Trial Outcomes & Findings for Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant (NCT NCT00408681)

NCT ID: NCT00408681

Last Updated: 2017-03-07

Results Overview

Functional recovery was defined as partial or complete resolution of gastrointestinal manifestations of acute graft-versus-host disease. Gastrointestinal manifestations of acute graft-versus-host disease include anorexia, nausea, vomiting, diarrhea, abdominal pain and bleeding. Complete response (CR) of intestinal GVHD was defined as the absence of any symptoms referable to intestinal GVHD. Partial response (PR) was defined as clearing of abdominal pain (or withdrawal of opioid analgesic requirements in patients treated for abdominal pain) and of grossly visible bleeding if present, and resolution of diarrhea or decrease in the three day average stool volume by ≥ 500 mL in patients with stool volumes of ≥ 500 mL. Progression of GVHD was defined as an increase in the three day average stool volume by \> 500 mL, or the development of new abdominal pain (or new opioid analgesic requirements) or new intestinal bleeding.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 20 participants
• Primary outcome timeframe: at 28 days after starting treatment with the study product
• Results posted on: 2017-03-07

Participant Flow

Patients with severe gastrointestinal acute graft-versus-host disease with or without mucosal denudation identified by endoscopy were recruited from a hospitalized population of patients who had recent allogeneic hematopoietic cell transplantation.

Patients were enrolled according to eligibility criteria in the protocol.

Participant milestones

Measure	Treated Patients Patients receive oral lithium carbonate once or twice daily orally. Treatment continues for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Overall Study STARTED	20
Overall Study COMPLETED	11
Overall Study NOT COMPLETED	9

Reasons for withdrawal

Measure	Treated Patients Patients receive oral lithium carbonate once or twice daily orally. Treatment continues for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Overall Study Lack of Efficacy	2
Overall Study Adverse Event	7

Baseline Characteristics

Lithium Carbonate in Treating Patients With Acute Intestinal Graft-Versus-Host-Disease (GVHD) After Donor Stem Cell Transplant

Baseline characteristics by cohort

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Age, Continuous	49.5 years n=93 Participants
Sex: Female, Male Female	13 Participants n=93 Participants
Sex: Female, Male Male	7 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=93 Participants
Race (NIH/OMB) Black or African American	1 Participants n=93 Participants
Race (NIH/OMB) White	14 Participants n=93 Participants
Race (NIH/OMB) More than one race	2 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=93 Participants
Region of Enrollment United States	20 Participants n=93 Participants
Indication for transplantation Non-Hodgkin lymphoma	3 Participants n=93 Participants
Indication for transplantation Acute myeloid leukemia	6 Participants n=93 Participants
Indication for transplantation Multiple myeloma	2 Participants n=93 Participants
Indication for transplantation Chronic myeloid leukemia	2 Participants n=93 Participants
Indication for transplantation Acute lymphoid leukemia	3 Participants n=93 Participants
Indication for transplantation Myelodysplastic syndrome	1 Participants n=93 Participants
Indication for transplantation Aplastic anemia	1 Participants n=93 Participants
Indication for transplantation Paroxysmal nocturnal hemoglobinuria	1 Participants n=93 Participants
Indication for transplantation Chronic lymphocytic leukemia	1 Participants n=93 Participants
Type of pretransplant conditioning regimen Myeloablative	12 Participants n=93 Participants
Type of pretransplant conditioning regimen Nonmyeloablative	8 Participants n=93 Participants
Graft-versus-host disease (GVHD) prophylaxis regimen Cyclosporine and mycophenolate mofetil (MMF)	8 Participants n=93 Participants
Graft-versus-host disease (GVHD) prophylaxis regimen Tacrolimus and methotrexate	10 Participants n=93 Participants
Graft-versus-host disease (GVHD) prophylaxis regimen Cyclophosphamide, tacrolimus, MMF	1 Participants n=93 Participants
Graft-versus-host disease (GVHD) prophylaxis regimen Tacrolimus and mycophenolate mofeftil	1 Participants n=93 Participants
Mucosal denudation Duodenum alone	7 Participants n=93 Participants
Mucosal denudation Colon alone	7 Participants n=93 Participants
Mucosal denudation Duodenum and colon	3 Participants n=93 Participants
Agents given to prevent GVHD at the time of enrollment Tacrolimus	8 Participants n=93 Participants
Agents given to prevent GVHD at the time of enrollment Cyclosporine	7 Participants n=93 Participants
Agents given to prevent GVHD at the time of enrollment Mycophenolate mofetil	8 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Infliximab	3 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Rabbit anti-thymocyte globulin	3 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Horse anti-thymocyte globulin	1 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Extracorporeal photopheresis	2 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Mesenchymal stem cells	1 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Mycophenolate mofetil	5 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Tacrolimus	3 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Sirolimus	1 Participants n=93 Participants
Agents given to treat GVHD more than 3 days before enrollment in the study Cyclosporine	1 Participants n=93 Participants
Interval from transplantation to start of study product administration	90 days n=93 Participants
Agents given to treat GVHD within 3 days before or after enrollment Methotrexate	1 Participants n=93 Participants
Agents given to treat GVHD within 3 days before or after enrollment Pentostatin	2 Participants n=93 Participants
Agents given to treat GVHD within 3 days before or after enrollment Rabbit anti-thymocyte globulin	4 Participants n=93 Participants
Agents given to treat GVHD within 3 days before or after enrollment Mycophenolate mofetil	1 Participants n=93 Participants
Agents given to treat GVHD within 3 days before or after enrollment Infliximab	2 Participants n=93 Participants
Agents given to treat GVHD within 3 days before or after enrollment Alemtuzumab	1 Participants n=93 Participants

PRIMARY outcome

Timeframe: at 28 days after starting treatment with the study product

Functional recovery was defined as partial or complete resolution of gastrointestinal manifestations of acute graft-versus-host disease. Gastrointestinal manifestations of acute graft-versus-host disease include anorexia, nausea, vomiting, diarrhea, abdominal pain and bleeding. Complete response (CR) of intestinal GVHD was defined as the absence of any symptoms referable to intestinal GVHD. Partial response (PR) was defined as clearing of abdominal pain (or withdrawal of opioid analgesic requirements in patients treated for abdominal pain) and of grossly visible bleeding if present, and resolution of diarrhea or decrease in the three day average stool volume by ≥ 500 mL in patients with stool volumes of ≥ 500 mL. Progression of GVHD was defined as an increase in the three day average stool volume by > 500 mL, or the development of new abdominal pain (or new opioid analgesic requirements) or new intestinal bleeding.

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Functional Recovery Complete clinical response	10 Participants
Functional Recovery Partial clinical response	1 Participants
Functional Recovery No response or clinical progression	6 Participants
Functional Recovery Death before day 28	3 Participants

SECONDARY outcome

Timeframe: Up to 6 months

Number of days from beginning of orally administered lithium carbonate to the end of orally administered lithium carbonate

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Duration of Treatment With the Study Product	30.5 days Interval 7.0 to 172.0

SECONDARY outcome

Timeframe: 2 to 3 weeks after starting treatment with the study product

Population: Only 8 of the 20 enrolled patients had endoscopic evaluation during this time window.

Endoscopic evaluation of improvement. Categories include 1) no improvement, 2) regenerative changes, 3) limited improvement, 4) partial improvement and 5) complete response. Endoscopic manifestations of acute graft-versus-host disease include edema, erythema, mucosal ulceration and denudation. Complete mucosal recovery was defined as the appearance of intact mucosa with at least 98% of the luminal surface covered by epithelium. Partial response was defined as the appearance of mostly intact mucosa with at least 80% improvement or less than 10% denuded. Limited response was retrospectively designated to describe visible improvement that was less than partial response. Regenerative change was retrospectively designated to describe early reappearance of mucosal integrity in a previously denuded area but not sufficient to meet criteria for partial response. Failure to respond was defined as failure to meet partial response criteria.

Outcome measures

Measure	Treated Patients n=8 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Mucosal Anatomic Recovery No improvement	3 Participants
Mucosal Anatomic Recovery Regenerative changes	3 Participants
Mucosal Anatomic Recovery Partial improvement	2 Participants

SECONDARY outcome

Timeframe: 4 weeks after starting treatment with the study product

Population: Only 2 patients had endoscopic evaluation during this time window.

Endoscopic evaluation of improvement. Categories include 1) no improvement, 2) regenerative changes, 3) limited improvement, 4) partial improvement and 5) complete response. Endoscopic manifestations of acute graft-versus-host disease include edema, erythema, mucosal ulceration and denudation. Complete mucosal recovery was defined as the appearance of intact mucosa with at least 98% of the luminal surface covered by epithelium. Partial response was defined as the appearance of mostly intact mucosa with at least 80% improvement or less than 10% denuded. Limited response was retrospectively designated to describe visible improvement that was less than partial response. Regenerative change was retrospectively designated to describe early reappearance of mucosal integrity in a previously denuded area but not sufficient to meet criteria for partial response. Failure to respond was defined as failure to meet partial response criteria.

Outcome measures

Measure	Treated Patients n=2 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Mucosal Anatomic Recovery Limited improvement	1 Participants
Mucosal Anatomic Recovery Partial improvement	1 Participants

SECONDARY outcome

Timeframe: 5 weeks after starting treatment with the study product

Population: Only 1 patient had endoscopic evaluation during this time window.

Endoscopic evaluation of improvement. Categories include 1) no improvement, 2) regenerative changes, 3) limited improvement, 4) partial improvement and 5) complete response. Endoscopic manifestations of acute graft-versus-host disease include edema, erythema, mucosal ulceration and denudation. Complete mucosal recovery was defined as the appearance of intact mucosa with at least 98% of the luminal surface covered by epithelium. Partial response was defined as the appearance of mostly intact mucosa with at least 80% improvement or less than 10% denuded. Limited response was retrospectively designated to describe visible improvement that was less than partial response. Regenerative change was retrospectively designated to describe early reappearance of mucosal integrity in a previously denuded area but not sufficient to meet criteria for partial response. Failure to respond was defined as failure to meet partial response criteria.

Outcome measures

Measure	Treated Patients n=1 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Mucosal Anatomic Recovery Partial improvement	1 Participants
Mucosal Anatomic Recovery Complete response	0 Participants

SECONDARY outcome

Timeframe: 6 to 7 weeks after starting treatment with the study product

Population: Only 3 patients had endoscopic evaluation during this time window.

Endoscopic evaluation of improvement. Categories include 1) no improvement, 2) regenerative changes, 3) limited improvement, 4) partial improvement and 5) complete response. Endoscopic manifestations of acute graft-versus-host disease include edema, erythema, mucosal ulceration and denudation. Complete mucosal recovery was defined as the appearance of intact mucosa with at least 98% of the luminal surface covered by epithelium. Partial response was defined as the appearance of mostly intact mucosa with at least 80% improvement or less than 10% denuded. Limited response was retrospectively designated to describe visible improvement that was less than partial response. Regenerative change was retrospectively designated to describe early reappearance of mucosal integrity in a previously denuded area but not sufficient to meet criteria for partial response. Failure to respond was defined as failure to meet partial response criteria.

Outcome measures

Measure	Treated Patients n=3 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Mucosal Anatomic Recovery Partial improvement	0 Participants
Mucosal Anatomic Recovery Complete response	3 Participants

SECONDARY outcome

Timeframe: 9 to 11 weeks after starting treatment with the study product

Population: Only 4 patients had endoscopic evaluation during this time window.

Endoscopic evaluation of improvement. Categories include 1) no improvement, 2) regenerative changes, 3) limited improvement, 4) partial improvement and 5) complete response. Endoscopic manifestations of acute graft-versus-host disease include edema, erythema, mucosal ulceration and denudation. Complete mucosal recovery was defined as the appearance of intact mucosa with at least 98% of the luminal surface covered by epithelium. Partial response was defined as the appearance of mostly intact mucosa with at least 80% improvement or less than 10% denuded. Limited response was retrospectively designated to describe visible improvement that was less than partial response. Regenerative change was retrospectively designated to describe early reappearance of mucosal integrity in a previously denuded area but not sufficient to meet criteria for partial response. Failure to respond was defined as failure to meet partial response criteria.

Outcome measures

Measure	Treated Patients n=4 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Mucosal Anatomic Recovery Partial improvement	2 Participants
Mucosal Anatomic Recovery Complete response	2 Participants

SECONDARY outcome

Timeframe: 2 years after enrollment

Recurrence or progression of the malignant disease that was the reason for hematopoietic cell transplantation

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Recurrent or Progressive Malignancy	1 Participants

SECONDARY outcome

Timeframe: 2 years after enrollment

Death without prior recurrent or progressive malignancy after transplantation.

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Non-relapse Mortality	13 Participants

SECONDARY outcome

Timeframe: 6 months after enrollment

Patients who were alive at the specified time after enrollment

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Survival	10 Participants

SECONDARY outcome

Timeframe: 1 year after enrollment

Patients who were alive at the specified time point

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Survival	8 Participants

SECONDARY outcome

Timeframe: 2 years after enrollment

Patients who were alive at the specified time point

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Survival	7 Participants

SECONDARY outcome

Timeframe: up to 6 years after enrollment

Medical condition that made the greatest contribution in causing death

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Causes of Death Recurrent or progressive malignancy	2 Participants
Causes of Death Acute graft-versus-host disease	11 Participants
Causes of Death Chronic GVHD with bronchiolitis obliterans	2 Participants
Causes of Death Infection	7 Participants
Causes of Death Multiorgan failure	2 Participants
Causes of Death Diffuse alveolar hemorrhage	1 Participants
Causes of Death Hemolytic uremic syndrome	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 100 days after enrollment

Any systemic medication given in an effort to control graft-versus-host disease

Outcome measures

Measure	Treated Patients n=20 Participants Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Agents Added to Treat GVHD More Than 3 Days After Enrollment Methotrexate	1 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Pentostatin	1 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Rabbit anti-thymocyte globulin	5 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Mycophenolate mofetil	4 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Tacrolimus	2 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Infliximab	4 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Etanercept	1 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Alemtuzumab	1 Participants
Agents Added to Treat GVHD More Than 3 Days After Enrollment Sirolimus	6 Participants

Adverse Events

Treated Patients

Serious events: 12 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Measure	Treated Patients n=20 participants at risk Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Immune system disorders Graft-versus-host disease	35.0% 7/20 • Up to 6 months
Infections and infestations Infection	35.0% 7/20 • Up to 6 months
Nervous system disorders Altered mental status	10.0% 2/20 • Up to 6 months
Respiratory, thoracic and mediastinal disorders Diffuse alveolar hemorrhage	5.0% 1/20 • Up to 6 months
Blood and lymphatic system disorders Recurrent malignancy	5.0% 1/20 • Up to 6 months

Other adverse events

Measure	Treated Patients n=20 participants at risk Patients received oral lithium carbonate once or twice daily. Treatment continued for up to 8 weeks in the absence of disease progression or unacceptable toxicity.
Nervous system disorders Somnolence or fatigue	30.0% 6/20 • Up to 6 months
Nervous system disorders Confusion	15.0% 3/20 • Up to 6 months
Renal and urinary disorders Polyuria	5.0% 1/20 • Up to 6 months
Blood and lymphatic system disorders Leukocytosis	5.0% 1/20 • Up to 6 months
Gastrointestinal disorders Nausea or vomiting	10.0% 2/20 • Up to 6 months

Additional Information

Paul J. Martin, M.D.

Fred Hutchinson Cancer Research Center

Phone: 206-667-4798

Email: pmartin@fredhutch.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place