Extracorporeal Photopheresis (ECP) With Methoxsalen for Chronic Graft Versus Host Disease (cGVHD)

• Sponsor: Mallinckrodt (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01380535
• Collaborator: Parexel (Industry)
• Enrollment: 60
• Locations: 32
• Arms: 2
• Actual Duration (Months): 40
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Chronic graft-versus-host disease (cGVHD) is a long-lasting complication that can occur after transplants. The transplanted cells seem to fight with the patient's own cells.

Extracorporeal photopheresis (ECP) is a fairly new procedure for cGVHD. The participant gets a port to hook up to a machine. The machine removes the white blood cells, mixes them with a light-sensitive drug, shines light on it, and puts all the blood back in.

This study will find out if patients respond better if they get ECP with methoxsalen, in addition to the pills normally used to treat cGVHD.

Condition or Disease	Intervention/Treatment	Phase
Chronic Graft Versus Host Disease	Drug: ECP Methoxsalen; Drug: Standard of Care	Early Phase 1

Detailed Description

The investigation of extracorporeal photopheresis (ECP) plus standard of care (SoC) (SoC+ECP) in chronic graft-versus-host disease (cGVHD) within prospective, randomized clinical studies is limited, despite its frequent clinical use.

This phase 1/pilot study was the first randomized, prospective study to investigate ECP use as first-line therapy in cGVHD, based on the 2015 National Institutes of Health (NIH) consensus criteria for diagnosis and response assessment.

Adult patients with new-onset (≤3 years of hematopoietic stem cell transplantation) moderate or severe cGVHD were randomized 1:1 to 26 weeks of SoC+ECP vs SoC (corticosteroids and cyclosporine A/tacrolimus) between 2011 and 2015. The primary endpoint was overall response rate (ORR), defined as complete or partial response, at week 28 in the intention-to-treat population (ITT).

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Pilot Study for the 2015 NIH Consensus Criteria to inform the design of subsequent studiesPilot Study for the 2015 NIH Consensus Criteria to inform the design of subsequent studies
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy With UVADEX for the Treatment of Patients With Moderate to Severe Chronic Graft-versus-Host Disease (cGvHD)
• Actual Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ECP Methoxsalen + Standard of Care Participants receive methoxsalen administered via ECP in addition to standard of care	Drug: ECP Methoxsalen; Methoxsalen delivered by ECP; Other Names: Uvadex Extracorporeal photopheresis (ECP) ; Drug: Standard of Care; Tapered prednisone with cyclosporine or tacrolimus via oral administration, consistent with local institutional practice (corticosteroids and cyclosporine A/tacrolimus); Other Names: Reference therapy
Active Comparator: Standard of Care Participants receive standard of care only	Drug: Standard of Care; Tapered prednisone with cyclosporine or tacrolimus via oral administration, consistent with local institutional practice (corticosteroids and cyclosporine A/tacrolimus); Other Names: Reference therapy

Outcome Measures

Primary Outcome Measures

1. Number of Participants With an Overall Response at Week 28 [Week 28]

   Participants with overall response included those with partial response or complete response, according to study staff who did not know which treatment they received (blinded assessment).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

To be eligible for inclusion in this trial, the patient must have moderate to severe chronic graft-versus-host disease [defined by the National Institutes of Health (NIH) 2015 Consensus Criteria] that started within 3 years after hematopoietic stem cell transplantation (HSCT).

Exclusion Criteria:

• Is intolerant to corticosteroids or hypersensitive to methoxsalen

• Received certain treatments during time periods disallowed by protocol

• Has infections and/or requires treatment that (per protocol or in the opinion of the investigator) might compromise:

1. safety and well-being of participant or offspring

2. safety of study staff

3. analysis of results

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami Hospital	Miami	Florida	United States	33136
2	Indiana Blood and Marrow Transplantation Research	Indianapolis	Indiana	United States	46237
3	Tulane University Health Sciences Center, 1430 Tulane Avenue, Rm 7551,	New Orleans	Louisiana	United States	70112
4	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
5	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
6	New York Presbyterian Hospital	New York	New York	United States	10065
7	Stony brook university medical Center	Stony Brook	New York	United States	11794
8	Vanderbilt Ingram Cancer Center	Nashville	Tennessee	United States	37232
9	Medical City Dallas Hospital,Transplant center	Dallas	Texas	United States	75230
10	Parkland Memorial Hospital	Dallas	Texas	United States	75235
11	Methodist healthcare system of san Antonio	San Antonio	Texas	United States	78229
12	General Hospital of Vienna (Medical University of Vienna)	Vienna		Austria
13	Hopital Saint Antoine	Saint Antoine	Paris	France	75571
14	CHU de Nantes	Nantes		France
15	Hospital Saint Louis	Paris		France
16	Universitätsklinik Köln	Cologne		Germany	50937
17	Universitäts-Klinikum Carl Gustav Carus	Dresden		Germany	01309
18	Universitatsklinikum Erlangen	Erlangen		Germany	91054
19	Universitätsklinikum Essen	Essen		Germany	45122
20	Universitatskrankenhaus Hamburg-Eppendorf	Hamburg		Germany	20246
21	Universitätsklinikum Leipzig AöR	Leipzig		Germany	04103
22	Universitätklinikum Mannheim	Mannheim		Germany	68167
23	Medizinische Universitatsklinik	Munchen		Germany	81377
24	Uniklinik für Kinder und Jugendmedizin	Tubingen		Germany	72076
25	Egyesített Szent István és Szent László Kórház, Gyáli út 5-7,	Budapest		Hungary	1097
26	A.O.U. Policlinico- Vittorio Emanuele	Catania		Italy
27	Universita de Genova - Ospedale S. Martino	Genova		Italy
28	Hospital Marques de Valdecilla	Santander	Cantabria	Spain	39008
29	Santa Creu I Sant Pau	Barcelona		Spain	08025
30	Kings College Hospital	London	Greater London	United Kingdom	SE5 9RS
31	University of Birmingham: Queen Elizabeth Hospital	Birmingham		United Kingdom
32	Royal Marsden Hospital	London		United Kingdom

Sponsors and Collaborators

• Mallinckrodt
• Parexel

Investigators

• Study Director: Global Clinical Leader, Mallinckrodt

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Cited article made available by the US National Library of Medicine, National Institutes of Health

Publications

None provided.

• Responsible Party: Mallinckrodt
• ClinicalTrials.gov Identifier: NCT01380535
• Other Study ID Numbers: 10-005; 2010-022780-35
• First Posted: Jun 27, 2011
• Last Update Posted: Feb 19, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Mallinckrodt: Extracorporeal photopheresis therapy; Methoxsalen; cGVHD; hematopoietic stem cell transplantation
• Additional relevant MeSH terms: Graft vs Host Disease; Methoxsalen

Study Results

Participant Flow

Recruitment Details	Patients were enrolled in Austria, France, Germany, Italy, Hungary, Spain, the United Kingdom, and the United States. Enrollment started in November 2011, and the last patient visit occurred in March 2015.
Pre-assignment Detail	All participants enrolled were included in the safety analysis set

Arm/Group Title	ECP Methoxsalen + SoC	Standard of Care (SoC)
Arm/Group Description	Participants receive ECP methoxsalen in addition to standard of care	Participants receive only standard of care
Period Title: Overall Study
STARTED	29	31
Baseline Population	29	31
Safety Population	28	28
Intent-to-treat Population	29	24
COMPLETED	22	16
NOT COMPLETED	7	15

Baseline Characteristics

Arm/Group Title	ECP Methoxsalen + SoC	Standard of Care (SOC)	Total
Arm/Group Description	Participants receive ECP methoxsalen in addition to standard of care	Participants receive only standard of care	Total of all reporting groups
Overall Participants	29	31	60
Age, Customized (Count of Participants)
18-44 years	8 27.6%	10 32.3%	18 30%
45-64 years	19 65.5%	19 61.3%	38 63.3%
65 years and over	2 6.9%	2 6.5%	4 6.7%
Sex: Female, Male (Count of Participants)
Female	7 24.1%	13 41.9%	20 33.3%
Male	22 75.9%	18 58.1%	40 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.9%	2 6.5%	4 6.7%
Not Hispanic or Latino	24 82.8%	24 77.4%	48 80%
Unknown or Not Reported	3 10.3%	5 16.1%	8 13.3%
Race/Ethnicity, Customized (Count of Participants)
White	22 75.9%	24 77.4%	46 76.7%
Black	2 6.9%	0 0%	2 3.3%
Asian	0 0%	0 0%	0 0%
Other	1 3.4%	1 3.2%	2 3.3%
Not Collected	4 13.8%	6 19.4%	10 16.7%
Region of Enrollment (participants) [Number]
Austria	3 10.3%	3 9.7%	6 10%
Hungary	4 13.8%	4 12.9%	8 13.3%
United States	6 20.7%	6 19.4%	12 20%
Italy	0 0%	3 9.7%	3 5%
United Kingdom	1 3.4%	1 3.2%	2 3.3%
France	4 13.8%	6 19.4%	10 16.7%
Germany	11 37.9%	7 22.6%	18 30%
Spain	0 0%	1 3.2%	1 1.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With an Overall Response at Week 28
Description	Participants with overall response included those with partial response or complete response, according to study staff who did not know which treatment they received (blinded assessment).
Time Frame	Week 28

Outcome Measure Data

Analysis Population Description

Intention to treat population

Arm/Group Title	ECP Methoxsalen + SoC	Standard of Care (SoC)
Arm/Group Description	Participants receive ECP methoxsalen in addition to standard of care	Participants receive only standard of care
Measure Participants	29	24
Count of Participants [Participants]	20 69%	14 45.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ECP Methoxsalen + SoC, Standard of Care (SoC)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.373
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Treatment emergent adverse events were recorded from the start of treatment through Week 28.
Adverse Event Reporting Description	Treatment emergent adverse events (TEAEs) are unpleasant events not there before the medical treatment, or that were there, but got worse or happened more often after the treatment. Both serious and non-serious adverse events reported here are TEAEs. All-cause mortality is based on baseline population, while serious adverse events and non-serious adverse events are based on the safety population.
Arm/Group Title	ECP Methoxsalen + SoC		Standard of Care (SoC)
Arm/Group Description	Participants receive ECP methoxsalen in addition to standard of care		Participants receive only standard of care
All Cause Mortality
	ECP Methoxsalen + SoC		Standard of Care (SoC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/29 (13.8%)		0/31 (0%)
Serious Adverse Events
	ECP Methoxsalen + SoC		Standard of Care (SoC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/28 (28.6%)		9/28 (32.1%)
Cardiac disorders
Cardiac Failure	0/28 (0%)		1/28 (3.6%)
Endocrine disorders
Thyroiditis subacute	1/28 (3.6%)		0/28 (0%)
Immune system disorders
Graft versus host disease in liver	0/28 (0%)		1/28 (3.6%)
Infections and infestations
Bronchopulmonary aspergillosis	1/28 (3.6%)		0/28 (0%)
Cytomegalovirus infection	1/28 (3.6%)		0/28 (0%)
Escherichia infection	1/28 (3.6%)		0/28 (0%)
Escherichia sepsis	1/28 (3.6%)		0/28 (0%)
Herpes simplex	0/28 (0%)		1/28 (3.6%)
Herpes zoster	1/28 (3.6%)		0/28 (0%)
Lower respiratory tract infection	0/28 (0%)		1/28 (3.6%)
Respiratory tract infection	0/28 (0%)		1/28 (3.6%)
Respiratory tract infection viral	1/28 (3.6%)		0/28 (0%)
Sepsis	2/28 (7.1%)		1/28 (3.6%)
Sinusitis	0/28 (0%)		1/28 (3.6%)
Toxoplasmosis	1/28 (3.6%)		0/28 (0%)
Viraemia	1/28 (3.6%)		0/28 (0%)
Metabolism and nutrition disorders
Dehydration	0/28 (0%)		1/28 (3.6%)
Hyperglycaemia	1/28 (3.6%)		0/28 (0%)
Hyperkalaemia	0/28 (0%)		1/28 (3.6%)
Hypokalaemia	1/28 (3.6%)		0/28 (0%)
Musculoskeletal and connective tissue disorders
Myopathy	0/28 (0%)		2/28 (7.1%)
Nervous system disorders
Polyneuropathy	0/28 (0%)		1/28 (3.6%)
Psychiatric disorders
Confusional state	0/28 (0%)		1/28 (3.6%)
Depression	0/28 (0%)		1/28 (3.6%)
Renal and urinary disorders
Renal failure acute	0/28 (0%)		1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/28 (3.6%)		0/28 (0%)
Pneumothorax	1/28 (3.6%)		0/28 (0%)
Respiratory failure	1/28 (3.6%)		0/28 (0%)
Vocal cord polyp	1/28 (3.6%)		0/28 (0%)
Dyspnoea	1/28 (3.6%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	ECP Methoxsalen + SoC		Standard of Care (SoC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/28 (92.9%)		24/28 (85.7%)
Blood and lymphatic system disorders
Anaemia	1/28 (3.6%)		2/28 (7.1%)
Thrombocytopenia	2/28 (7.1%)		4/28 (14.3%)
Eye disorders
Dry Eye	2/28 (7.1%)		1/28 (3.6%)
Gastrointestinal disorders
Abdominal Pain	1/28 (3.6%)		2/28 (7.1%)
Constipation	1/28 (3.6%)		3/28 (10.7%)
Diarrhoea	1/28 (3.6%)		4/28 (14.3%)
Dry mouth	3/28 (10.7%)		0/28 (0%)
General disorders
Asthenia	1/28 (3.6%)		2/28 (7.1%)
Fatigue	5/28 (17.9%)		1/28 (3.6%)
Oedema peripheral	2/28 (7.1%)		4/28 (14.3%)
Pyrexia	0/28 (0%)		4/28 (14.3%)
Infections and infestations
Epstein-Barr virus infection	1/28 (3.6%)		3/28 (10.7%)
Rhinitis	2/28 (7.1%)		1/28 (3.6%)
Respiratory tract infection	1/28 (3.6%)		2/28 (7.1%)
Investigations
Alanine aminotransferase increased	1/28 (3.6%)		2/28 (7.1%)
Aspartate aminotransferase increased	1/28 (3.6%)		2/28 (7.1%)
Blood alkaline phosphatase increased	1/28 (3.6%)		2/28 (7.1%)
Blood cholesterol increased	3/28 (10.7%)		1/28 (3.6%)
Blood creatinine increased	2/28 (7.1%)		1/28 (3.6%)
Blood lactate dehydrogenase increased	1/28 (3.6%)		2/28 (7.1%)
Blood pressure increased	1/28 (3.6%)		3/28 (10.7%)
Blood urea increased	1/28 (3.6%)		2/28 (7.1%)
Gamma-glutamyltransferase increased	4/28 (14.3%)		3/28 (10.7%)
Platelet count decreased	3/28 (10.7%)		2/28 (7.1%)
Metabolism and nutrition disorders
Hyperglycaemia	3/28 (10.7%)		1/28 (3.6%)
Hypertriglyceridaemia	3/28 (10.7%)		4/28 (14.3%)
Hypokalaemia	2/28 (7.1%)		1/28 (3.6%)
Hypomagnesaemia	1/28 (3.6%)		2/28 (7.1%)
Hypoproteinaemia	1/28 (3.6%)		2/28 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/28 (0%)		3/28 (10.7%)
Back pain	2/28 (7.1%)		5/28 (17.9%)
Muscle spasms	2/28 (7.1%)		4/28 (14.3%)
Myopathy	2/28 (7.1%)		0/28 (0%)
Pain in extremity	1/28 (3.6%)		2/28 (7.1%)
Nervous system disorders
Paraesthesia	2/28 (7.1%)		2/28 (7.1%)
Dizziness	4/28 (14.3%)		2/28 (7.1%)
Tremor	2/28 (7.1%)		2/28 (7.1%)
Headache	2/28 (7.1%)		1/28 (3.6%)
Psychiatric disorders
Insomnia	2/28 (7.1%)		3/28 (10.7%)
Sleep disorder	2/28 (7.1%)		1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Cough	6/28 (21.4%)		1/28 (3.6%)
Dyspnoea	5/28 (17.9%)		2/28 (7.1%)
Skin and subcutaneous tissue disorders
Dry Skin	1/28 (3.6%)		2/28 (7.1%)
Vascular disorders
Hypertension	9/28 (32.1%)		4/28 (14.3%)

Limitations/Caveats

Long term follow-up (LTFU) safety data were provided to health authorities in safety reports; not the 28-week protocol. LTFU pre-specified outcome measures previously entered in error were removed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.