Heart Failure
Conditions
Keywords
Heart Failure, Congestive Heart Failure, Oxidative Stress, Hydrogen Sulfide
Brief summary
Patients with heart failure are reported to have lower levels of hydrogen sulfide in their blood, even though sulfur is available naturally in the diet. Hydrogen sulfide is a molecule that has been shown to have a number of beneficial effects and thus the low levels may contribute to the disease. This trial is testing whether a medical food product of synthetic sulfur molecules, SG1002, can overcome this deficit in blood levels of hydrogen sulfide.
Detailed description
Subjects with heart failure have been shown to have a deficit in circulating hydrogen sulfide levels, which, since sulfur is not readily bioavailable and is declining in food substances, cannot be treated adequately by diet alone. This deficit in circulating hydrogen sulfide is thought to lead to increases in oxidative stress and with this, associated problems that can contribute to heart failure. This is a study to evaluate the safety and ability of multiple doses of oral SG1002 in subjects with heart failure to reverse the deficits in circulating hydrogen sulfide. The primary objective is to assess the safety and the ability of multiple doses of twice daily administration of SG1002 compared with placebo to increase circulating levels of hydrogen sulfide. Initially, a dose escalation study will be carried out for 21 days in 4 normal subjects, randomized 3:1 active:placebo. Subjects will receive a 200 mg dose BID for 7 days and in no adverse events, escalate to 400 mg for 7 days then 800 mg for 7 days. Safety parameters will be assessed for each dose, along with pharmacokinetic analysis and markers of oxidative stress and heart failure. Following completion of the normal healthy subjects, 10 heart failure subjects will be randomized 4:1 active:placebo and tested as described above.
Interventions
OTHERSG1002
200 mg capsules will be administered BID for 7 days, then doubled to 2 capsules BID for 7 days and doubled again to 4 capsules BID for the final 7 days.
OTHERPlacebo
200 mg capsules containing placebo will be administered BID for 7 days, then doubled to 2 capsules BID for 7 days and doubled again to 4 capsules BID for the final 7 days.
Sponsors
Sulfagenix Australia Pty Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
(healthy volunteers): * Healthy male volunteers aged between 18 and 45 years (inclusive); * Body mass index between 19 and 30 kg/m\^2 (inclusive); * No clinically significant findings in the medical history and physical examination; * No clinically significant laboratory values and urinalysis, unless the investigator considers any abnormality to be clinically irrelevant; * Normal ECG, blood pressure and heart rate, unless the Investigator considers any abnormality to be not clinically significant (NCS); * Willing to use contraception (single barrier methods); and * Willing and able to provide written informed consent.
Exclusion criteria
(healthy volunteers): * Have received blood products within 1 month prior to Screening; * Have received any investigational research agent within 30 days or 5 half-lives (whichever is longer) prior to the first dose of trial medical food; * Have received an investigational vaccine within 6 months, a live attenuated vaccine within 60 days or a registered vaccine within 30 days prior to the first dose of the trial medical food; * Have a history of thyroidectomy or thyroid disease that required medication within the past 12 months; * Have had serious angioedema episodes within the previous 3 years or requiring medication in the previous two years; * Have a bleeding disorder diagnosed by a doctor (for example factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties during blood draws; * Have a psychiatric condition that precludes compliance with the protocol, past or present psychoses, past or present bipolar disorder, or a disorder requiring lithium, within five years prior to enrolment; * Has a history of suicide plan; * Any clinically significant abnormality at Screening determined by medical history, physical examination, blood chemistry, haematology, urinalysis and a 12-lead ECG, or positive urine screen for drugs of abuse; * Any other condition which in the view of the Investigator is likely to interfere with the study or put the subject at risk; * HIV, or hepatitis B or C positive; * Have a history of or current clinically significant gastrointestinal, hepatic, renal, cardiovascular, respiratory, endocrine, oncological, immunodeficiency, neurological, metabolic, haematological or autoimmune disorder; * Have a history of or current tuberculosis, epilepsy, diabetes or glaucoma; * Have clinical signs of active infection or a temperature more than 38.0°C at the time of screening. Study entry may be deferred at the discretion of the Principal Investigator; * Have evidence of drug or alcohol abuse; * Be unable to provide repeated blood samples without undue trauma or distress; * Anticipate surgery within the trial period; or * Inability to speak English (due to need to administer standardized English-language questionnaire). Inclusion Criteria (heart failure subjects): * Aged between 35 and 85 years (inclusive); * Has symptomatic heart failure, with New York Heart Association (NYHA)classification of II or III; * Ambulatory; * Left ventricular ejection fraction less than 40%; * Congestive heart failure has been stable for the previous 3 months (defined by no change in baseline therapy or symptoms of heart failure for the previous 3 months); and * Willing and able to provide written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events | Following 7 days of treatment at each of three doses | The number of subjects reporting Treatment Emergent Adverse Events at any time during the study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessing Changes in Peak Hydrogen Sulfide Levels in Heart Failure Subjects Following SG1002 Administration. | 24 hours | At the start of each dose, blood samples will be obtained and circulating hydrogen sulfide levels will be assessed over a 24 hour period to determine whether SG1002 can overcome the deficits reported in heart failure patients. Peak hydrogen sulfide levels were measured during the first 4 hours post-administration when maximum concentrations of hydrogen sulfide were reached. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 7 days at each dose. | BNP levels were measured for the each subject prior to treatment and after 7 days on each treatment dose, thus representing a change in BNP over the 21 day treatment period. Increased BNP levels are associated with worsening heart failure. |
Countries
Australia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sugar Capsule Two normal healthy subject and two heart failure subjects will be randomized and given placebo throughout the trial period. | 4 |
| SG1002 200 mg capsule of SG1002 (alpha sulfur/sodium sulfate)
SG1002: 200 mg capsules will be administered BID for 7 days, then doubled to 2 capsules BID for 7 days and doubled again to 4 capsules BID for the final 7 days.
Six normal healthy subject and six heart failure subjects will be randomized and given SG1002 throughout the trial period. | 12 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 200 mg (7 Days) | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Sugar Capsule | SG1002 |
|---|---|---|---|
| Age, Customized Heart Failure Subjects | 74.9 years | 73.0 years | 75.5 years |
| Age, Customized Normal Healthy Subjects | 27.5 years | 27.0 years | 27.7 years |
| Condition Heart Failure Subjects | 8 participants | 2 participants | 6 participants |
| Condition Normal Healthy Subjects | 8 participants | 2 participants | 6 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 4 Participants | 11 Participants |
| Region of Enrollment Australia | 16 participants | 4 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 14 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 4 | 3 / 12 |
| serious Total, serious adverse events | 0 / 4 | 0 / 12 |
Outcome results
Primary
Number of Subjects With Adverse Events
The number of subjects reporting Treatment Emergent Adverse Events at any time during the study period.
Time frame: Following 7 days of treatment at each of three doses
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sugar Capsule | Number of Subjects With Adverse Events | Subjects with Treatment Adverse Events | 2 participants |
| Sugar Capsule | Number of Subjects With Adverse Events | Subjects with no Treatment Emergent Adverse Events | 2 participants |
| SG1002 | Number of Subjects With Adverse Events | Subjects with Treatment Adverse Events | 3 participants |
| SG1002 | Number of Subjects With Adverse Events | Subjects with no Treatment Emergent Adverse Events | 9 participants |
Secondary
Assessing Changes in Peak Hydrogen Sulfide Levels in Heart Failure Subjects Following SG1002 Administration.
At the start of each dose, blood samples will be obtained and circulating hydrogen sulfide levels will be assessed over a 24 hour period to determine whether SG1002 can overcome the deficits reported in heart failure patients. Peak hydrogen sulfide levels were measured during the first 4 hours post-administration when maximum concentrations of hydrogen sulfide were reached.
Time frame: 24 hours
Population: Heart failure subject (n=6) had baseline levels of hydrogen sulfide recorded at 0, 0.5, 1, 2, 4, 6, 12 and 24 hours after the administration of the first dose of each of the escalating doses of SG1002.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Capsule | Assessing Changes in Peak Hydrogen Sulfide Levels in Heart Failure Subjects Following SG1002 Administration. | 0.37 uM | Standard Error 0.05 |
| SG1002 | Assessing Changes in Peak Hydrogen Sulfide Levels in Heart Failure Subjects Following SG1002 Administration. | 0.44 uM | Standard Error 0.04 |
| 400 mg SG002 | Assessing Changes in Peak Hydrogen Sulfide Levels in Heart Failure Subjects Following SG1002 Administration. | 0.50 uM | Standard Error 0.08 |
| 800 mg SG1002 | Assessing Changes in Peak Hydrogen Sulfide Levels in Heart Failure Subjects Following SG1002 Administration. | 0.51 uM | Standard Error 0.09 |
Other Pre-specified
Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels.
BNP levels were measured for the each subject prior to treatment and after 7 days on each treatment dose, thus representing a change in BNP over the 21 day treatment period. Increased BNP levels are associated with worsening heart failure.
Time frame: 7 days at each dose.
Population: Levels of BNP were recorded at baseline and every 7 days in the placebo group or the SG1002 dose escalation group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sugar Capsule | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 85.0 pg/ml | Standard Error 49 |
| SG1002 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 123.0 pg/ml | Standard Error 72 |
| 400 mg SG002 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 156.5 pg/ml | Standard Error 97.5 |
| 800 mg SG1002 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 149.5 pg/ml | Standard Error 53.5 |
| SG1002: Day 0 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 77.5 pg/ml | Standard Error 30.5 |
| SG1002: Day 7 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 69.8 pg/ml | Standard Error 26.9 |
| SG1002: Day 14 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 79.0 pg/ml | Standard Error 31.6 |
| SG1002: Day 21 | Assessing Potential Clinical Benefits of SG1002 Administration by Analyzing BNP Levels. | 72.0 pg/ml | Standard Error 38.7 |