HIMSUM: Stem Cell Transplant for Hematologic Diseases

• Sponsor: Baylor College of Medicine (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00058825
• Collaborator: The Methodist Hospital Research Institute (Other)
• Enrollment: 27
• Locations: 2
• Arm: 1
• Duration (Months): 169
• Patients Per Site: 13.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Patients are being asked to participate in this study because they have a cancer in their blood, Fanconi's Anemia, or have been unsuccessfully treated for bone marrow failure such as Aplastic Anemia or Paroxysmal Nocturnal Hemoglobinuria. Any of these conditions could benefit from an allogeneic stem cell transplant using a donor that is related to the patient.

Stem cells are created in the bone marrow. They grow into different types of blood cells that the patient needs, including red blood cells, white blood cells, and platelets. In a transplant, the patient's own stem cells are killed and then replaced by stem cells from the donor.

Usually, patients are given very strong doses of chemotherapy prior to receiving a stem cell transplant. However, because of the patient's condition, they have a high risk of experiencing life-threatening treatment-related side-effects. Recently, some doctors have begun to use chemotherapy that does not cause as many side-effects before patients receive a transplant.

This research study adds CAMPATH 1H to a low-dose chemotherapy regimen, followed by an allogeneic stem cell transplantation. We want to see whether adding CAMPATH 1H to the transplant medications helps in treating the disease. We also want to see whether there are fewer life-threatening side-effects from the treatment. CAMPATH 1H is a drug that is still being studied. CAMPATH 1H stays active in the body for a long time after patients receive it, which means it may work longer at preventing graft-versus-host-disease (GvHD) symptoms.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancies	Biological: Campath 1H; Drug: Fludarabine; Procedure: Stem Cell Transplant; Radiation: Total Body Irradiation (TBI); Drug: FK506 (Tacrolimus) or Cyclosporine	Phase 1/Phase 2

Detailed Description

Before treatment begins, stem cells will be collected from the donor's blood or bone marrow. The stem cells will be collected and frozen before we start to give the patient chemotherapy.

After admission to the hospital, patients will receive total body irradiation (very strong x-rays that kill cells in the bone marrow), Fludarabine and Campath 1H prior to the stem cell transplant (infusion of the donor's stem cells).

Starting 7 days after the transplant, the patient will be given G-CSF by subcutaneous injection, until a blood test shows that numbers of granulocytes (a type of white blood cell) in the blood are more than 1,000/uL. This is to help increase blood cell counts.

After transplantation, the patient will undergo several evaluations at different times. These are standard evaluations and tests performed for any patient who has received a stem cell transplant, as part of routine clinical monitoring.

We will also be looking at the patient's immune function (how the body protects itself to prevent and fight infections and diseases). To do this, blood tests will be performed at regular intervals (every 3 to 6 months) for 2 years.

Depending on how well the donor stem cells work in the body after the transplant, the patient may receive one or more Donor Leukocyte Infusions (DLI). This is when leukocytes (a type of white blood cell) collected from the same donor that provided the stem cells are given to the patient through a central line into a vein.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Allogeneic Stem Cell Transplantation for Patients With Hematologic Diseases Using Haploidentical Family Donors and Sub-Myeloablative Conditioning With Campath 1H
• Study Start Date: Aug 1, 2000
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Stem Cell Transplant Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF.

Biological: Campath 1H; Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP.; Drug: Fludarabine; Day -5 to Day -2: Fludarabine 30 mg/m2.; Procedure: Stem Cell Transplant; Day 0: Donor stem cells infused.; Radiation: Total Body Irradiation (TBI); Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute.; Drug: FK506 (Tacrolimus) or Cyclosporine; Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.

Outcome Measures

Primary Outcome Measures

1. Transplant Related Mortality (TRM) [100 days]

   Percentage of patients with transplant related mortality

Secondary Outcome Measures

1. Time in Days to ANC Engraftment [30 days]

   Engraftment was defined as the day of absolute neutrophil counts (ANC) exceeded 0.5 X 10^9/L on the first of 3 days.

2. Donor Chimerism Engraftment of Greater Than 50% [30 days]

   Number of patients that engrafted who showed a chimerism (donor cells) of greater than 50% in the first 30 days

3. Acute Graft Versus Host Disease [100 days]

   Number of patients with Acute Graft Versus Host Disease within 100 days post-transplant

4. Chronic Graft Versus Host Disease [1 year]

   Number of patients with Chronic Graft Versus Host Disease within 1 year post-transplant

5. 2-year Relapse-free Survival [2 years]

   Relapse-free survival (RFS) was calculated from the time of transplant to the date of relapse, death, or last follow-up, whichever occurred first. Survival data were analyzed by Kaplan-Meier method.

6. 2-year Overall Survival [2 years]

   Overall survival (OS) was calculated from the time of transplant to death from any cause or censored at last follow-up. Survival data were analyzed by Kaplan-Meier method.

7. Number of Patients Who Engrafted With the Isolex/CLINIMACs System [30 days]

   Engraftment was defined as the day of absolute neutrophil counts (ANC) exceeded 0.5 X 10^9/L on the first of 3 days.

8. Median Time to Engraftment With the Isolex/CLINIMACs System [30 days]

   Engraftment was defined as the day of absolute neutrophil counts (ANC) exceeded 0.5 X 10^9/L on the first of 3 days.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

1. Diagnosis of myelodysplastic disorders; Fanconi's Anemia; Acute Myelogenous Leukemia (including secondary); Acute Lymphoblastic Leukemia; Multiple Myeloma; Plasma Cell Dyscrasia; lymphoproliferative disorders (Non-Hodgkin Lymphoma, Hairy Cell Leukemia, Chronic Lymphocytic Leukemia, and Hodgkin's Disease). Diagnosis of myelodysplastic disorders which is not good risk by IPSS: Fanconi's Anemia; Acute Myelogenous Leukemia (1st or subsequent relapse, or 2nd or subsequent CR, or refractory disease); Acute Lymphoblastic Leukemia in 2nd or subsequent remission or relapse or refractory disease; Philadelphia Chromosome-positive Chronic Myelogenous Leukemia (failed STI and interferon); Multiple Myeloma (Stage II or III); Lymphoma; Chronic Lymphocytic Leukemia (primary refractory or recurrent disease); Hodgkin's Disease (after relapse); Hemophagocytic Lymphohistiocytosis (failed chemotherapy and/or anti-viral therapy); bone marrow failure such as Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria; PNH (failed prior therapies).

2. Conditions that increase treatment related mortality: (need one or more to be eligible): Age > / = 50 years; EF of less than 45%; DLCO less than 50% or FEVI 50-75% of predicted value; Diabetes Mellitus; Renal Insufficiency (but creatinine clearance not less than 25 mL/min); Prior recent history of systemic fungal infection; 3rd or greater remission of AML or ALL; Significant Grade III or IV neurologic or hepatic toxicity from previous treatment; More than 1 year from diagnosis (CML or Myeloma patients ONLY); Multiple types of treatment regimens (equal to or more than 3); Significant Grade III or IV neurologic or hepatic toxicity from previous treatment; Prior autologous or allogeneic stem cell transplantation.

3. Haploidentical family member donor. This protocol is open to patients who lack a 5/6 or 6/6 HLA antigen-matched donor. Due to the increased risk of GvHD, patients with Fanconi Anemia and a 5/6 HLA match will also be eligible.

For this protocol, the "best" donor will be defined as a first-degree haploidentical family member who matches at the greatest number of MHC loci. Matching will be determined by Class I and Class II DNA typing. The donor should be sufficiently healthy as to not be at increased risk from the stem cell mobilization procedure. Should more than one "equally" MHC-incompatible donor be identified, other selection criteria will include: age and size of donor, CMV status, and sex. The Principal Investigator will make final decisions.

1. Available healthy donor without any contraindications for donation.

2. Patient and/or legal representative and/or legal guardian able to understand and sign consent.

3. Age between birth and 70 years.

4. Women of child-bearing potential must have a negative pregnancy test.

EXCLUSION CRITERIA:

1. Pregnant, lactating or unwilling to use contraception.

2. HIV-positive patient.

3. Uncontrolled intercurrent infection.

4. Untreated blast crisis for CML.

5. Uncontrolled high-grade lymphoproliferative disease / lymphoma.

6. Unstable angina and uncompensated congestive heart failure (Zubrod of 3 or greater).

7. Severe chronic pulmonary disease requiring oxygen (Zubrod of 3 or greater).

8. Hemodialysis dependent.

9. Active hepatitis or cirrhosis with total bilirubin, SGOT, and SGPT greater than 3X upper limit of normal.

10. Unstable cerebral vascular disease and recent hemorrhagic stroke (less than 6 months).

11. Active CNS disease from hematological disorder.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Texas Children's Hospital	Houston	Texas	United States	77030
2	The Methodist Hospital	Houston	Texas	United States	77030

Sponsors and Collaborators

• Baylor College of Medicine
• The Methodist Hospital Research Institute

Investigators

• Principal Investigator: George Carrum, MD, Baylor College of Medicine; The Methodist Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: George Carrum, Principal Investigator, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT00058825
• Other Study ID Numbers: 8713-HIMSUM
• First Posted: Apr 15, 2003
• Last Update Posted: Nov 6, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by George Carrum, Principal Investigator, Baylor College of Medicine: Campath; stem cell transplant
• Additional relevant MeSH terms: Hematologic Neoplasms; Hematologic Diseases; Cyclosporine; Fludarabine; Alemtuzumab; Tacrolimus; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Period Title: Overall Study
STARTED	27
COMPLETED	5
NOT COMPLETED	22

Baseline Characteristics

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Overall Participants	27
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	15
Sex: Female, Male (Count of Participants)
Female	8 29.6%
Male	19 70.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 51.9%
Not Hispanic or Latino	13 48.1%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Transplant Related Mortality (TRM)
Description	Percentage of patients with transplant related mortality
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	27
Number (97.5% Confidence Interval) [percentage of participants]	0 0%

2. Secondary Outcome

Title	Time in Days to ANC Engraftment
Description	Engraftment was defined as the day of absolute neutrophil counts (ANC) exceeded 0.5 X 10^9/L on the first of 3 days.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	27
Median (Full Range) [days]	12

3. Secondary Outcome

Title	Donor Chimerism Engraftment of Greater Than 50%
Description	Number of patients that engrafted who showed a chimerism (donor cells) of greater than 50% in the first 30 days
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

Patients engrafted

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	22
Yes	20 74.1%
No	2 7.4%

4. Secondary Outcome

Title	Acute Graft Versus Host Disease
Description	Number of patients with Acute Graft Versus Host Disease within 100 days post-transplant
Time Frame	100 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	27
Grade 0	26 96.3%
Grade I	0 0%
Grade II	0 0%
Grade III	1 3.7%
Grade IV	0 0%

5. Secondary Outcome

Title	Chronic Graft Versus Host Disease
Description	Number of patients with Chronic Graft Versus Host Disease within 1 year post-transplant
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	27
Yes	1 3.7%
No	26 96.3%

6. Secondary Outcome

Title	2-year Relapse-free Survival
Description	Relapse-free survival (RFS) was calculated from the time of transplant to the date of relapse, death, or last follow-up, whichever occurred first. Survival data were analyzed by Kaplan-Meier method.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	27
Number (95% Confidence Interval) [percentage of participants]	25.9 95.9%

7. Secondary Outcome

Title	2-year Overall Survival
Description	Overall survival (OS) was calculated from the time of transplant to death from any cause or censored at last follow-up. Survival data were analyzed by Kaplan-Meier method.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
Measure Participants	27
Number (95% Confidence Interval) [percentage of participants]	33.3 123.3%

8. Secondary Outcome

Title	Number of Patients Who Engrafted With the Isolex/CLINIMACs System
Description	Engraftment was defined as the day of absolute neutrophil counts (ANC) exceeded 0.5 X 10^9/L on the first of 3 days.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isolex	CLINIMACs
Arm/Group Description	The Isolex system was used for cell selection.	The CLINIMACS CD34 Reagent system was used for cell selection.
Measure Participants	19	8
Number [participants]	15 55.6%	7 NaN

9. Secondary Outcome

Title	Median Time to Engraftment With the Isolex/CLINIMACs System
Description	Engraftment was defined as the day of absolute neutrophil counts (ANC) exceeded 0.5 X 10^9/L on the first of 3 days.
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isolex	CLINIMACs
Arm/Group Description	The Isolex system was used for cell selection.	The CLINIMACS CD34 Reagent system was used for cell selection.
Measure Participants	19	8
Median (Full Range) [days]	12	12

Adverse Events

Time Frame	Adverse event data were collected until 30 days after autologous transplants and until 100 days after allogeneic transplants.
Arm/Group Title	Stem Cell Transplant
Arm/Group Description	Total body irradiation (TBI); Fludarabine and Campath 1H; FK506 or Cyclosporine; Stem Cell Transplant; G-CSF. Campath 1H: Day -5 to Day -2: Campath 1H dose schedule as per institutional SOP. Fludarabine: Day -5 to Day -2: Fludarabine 30 mg/m2. Stem Cell Transplant: Day 0: Donor stem cells infused. Total Body Irradiation (TBI): Day -6: Total body irradiation of 600 cGy as two doses without blocks at a rate of less than or equal to 10 cGy/minute. FK506 (Tacrolimus) or Cyclosporine: Day -2: FK506 or Cyclosporine as medically indicated to prevent GvHD.
All Cause Mortality
	Stem Cell Transplant
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Stem Cell Transplant
	Affected / at Risk (%)	# Events
Total	4/27 (14.8%)
Blood and lymphatic system disorders
Failure to engraft	1/27 (3.7%)	1
Infections and infestations
Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia	1/27 (3.7%)	1
Infection without neutropenia	2/27 (7.4%)	4
Metabolism and nutrition disorders
Hypokalemia	1/27 (3.7%)	6
Respiratory, thoracic and mediastinal disorders
Cough	1/27 (3.7%)	1
Other (Not Including Serious) Adverse Events
	Stem Cell Transplant
	Affected / at Risk (%)	# Events
Total	19/27 (70.4%)
Blood and lymphatic system disorders
Failure to engraft	4/27 (14.8%)	4
Transfusion: Platelets	7/27 (25.9%)	16
Gastrointestinal disorders
Anorexia	7/27 (25.9%)	7
Nausea	3/27 (11.1%)	7
Vomiting	2/27 (7.4%)	5
General disorders
Abdominal Pain or Cramping	2/27 (7.4%)	2
Bone Pain	3/27 (11.1%)	3
Hepatobiliary disorders
GGT (Gamma-Glutamyl transpeptidase)	3/27 (11.1%)	5
SGPT (ALT) (serum glutamic pyruvic transaminase)	2/27 (7.4%)	4
Infections and infestations
Catheter-related infection	2/27 (7.4%)	3
Febrile Neutropenia	3/27 (11.1%)	3
Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia	8/27 (29.6%)	11
Infection without neutropenia	5/27 (18.5%)	12
Metabolism and nutrition disorders
Hyperglycemia	2/27 (7.4%)	3
Hypokalemia	3/27 (11.1%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	2/27 (7.4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.