodt Company )
ClinicalTrials.gov Identifier: NCT02524847    
Other Study ID Numbers: TKS-2014-001
First Submitted: August 13, 2015
First Posted: August 17, 2015
Results First Submitted: July 16, 2020
Results First Posted: September 11, 2020
Last Update Posted: September 11, 2020