Chronic Kidney Disease, End-Stage Renal Disease
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe, North and South America and Oceania. The aim of the trial is to evaluate the effect of somatropin (human growth hormone) on survival (primary end-point; time to death and health related quality of life in adult patients on chronic haemodialysis.
Detailed description
The decision to discontinue the trial is not due to safety concerns. The discontinuation is based on an analysis of the significant delay in recruitment of patients which is expected to have a negative impact on the outcome of the trial.
Interventions
DRUGsomatropin
20 mcg/kg/day, injected s.c. (under the skin)
DRUGplacebo
Placebo injected s.c (under the skin)
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Serum albumin as specified in protocol * Malnourished (based on serum albumin value below 40 g/L, assessed centrally) * Stable (for 3 months or more) and adequate haemodialysis treatment three months prior to enrolment as defined by Kt/V of more than 1.2
Exclusion criteria
* Active malignant disease * Critical illness requiring treatment in an intensive care unit (ICU) * Uncontrolled treated/untreated hypertension * Patients on chronic (more than 3 months) treatment with steroids in doses of more than 10 mg/day prednisolone (or equivalent) * Patients treated with immunosuppressive agents * Known Growth Hormone Deficiency * Patients suffering from any clinically significant disease history in the opinion of the investigator * Severe illness as defined in the protocol (as judged by the investigator)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality - Time to All-cause Death | week 0, trial termination | Time to all-cause death. Statistical analysis is based on all available information from week 0 to trial termination. Summary data illustrates percentage (%) participants dead estimated using Kaplan-Meier. Summary data illustrates mortality until 52 weeks, because very few subjects had trial time longer than 52 weeks. Due to early trial termination, median trial time was 17.4 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality - Two-year Mortality Rate | week 0, trial termination | — |
| Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | week 0, trial termination | Morbidity - time from week 0 to next cardiovascular event (composite of all-cause mortality and cardiovascular events defined as adjudicated medical event of special interest and categorised as myocardial infarctions, cardiac insufficiencies, strokes or other thrombo-embolic events). Statistical analysis is based on all available information from week 0 to trial termination. Summary data illustrates percentage (%) participants with events estimated using Kaplan-Meier. Summary data illustrates morbidity until 52 weeks, because very few subjects had trial time longer than 52 weeks. |
| Morbidity - Number of Hospitalisations, in Addition to Normal Dialysis Procedures | week 0, trial termination | The number of times that the patient was hospitalised in addition to hospitalisation for normal dialysis procedures measured from week 0 (randomisation) to the time the trial was terminated. |
| Health Related Quality of Life Assessments | week 0, trial termination | Summary from activity of daily living from the Rotterdam Symptom Checklist (RSCL) measuring activity from 1 (active) to 5 (inactive). The Edmonton Symptom Assessment System (ESAS), subjects assess their health in the last 24 hours on a scale from 1 (good health) to 3 (feeling poorly). The EQ-5D is a measure of subjects' health outcome from 0 (death) to 1 (full health). SF-36 (Short Form (36)) covering mental and physicial health is provided in a scale from 0-100 with higher scores indicating greater satisfaction. |
Countries
Argentina, Brazil, Canada, China, Denmark, France, Germany, Hungary, India, Israel, Italy, Poland, Portugal, Puerto Rico, Russia, South Africa, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 202 sites in 17 countries: United States, Canada, United Kingdom, Sweden, Denmark, France, Germany, Poland, Hungary, Spain, Portugal, Turkey, Israel, Argentina, Brazil, Russia, South Africa. Italy planned to participate but never randomised any subjects.
Pre-assignment details
Subjects who were malnourished (based on serum albumin value below 40 g/L, assessed centrally) and had received adequate haemodialysis treatment for more than three months at time of trial entry, were eligible.
Participants by arm
| Arm | Count |
|---|---|
| Somatropin Somatropin 20 mcg/kg once daily, week 0 to end of trial | 346 |
| Placebo Placebo once daily, week 0 to end of trial | 349 |
| Total | 695 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 52 | 41 |
| Overall Study | Any condition in exclusion criteria | 4 | 6 |
| Overall Study | Critically ill | 2 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | End hemodialysis due to renal transplant | 10 | 4 |
| Overall Study | Lack of Efficacy | 3 | 4 |
| Overall Study | Move to nonparticipating dialysis center | 2 | 1 |
| Overall Study | Not exposed to trial drug | 11 | 6 |
| Overall Study | Pregnancy/intention to become pregnant | 1 | 0 |
| Overall Study | Protocol Violation | 5 | 6 |
| Overall Study | Switch to peritoneal or home dialysis | 2 | 2 |
| Overall Study | Trial terminated | 216 | 253 |
| Overall Study | Unclassified | 48 | 32 |
Baseline characteristics
| Characteristic | Somatropin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 62.2 years STANDARD_DEVIATION 13.5 | 61.6 years STANDARD_DEVIATION 13.8 | 61.0 years STANDARD_DEVIATION 14.2 |
| BMI | 28.9 kg/m2 STANDARD_DEVIATION 8.6 | 28.7 kg/m2 STANDARD_DEVIATION 8.3 | 28.4 kg/m2 STANDARD_DEVIATION 8 |
| Diabetes Not Diabetic | 173 participants | 356 participants | 183 participants |
| Diabetes Type 1 diabetes mellitus | 12 participants | 28 participants | 16 participants |
| Diabetes Type 2 diabetes mellitus | 161 participants | 311 participants | 150 participants |
| Duration of Diabetes | 17.5 years | 18.4 years | 20.3 years |
| Duration of Dialysis | 2.9 years | 2.9 years | 2.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 55 Participants | 121 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 286 Participants | 565 Participants | 279 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 9 Participants | 4 Participants |
| Height | 167.1 cm STANDARD_DEVIATION 11.2 | 167.6 cm STANDARD_DEVIATION 10.8 | 168.1 cm STANDARD_DEVIATION 10.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 12 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 114 Participants | 227 Participants | 113 Participants |
| Race (NIH/OMB) More than one race | 14 Participants | 31 Participants | 17 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 205 Participants | 418 Participants | 213 Participants |
| Sex: Female, Male Female | 175 Participants | 314 Participants | 139 Participants |
| Sex: Female, Male Male | 171 Participants | 381 Participants | 210 Participants |
| Weight | 80.6 kg STANDARD_DEVIATION 24.3 | 80.6 kg STANDARD_DEVIATION 24.6 | 80.6 kg STANDARD_DEVIATION 25 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 225 / 346 | 264 / 349 |
| serious Total, serious adverse events | 122 / 346 | 136 / 349 |
Outcome results
Primary
Mortality - Time to All-cause Death
Time to all-cause death. Statistical analysis is based on all available information from week 0 to trial termination. Summary data illustrates percentage (%) participants dead estimated using Kaplan-Meier. Summary data illustrates mortality until 52 weeks, because very few subjects had trial time longer than 52 weeks. Due to early trial termination, median trial time was 17.4 weeks.
Time frame: week 0, trial termination
Population: FAS (full analysis set) is all subjects exposed to at least one dose of trial drug. Due to the early termination of this trial, observations from end of trial visit are substituted for week 104 visit (end of trial as per protocol).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Somatropin | Mortality - Time to All-cause Death | Baseline (week 0) | 0 percentage of participants |
| Somatropin | Mortality - Time to All-cause Death | Week 26 | 8 percentage of participants |
| Somatropin | Mortality - Time to All-cause Death | Week 44 | 13 percentage of participants |
| Somatropin | Mortality - Time to All-cause Death | Week 52 | 29 percentage of participants |
| Placebo | Mortality - Time to All-cause Death | Week 52 | 23 percentage of participants |
| Placebo | Mortality - Time to All-cause Death | Baseline (week 0) | 0 percentage of participants |
| Placebo | Mortality - Time to All-cause Death | Week 44 | 17 percentage of participants |
| Placebo | Mortality - Time to All-cause Death | Week 26 | 8 percentage of participants |
p-value: 0.9195% CI: [0.6, 1.57]Regression, Cox
Secondary
Health Related Quality of Life Assessments
Summary from activity of daily living from the Rotterdam Symptom Checklist (RSCL) measuring activity from 1 (active) to 5 (inactive). The Edmonton Symptom Assessment System (ESAS), subjects assess their health in the last 24 hours on a scale from 1 (good health) to 3 (feeling poorly). The EQ-5D is a measure of subjects' health outcome from 0 (death) to 1 (full health). SF-36 (Short Form (36)) covering mental and physicial health is provided in a scale from 0-100 with higher scores indicating greater satisfaction.
Time frame: week 0, trial termination
Population: FAS (full analysis set) is all subjects exposed to at least one dose of trial drug. Observations from end of trial visit is substitute for week 104. Not all subjects provided 'quality of life' data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Somatropin | Health Related Quality of Life Assessments | ESAS (overall mean), N= 309, 313 | 3.0 scores on a scale | Standard Deviation 1.9 |
| Somatropin | Health Related Quality of Life Assessments | SF-36 (overall physical health), N= 318, 315 | 48 scores on a scale | Standard Deviation 22 |
| Somatropin | Health Related Quality of Life Assessments | EQ-5D (UK overall score), N= 305, 299 | 0.596 scores on a scale | Standard Deviation 0.31 |
| Somatropin | Health Related Quality of Life Assessments | SF-36 (overall mental health), N= 318, 315 | 61 scores on a scale | Standard Deviation 21 |
| Somatropin | Health Related Quality of Life Assessments | RSCL (overall mean), N= 316, 312 | 2.9 scores on a scale | Standard Deviation 0.9 |
| Placebo | Health Related Quality of Life Assessments | SF-36 (overall mental health), N= 318, 315 | 62 scores on a scale | Standard Deviation 21 |
| Placebo | Health Related Quality of Life Assessments | RSCL (overall mean), N= 316, 312 | 3.0 scores on a scale | Standard Deviation 0.9 |
| Placebo | Health Related Quality of Life Assessments | ESAS (overall mean), N= 309, 313 | 3.0 scores on a scale | Standard Deviation 2 |
| Placebo | Health Related Quality of Life Assessments | EQ-5D (UK overall score), N= 305, 299 | 0.597 scores on a scale | Standard Deviation 0.321 |
| Placebo | Health Related Quality of Life Assessments | SF-36 (overall physical health), N= 318, 315 | 49 scores on a scale | Standard Deviation 22 |
Secondary
Morbidity - Number of Hospitalisations, in Addition to Normal Dialysis Procedures
The number of times that the patient was hospitalised in addition to hospitalisation for normal dialysis procedures measured from week 0 (randomisation) to the time the trial was terminated.
Time frame: week 0, trial termination
Population: FAS (full analysis set) is all subjects exposed to at least one dose of trial drug. Due to the early termination of this trial, observations from end of trial visit are substituted for week 104 visit (end of trial as per protocol).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Somatropin | Morbidity - Number of Hospitalisations, in Addition to Normal Dialysis Procedures | 0.5 hospitalisations | Standard Deviation 0.9 |
| Placebo | Morbidity - Number of Hospitalisations, in Addition to Normal Dialysis Procedures | 0.5 hospitalisations | Standard Deviation 1 |
p-value: 0.440995% CI: [0.83, 1.53]Negative binomial regression
Secondary
Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event)
Morbidity - time from week 0 to next cardiovascular event (composite of all-cause mortality and cardiovascular events defined as adjudicated medical event of special interest and categorised as myocardial infarctions, cardiac insufficiencies, strokes or other thrombo-embolic events). Statistical analysis is based on all available information from week 0 to trial termination. Summary data illustrates percentage (%) participants with events estimated using Kaplan-Meier. Summary data illustrates morbidity until 52 weeks, because very few subjects had trial time longer than 52 weeks.
Time frame: week 0, trial termination
Population: FAS (full analysis set) is all subjects exposed to at least one dose of trial drug. Due to the early termination of this trial, observations from end of trial visit are substituted for week 104 (end of trial per protocol).
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Somatropin | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Baseline (week 0) | 0 percentage of participants | 0 |
| Somatropin | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Week 40 | 18 percentage of participants | — |
| Somatropin | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Week 52 | 31 percentage of participants | — |
| Somatropin | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Week 26 | 12 percentage of participants | — |
| Placebo | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Week 52 | 24 percentage of participants | — |
| Placebo | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Baseline (week 0) | 0 percentage of participants | 0 |
| Placebo | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Week 26 | 17 percentage of participants | — |
| Placebo | Morbidity - Time From Randomisation to Next Cardiovascular Event (Defined as Composite of All-cause Mortality, Non-fatal Myocardial Infarction, Stroke, Cardiac Insufficiency and Other Thrombo-embolic Event) | Week 40 | 23 percentage of participants | — |
p-value: 0.497795% CI: [0.6, 1.28]Regression, Cox
Secondary
Mortality - Two-year Mortality Rate
Time frame: week 0, trial termination
Population: No analysis was done since the trial was prematurely terminated before week 104 of the trial. Trial was terminated January 16th, 2009.